Trial Outcomes & Findings for BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer (NCT NCT02608229)

Last Updated: 2021-04-21

Results Overview

-The maximum tolerated dose (MTD) is defined as the Dose Level 1 if 0 or 1 dose-limiting toxicities (DLTs) are seen in patients at that dose level or Dose Level -1 if 2+ DLTs are seen in Dose Level 1 but only 0 or 1 DLTs are seen in patients at Dose Level -1.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

18 participants

Primary outcome timeframe

Completion of cycle 1 for all dose de-escalation patients (1.8 years), the first cycle is 28 days for each individual patient

Results posted on

2021-04-21

Participant Flow

The study opened to participant enrollment on 06/06/2016 and closed to participant enrollment on 08/19/2019.

Participant milestones

Participant milestones
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Overall Study STARTED	10	8
Overall Study 600 mg BVD-523	10	2
Overall Study 450 mg BVD-523	0	6
Overall Study COMPLETED	10	8
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=10 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine n=8 Participants * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)	Total n=18 Participants Total of all reporting groups
Age, Continuous	65.5 years n=5 Participants	61.5 years n=7 Participants	63.5 years n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=5 Participants	8 Participants n=7 Participants	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	10 participants n=5 Participants	8 participants n=7 Participants	18 participants n=5 Participants

PRIMARY outcome

Timeframe: Completion of cycle 1 for all dose de-escalation patients (1.8 years), the first cycle is 28 days for each individual patient

Population: -The MTD was not determined by DLTs in Dose De-escalation. 2 patients in Dose Expansion were treated at 600 mg but due to poor performance (inability to complete Cycle 1) the principal investigator felt it was reasonable to treat the remaining patients with 450 mg BVD-523 twice daily in the dose expansion portion of the study.

Outcome measures

Outcome measures
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=10 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Maximum Tolerated Dose (MTD) of BVD-523	450 mg	—

SECONDARY outcome

Timeframe: 30 days after completion of treatment (median time was 67.5 days)

-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

Outcome measures

Outcome measures
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=12 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine n=6 Participants * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 Hearing Impaired	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 blurred vision	3 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 abdominal infection	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 constipation	5 Participants	2 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 diarrhea	5 Participants	4 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 diarrhea	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 dry mouth	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 dyspepsia	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 flatulence	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 gastrointestinal pain	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 mucositis oral	2 Participants	2 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 nausea	5 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 nausea	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 taste change	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 vomiting	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 vomiting	2 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 acute kidney injury	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 lower GI hemorrhage	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 chills	3 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 edema limbs	3 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 edema trunk	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 fatigue	3 Participants	2 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 fever	5 Participants	2 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 thrush	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 5 death due to disease progression	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 alanine aminotransferase increased	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 alkaline phosphtase	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 4 blood bilirubin increased	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3/4 neutrophil count decreased	3 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 platelet count decreased	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 lymphocyte count	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 white blood cell count decreased	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 hypercalcemia	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 hyperglycemia	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 hyperkalemia	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 hypoalbuminemia	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 hypocalcemia	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 dehydration	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 arthralgia	4 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 back pain	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 dizziness	4 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 headache	3 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 peripheral sensory neuropathy	5 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 numbness	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 insomnia	2 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 anxiety	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 cough	1 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 dyspnea	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 epistaxis	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 5 adult respiratory distress syndrome	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 alopecia	5 Participants	3 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 rash acneiform	3 Participants	4 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 rash acneiform	2 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 rash maculo-papular	4 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 sweating	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1 scalp sun burned	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 hypertension	3 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 hypertension	1 Participants	0 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 hyperhydrosis	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 pruritus	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 myalgia	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 blood in stool	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 anorexia	3 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 anorexia	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 abdominal pain	2 Participants	2 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 abdominal pain	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 portal vein thrombosis	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 lung infection	0 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 1/2 anemia	3 Participants	1 Participants
Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events Grade 3 anemia	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Through completion of treatment (median time was 37.5 days)

Population: Participants who did not have a follow-up CT scan were excluded from this outcome measure. The 2 participants analyzed in the Dose Expansion arm received 450 mg of BVD-523.

* Response rate is the percentage of participants with best response of complete response or partial response per RECIST 1.1 * Complete response (CR): disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Outcome measures
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=5 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine n=2 Participants * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Response Rate	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Through completion of treatment (median time was 37.5 days)

Population: -Participants with normal CA19-9 levels at baseline were excluded from this outcome measure and those who did not have an additional CA19-9 level drawn after baseline. Of the 5 participants analyzed in Dose Expansion Arm, 1 received 600 mg BVD-523 and 4 participants received 450 mg BVD-523.

-The biochemical response (BR) is defined as more than 50% of decrease from baseline CA 19-9

Outcome measures

Outcome measures
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=7 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine n=5 Participants * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Biochemical Response of Treatment Regimen	3 Participants	1 Participants

SECONDARY outcome

Timeframe: Up to 2 years

Population: Participants who did not have a follow-up CT scan were excluded from this outcome measure. The 2 participants analyzed in the Dose Expansion Arm received 450 mg BVD-523.

* Time to tumor progression is defined as the days from start of treatment until progressive disease. * Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Outcome measures

Outcome measures
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=5 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine n=2 Participants * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Time to Tumor Progression (TTP)	85 days Interval 63.0 to 243.0	39.5 days Interval 30.0 to 49.0

SECONDARY outcome

Timeframe: Up to 2 years

Population: Participants who did not have a follow-up CT scan were excluded from this outcome measure. The 2 participants analyzed in the Dose Expansion Arm received 450 mg BVD-523.

* Progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). * PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Patients alive without progression or lost to follow-up are censored.

Outcome measures

Outcome measures
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=5 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine n=2 Participants * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Progression-free Survival (PFS)	85 days Interval 63.0 to 243.0	39.5 days Interval 30.0 to 49.0

SECONDARY outcome

Timeframe: Up to 2 years

Population: Participants were not considered evaluable for this outcome measure if they were not evaluable for dose-limiting toxicities per protocol and any participants that were alive were censored.

-OS is defined as the days from the date of treatment start and death from any cause. Participants alive or lost to follow-up are censored.

Outcome measures

Outcome measures
Measure	Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine n=6 Participants * Treatment will be given in a 28-day cycle. * BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals). * BVD-523 at 600 mg twice daily on its own for two weeks before initiating Cycle 1 treatment with gemcitabine and nab-paclitaxel. * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes. * Mandatory biopsy at baseline and baseline at end of 2 week BVD-523 lead in.	Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine n=6 Participants * Treatment will be given in a 28-day cycle. * First 2 patients enrolled: BVD-523 600 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Remaining 6 patients enrolled: BVD-523 450 mg on a twice daily basis (at approximately 12-hour intervals), nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes, and gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes * Mandatory biopsy at baseline and at end of cycle 2 (if deemed safe for participant and feasible to obtain)
Overall Survival (OS)	13.8 months Interval 10.7 to 22.8	5.7 months Interval 1.1 to There were too few participants to provide upper estimate on the 95% confidence interval.

Adverse Events

600 mg BVD-523/Nab-paclitaxel/Gemcitabine

Serious events: 8 serious events

Other events: 12 other events

Deaths: 11 deaths

450 mg BVD-523/Nab-paclitaxel/Gemcitabine

Serious events: 4 serious events

Other events: 6 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Additional Information

Kian-Huat Lim, M.D., Ph.D.

Washington University School of Medicine

Phone: 314-362-6157

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	600 mg BVD-523/Nab-paclitaxel/Gemcitabine n=12 participants at risk * Treatment will be given in a 28-day cycle. * All patients who received 600 mg BVD-523 on a twice daily basis (at approximately 12-hour intervals) are included in this group * Nab-paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes.	450 mg BVD-523/Nab-paclitaxel/Gemcitabine n=6 participants at risk * Treatment will be given in a 28-day cycle. * All patients who received 450 mg BVD-523 on a twice daily basis (at approximately 12-hour intervals) are included in this group * Nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes. * Gemcitabine 800 mg/m\^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30 minutes.
Blood and lymphatic system disorders Anemia	0.00% 0/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	16.7% 1/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Gastrointestinal disorders Abdominal pain	0.00% 0/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	16.7% 1/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Gastrointestinal disorders Diarrhea	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Gastrointestinal disorders Lower GI hemorrhage	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Gastrointestinal disorders Nausea	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	16.7% 1/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Gastrointestinal disorders Vomiting	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
General disorders Death due to disease progression	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	16.7% 1/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
General disorders Fever	41.7% 5/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Infections and infestations Abdominal infection	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Infections and infestations Lung infection	0.00% 0/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	16.7% 1/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Investigations Blood bilirubin increased	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Investigations Neutrophil count decreased	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Metabolism and nutrition disorders Anorexia	0.00% 0/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	16.7% 1/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Renal and urinary disorders Acute kidney injury	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.
Respiratory, thoracic and mediastinal disorders Adult respiratory distress syndrome	8.3% 1/12 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.	0.00% 0/6 • Adverse events were collected from start of study treatment until 30 days following completion of study treatment. Median length of follow-up for adverse events was 67.5 days.