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

• 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: BioMed Valley Discoveries, Inc
• 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

Participant Flow

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
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

Baseline Characteristics

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
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
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

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Dose Limiting Toxicities
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

Outcome Measure Data

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
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%

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
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

Outcome Measure Data

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
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
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose-escalation	Cohort-expansion
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
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

Outcome Measure Data

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
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.
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

Outcome Measure Data

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
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)

Adverse Events

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
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%)
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
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'

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Dean Welsch, PhD
• Organization: BioMed Valley Discoveries
• Phone: 8163898831
• EMail: dwelsch@biomed-valley.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351-2363. doi: 10.1158/1535-7163.MCT-17-0456. Epub 2017 Sep 22.

• 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