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Trial record 83 of 1318 for:    Hematologic neoplasm

Trial of Pimasertib in Hematological Malignancies

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ClinicalTrials.gov Identifier: NCT00957580
Recruitment Status : Terminated (The trial has been terminated due to an estimated low probability of clinical benefit based on limited anti-leukemic effects observed in safety run-in (Part 1))
First Posted : August 12, 2009
Results First Posted : March 29, 2017
Last Update Posted : August 21, 2017
Sponsor:
Information provided by (Responsible Party):
EMD Serono

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Leukemia, Myeloid, Acute
Hematologic Neoplasms
Intervention Drug: Pimasertib
Enrollment 81
Recruitment Details First/last subject (informed consent): September 2009/12 April 2012. Last subject completed : December 2012; Clinical data cut-off: December 2012.
Pre-assignment Details Enrolled: 116 screened for eligibility; 35 were excluded (mainly non-fulfillment of inclusion or exclusion). 81 subjects were randomized.
Arm/Group Title Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Hide Arm/Group Description Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Period Title: Overall Study
Started 33 33 15
Treated 33 32 15
Completed 33 31 15
Not Completed 0 2 0
Reason Not Completed
Ongoing at data cut-off             0             1             0
Enrolled but not treated             0             1             0
Arm/Group Title Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1) Total
Hide Arm/Group Description Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. Total of all reporting groups
Overall Number of Baseline Participants 33 32 15 80
Hide Baseline Analysis Population Description
Baseline analysis population included all the subjects who were treated with at least one administration of pimasertib.
Age, Customized  
Measure Type: Number
Unit of measure:  Subjects
Number Analyzed 33 participants 32 participants 15 participants 80 participants
18 to less than (<) 60 14 12 6 32
60 to <75 13 16 6 35
Greater than or equal to (>=) 75 6 4 3 13
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 33 participants 32 participants 15 participants 80 participants
Female
9
  27.3%
13
  40.6%
7
  46.7%
29
  36.3%
Male
24
  72.7%
19
  59.4%
8
  53.3%
51
  63.7%
1.Primary Outcome
Title Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs)
Hide Description The DLT was any toxicity that resulted in treatment delay for more than (>) 2 weeks due to treatment-related adverse effects, or any Grade greater than or equal to (>=) 3 non-hematological toxicity excluding Grade 4 asymptomatic increases in liver function tests reversible within 7 days in subjects with liver involvement, and Grade 3 asymptomatic increases in liver function tests reversible within 7 days for subjects without liver involvement, Grade 3 vomiting unless encountered and persistent for more than 3 days despite adequate and optimal therapy, and Grade 3 diarrhea unless encountered and persistent for more than 3 days despite adequate and optimal anti-diarrhea therapy at any DL and judged to be possibly or probably related to the trial treatment by the Investigator and/or the Sponsor.
Time Frame Baseline Up to Day 29 of Cycle 1
Hide Outcome Measure Data
Hide Analysis Population Description
The DLT analysis set included all subjects who received over 90 percent (%) administration of trial medication in Cycle 1 or showed a DLT.
Arm/Group Title Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 21 22 13
Measure Type: Number
Unit of Measure: subjects
1 0 5
2.Primary Outcome
Title Part 2: Percentage of Subjects With Best Overall Response
Hide Description The best overall response was to be reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) >1.0x10^9 per liter (/L), platelets >100x10^9 /L, bone marrow aspirate with less than or equal to (<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC >1.0x10^9/L, platelets >100x10^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (<) 5%. (4) Progressive disease (PD) = >50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = subjects who failed to achieve CR, CRi or PR and without criteria for PD.
Time Frame Day 29 of every 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012
Hide Outcome Measure Data
Hide Analysis Population Description
Due to limited anti-leukemic effects observed in the safety run-in part decision was made not to conduct part 2 hence this outcome measure was not assessed. Effects observed in the safety run-in part decision was made not to conduct part 2 hence this outcome measure was not assessed.
Arm/Group Title Regimen 1 (Part 2) Regimen 2 (Part 2)
Hide Arm/Group Description:
Pimasertib was to be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was to be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
3.Secondary Outcome
Title Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation
Hide Description An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs include both SAEs and non-SAEs.
Time Frame Baseline up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set included all the subjects who received at least one administration of the trial medication.
Arm/Group Title Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 33 32 15
Measure Type: Number
Unit of Measure: Subjects
TEAEs 33 32 15
Serious TEAEs 24 28 12
TEAEs Leading to Death 6 6 5
TEAEs Leading to Treatment Discontinuation 7 7 7
4.Secondary Outcome
Title Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose
Hide Description [Not Specified]
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided adequate PK samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 6 9 7 9 4 19 10 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanogram/milliliter
14.8
(43.0%)
29.3
(32.0%)
59.1
(86.2%)
132.8
(29.6%)
151.6
(38.8%)
207.0
(27.8%)
269.9
(46.1%)
241.9
(81.0%)
342.6
(18.5%)
5.Secondary Outcome
Title Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose
Hide Description [Not Specified]
Time Frame Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided adequate PK samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 11 10 8 9 13 2 16 5 1
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanogram/milliliter
23.6
(40.1%)
59.3
(53.1%)
69.6
(39.2%)
150.1
(63.7%)
187.8
(25.3%)
123.2
(63.4%)
231.4
(48.2%)
383.2
(57.6%)
486.3 [1] 
(NA%)
[1]
Geometric coefficient of variation was not available as only 1 subject was evaluated for this group
6.Secondary Outcome
Title Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose
Hide Description [Not Specified]
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 7 9 7 9 4 19 10 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour
0.94
(41.18%)
2.25
(53.20%)
1.56
(151.73%)
1.09
(38.74%)
1.11
(78.05%)
1.12
(19.62%)
1.03
(40.27%)
2.70
(96.84%)
1.17
(76.62%)
7.Secondary Outcome
Title Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose
Hide Description [Not Specified]
Time Frame Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples per protocol. Number of subjects analysed refer to the subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 11 10 8 9 13 2 16 5 1
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour
1.44
(78.61%)
1.75
(83.12%)
2.03
(59.04%)
1.99
(70.40%)
1.64
(73.93%)
1.41
(52.11%)
1.78
(112.59%)
2.75
(21.83%)
2.00 [1] 
(NA%)
[1]
Geometric coefficient of variation was not available as only 1 subject was evaluated for this group.
8.Secondary Outcome
Title Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose
Hide Description The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination.
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 4 6 7 8 4 18 5 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour
5.28
(41.55%)
3.52
(19.75%)
3.05
(13.96%)
4.01
(36.61%)
3.88
(42.26%)
3.45
(23.80%)
2.97
(21.92%)
4.21
(92.04%)
3.39
(49.59%)
9.Secondary Outcome
Title Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose
Hide Description The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination.
Time Frame Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 7 6 6 11 2 11 2 1
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour
6.97
(75.47%)
10.91
(590.54%)
3.69
(22.69%)
3.93
(32.17%)
3.71
(21.38%)
3.96
(17.24%)
4.52
(66.99%)
8.44
(175.10%)
5.04 [1] 
(NA%)
[1]
Geometric coefficient of variation was not available as only 1 subject was evaluated for this group
10.Secondary Outcome
Title Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Single Dose
Hide Description [Not Specified]
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 6 9 7 9 4 19 10 4
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour*nanogram/milliliter
54.0
(57.2%)
125.4
(42.4%)
230.9
(60.9%)
456.2
(25.5%)
581.8
(45.4%)
735.2
(47.2%)
863.8
(52.8%)
905.0
(92.8%)
1268.2
(31.9%)
11.Secondary Outcome
Title Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Multiple Dose
Hide Description [Not Specified]
Time Frame Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. ‘"n" =Subjects evaluable for this outcome measure for specified categories for each reporting group, respectively.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 11 10 8 9 13 2 16 5 1
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour*nanogram/milliliter
131.4
(45.5%)
307.2
(75.4%)
321.9
(29.9%)
679.4
(53.7%)
761.2
(35.5%)
628.0
(28.2%)
991.6
(66.1%)
2195.2
(97.3%)
2144.7 [1] 
(NA%)
[1]
Geometric coefficient of variation was not available as only 1 subject was evaluated for this group.
12.Secondary Outcome
Title Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose
Hide Description The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. It is obtained from AUC0-t plus AUCt-infinity.
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. ‘N’(number of subjects analyzed)=subjects evaluable for this measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 4 6 7 8 4 18 5 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour*nanogram/milliliter
80.5
(52.9%)
145.2
(42.1%)
315.6
(76.3%)
562.1
(33.3%)
734.9
(49.7%)
858.4
(49.6%)
1027.4
(49.2%)
1530.7
(135.3%)
1873.9
(68.8%)
13.Secondary Outcome
Title Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose
Hide Description The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. It is obtained from AUC0-t plus AUCt-infinity.
Time Frame Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 7 6 6 11 2 11 2 1
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour*nanogram/milliliter
226.2
(91.0%)
789.3
(1038.0%)
451.2
(39.4%)
1030.2
(51.6%)
938.0
(46.6%)
786.7
(21.2%)
1270.8
(104.3%)
2712.6
(456.7%)
2830.7 [1] 
(NA%)
[1]
Geometric coefficient of variation was not available as only 1 subject was evaluated for this group.
14.Secondary Outcome
Title Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose
Hide Description Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. Data for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome.
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. ‘N’(number of subjects analyzed)=subjects evaluable for this measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 4 6 7 8 4 18 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter/hour
99.43
(52.86%)
103.29
(42.07%)
72.88
(76.28%)
53.37
(33.26%)
57.15
(49.72%)
52.42
(49.59%)
58.40
(49.21%)
48.03
(68.78%)
15.Secondary Outcome
Title Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose
Hide Description Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. ‘N’(number of subjects analyzed)=subjects evaluable for this measure and "n" = subjects evaluable for the specified regimen.
Arm/Group Title Pimasertib 75 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: liter/hour
Regimen 1 (n=0) NA [1]   (NA)
Regimen 2 (n=3) 93  (103.367)
Regimen 3 (n=1) 45 [2]   (NA)
[1]
For Regimen 1, number of subjects analyzed = 0 as no subject received 75 mg dose.
[2]
Standard Deviation could not be estimated as there was only 1 participant assessed for the specified category.
16.Secondary Outcome
Title Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose
Hide Description Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
Time Frame Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. ‘N’(number of subjects analyzed)=subjects evaluable for this measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 11 9 8 7 12 2 13 4 1
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter/hour
60.90
(45.51%)
46.74
(78.85%)
66.52
(33.40%)
37.95
(47.59%)
55.80
(35.90%)
69.23
(33.40%)
65.11
(65.69%)
34.44
(119.51%)
41.96 [1] 
(NA%)
[1]
Geometric coefficient of variation was not available as only 1 subject was evaluated for this group.
17.Secondary Outcome
Title Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose
Hide Description Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Data for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome.
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. ‘N’(number of subjects analyzed)=subjects evaluable for this measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 4 6 7 8 4 18 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter
757.5
(48.3%)
524.8
(51.5%)
320.8
(60.1%)
308.8
(27.1%)
320.2
(40.4%)
260.8
(46.9%)
250.3
(48.5%)
235.2
(24.2%)
18.Secondary Outcome
Title Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose
Hide Description Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.
Time Frame Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure and "n" = subjects evaluable for the specified regimen.
Arm/Group Title Pimasertib 75 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 4
Mean (Standard Deviation)
Unit of Measure: liter
Regimen 1 (n = 0) NA [1]   (NA)
Regimen 2 (n = 3) 442.2  (214.6)
Regimen 3 (n = 1) 196.0 [2]   (NA)
[1]
For Regimen 1, number of subjects analyzed = 0 as no subject received 75 mg dose.
[2]
Standard Deviation could not be estimated as there was only 1 participant assessed for the specified category.
19.Secondary Outcome
Title Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose
Hide Description Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.
Time Frame Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. ‘N’(number of subjects analyzed)=subjects evaluable for this measure.
Arm/Group Title Pimasertib 8 mg (All Regimens [Part 1]) Pimasertib 15 mg (All Regimens [Part 1]) Pimasertib 23 mg (All Regimens [Part 1]) Pimasertib 30 mg (All Regimens [Part 1]) Pimasertib 42 mg (All Regimens [Part 1]) Pimasertib 45 mg (All Regimens [Part 1]) Pimasertib 60 mg (All Regimens [Part 1]) Pimasertib 75 mg (All Regimens [Part 1]) Pimasertib 90 mg (All Regimens [Part 1])
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 9 7 6 6 11 2 11 2 1
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter
601.7
(79.2%)
863.7
(193.5%)
332.8
(14.5%)
207.8
(46.8%)
293.1
(27.6%)
395.1
(52.9%)
422.0
(79.2%)
689.9
(16.0%)
305.2 [1] 
(NA%)
[1]
Geometric coefficient of variation was not available as only 1 subject was evaluated for this group.
20.Secondary Outcome
Title Part 1: Percentage of Subjects With Best Overall Response
Hide Description The best overall response was reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) >1.0x10^9 per liter (/L), platelets >100x10^9 /L, bone marrow aspirate with less than or equal to (<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC >1.0x10^9/L, platelets >100x10^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (<) 5%. (4) Progressive disease (PD) = >50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = Subjects who failed to achieve CR, CRi or PR and without criteria for PD.
Time Frame Day 29 of every alternate 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy analysis set included all subjects who received at least 1 administration of planned dose of pimasertib and had at least 1 efficacy assessment after the first dose. 'N’ (number of subjects analyzed)=subjects evaluable for this outcome measure.
Arm/Group Title Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Hide Arm/Group Description:
Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 20 22 7
Measure Type: Number
Unit of Measure: Percentage of Subjects
CR 0.0 0.0 0.0
CRi 0.0 0.0 0.0
PR 0.0 0.0 0.0
SD 60.0 77.3 71.4
PD 40.0 22.7 28.6
21.Secondary Outcome
Title Part 2: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation
Hide Description An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Time Frame Up to 3 years
Hide Outcome Measure Data
Hide Analysis Population Description
This outcome measure was not analyzed as the trial was terminated during safety run-in (Part 1).
Arm/Group Title Regimen 1 (Part 2) Regimen 2 (Part 2)
Hide Arm/Group Description:
Pimasertib was to be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Pimasertib was to be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Up to 3 years
Adverse Event Reporting Description A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. SAEs and Other AEs (non-SAEs) were reported.
 
Arm/Group Title Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Hide Arm/Group Description Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision.
All-Cause Mortality
Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   24/33 (72.73%)   28/32 (87.50%)   12/15 (80.00%) 
Blood and lymphatic system disorders       
Anaemia * 1  1/33 (3.03%)  2/32 (6.25%)  0/15 (0.00%) 
Febrile Neutropenia * 1  4/33 (12.12%)  9/32 (28.13%)  2/15 (13.33%) 
Neutropenia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Thrombocytopenia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Thrombocytosis * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Cardiac disorders       
Acute coronary syndrome * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Atrial fibrillation * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Cardiac failure congestive * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Sinus bradycardia * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Eye disorders       
Photopsia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Retinal detachment * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Visual impairment * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Gastrointestinal disorders       
Abdominal pain * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Caecitis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Colitis * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Diarrhoea * 1  2/33 (6.06%)  2/32 (6.25%)  2/15 (13.33%) 
Gastrointestinal haemorrhage * 1  1/33 (3.03%)  1/32 (3.13%)  1/15 (6.67%) 
Ileus * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Large intestinal obstruction * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Lower gastrointestinal haemorrhage * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Mouth haemorrhage * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Nausea * 1  1/33 (3.03%)  1/32 (3.13%)  1/15 (6.67%) 
Stomatitis * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Toothache * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Upper gastrointestinal haemorrhage * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Vomiting * 1  1/33 (3.03%)  1/32 (3.13%)  1/15 (6.67%) 
General disorders       
Asthenia * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Disease progression * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Face oedema * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Fatigue * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
General physical health deterioration * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Mucosal inflammation * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Oedema peripheral * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Pyrexia * 1  1/33 (3.03%)  5/32 (15.63%)  1/15 (6.67%) 
Infections and infestations       
Bacteraemia * 1  2/33 (6.06%)  2/32 (6.25%)  0/15 (0.00%) 
Bronchopulmonary aspergillosis * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Cellulitis * 1  2/33 (6.06%)  3/32 (9.38%)  0/15 (0.00%) 
Clostridial infection * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Clostridium difficile colitis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Device related infection * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Diverticulitis * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Enterococcal bacteraemia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Enterocolitis infectious * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Escherichia bacteraemia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Human herpes virus 6 infection * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Infection * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Influenza * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Lung Infection * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
Parainfluenzae virus infection * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Pneumonia * 1  7/33 (21.21%)  4/32 (12.50%)  3/15 (20.00%) 
Pneumonia fungal * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Sepsis * 1  2/33 (6.06%)  3/32 (9.38%)  1/15 (6.67%) 
Septic shock * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Tonsillitis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Urinary tract infection * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Urinary tract infection enterococcal * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Injury, poisoning and procedural complications       
Hip fracture * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Overdose * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Subdural haematoma * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Investigations       
Alanine aminotransferase increased * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Asparatate aminotransferase increased * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Neutrophil count decreased * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
White Blood Cell Count Increased * 1  0/33 (0.00%)  2/32 (6.25%)  0/15 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Dehydration * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Hyponatraemia * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Tumor lysis syndrome * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Nervous system disorders       
Depressed level of consciousness * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Haemorrhage intracranial * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Subdural hygroma * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Syncope * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Psychiatric disorders       
Delirium * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Renal and urinary disorders       
Nephritic syndrome * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Renal failure * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Renal failure acute * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Renal tubular necrosis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Reproductive system and breast disorders       
Cystocele * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Acute respiratory distress syndrome * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Acute respiratory failure * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Dyspnoea * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Epistaxis * 1  3/33 (9.09%)  0/32 (0.00%)  1/15 (6.67%) 
Hypoxia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Lung disorder * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Pleural Effusion * 1  1/33 (3.03%)  0/32 (0.00%)  2/15 (13.33%) 
Skin and subcutaneous tissue disorders       
Angioedema * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Rash maculo-papular * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Swelling face * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Vascular disorders       
Deep vein thrombosis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Hypotension * 1  2/33 (6.06%)  1/32 (3.13%)  0/15 (0.00%) 
Shock haemorrhagic * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Varicose vein * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA Version 15.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Regimen 1 (Part 1) Regimen 2 (Part 1) Regimen 3 (Part 1)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   32/33 (96.97%)   30/32 (93.75%)   15/15 (100.00%) 
Blood and lymphatic system disorders       
Anaemia * 1  3/33 (9.09%)  2/32 (6.25%)  0/15 (0.00%) 
Febrile bone marrow aplasia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Febrile neutropenia * 1  1/33 (3.03%)  2/32 (6.25%)  0/15 (0.00%) 
Leukocytosis * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Lymphadenopathy * 1  1/33 (3.03%)  2/32 (6.25%)  0/15 (0.00%) 
Neutropenia * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Spontaneous haematoma * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Cardiac disorders       
Atrial fibrillation * 1  2/33 (6.06%)  1/32 (3.13%)  0/15 (0.00%) 
Atrioventricular block second degree * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Bradycardia * 1  1/33 (3.03%)  2/32 (6.25%)  0/15 (0.00%) 
Pericardial effusion * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Pneumopericardium * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Sinus tachycardia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Tachycardia * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Ear and labyrinth disorders       
Ear Pain * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Hypoacusis * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Vertigo * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Eye disorders       
Blepharitis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Chorioretinopathy * 1  0/33 (0.00%)  3/32 (9.38%)  0/15 (0.00%) 
Conjunctival hyperaemia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Conjunctival oedema * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Conjunctivitis * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Detachment of retinal pigment epithelium * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Dry eye * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Erythema of eyelid * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Eyelid disorder * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Eyelid oedema * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Lacrimation increased * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Macular Degeneration * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Macular oedema * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Metamorphopsia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Ocular hypertension * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Optic disc haemorrhage * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Periorbital oedema * 1  1/33 (3.03%)  2/32 (6.25%)  0/15 (0.00%) 
Photopsia * 1  0/33 (0.00%)  2/32 (6.25%)  0/15 (0.00%) 
Retinal detachment * 1  2/33 (6.06%)  4/32 (12.50%)  1/15 (6.67%) 
Retinal haemorrhage * 1  0/33 (0.00%)  0/32 (0.00%)  2/15 (13.33%) 
Retinal oedema * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Retinal vein occlusion * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Scotoma * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Vision blurred * 1  4/33 (12.12%)  5/32 (15.63%)  1/15 (6.67%) 
Visual acuity reduced * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Visual impairment * 1  0/33 (0.00%)  2/32 (6.25%)  0/15 (0.00%) 
Vitreous floaters * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Xerophthalmia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Gastrointestinal disorders       
Abdominal distension * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Abdominal pain * 1  4/33 (12.12%)  2/32 (6.25%)  0/15 (0.00%) 
Abdominal pain upper * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Anal fissure * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Aphthous stomatitis * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Constipation * 1  3/33 (9.09%)  3/32 (9.38%)  1/15 (6.67%) 
Diarrhoea * 1  14/33 (42.42%)  16/32 (50.00%)  8/15 (53.33%) 
Dry mouth * 1  2/33 (6.06%)  2/32 (6.25%)  0/15 (0.00%) 
Dysphagia * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Faecal incontinence * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Flatulence * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Gastrooesophageal reflux disease * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Gingival bleeding * 1  1/33 (3.03%)  2/32 (6.25%)  1/15 (6.67%) 
Gingival inflammation * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Haematemesis * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Hyperchlorhydria * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Lip oedema * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Melaena * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Mouth haemorrhage * 1  4/33 (12.12%)  2/32 (6.25%)  1/15 (6.67%) 
Mouth ulceration * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Nausea * 1  10/33 (30.30%)  7/32 (21.88%)  2/15 (13.33%) 
Oral disorder * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Oral pain * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Proctalgia * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Rectal haemorrhage * 1  2/33 (6.06%)  1/32 (3.13%)  0/15 (0.00%) 
Stomatitis * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Stomatitis necrotising * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Vomiting * 1  6/33 (18.18%)  6/32 (18.75%)  1/15 (6.67%) 
General disorders       
Asthenia * 1  4/33 (12.12%)  5/32 (15.63%)  2/15 (13.33%) 
Chest pain * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Chills * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Face oedema * 1  0/33 (0.00%)  1/32 (3.13%)  2/15 (13.33%) 
Fatigue * 1  5/33 (15.15%)  5/32 (15.63%)  2/15 (13.33%) 
Generalised oedema * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Hyperthermia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Influenza like illness * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Localised oedema * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Malaise * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Mucosal inflammation * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Oedema * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Oedema peripheral * 1  6/33 (18.18%)  8/32 (25.00%)  4/15 (26.67%) 
Pyrexia * 1  7/33 (21.21%)  8/32 (25.00%)  1/15 (6.67%) 
Infusion site oedema * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Hepatobiliary disorders       
Hyperbilirubinaemia * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Immune system disorders       
Graft versus host disease in intestine * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Graft versus host disease in skin * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Infections and infestations       
Anal abscess * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Bacteraemia * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
Bronchitis * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Cellulitis * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
Clostridial infection * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Gastroenteritis * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Herpes simplex ophthalmic * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Human herpesvirus 6 virus infection * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Localised infection * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Nasopharyngitis * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Oral candidiasis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Oral fungal infection * 1  0/33 (0.00%)  2/32 (6.25%)  0/15 (0.00%) 
Paronychia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Pneumonia * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Rhinitis * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Sepsis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Sinusitis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Staphylococcal sepsis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Upper respiratory tract infection * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Urinary tract infection * 1  2/33 (6.06%)  0/32 (0.00%)  1/15 (6.67%) 
Hordeolum * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Injury, poisoning and procedural complications       
Contusion * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Craniocerebral injury * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Eschar * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Muscle strain * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Overdose * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Procedural pain * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Subdural haematoma * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Transfusion reaction * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
Wound * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Investigations       
Activated partial thromboplastin time prolonged * 1  3/33 (9.09%)  0/32 (0.00%)  1/15 (6.67%) 
Alanine aminotransferase increased * 1  6/33 (18.18%)  4/32 (12.50%)  1/15 (6.67%) 
Aspartate aminotransferase increased * 1  8/33 (24.24%)  7/32 (21.88%)  3/15 (20.00%) 
Blood albumin decreased * 1  4/33 (12.12%)  1/32 (3.13%)  0/15 (0.00%) 
Blood alkaline phosphatase increased * 1  5/33 (15.15%)  3/32 (9.38%)  2/15 (13.33%) 
Blood bilirubin increased * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
Blood calcium decreased * 1  4/33 (12.12%)  2/32 (6.25%)  0/15 (0.00%) 
Blood creatine increased * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Blood creatinine * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Blood creatinine increased * 1  0/33 (0.00%)  1/32 (3.13%)  1/15 (6.67%) 
Blood glucose increased * 1  2/33 (6.06%)  1/32 (3.13%)  1/15 (6.67%) 
Blood magnesium decreased * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
Blood phosphorus increased * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Blood potassium decreased * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Blood sodium decreased * 1  4/33 (12.12%)  1/32 (3.13%)  0/15 (0.00%) 
Blood urea increased * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Blood uric acid increased * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Electrocardiogram QT prolonged * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Gamma−glutamyltransferase * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Gamma−glutamyltransferase increased * 1  3/33 (9.09%)  0/32 (0.00%)  1/15 (6.67%) 
Haemoglobin decreased * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
International normalised ratio increased * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Neutrophil count decreased * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Weight decreased * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Weight increased * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Metabolism and nutrition disorders       
Decreased appetite * 1  0/33 (0.00%)  3/32 (9.38%)  1/15 (6.67%) 
Dehydration * 1  0/33 (0.00%)  2/32 (6.25%)  2/15 (13.33%) 
Hyperglycaemia * 1  3/33 (9.09%)  0/32 (0.00%)  1/15 (6.67%) 
Hyperkalaemia * 1  2/33 (6.06%)  1/32 (3.13%)  1/15 (6.67%) 
Hypermagnesaemia * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Hypernatraemia * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Hyperphosphataemia * 1  1/33 (3.03%)  1/32 (3.13%)  1/15 (6.67%) 
Hyperuricaemia * 1  2/33 (6.06%)  3/32 (9.38%)  3/15 (20.00%) 
Hypoalbuminaemia * 1  1/33 (3.03%)  2/32 (6.25%)  3/15 (20.00%) 
Hypocalcaemia * 1  1/33 (3.03%)  2/32 (6.25%)  4/15 (26.67%) 
Hypoglycaemia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Hypokalaemia * 1  3/33 (9.09%)  5/32 (15.63%)  1/15 (6.67%) 
Hypomagnesaemia * 1  0/33 (0.00%)  3/32 (9.38%)  0/15 (0.00%) 
Hyponatraemia * 1  2/33 (6.06%)  1/32 (3.13%)  1/15 (6.67%) 
Hypophosphataemia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Malnutrition * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Metabolic acidosis * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  2/33 (6.06%)  1/32 (3.13%)  0/15 (0.00%) 
Back pain * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Hypercreatinaemia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Muscle spasms * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Muscular weakness * 1  0/33 (0.00%)  2/32 (6.25%)  0/15 (0.00%) 
Musculoskeletal chest pain * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Musculoskeletal pain * 1  1/33 (3.03%)  2/32 (6.25%)  0/15 (0.00%) 
Pain in extremity * 1  4/33 (12.12%)  2/32 (6.25%)  0/15 (0.00%) 
Synovial cyst * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Benign neoplasm of skin * 1  0/33 (0.00%)  2/32 (6.25%)  0/15 (0.00%) 
Nervous system disorders       
Aphonia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Cognitive disorder * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Convulsion * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Dizziness * 1  7/33 (21.21%)  5/32 (15.63%)  2/15 (13.33%) 
Dysgeusia * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Headache * 1  3/33 (9.09%)  6/32 (18.75%)  1/15 (6.67%) 
Hypoaesthesia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Hypokinesia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Lethargy * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Neuropathy peripheral * 1  2/33 (6.06%)  1/32 (3.13%)  0/15 (0.00%) 
Paraesthesia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Sciatica * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Somnolence * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Syncope * 1  2/33 (6.06%)  2/32 (6.25%)  0/15 (0.00%) 
Psychiatric disorders       
Agitation * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Anxiety * 1  3/33 (9.09%)  1/32 (3.13%)  1/15 (6.67%) 
Confusional state * 1  3/33 (9.09%)  3/32 (9.38%)  0/15 (0.00%) 
Hallucination * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Hallucination, visual * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Insomnia * 1  1/33 (3.03%)  2/32 (6.25%)  1/15 (6.67%) 
Renal and urinary disorders       
Dysuria * 1  2/33 (6.06%)  0/32 (0.00%)  1/15 (6.67%) 
Haematuria * 1  2/33 (6.06%)  0/32 (0.00%)  0/15 (0.00%) 
Pollakiuria * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Proteinuria * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Renal failure acute * 1  2/33 (6.06%)  0/32 (0.00%)  1/15 (6.67%) 
Reproductive system and breast disorders       
Testis discomfort * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Uterine prolapse * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Vulvovaginal pain * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Acute pulmonary oedema * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Acute respiratory distress syndrome * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Acute respiratory failure * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Cough * 1  5/33 (15.15%)  3/32 (9.38%)  0/15 (0.00%) 
Dysphonia * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Dyspnoea * 1  2/33 (6.06%)  2/32 (6.25%)  2/15 (13.33%) 
Dyspnoea exertional * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Epistaxis * 1  5/33 (15.15%)  5/32 (15.63%)  0/15 (0.00%) 
Nasal congestion * 1  0/33 (0.00%)  0/32 (0.00%)  2/15 (13.33%) 
Oropharyngeal pain * 1  1/33 (3.03%)  2/32 (6.25%)  0/15 (0.00%) 
Pleural effusion * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Productive cough * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Respiratory failure * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Rhinorrhoea * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Tachypnoea * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Wheezing * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Skin and subcutaneous tissue disorders       
Acne * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Alopecia * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Blood blister * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Decubitus ulcer * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Dermatitis acneiform * 1  1/33 (3.03%)  1/32 (3.13%)  1/15 (6.67%) 
Dermatitis diaper * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Dry skin * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Erythema * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Exfoliative rash * 1  2/33 (6.06%)  1/32 (3.13%)  0/15 (0.00%) 
Hyperhidrosis * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Petechiae * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
Pruritus * 1  2/33 (6.06%)  1/32 (3.13%)  0/15 (0.00%) 
Purpura * 1  1/33 (3.03%)  1/32 (3.13%)  0/15 (0.00%) 
Rash * 1  4/33 (12.12%)  6/32 (18.75%)  4/15 (26.67%) 
Rash generalised * 1  1/33 (3.03%)  0/32 (0.00%)  1/15 (6.67%) 
Rash macular * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Rash maculo−papular * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Skin disorder * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Skin lesion * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Skin reaction * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Swelling face * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Vascular disorders       
Deep vein thrombosis * 1  0/33 (0.00%)  0/32 (0.00%)  1/15 (6.67%) 
Flushing * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Hot flush * 1  1/33 (3.03%)  0/32 (0.00%)  0/15 (0.00%) 
Hypertension * 1  1/33 (3.03%)  2/32 (6.25%)  1/15 (6.67%) 
Hypotension * 1  4/33 (12.12%)  6/32 (18.75%)  1/15 (6.67%) 
Orthostatic hypotension * 1  0/33 (0.00%)  1/32 (3.13%)  0/15 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA Version 15.1
The trial has been terminated due to an estimated low probability of clinical benefit based on limited anti-leukemic effects observed in safety run-in (Part 1).
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
 
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Merck KGaA Communication Center
Organization: Merck Serono, a division of Merck KGaA
Phone: +49-6151-72-5200
EMail: service@merckgroup.com
Layout table for additonal information
Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00957580     History of Changes
Other Study ID Numbers: EMR200066_002
2009-010866-49 ( EudraCT Number )
First Submitted: August 11, 2009
First Posted: August 12, 2009
Results First Submitted: July 4, 2016
Results First Posted: March 29, 2017
Last Update Posted: August 21, 2017