BVD-523 Plus Nab-paclitaxel And Gemcitabine In Patients With Metastatic Pancreatic Cancer

Study Overview

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.

N/A

Pancreatic Cancer
Cancer of Pancreas
Cancer of the Pancreas
Pancreas Cancer

DRUG: BVD-523
DRUG: Nab-paclitaxel
DRUG: Gemcitabine
PROCEDURE: Tumor biopsy

201601098
5P50CA196510-02 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2015-11-16	Results First Submitted 2020-03-27	Last Update Submitted that met QC Criteria 2021-04-19
First Submitted that Met QC Criteria 2015-11-17	Results First Submitted that Met QC Criteria 2020-04-21	Last Update Posted (ACTUAL) 2021-04-21
First Posted (ACTUAL) 2015-11-18	Results First Posted 2020-05-01	Last Verified 2021-04

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Parallel

Masking:
None

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. *	DRUG: BVD-523 DRUG: Nab-paclitaxel DRUG: Gemcitabine PROCEDURE: Tumor biopsy
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	DRUG: BVD-523 DRUG: Nab-paclitaxel DRUG: Gemcitabine PROCEDURE: Tumor biopsy

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. *

DRUG: BVD-523

DRUG: Nab-paclitaxel

DRUG: Gemcitabine

PROCEDURE: Tumor biopsy

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

DRUG: BVD-523

DRUG: Nab-paclitaxel

DRUG: Gemcitabine

PROCEDURE: Tumor biopsy

Primary Outcome Measures	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	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

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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).

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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

BioMed Valley Discoveries, Inc
National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Kian-Huat Lim, M.D., Ph.D., Washington University School of Medicine

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

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.

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