Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies

March 18, 2020 updated by: BioMed Valley Discoveries, Inc
This open-label, multi-center Phase 1/2 study will assess the safety, pharmacokinetics, and pharmacodynamics of escalating doses of BVD-523 in patients with advanced malignancies. The study also seeks to demonstrate target modulation and early signs of clinical response in select patient populations.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The study is being performed to assess the safety and tolerability of BVD-523

In Part 1 of the study, an accelerated dose escalation plan will be used to establish dose limiting toxicities, maximum tolerated dose, and the recommended Phase 2 dose.

In Part 2 of the study, additional patients with particular tumor types and/or cancers harboring specific genetic mutations will be recruited for treatment at the Recommended Phase 2 Dose. Patients may also be assessed pharmacodynamic measures in healthy or malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic measures.

Study Type

Interventional

Enrollment (Actual)

136

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

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

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90095
        • UCLA Med-Hematology & Oncology
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Yale Cancer Center
    • Florida
      • Sarasota, Florida, United States, 34232
        • Florida Cancer Specialists and Research Group (Sarah Cannon Research Institute)
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital (MGH)
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine
    • New York
      • New York, New York, United States, 10065
        • Memorial Sloan-Kettering Cancer Center
    • Tennessee
      • Nashville, Tennessee, United States, 37212
        • Vanderbilt-Ingram Cancer Center
      • Nashville, Tennessee, United States, 37203
        • Sarah Cannon Research Institute Hospital at Vanderbilt
    • Texas
      • Houston, Texas, United States, 77030
        • UT M.D Anderson Cancer Center

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.

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:

  • Patients with metastatic or advanced-stage malignant tumor. Patients may have received up to 2 prior lines of chemotherapy for their metastatic disease
  • ECOG score of 0 or 1
  • Predicted life expectancy of ≥ 3 months
  • Adequate bone marrow, liver and renal function renal function
  • Adequate cardiac function
  • For women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal, or compliant with a contraceptive regimen during and for 3 months after the treatment period
  • For men: Must be surgically sterile, or compliant with a contraceptive regimen during and for 3 months after the treatment period

  • For Part 2 of the Study only, patients must have measurable disease by RECIST 1.1 and be in one of the the groups below. Patients in groups 1, 2, 4, 5 and 6 may not have been previously treated with BRAF and/or MEK inhibitors

    • Group 1: Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers
    • Group 2: Patients with BRAF mutated colorectal cancer
    • Group 3: Patients with BRAF mutated melanoma who have progressed on, or are refractory to BRAF and/or MEK inhibitors
    • Group 4: Patients with NRAS mutated melanoma
    • Group 5: Patients with MEK mutated cancer
    • Group 6: Patients with BRAF mutated non-small cell lung cancer
    • Group 7: Patients with ERK mutated cancer

Exclusion Criteria:

  • Gastrointestinal condition which could impair absorption of study medication
  • Uncontrolled or severe intercurrent medical condition
  • Known uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants
  • Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, etc.) within 28 days or 5 half-lives, whichever is shorter
  • Major surgery within 4 weeks prior to first dose
  • Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of BVD-523.
  • Pregnant or breast-feeding women
  • Any evidence of serious active infections
  • Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study
  • A history or current evidence/risk of retinal vein occlusion or central serous retinopathy
  • Concurrent therapy with any other investigational agent
  • Concomitant malignancies or previous malignancies with less than 2 years disease-free interval at the time of enrollment

Study Plan

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

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: BVD-523
Drug: BVD-523
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT).
Time Frame: As indicated by safety and tolerability during study conduct; ~42 months

DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in:

  1. ≥Grade 4 hematologic toxicity for >1 day;
  2. Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding;
  3. ≥Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain and rash (these become DLTs if the adverse event (AE) persists despite adequate treatment), a doubling of aspartate transaminase (AST)/alanine transaminase (ALT) in patients with grade 2 ALT/AST at baseline;
  4. A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for > 7 days) due to BVD-523-related toxicity.
As indicated by safety and tolerability during study conduct; ~42 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites.
Time Frame: Samples will be collected on day 1 and day 15 of Cycle 1
Data provided is for BVD-523.
Samples will be collected on day 1 and day 15 of Cycle 1
Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam.
Time Frame: Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is completion. The best responses presented occurred at different time points for each patient.
At enrollment, all study patients had metastatic or advanced-stage malignant tumor for which no curative therapy was known to exist. Patients entering Part 2 additionally had to have measurable disease by RECIST version 1.1. Data shown is best response.
Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is completion. The best responses presented occurred at different time points for each patient.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK)
Time Frame: Patients will be evaluated at baseline and on ~day 15 of Cycle 1
RSK1, a member of the RSK serine/threonine kinase family, is a direct substrate of the MAP Kinases ERK1 & ERK2. RSK1 and ERK1/2 form an inactive complex in unstimulated cells. Upon activation of the mitogenic pathway, ERK1/2 phosphorylates Thr573, Thr359 and Ser363 on RSK1. Thr573 resides in the activation loop of the carboxy terminal kinase domain of RSK1 and once phosphorylated, enables RSK1 to autophosphorylate Ser380. Phosphorylation of Ser380 on RSK1 can therefore be used as a target biomarker for ERK1 and ERK2 activity. BVD-523 inhibits the activity of ERK. In this study, phosphorylation of RSK1 Ser 380 (pRSK) was used as a target biomarker for assessment of ERK inhibition by BVD-523 in human whole blood samples.
Patients will be evaluated at baseline and on ~day 15 of Cycle 1

Collaborators and Investigators

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

Sponsor

BioMed Valley Discoveries, Inc

Publications and helpful links

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

General Publications

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 Major Dates

Study Start (ACTUAL)

March 1, 2013

Primary Completion (ACTUAL)

February 1, 2018

Study Completion (ACTUAL)

September 1, 2018

Study Registration Dates

First Submitted

January 28, 2013

First Submitted That Met QC Criteria

January 30, 2013

First Posted (ESTIMATE)

February 1, 2013

Study Record Updates

Last Update Posted (ACTUAL)

March 20, 2020

Last Update Submitted That Met QC Criteria

March 18, 2020

Last Verified

March 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BVD-523-01 (OTHER: BioMed Valley Discoveries, Inc.)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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