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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02608229
Recruitment Status : Active, not recruiting
First Posted : November 18, 2015
Last Update Posted : September 24, 2019
Sponsor:
Collaborators:
BioMed Valley Discoveries, Inc
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE November 16, 2015
First Posted Date  ICMJE November 18, 2015
Last Update Posted Date September 24, 2019
Actual Study Start Date  ICMJE June 6, 2016
Actual Primary Completion Date March 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 17, 2015)
Maximum tolerated dose (MTD) of treatment regimen [ Time Frame: Completion of cycle 1 for all dose de-escalation patients (approximately 1 year and 1 month) ]
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02608229 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 17, 2015)
  • Safety and toxicity profile of treatment regimen as measured by grade and frequency of adverse events [ Time Frame: 30 days after completion of treatment (estimated to be 28 weeks) ]
    -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.
  • Biochemical response of treatment regimen (MTD or above only) [ Time Frame: Completion of treatment (estimated to be 24 weeks) ]
    -The biochemical response (BR) is defined as more than 50% of decrease from baseline CA 19-9
  • Time to tumor progression (TTP) [ Time Frame: Up to 2 years ]
    • Time to tumor progression is defined as the days from registration to time of progressive disease.
    • 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).
  • Progression-free survival (PFS) [ Time Frame: Up to 2 years ]
    • 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.
  • Overall survival (OS) [ Time Frame: Up to 2 years ]
    -OS is defined as the days from the date of treatment start and death from any cause. Patients alive or lost to follow-up are censored.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer
Official Title  ICMJE Phase Ib Study of BVD-523 Plus Nab-paclitaxel and Gemcitabine in Patients With Metastatic Pancreatic Cancer
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pancreatic Cancer
  • Cancer of Pancreas
  • Cancer of the Pancreas
  • Pancreas Cancer
Intervention  ICMJE
  • Drug: BVD-523
  • Drug: Nab-paclitaxel
    Other Names:
    • Abraxane
    • Paclitaxel Albumin-stabilized Nanoparticle Formulation
  • Drug: Gemcitabine
    Other Names:
    • Gemcitabine hydrochloride
    • Gemzar
  • Procedure: Tumor biopsy
Study Arms  ICMJE
  • Experimental: Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine
    • Treatment will be given in a 28-day cycle.
    • BVD-523 is an oral drug which will given at the protocol-dictated dose on a twice daily basis (at approximately 12-hour intervals).
    • Dose de-escalation patients will take 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 will be given at a dose of 125 mg/m^2 on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes.
    • Gemcitabine will be given at a dose of 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.
    Interventions:
    • 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.
    • BVD-523 is an oral drug which will given at the protocol-dictated dose on a twice daily basis (at approximately 12-hour intervals).
    • Nab-paclitaxel will be given at a dose of 100 mg/m^2 or 125 mg/m^2 (depending on dose level assigned) on Days 1, 8, and 15 of each 28-day cycle over the course of 30-40 minutes.
    • Gemcitabine will be given at a dose of 800 mg/m^2 or 1000 mg/m^2 (depending on dose level assigned) 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)
    Interventions:
    • Drug: BVD-523
    • Drug: Nab-paclitaxel
    • Drug: Gemcitabine
    • Procedure: Tumor biopsy
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 17, 2015)
25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2021
Actual Primary Completion Date March 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02608229
Other Study ID Numbers  ICMJE 201601098
5P50CA196510-02 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE
  • BioMed Valley Discoveries, Inc
  • National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Andrea Wang-Gillam, M.D., Ph.D. Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP