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Phase 1/2 Study of the ERK1/2 Inhibitor BVD-523 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndromes

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ClinicalTrials.gov Identifier: NCT02296242
Recruitment Status : Completed
First Posted : November 20, 2014
Results First Posted : September 5, 2018
Last Update Posted : January 29, 2019
Sponsor:
Information provided by (Responsible Party):
BioMed Valley Discoveries, Inc

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Intervention Drug: BVD-523
Enrollment 53
Recruitment Details Up to 6 study centers were to enroll up to 20 AML or MDS patients for Part 1 (dose-escalation) and 40 evaluable patients (≤ 20 RAS mutant positive AML or MDS patients and ≤ 20 RAS mutant negative AML or MDS patients) for Part 2 (cohort expansion). The last patient completed in May 2017.
Pre-assignment Details  
Arm/Group Title Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group
Hide Arm/Group Description Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Period Title: Overall Study
Started 5 6 7 14 21
Completed 0 0 0 0 0
Not Completed 5 6 7 14 21
Reason Not Completed
Death             1             1             1             1             1
Withdrawal by Subject             0             0             1             1             3
Disease Progression             1             3             2             8             11
Unacceptable Toxicity             0             0             0             0             1
Patient Condition Changed             0             0             2             0             1
At Least 3 Drug Interruptions             0             0             1             1             1
Lost to Follow-up             1             0             0             0             0
Need for Hydroxyurea             2             0             0             0             0
Screened for Other Protocol             0             1             0             0             0
Physician Decision             0             1             0             1             0
Alternative Treatment             0             0             0             1             0
Adverse Event             0             0             0             1             0
Lack of Efficacy             0             0             0             0             3
Arm/Group Title Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group Total
Hide Arm/Group Description Patients received 300mg oral doses of BVD-523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 600mg oral doses of BVD-523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 750mg oral doses of BVD-523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Total of all reporting groups
Overall Number of Baseline Participants 5 6 7 14 21 53
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 5 participants 6 participants 7 participants 14 participants 21 participants 53 participants
71.6  (9.21) 58.7  (19.18) 65.6  (18.11) 70.6  (10.08) 66.0  (15.66) 66.8  (14.62)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 6 participants 7 participants 14 participants 21 participants 53 participants
Female
2
  40.0%
1
  16.7%
4
  57.1%
5
  35.7%
8
  38.1%
20
  37.7%
Male
3
  60.0%
5
  83.3%
3
  42.9%
9
  64.3%
13
  61.9%
33
  62.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 6 participants 7 participants 14 participants 21 participants 53 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
2
  28.6%
4
  28.6%
1
   4.8%
7
  13.2%
Not Hispanic or Latino
5
 100.0%
6
 100.0%
5
  71.4%
10
  71.4%
20
  95.2%
46
  86.8%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants 6 participants 7 participants 14 participants 21 participants 53 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
1
  16.7%
1
  14.3%
0
   0.0%
1
   4.8%
3
   5.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
1
   7.1%
2
   9.5%
3
   5.7%
White
5
 100.0%
4
  66.7%
4
  57.1%
11
  78.6%
17
  81.0%
41
  77.4%
More than one race
0
   0.0%
1
  16.7%
2
  28.6%
0
   0.0%
0
   0.0%
3
   5.7%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
2
  14.3%
1
   4.8%
3
   5.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 5 participants 6 participants 7 participants 14 participants 21 participants 53 participants
5 6 7 14 21 53
1.Primary Outcome
Title Number of Patients With Dose Limiting Toxicities
Hide Description DLT defined using CTCAE v.4.03. All toxicities were considered to be related to BVD523 if not definitively explained by underlying disease, intercurrent illness, or con meds.
Time Frame In the first 21 days of treatment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group
Hide Arm/Group Description:
Patients received 300mg oral doses of BVD-523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 600mg oral doses of BVD-523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 750mg oral doses of BVD-523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 5 6 7 14 21
Measure Type: Count of Participants
Unit of Measure: Participants
Any BVD-523-related DLTs? Yes
0
   0.0%
0
   0.0%
2
  28.6%
0
   0.0%
0
   0.0%
No
5
 100.0%
6
 100.0%
5
  71.4%
14
 100.0%
21
 100.0%
Related tox causing tx delay >4 days (rash >7days) Yes
0
   0.0%
0
   0.0%
2
  28.6%
0
   0.0%
0
   0.0%
No
5
 100.0%
6
 100.0%
5
  71.4%
14
 100.0%
21
 100.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dose-escalation 300mg b.i.d. Cohort, Dose-escalation 600mg b.i.d. Cohort, Dose-escalation 750mg b.i.d. Cohort
Comments In Part 1, 2 patients experienced DLTs in the 750 mg b.i.d. treatment group (2/7; 29%). There were no dose-limiting toxicities in the 600 mg b.i.d. group or 300 mg b.i.d. group. Therefore, based on these results, 600 mg b.i.d. was selected as the MTD dose (and RP2D dose) which was used as the treatment dose in Part 2 of the study.
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Highest dose (mg) with no DLTs.
Estimated Value 600
Estimation Comments [Not Specified]
2.Primary Outcome
Title Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours
Hide Description The PK population consisted of patients who received at least one dose of BVD-523 and had evaluable PK data in plasma.
Time Frame Samples will be collected on or about Day 22 of the protocol
Hide Outcome Measure Data
Hide Analysis Population Description
The cohort-expansion patients were not separated by RAS status for the purposes of this assessment. Two patients in the cohort expansion had to have their dose reduced to 300mg BID and were analyzed separately (Cmax 1000 & 1340 ng/mL on Day 22). 00 = not calculated (only 1 evaluable patient).
Arm/Group Title Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) & RAS(-) Groups
Hide Arm/Group Description:
Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 4 1 4 12
Mean (Standard Deviation)
Unit of Measure: ng/mL
0 hr (predose) Number Analyzed 4 participants 1 participants 4 participants 11 participants
455  (212) 1860  (00) 2080  (1310) 1540  (800)
0.5 hr Number Analyzed 4 participants 1 participants 4 participants 12 participants
428  (193) 1670  (00) 2020  (1240) 1280  (767)
1 hr Number Analyzed 4 participants 1 participants 4 participants 12 participants
506  (159) 1590  (00) 2130  (693) 1440  (698)
2 hr Number Analyzed 4 participants 1 participants 3 participants 12 participants
1300  (1090) 1760  (00) 2220  (1500) 1790  (776)
4 hr Number Analyzed 4 participants 1 participants 4 participants 12 participants
1150  (555) 1520  (00) 2670  (1490) 1800  (914)
6 hr Number Analyzed 3 participants 1 participants 4 participants 12 participants
728  (435) 1510  (00) 2360  (1510) 1400  (741)
8 hr Number Analyzed 3 participants 1 participants 4 participants 12 participants
480  (301) 1100  (00) 1870  (1150) 1140  (623)
12 hr Number Analyzed 4 participants 1 participants 4 participants 11 participants
528  (364) 902  (00) 1650  (1070) 974  (567)
3.Secondary Outcome
Title Clinical Evidence of Cancer Response in Bone Marrow Biopsies
Hide Description Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Bone marrow assessments (aspiration or biopsy, cytogenetics) were collected prior to therapy on Day 1 and Day 22, every 2 cycles thereafter, as well as at the final study visit if discontinuation was not due to disease progression. Some patients were unable to have bone marrow assessments taken at any or all of the time points. Shown is best response across all time points. Less than partial remission/response (<PR), partial remission/response (PR), complete remission/response with incomplete platelet recovery (CRp), or complete remission/response (CR).
Time Frame Until patient discontinuation; ~24 months on average
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Dose-escalation Cohort-expansion
Hide Arm/Group Description:
Patients received 300-750mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 18 35
Overall Number of Units Analyzed
Type of Units Analyzed: Response(s)
20 26
Count of Units
Unit of Measure: Response(s)
< PR
20
 100.0%
22
  84.6%
PR
0
   0.0%
1
   3.8%
CRp
0
   0.0%
2
   7.7%
CR
0
   0.0%
1
   3.8%
4.Secondary Outcome
Title Duration of Disease Control in Patients That Respond
Hide Description Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Progression-free survival (PFS) and duration of response (DOR) of AML or MDS patients was assessed in patients treated with BVD-523 that achieved complete remission/response (CR) or complete remission/response with incomplete platelet recovery (CRp). <PR = less than partial remission/response. Shown is the duration (number of days) of CR or CRp response for the 2 patients in part 2 that obtained this level of response.
Time Frame Until patient discontinuation; ~24 months on average
Hide Outcome Measure Data
Hide Analysis Population Description
Part 1: <PR for all data points. Part 2: One patient had a CRp at 2 visits. One patient had a CR.
Arm/Group Title Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group
Hide Arm/Group Description:
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 14 21
Measure Type: Number
Unit of Measure: Days
64 5
5.Other Pre-specified Outcome
Title Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses.
Hide Description Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism of action were investigated from blood and/or bone marrow aspirate samples. Phosphorylation of ERK enzyme substrate proteins (e.g. RSK1 and RSK2 genes) were measured. Additional biomarkers, including PBMCs and/or DNA sequence analysis, were identified and measured as appropriate. Measurements were by ELISA. The pharmacodynamics (PD) population was defined as all patients who received at least one dose of study drug and had sufficient, valid PD samples to estimate key parameters for at least one of the days of sampling.
Time Frame Patients will be evaluated at baseline and on or about Day 22 of the protocol
Hide Outcome Measure Data
Hide Analysis Population Description
Data was not collected/reported for patient at time point or patient did not start a second cycle.
Arm/Group Title Dose-escalation Cohort-expansion
Hide Arm/Group Description:
Patients received 300-750mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle).
Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
Overall Number of Participants Analyzed 18 35
Mean (Standard Deviation)
Unit of Measure: Percent (%) Inhibition
Baseline (Cycle 1, Day 1) Pre-Dose Number Analyzed 18 participants 28 participants
0.0  (0.00) 0.0  (0.00)
Baseline (Cycle 1, Day 1) 4 Hours Post-Dose Number Analyzed 18 participants 28 participants
78.1  (30.86) 56.9  (177.46)
Cycle 2, Day 1 Pre-Dose Number Analyzed 9 participants 19 participants
73.6  (33.55) 71.5  (58.36)
Cycle 2, Day 1 - 4 Hours Post-Dose Number Analyzed 10 participants 17 participants
75.9  (32.75) 83.0  (41.82)
Time Frame A treatment-emergent adverse event (TEAE) is any AE temporally associated with the use of BVD-523 from initiation of BVD-523 initiation until 30 calendar days following the last administration of BVD-523, whether or not the AE was considered related to study drug. TEAEs were monitored/assessed until 30 calendar days following the last administration of BVD-523.
Adverse Event Reporting Description

TEAEs were analyzed for the safety population. Analyses were performed for any TEAEs by SOC and PT. Patients were counted only once if they had more than one TEAE within a SOC or experienced a PT more than once. A patient who reported multiple AEs that map to a common PT or SOC is counted only once for that PT or SOC at the highest severity reported and at the greatest relationship to study drug.

AEs were collected/assessed at each study visit.

 
Arm/Group Title Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group
Hide Arm/Group Description Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 21 days (1 cycle). Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a “Cycle”). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.
All-Cause Mortality
Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   4/5 (80.00%)   2/6 (33.33%)   4/7 (57.14%)   2/14 (14.29%)   4/21 (19.05%) 
Show Serious Adverse Events Hide Serious Adverse Events
Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/5 (100.00%)   4/6 (66.67%)   6/7 (85.71%)   10/14 (71.43%)   18/21 (85.71%) 
Blood and lymphatic system disorders           
Febrile neutropenia  1  1/5 (20.00%)  0/6 (0.00%)  2/7 (28.57%)  3/14 (21.43%)  6/21 (28.57%) 
Leukocytosis  1  1/5 (20.00%)  0/6 (0.00%)  0/7 (0.00%)  2/14 (14.29%)  1/21 (4.76%) 
Gastrointestinal disorders           
Diarrhea  1  0/5 (0.00%)  2/6 (33.33%)  0/7 (0.00%)  2/14 (14.29%)  1/21 (4.76%) 
Gastrointestinal hemorrhage  1  1/5 (20.00%)  2/6 (33.33%)  1/7 (14.29%)  0/14 (0.00%)  2/21 (9.52%) 
Disease progression  1  1/5 (20.00%)  1/6 (16.67%)  1/7 (14.29%)  0/14 (0.00%)  2/21 (9.52%) 
Pyrexia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/14 (14.29%)  3/21 (14.29%) 
General disorders           
Death  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  1/21 (4.76%) 
Infections and infestations           
Bacteremia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  3/21 (14.29%) 
Pneumonia  1  3/5 (60.00%)  0/6 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  4/21 (19.05%) 
Sepsis  1  1/5 (20.00%)  0/6 (0.00%)  2/7 (28.57%)  0/14 (0.00%)  2/21 (9.52%) 
Metabolism and nutrition disorders           
Dehydration  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/14 (14.29%)  0/21 (0.00%) 
Renal and urinary disorders           
Renal failure acute  1  1/5 (20.00%)  0/6 (0.00%)  2/7 (28.57%)  0/14 (0.00%)  0/21 (0.00%) 
Vascular disorders           
Hypotension  1  1/5 (20.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  2/21 (9.52%) 
1
Term from vocabulary, MedDRA (17.1)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Dose-escalation 300mg b.i.d. Cohort Dose-escalation 600mg b.i.d. Cohort Dose-escalation 750mg b.i.d. Cohort Cohort-expansion RAS(+) Group Cohort-expansion RAS(-) Group
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/5 (40.00%)   1/6 (16.67%)   6/7 (85.71%)   9/14 (64.29%)   11/21 (52.38%) 
Blood and lymphatic system disorders           
Febrile Neutropenia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Leukocytosis  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Thrombocytopenia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Eye disorders           
Vision Blurred  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/14 (7.14%)  0/21 (0.00%) 
Lacrimation Increased  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/14 (14.29%)  0/21 (0.00%) 
Gastrointestinal disorders           
Diarrhea  1  0/5 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  5/14 (35.71%)  6/21 (28.57%) 
Gastroesophageal Reflux Disease  1  1/5 (20.00%)  0/6 (0.00%)  1/7 (14.29%)  1/14 (7.14%)  1/21 (4.76%) 
Nausea  1  0/5 (0.00%)  0/6 (0.00%)  3/7 (42.86%)  2/14 (14.29%)  5/21 (23.81%) 
Oral Mucosal Eruption  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/21 (0.00%) 
Vomiting  1  0/5 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  0/14 (0.00%)  3/21 (14.29%) 
Abdominal Pain  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Constipation  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Dyspepsia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
General disorders           
Fatigue  1  0/5 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  1/14 (7.14%)  1/21 (4.76%) 
Asthenia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  1/21 (4.76%) 
Oedema Peripheral  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  2/14 (14.29%)  0/21 (0.00%) 
Pyrexia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Hepatobiliary disorders           
Hypertransaminasaemia  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/21 (0.00%) 
Hyperbilirubinaemia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  2/21 (9.52%) 
Infections and infestations           
Sepsis  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/21 (0.00%) 
Diverticulitis  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Upper Respiratory Tract Infection  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Injury, poisoning and procedural complications           
Subdural Hematoma  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Investigations           
Blood Creatinine Increased  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  4/14 (28.57%)  2/21 (9.52%) 
Liver Function Test Abnormal  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/21 (0.00%) 
Alanine Aminotransferase Increased  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Aspartate Aminotransferase Increased  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Electrocardiogram QT Prolonged  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Neutrophil Count Decreased  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Platelet Count Decreased  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Weight Decreased  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Metabolism and nutrition disorders           
Decreased Appetite  1  0/5 (0.00%)  1/6 (16.67%)  1/7 (14.29%)  1/14 (7.14%)  0/21 (0.00%) 
Hyperkalaemia  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/21 (0.00%) 
Dehydration  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Hypoalbuminaemia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Hypomagnesaemia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Hyponatraemia  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Musculoskeletal and connective tissue disorders           
Arthritis  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Nervous system disorders           
Dizziness  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Headache  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Presyncope  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Psychiatric disorders           
Hallucination  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Renal and urinary disorders           
Renal Failure Acute  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  1/14 (7.14%)  0/21 (0.00%) 
Acute Prerenal Failure  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Dyspnoea  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Hiccups  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Skin and subcutaneous tissue disorders           
Eczema  1  1/5 (20.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  0/21 (0.00%) 
Erythema Multiforme  1  0/5 (0.00%)  0/6 (0.00%)  1/7 (14.29%)  0/14 (0.00%)  0/21 (0.00%) 
Pruritus Generalized  1 [1]  0/5 (0.00%)  0/6 (0.00%)  2/7 (28.57%)  1/14 (7.14%)  1/21 (4.76%) 
Rash  1  1/5 (20.00%)  0/6 (0.00%)  1/7 (14.29%)  1/14 (7.14%)  2/21 (9.52%) 
Dry Skin  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Rash Macular  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  0/14 (0.00%)  1/21 (4.76%) 
Vascular disorders           
Hypotension  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
Orthostatic Hypotension  1  0/5 (0.00%)  0/6 (0.00%)  0/7 (0.00%)  1/14 (7.14%)  0/21 (0.00%) 
1
Term from vocabulary, MedDRA (17.1)
Indicates events were collected by systematic assessment
[1]
Also includes 'Pruritus'
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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: Dean Welsch, PhD
Organization: BioMed Valley Discoveries
Phone: 8163898831
EMail: dwelsch@biomed-valley.com
Layout table for additonal information
Responsible Party: BioMed Valley Discoveries, Inc
ClinicalTrials.gov Identifier: NCT02296242     History of Changes
Other Study ID Numbers: BVD-523-02
BVD-523-02 ( Other Identifier: BioMed Valley Discoveries, Inc. )
First Submitted: November 13, 2014
First Posted: November 20, 2014
Results First Submitted: June 28, 2018
Results First Posted: September 5, 2018
Last Update Posted: January 29, 2019