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

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

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.

Study Overview

• Status: Terminated
• Conditions: Pancreatic Cancer; Pancreas Cancer; Cancer of Pancreas; Cancer of the Pancreas
• Intervention / Treatment: Drug: Gemcitabine; Procedure: Tumor biopsy; Drug: Nab-paclitaxel; Drug: BVD-523

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Gemcitabine; Other Names: Gemzar; Gemcitabine hydrochloride; Procedure: Tumor biopsy; Drug: Nab-paclitaxel; Other Names: Abraxane; Paclitaxel Albumin-stabilized Nanoparticle Formulation; Drug: BVD-523
Experimental: 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)	Drug: Gemcitabine; Other Names: Gemzar; Gemcitabine hydrochloride; Procedure: Tumor biopsy; Drug: Nab-paclitaxel; Other Names: Abraxane; Paclitaxel Albumin-stabilized Nanoparticle Formulation; Drug: BVD-523

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Cancer Institute (NCI); BioMed Valley Discoveries, Inc

Publications and helpful links

General Publications

• 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.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2016
• Primary Completion (Actual): March 27, 2019
• Study Completion (Actual): May 21, 2020

Study Registration Dates

• First Submitted: November 16, 2015
• First Submitted That Met QC Criteria: November 17, 2015
• First Posted (Estimate): November 18, 2015

Study Record Updates

• Last Update Posted (Actual): April 21, 2021
• Last Update Submitted That Met QC Criteria: April 19, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Gemcitabine; Paclitaxel; Albumin-Bound Paclitaxel
• Other Study ID Numbers: 201601098; 5P50CA196510-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No