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Safety and Efficacy of INC280 and Buparlisib (BKM120) in Patients With Recurrent Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01870726
Recruitment Status : Terminated
First Posted : June 6, 2013
Results First Posted : May 24, 2018
Last Update Posted : May 30, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition c-MET Inhibitor; PI3K Inhibitor, PTEN Mutations, Homozygous Del. of PTEN or PTEN Neg. by IHC, c-Met Ampli. by FISH, INC280, BKM120, Buparlisib; Recurrent GBM
Interventions Drug: INC280
Drug: Buparlisib
Enrollment 43
Recruitment Details  
Pre-assignment Details A total of 43 patients enrolled in this trial, 33 patients in the Phase Ib part of the study (patients were assigned to 6 dose combinations of INC280 with buparlisib) and 10 patients in the Phase II part of the study.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab
Hide Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase II: 400 mg INC280 (BID) tablet
Period Title: Overall Study
Started 5 6 4 6 7 5 10
Completed 0 0 0 0 0 0 0
Not Completed 5 6 4 6 7 5 10
Reason Not Completed
Withdrawal of informed consent             0             0             0             1             0             0             0
Withdrawal by Subject             0             1             0             0             0             0             0
Adverse Event             0             0             0             0             1             1             0
Progressive disease             5             5             4             5             6             4             10
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab +80 mg QD 400 mg BID Tab Total
Hide Arm/Group Description Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib. Phase II: 400 mg INC280 (BID) tablet Total of all reporting groups
Overall Number of Baseline Participants 5 6 4 6 7 5 10 43
Hide Baseline Analysis Population Description
Full Analysis Set (FAS): The FAS comprised all patients who received at least one full or partial dose of study treatment. Patients were classified according to the planned treatment.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 6 participants 4 participants 6 participants 7 participants 5 participants 10 participants 43 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
2
  40.0%
6
 100.0%
4
 100.0%
5
  83.3%
4
  57.1%
4
  80.0%
10
 100.0%
35
  81.4%
>=65 years
3
  60.0%
0
   0.0%
0
   0.0%
1
  16.7%
3
  42.9%
1
  20.0%
0
   0.0%
8
  18.6%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 6 participants 4 participants 6 participants 7 participants 5 participants 10 participants 43 participants
Female
0
   0.0%
2
  33.3%
2
  50.0%
3
  50.0%
0
   0.0%
2
  40.0%
7
  70.0%
16
  37.2%
Male
5
 100.0%
4
  66.7%
2
  50.0%
3
  50.0%
7
 100.0%
3
  60.0%
3
  30.0%
27
  62.8%
1.Primary Outcome
Title Number of Patients Reporting Dose Limiting Toxicities (DLTs) in Cycle 1
Hide Description A DLT is defined as an adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and is not primarily related to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment (28 days) with INC280 in combination with buparlisib and meets any of the pre-defined criteria. The maximum tolerated dose was identified as INC280 300 mg BID + buparlisib 80 mg QD.
Time Frame Cycle 1, 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Dose determining set (DDS) consisted of all patients from the SAS who either met the minimum exposure criterion and had sufficient safety evaluations during Cycle 1, or discontinued earlier due to DLT during Cycle 1.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 4 5 4 6 7 4
Measure Type: Number
Unit of Measure: Number of Patients
Personality Change 0 1 0 0 0 0
Nausea 0 0 0 0 1 0
Aspartate Aminotransferase Increased 0 0 0 0 0 2
2.Primary Outcome
Title Phase II: Progression Free Survival Rate (PFSR)
Hide Description

Estimated rate of patients treated during 6 months without experiencing disease progression.

The Progression Free Survival Rate at 6 months was to be estimated using a Bayesian model described in the protocol. The models operating characteristics were evaluated based on the enrollment of at least 30 patients enrolled. Patients did not reach the milestone for the PFSR analysis (trial terminated); as such no analysis was performed.

Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Based on the phase I, a RP2D was not determined for the combination arm (Phase II combination arms were not opened). Patients did not reach the milestone needed for the PFSR analysis (at minimum the Bayesian model requires 30 patients) due to early termination, as such no analysis for PFSR was performed.
Arm/Group Title BID Tab+Buparlisib
Hide Arm/Group Description:
Phase II: INC280 (BID) as a single agent and in combination with buparlisib
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
3.Primary Outcome
Title Phase II Surgical Arm: Concentrations of INC280 and Buparlisib in Tumor.
Hide Description Concentrations of INC280 and buparlisib in tumor tissue.
Time Frame 7 days
Hide Outcome Measure Data
Hide Analysis Population Description
Based on the phase I, a RP2D was not determined for the combination and the phase II combination arms were not opened.
Arm/Group Title BID + QD
Hide Arm/Group Description:
The combination of INC280 (BID) and Buparlisib (QD).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
4.Secondary Outcome
Title Number of Participants With Adverse Events
Hide Description

To characterize the safety of INC280 single agent and in combination with buparlisib including type, frequency, severity of adverse events, serious adverse events, and dose interruptions and adjustments. Adverse events will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, unless otherwise specified.

If CTCAE grading did not exist for an AE, the severity of mild, moderate, severe, and lifethreatening, corresponding to Grades 1 - 4, were used. CTCAE Grade 5 (death) was not used in this study but was collected as a seriousness criterion; rather, information about deaths was collected though a Death form.

Time Frame throughout the duration of the trial, approximately 3 years from FPFV to LPLV
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Set (SAS): The SAS comprised all patients who received at least one full or partial dose of study treatment. Patients were analyzed according to the treatment actually received. The SAS was used for all safety analyses.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab + 80 mg QD 400 mg BID Tab + 80 mg QD 400 mg BID Tab
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: the combination of 400 mg INC280 (BID) tablet and 80 mg Buparlisib (QD) once daily
Phase II: 400 mg INC280 (BID) tablet
Overall Number of Participants Analyzed 5 6 4 6 7 5 9
Measure Type: Number
Unit of Measure: Participants
Adverse events 5 6 4 6 7 5 9
Treatment-related AEs 4 4 4 4 7 5 6
AEs with grade ≥ 3 5 4 4 2 5 4 8
SAEs 3 2 3 3 3 4 2
AEs leading to discontinuation 0 0 0 0 1 1 0
AEs leading to dose adjustment/interruption 2 3 2 4 4 4 5
AEs requiring additional therapy 4 5 3 5 7 5 7
5.Secondary Outcome
Title Pharmacokinetic Profile of INC280 - AUCtau
Hide Description Plasma concentration profile of INC280 in combination with Buparlisib. AUCtau is the AUC from time zero to the end of dosing interval.
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: hr*ng/ml
Cycle 1 Day 1
2435.6
(1870.1 to 4978.4)
3005.9
(1010.1 to 5581.5)
4789.7
(1716.5 to 8086.8)
5071.7
(2463.8 to 8018.8)
5732.2
(1657.2 to 8924.7)
11127.7
(2978.3 to 13776.6)
Cycle 1 Day 15
5749.3
(4045.6 to 10405.8)
11261.7
(3069.8 to 13946.9)
10581.0
(6276.0 to 31532.5)
2779.4
(1940.8 to 3618.0)
12801.3
(8606.0 to 16381.0)
16590.6
(11576.1 to 17422.8)
Cycle 2 Day 1
4894.6
(3880.4 to 7192.8)
2655.6
(2655.6 to 2655.6)
23498.3
(19903.7 to 27092.8)
10554.3
(4793.3 to 14289.7)
9593.5
(7002.3 to 12184.7)
13051.1
(13051.1 to 13051.1)
6.Secondary Outcome
Title Pharmacokinetic Profile of INC280 - Cmax
Hide Description Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: ng/ml
Cycle 1 Day 1
618.0
(406.0 to 1680.0)
880.0
(219.0 to 1410.0)
960.5
(434.0 to 2510.0)
860.0
(195.0 to 2770.0)
1990.0
(423.0 to 2510.0)
3635.0
(1210.0 to 4640.0)
Cycle 1 Day 15
1560.0
(745.0 to 2610.0)
2005.0
(763.0 to 3930.0)
3480.0
(1350.0 to 8350.0)
545.5
(315.0 to 776.0)
3610.0
(2320.0 to 4940.0)
4850.0
(1800.0 to 5350.0)
Cycle 2 Day 1
1200.0
(578.0 to 1540.0)
2142.5
(675.0 to 3610.0)
5010.0
(4230.0 to 5790.0)
2254.5
(479.0 to 3740.0)
3080.0
(2720.0 to 3440.0)
3220.0
(3220.0 to 3220.0)
7.Secondary Outcome
Title Pharmacokinetic Profile of INC280 - Tmax
Hide Description Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: hr
Cycle 1 Day 1
1.1
(1.0 to 2.0)
2.0
(2.0 to 4.0)
1.5
(1.0 to 2.2)
1.3
(1.1 to 4.0)
1.6
(1.0 to 2.2)
2.0
(0.9 to 2.0)
Cycle 1 Day 15
1.9
(0.9 to 2.0)
2.0
(1.0 to 2.1)
2.0
(1.0 to 2.1)
2.6
(1.2 to 4.0)
1.0
(1.0 to 1.0)
1.5
(1.0 to 2.1)
Cycle 2 Day 1
2.0
(1.0 to 4.0)
2.0
(2.0 to 2.0)
1.5
(1.0 to 2.1)
2.1
(1.5 to 4.0)
1.5
(1.0 to 2.0)
1.0
(1.0 to 1.0)
8.Secondary Outcome
Title Pharmacokinetic Profile of INC280 - T1/2
Hide Description Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: hr
Cycle 1 Day 15
13.4
(4.1 to 31.2)
20.8
(16.3 to 28.6)
26.0
(13.2 to 28.1)
7.3
(7.3 to 7.3)
13.1
(7.0 to 19.3)
8.0
(4.2 to 28.0)
Cycle 2 Day 1
9.9
(3.8 to 20.1)
17.4
(17.4 to 17.4)
26.3
(23.5 to 29.1)
8.7
(5.8 to 11.5)
6.3
(6.3 to 6.3)
4.3
(4.3 to 4.3)
9.Secondary Outcome
Title Pharmacokinetic Profile of Buparlisib - AUCtau
Hide Description Plasma concentration profile of Buparlisib in combination with INC280. AUCtau is the AUC from time zero to the end of dosing interval.
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: hr*ng/ml
Cycle 1 Day 1
3072.0
(2119.7 to 3448.0)
1865.0
(1383.2 to 3840.8)
3328.2
(2830.2 to 4104.1)
3825.8
(2784.0 to 5201.4)
4425.3
(3109.8 to 5238.2)
3658.8
(3347.7 to 5509.4)
Cycle 1 Day 15
8728.5
(4874.3 to 10962.7)
4591.9
(3167.1 to 10562.3)
6108.4
(5300.5 to 7605.5)
10844.6
(6761.7 to 14927.4)
10366.5
(8257.8 to 11052.6)
8535.1
(4102.2 to 8908.3)
Cycle 2 Day 1
7930.8
(3563.5 to 9712.2)
3776.7
(3477.6 to 4075.7)
6976.0
(3436.1 to 10515.9)
5903.0
(4850.4 to 12072.9)
7857.2
(7757.7 to 9361.9)
7344.3
(7344.3 to 7344.3)
10.Secondary Outcome
Title Pharmacokinetic Profile of Buparlisib - Cmax
Hide Description Plasma concentration profile of INC280 in combination with Buparlisib. Cmax is the Maximum (peak) observed drug concentration after dose administration.
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: ng/ml
Cycle 1 Day 1
484.0
(234.0 to 590.0)
351.0
(162.0 to 488.0)
399.0
(347.0 to 469.0)
522.0
(333.0 to 776.0)
508.0
(373.0 to 711.0)
475.0
(361.0 to 542.0)
Cycle 1 Day 15
664.0
(568.0 to 791.0)
459.0
(294.0 to 623.0)
542.0
(456.0 to 791.0)
785.0
(684.0 to 886.0)
814.0
(628.0 to 1330.0)
788.5
(390.0 to 1700.0)
Cycle 2 Day 1
560.0
(290.0 to 813.0)
377.5
(285.0 to 470.0)
611.0
(409.0 to 813.0)
529.5
(383.0 to 865.0)
735.0
(558.0 to 890.0)
600.0
(600.0 to 600.0)
11.Secondary Outcome
Title Pharmacokinetic Profile of Buparlisib - Tmax
Hide Description Plasma concentration profile of INC280 in combination with Buparlisib. Tmax is the time to reach maximum (peak) observed concentration (Cmax) after dose administration
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: hr
Cycle 1 Day 1
1.0
(0.6 to 1.2)
1.0
(0.6 to 2.0)
1.0
(0.5 to 1.2)
0.6
(0.5 to 2.0)
1.2
(0.5 to 2.0)
1.0
(0.9 to 2.0)
Cycle 1 Day 15
0.9
(0.9 to 1.0)
2.0
(1.0 to 2.1)
1.0
(1.0 to 2.0)
1.6
(1.2 to 2.0)
1.0
(0.5 to 1.0)
1.3
(0.5 to 2.1)
Cycle 2 Day 1
1.0
(0.5 to 2.0)
1.5
(1.0 to 2.0)
1.0
(1.0 to 1.0)
1.8
(1.0 to 2.1)
1.0
(1.0 to 1.0)
1.0
(1.0 to 1.0)
12.Secondary Outcome
Title Pharmacokinetic Profile of Buparlisib - T1/2
Hide Description Plasma concentration profile of INC280 in combination with Buparlisib. T1/2 is the terminal half life
Time Frame Cycle 1 Day 1, Cycle 1 Day 15, and Cycle 2 Day 1, approximately 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic analysis set (PAS): The PAS consisted of all patients who provided an evaluable PK profile.
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Overall Number of Participants Analyzed 5 5 4 6 4 5
Median (Full Range)
Unit of Measure: hr
Cycle 1 Day 15
37.3
(29.1 to 52.4)
31.1
(18.7 to 46.4)
21.8
(20.8 to 29.4)
30.9
(19.9 to 41.8)
38.0
(21.3 to 44.9)
22.8
(5.8 to 31.5)
Cycle 2 Day 1
34.0
(10.4 to 37.9)
21.3
(16.4 to 26.1)
27.0
(9.6 to 44.3)
17.2
(16.8 to 31.9)
20.1
(19.4 to 41.2)
12.0
(12.0 to 12.0)
13.Secondary Outcome
Title Best Overall Response (BOR)
Hide Description

Best Overall Response (BOR) observed in the study population of INC280 Single Agent and in Combination with Buparlisib. Responses will be assessed by the investigators following the RANO criteria with MRI or CT scans scheduled every 8 weeks.

Summary of the RANO response criteria: CR has no T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PR has ≥50% decrease T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; SD has ≥50% decrease but <25% increase T1-Gd+ (enhancing lesion), stable or decrease T2/FLAIR (non-enhancing lesion), absence of new lesion, stable or improve in clinical status; PD has ≥25% increase in T1-Gd+ (enhancing lesion), increase T2/FLAIR (non-enhancing lesion), presence of new lesion, deterioration in clinical status.

Time Frame throughout the duration of the trial - approximately 3 years (from FPFV to LPLV)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS
Arm/Group Title 200 mg BID Cap+50 mg QD 400 mg BID Cap+50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab +80 mg QD 400 mg BID Tab+80 mg QD 400 mg BID Tab
Hide Arm/Group Description:
Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 500 mg INC280 (BID) capsule and 50mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 300 mg INC280 (BID) tablet and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase Ib: The combination of 400 mg INC280 (BID) capsule and 80mg Buparlisib (QD) once daily for Phase Ib.
Phase II: 400 mg INC280 (BID) tablet
Overall Number of Participants Analyzed 5 6 4 6 7 5 10
Measure Type: Number
Unit of Measure: Participants
Complete Response (CR) 0 0 0 0 0 0 0
Partial Response (PR) 0 0 0 0 0 0 0
Stable Disease (SD) 0 0 0 1 0 0 3
Progressive Disease (PD) 5 5 4 4 7 4 6
Unknown (UNK) 0 0 0 0 0 0 0
Not Assessed 0 1 0 1 0 1 1
14.Secondary Outcome
Title Overall Survival (OS)
Hide Description

Survival rate of patients from start of treatment to date of death due to any cause.

Patients did not reach the milestone for the survival data analysis (terminated early); as such no analysis was done.

Time Frame throughout the duration of the trial - approximately 3 years (FPFV to LPLV)
Hide Outcome Measure Data
Hide Analysis Population Description
Based on the phase I, a RP2D was not determined for the combination arm (Phase II combination arms were not opened). Patients did not reach the milestone needed for the OS analysis (at minimum the Bayesian model requires 30 patients) due to early termination, as such no analysis for OS was done.
Arm/Group Title All Patients
Hide Arm/Group Description:
The combination of INC280 (BID) and Buparlisib (QD).
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Treatment Emergent Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit, approximately 3 years.
Adverse Event Reporting Description Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
 
Arm/Group Title INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
Hide Arm/Group Description Phase II: 200mg INC280 (BID) tablet in Phase II. A patient never received the intended PhII dose as planned (400 mg BID) but is resented as a separate group for safety. Phase Ib: The combination of 200mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500mg INC280 (BID) capsule and 50 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 500mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 300mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: The combination of 400mg INC280 (BID) capsule and 80 mg Buparlisib (QD) once daily for Phase Ib. Phase Ib: All Patients with the combination of INC280 (BID) and Buparlisib (QD) once daily. Phase II: 400mg INC280 (BID) tablet in Phase II. Phase II: All patients treated with INC280 (BID) tablet once daily in the Phase II.
All-Cause Mortality
INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Hide Serious Adverse Events
INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/1 (100.00%)   3/5 (60.00%)   2/6 (33.33%)   3/4 (75.00%)   3/6 (50.00%)   3/7 (42.86%)   4/5 (80.00%)   18/33 (54.55%)   2/9 (22.22%)   3/10 (30.00%) 
Gastrointestinal disorders                     
ABDOMINAL PAIN  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
DIARRHOEA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
GASTRIC ULCER  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
NAUSEA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
General disorders                     
PYREXIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Infections and infestations                     
FEBRILE INFECTION  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
INFLUENZA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PERITONITIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
PNEUMOCYSTIS JIROVECII PNEUMONIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PNEUMONIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
URINARY TRACT INFECTION  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Injury, poisoning and procedural complications                     
FALL  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Investigations                     
ALANINE AMINOTRANSFERASE INCREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  3/5 (60.00%)  4/33 (12.12%)  0/9 (0.00%)  0/10 (0.00%) 
ASPARTATE AMINOTRANSFERASE INCREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  3/5 (60.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
Metabolism and nutrition disorders                     
HYPONATRAEMIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Nervous system disorders                     
APHASIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
ATAXIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/5 (20.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
BRAIN OEDEMA  1  1/1 (100.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  0/9 (0.00%)  1/10 (10.00%) 
HAEMORRHAGE INTRACRANIAL  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
HEMIPARESIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
LETHARGY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
NEUROLOGICAL DECOMPENSATION  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PARAPARESIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PARTIAL SEIZURES  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
SEIZURE  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  2/4 (50.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
Psychiatric disorders                     
APATHY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Skin and subcutaneous tissue disorders                     
DERMATITIS ALLERGIC  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
RASH  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Vascular disorders                     
EMBOLISM  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HYPERTENSION  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (19.1)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
INC280 200 mg BID Tab 200 mg BID Cap+50 mg QD 400 mg BID Cap + 50 mg QD 500 mg BID Cap+50 mg QD 500 mg BID Cap+80 mg QD 300 mg BID Tab+ 80 mg QD 400 mg BID Tab+80 mg QD All Patients (Phase Ib) 400 mg BID Tab All Patients (Phase II)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/1 (0.00%)   5/5 (100.00%)   6/6 (100.00%)   4/4 (100.00%)   6/6 (100.00%)   7/7 (100.00%)   5/5 (100.00%)   33/33 (100.00%)   9/9 (100.00%)   9/10 (90.00%) 
Blood and lymphatic system disorders                     
ANAEMIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
LEUKOPENIA  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
NEUTROPENIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
THROMBOCYTOPENIA  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
Cardiac disorders                     
LEFT VENTRICULAR DYSFUNCTION  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
SINUS BRADYCARDIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Eye disorders                     
DIPLOPIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
VISION BLURRED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
Gastrointestinal disorders                     
ABDOMINAL PAIN  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/5 (20.00%)  2/33 (6.06%)  1/9 (11.11%)  1/10 (10.00%) 
ABDOMINAL PAIN UPPER  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
CONSTIPATION  1  0/1 (0.00%)  2/5 (40.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  5/33 (15.15%)  3/9 (33.33%)  3/10 (30.00%) 
DIARRHOEA  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  1/4 (25.00%)  1/6 (16.67%)  2/7 (28.57%)  1/5 (20.00%)  7/33 (21.21%)  1/9 (11.11%)  1/10 (10.00%) 
DYSPEPSIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  2/6 (33.33%)  2/7 (28.57%)  1/5 (20.00%)  6/33 (18.18%)  1/9 (11.11%)  1/10 (10.00%) 
DYSPHAGIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
GASTROOESOPHAGEAL REFLUX DISEASE  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
HAEMORRHOIDS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
NAUSEA  1  0/1 (0.00%)  1/5 (20.00%)  2/6 (33.33%)  1/4 (25.00%)  1/6 (16.67%)  3/7 (42.86%)  2/5 (40.00%)  10/33 (30.30%)  2/9 (22.22%)  2/10 (20.00%) 
RECTAL ULCER HAEMORRHAGE  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
STOMATITIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/5 (20.00%)  2/33 (6.06%)  1/9 (11.11%)  1/10 (10.00%) 
VOMITING  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  2/5 (40.00%)  5/33 (15.15%)  1/9 (11.11%)  1/10 (10.00%) 
General disorders                     
ASTHENIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  2/33 (6.06%)  1/9 (11.11%)  1/10 (10.00%) 
CHILLS  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
FATIGUE  1  0/1 (0.00%)  2/5 (40.00%)  3/6 (50.00%)  1/4 (25.00%)  2/6 (33.33%)  2/7 (28.57%)  2/5 (40.00%)  12/33 (36.36%)  3/9 (33.33%)  3/10 (30.00%) 
GAIT DISTURBANCE  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
GENERAL PHYSICAL HEALTH DETERIORATION  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
OEDEMA PERIPHERAL  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  1/6 (16.67%)  0/7 (0.00%)  2/5 (40.00%)  4/33 (12.12%)  1/9 (11.11%)  1/10 (10.00%) 
PYREXIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Hepatobiliary disorders                     
HEPATIC STEATOSIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HYPERBILIRUBINAEMIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Infections and infestations                     
ORAL HERPES  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
ORCHITIS  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Injury, poisoning and procedural complications                     
CONTUSION  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
FALL  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  2/5 (40.00%)  3/33 (9.09%)  2/9 (22.22%)  2/10 (20.00%) 
LACERATION  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
Investigations                     
ALANINE AMINOTRANSFERASE INCREASED  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  2/7 (28.57%)  4/5 (80.00%)  9/33 (27.27%)  0/9 (0.00%)  0/10 (0.00%) 
AMYLASE INCREASED  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  2/9 (22.22%)  2/10 (20.00%) 
ASPARTATE AMINOTRANSFERASE INCREASED  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  2/7 (28.57%)  3/5 (60.00%)  8/33 (24.24%)  0/9 (0.00%)  0/10 (0.00%) 
BLOOD ALBUMIN DECREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
BLOOD BILIRUBIN INCREASED  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  2/4 (50.00%)  0/6 (0.00%)  1/7 (14.29%)  1/5 (20.00%)  5/33 (15.15%)  1/9 (11.11%)  1/10 (10.00%) 
BLOOD CREATININE INCREASED  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  2/5 (40.00%)  5/33 (15.15%)  1/9 (11.11%)  1/10 (10.00%) 
BLOOD GLUCOSE INCREASED  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
BLOOD POTASSIUM INCREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
BLOOD TRIGLYCERIDES INCREASED  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
GLOMERULAR FILTRATION RATE DECREASED  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  4/33 (12.12%)  0/9 (0.00%)  0/10 (0.00%) 
INSULIN C-PEPTIDE INCREASED  1  0/1 (0.00%)  2/5 (40.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  2/7 (28.57%)  0/5 (0.00%)  6/33 (18.18%)  0/9 (0.00%)  0/10 (0.00%) 
LIPASE INCREASED  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  1/4 (25.00%)  1/6 (16.67%)  0/7 (0.00%)  1/5 (20.00%)  4/33 (12.12%)  3/9 (33.33%)  3/10 (30.00%) 
LYMPHOCYTE COUNT DECREASED  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  0/5 (0.00%)  3/33 (9.09%)  1/9 (11.11%)  1/10 (10.00%) 
NEUTROPHIL COUNT DECREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PLATELET COUNT DECREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  2/5 (40.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
PROTEIN TOTAL DECREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PROTHROMBIN TIME PROLONGED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
WEIGHT DECREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
WEIGHT INCREASED  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
Metabolism and nutrition disorders                     
DECREASED APPETITE  1  0/1 (0.00%)  2/5 (40.00%)  1/6 (16.67%)  1/4 (25.00%)  1/6 (16.67%)  1/7 (14.29%)  0/5 (0.00%)  6/33 (18.18%)  0/9 (0.00%)  0/10 (0.00%) 
HYPERGLYCAEMIA  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  2/4 (50.00%)  1/6 (16.67%)  2/7 (28.57%)  0/5 (0.00%)  7/33 (21.21%)  1/9 (11.11%)  1/10 (10.00%) 
HYPERURICAEMIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HYPOALBUMINAEMIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HYPOGLYCAEMIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HYPOKALAEMIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HYPONATRAEMIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HYPOPHOSPHATAEMIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  2/7 (28.57%)  0/5 (0.00%)  4/33 (12.12%)  0/9 (0.00%)  0/10 (0.00%) 
Musculoskeletal and connective tissue disorders                     
BACK PAIN  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
MUSCLE SPASMS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
MUSCULAR WEAKNESS  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/5 (20.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
MUSCULOSKELETAL PAIN  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
MYALGIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
PAIN IN EXTREMITY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
Nervous system disorders                     
AMNESIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
APHASIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  1/5 (20.00%)  4/33 (12.12%)  0/9 (0.00%)  0/10 (0.00%) 
ATAXIA  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
BRAIN OEDEMA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
COGNITIVE DISORDER  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
DISTURBANCE IN ATTENTION  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  1/4 (25.00%)  1/6 (16.67%)  1/7 (14.29%)  2/5 (40.00%)  7/33 (21.21%)  0/9 (0.00%)  0/10 (0.00%) 
DIZZINESS  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  1/9 (11.11%)  1/10 (10.00%) 
DYSARTHRIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  1/5 (20.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
DYSKINESIA  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
DYSMETRIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
EPILEPSY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
FACIAL PARALYSIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
FACIAL PARESIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HEADACHE  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  1/4 (25.00%)  2/6 (33.33%)  2/7 (28.57%)  2/5 (40.00%)  9/33 (27.27%)  4/9 (44.44%)  4/10 (40.00%) 
HEMIANOPIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
HEMIANOPIA HOMONYMOUS  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
HEMIPARESIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  2/4 (50.00%)  1/6 (16.67%)  1/7 (14.29%)  1/5 (20.00%)  5/33 (15.15%)  1/9 (11.11%)  1/10 (10.00%) 
HEMIPLEGIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
LETHARGY  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
MEMORY IMPAIRMENT  1  0/1 (0.00%)  0/5 (0.00%)  2/6 (33.33%)  1/4 (25.00%)  0/6 (0.00%)  2/7 (28.57%)  2/5 (40.00%)  7/33 (21.21%)  0/9 (0.00%)  0/10 (0.00%) 
NEUROLOGIC NEGLECT SYNDROME  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
NEUROLOGICAL SYMPTOM  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
PARAESTHESIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PARALYSIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PARAPARESIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
PARESIS  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
PERIPHERAL MOTOR NEUROPATHY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
PERIPHERAL SENSORY NEUROPATHY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  2/33 (6.06%)  1/9 (11.11%)  1/10 (10.00%) 
PYRAMIDAL TRACT SYNDROME  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
RESTLESS LEGS SYNDROME  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
SEIZURE  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  3/33 (9.09%)  1/9 (11.11%)  1/10 (10.00%) 
SOMNOLENCE  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  4/33 (12.12%)  1/9 (11.11%)  1/10 (10.00%) 
TREMOR  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
VITH NERVE PARALYSIS  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Psychiatric disorders                     
AGITATION  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
ANXIETY  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  2/7 (28.57%)  1/5 (20.00%)  6/33 (18.18%)  1/9 (11.11%)  1/10 (10.00%) 
APATHY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
BRADYPHRENIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
CONFUSIONAL STATE  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
DEPRESSED MOOD  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
DEPRESSION  1  0/1 (0.00%)  2/5 (40.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  3/7 (42.86%)  2/5 (40.00%)  8/33 (24.24%)  1/9 (11.11%)  1/10 (10.00%) 
DISORIENTATION  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
INSOMNIA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  0/5 (0.00%)  3/33 (9.09%)  1/9 (11.11%)  1/10 (10.00%) 
IRRITABILITY  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
MOOD ALTERED  1  0/1 (0.00%)  1/5 (20.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
PERSONALITY CHANGE  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
SLEEP DISORDER  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Renal and urinary disorders                     
ACUTE KIDNEY INJURY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
CHRONIC KIDNEY DISEASE  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
CYSTITIS NONINFECTIVE  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HAEMATURIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
MICTURITION URGENCY  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
URINARY INCONTINENCE  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  1/4 (25.00%)  0/6 (0.00%)  1/7 (14.29%)  1/5 (20.00%)  4/33 (12.12%)  0/9 (0.00%)  0/10 (0.00%) 
URINARY RETENTION  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
Reproductive system and breast disorders                     
TESTICULAR PAIN  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Respiratory, thoracic and mediastinal disorders                     
BRONCHOSPASM  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
COUGH  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/5 (20.00%)  3/33 (9.09%)  2/9 (22.22%)  2/10 (20.00%) 
HICCUPS  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
OROPHARYNGEAL PAIN  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
PRODUCTIVE COUGH  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
RHINORRHOEA  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Skin and subcutaneous tissue disorders                     
ALOPECIA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
DERMATITIS ACNEIFORM  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
DRY SKIN  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/5 (40.00%)  2/33 (6.06%)  1/9 (11.11%)  1/10 (10.00%) 
PRURITUS  1  0/1 (0.00%)  1/5 (20.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/5 (20.00%)  3/33 (9.09%)  0/9 (0.00%)  0/10 (0.00%) 
RASH  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  1/9 (11.11%)  1/10 (10.00%) 
RASH MACULAR  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
RASH MACULO-PAPULAR  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/5 (20.00%)  2/33 (6.06%)  0/9 (0.00%)  0/10 (0.00%) 
SKIN ATROPHY  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Vascular disorders                     
EMBOLISM  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  1/6 (16.67%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HAEMATOMA  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/5 (20.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
HOT FLUSH  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  0/33 (0.00%)  1/9 (11.11%)  1/10 (10.00%) 
HYPERTENSION  1  0/1 (0.00%)  0/5 (0.00%)  0/6 (0.00%)  0/4 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/5 (20.00%)  2/33 (6.06%)  1/9 (11.11%)  1/10 (10.00%) 
HYPOTENSION  1  0/1 (0.00%)  0/5 (0.00%)  1/6 (16.67%)  0/4 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/5 (0.00%)  1/33 (3.03%)  0/9 (0.00%)  0/10 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (19.1)
At the end of Phase Ib, it was decided not to enroll patients in the two Phase II arms evaluating INC280 with buparlisib. The phase II INC280 single agent arm was halted before it reached target enrollment.
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.
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
EMail: Novartis.email@novartis.com
Layout table for additonal information
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01870726    
Other Study ID Numbers: CINC280X2204
2013-000699-14 ( EudraCT Number )
First Submitted: June 3, 2013
First Posted: June 6, 2013
Results First Submitted: December 8, 2017
Results First Posted: May 24, 2018
Last Update Posted: May 30, 2018