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

NCT02608229 | Terminated Phase 1 Results DMC FDA Drug

• 2 other identifiers: 2016010985P50CA196510-02
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

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.

Conditions

Pancreatic Cancer; Cancer of Pancreas; Cancer of the Pancreas; Pancreas Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Safety and Toxicity Profile of Treatment Regimen as Measured by Grade and Frequency of Adverse Events

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

• Response Rate

  Through completion of treatment (median time was 37.5 days)

• Biochemical Response of Treatment Regimen

  Through completion of treatment (median time was 37.5 days)

• Time to Tumor Progression (TTP)

  Up to 2 years

• Progression-free Survival (PFS)

  Up to 2 years

Study Arms (2)

Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine

EXPERIMENTAL

* 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; Drug: Nab-paclitaxel; Drug: Gemcitabine; Procedure: Tumor biopsy

Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine

EXPERIMENTAL

* 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; Drug: Nab-paclitaxel; Drug: Gemcitabine; Procedure: Tumor biopsy

Interventions

BVD-523 DRUG

Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine; Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine

Nab-paclitaxel DRUG

Also known as: Abraxane, Paclitaxel Albumin-stabilized Nanoparticle Formulation

Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine; Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine

Gemcitabine DRUG

Also known as: Gemcitabine hydrochloride, Gemzar

Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine; Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine

Tumor biopsy PROCEDURE

Dose De-escalation: BVD-523/Nab-paclitaxel/Gemcitabine; Dose Expansion: BVD-523/Nab-paclitaxel/Gemcitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• BioMed Valley Discoveries, Inc: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (2)

• Grierson PM, Tan B, Pedersen KS, Park H, Suresh R, Amin MA, Trikalinos NA, Knoerzer D, Kreider B, Reddy A, Liu J, Der CJ, Wang-Gillam A, Lim KH. Phase Ib Study of Ulixertinib Plus Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Adenocarcinoma. Oncologist. 2023 Feb 8;28(2):e115-e123. doi: 10.1093/oncolo/oyac237.

  PMID: 36427020 DERIVED

• 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.

  PMID: 28939558 DERIVED

Related Links

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

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

ulixertinib; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel; Taxes; Gemcitabine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Economics; Health Care Economics and Organizations; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Kian-Huat Lim, M.D., Ph.D.
• Organization: Washington University School of Medicine

kian-huat.lim@wustl.edu

314-362-6157

Study Officials

• Kian-Huat Lim, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2015
• First Posted: November 18, 2015
• Study Start: June 6, 2016
• Primary Completion: March 27, 2019
• Study Completion: May 21, 2020
• Last Updated: April 21, 2021
• Results First Posted: May 1, 2020

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)