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

Study Overview
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Brief Summary
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In light of the central role of extracellular signal-regulated kinases (ERK) in pancreatic cancer, the investigators propose a phase I study to evaluate the ERK inhibitor BVD-523 at the recommended phase 2 dose in combination with nab-paclitaxel plus gemcitabine in patients with newly diagnosed metastatic pancreatic cancer. The primary endpoint will be maximum tolerated dose (MTD) or RP2D and safety. The secondary endpoints include safety, response rate, biochemical response, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints include the assessing the impact of BVD-523 on the MEK/ERK pathway and other major pathway pertain to pancreatic cancer.

Official Title
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Phase Ib Study of BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer

Conditions
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Pancreatic Cancer, Cancer of Pancreas, Cancer of the Pancreas, Pancreas Cancer

Intervention / Treatment
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* Drug: BVD-523
* Drug: Nab-paclitaxel
* Drug: Gemcitabine
* Procedure: Tumor biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed newly diagnosed treatment-naïve metastatic adenocarcinoma of the pancreas with metastatic disease diagnosed no more than 6 weeks prior to enrollment. Patients with advanced pancreatic cancer progressed on 5-FU (or capecitabine) based regimen will be allowed in the expansion cohort. Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan or MRI, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. At least 18 years of age. Life expectancy > 3 months. ECOG performance status ≤ 1 Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Hemoglobin ≥ 9.0 g/dL Total bilirubin ≤ IULN AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN, unless there are liver metastases in which case AST and ALT ≤ 5.0 x IULN Creatinine ≤ 1.5 x IULN OR GFR of ≥ 50 mL/min Cardiac function ≥ ILLN, e.g., LVEF of > 50% as assessed by MUGA or ECHO, QTc < 470 ms Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for three months following study discontinuation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Current use or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment. A history of other malignancy with the exception of those treated with curative intent with no evidence of disease for 2 years. Currently receiving any other investigational agents. Known brain metastases or CNS involvement. Significant ascites that require therapeutic paracentesis. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to BVD-523, gemcitabine, nab-paclitaxel, or other agents used in the study. Neuropathy ≥ grade 2. History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR). History of interstitial lung disease or pneumonitis. Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of CYP3A4 (see Appendix B). Gastrointestinal condition which could impair absorption of BVD-523 or inability to ingest BVD-523. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry. Known HIV-positivity.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine<br>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. | Drug: BVD-523<br> <br> Drug: Nab-paclitaxel<br> <br> * Other names: Paclitaxel Albumin-stabilized Nanoparticle Formulation;Drug: Gemcitabine<br> <br> * Other names: Gemzar;Procedure: Tumor biopsy<br> <br> |
| Experimental: Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine<br>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) | Drug: BVD-523<br> <br> Drug: Nab-paclitaxel<br> <br> * Other names: Paclitaxel Albumin-stabilized Nanoparticle Formulation;Drug: Gemcitabine<br> <br> * Other names: Gemzar;Procedure: Tumor biopsy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of BVD-523 | -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. | Completion of cycle 1 for all dose de-escalation patients (1.8 years), the first cycle is 28 days for each individual patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events | -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. | 30 days after completion of treatment (median time was 67.5 days) | 
| Response Rate | 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. | Through completion of treatment (median time was 37.5 days) | 
| Biochemical Response of Treatment Regimen | -The biochemical response (BR) is defined as more than 50% of decrease from baseline CA 19-9 | Through completion of treatment (median time was 37.5 days) | 
| Time to Tumor Progression (TTP) | 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). | Up to 2 years | 
| Progression-free Survival (PFS) | 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. | Up to 2 years | 
| Overall Survival (OS) | -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. | Up to 2 years |