Phase 1/2 Study of the ERK1/2 Inhibitor BVD-523 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndromes

January 9, 2019 updated by: BioMed Valley Discoveries, Inc

Phase 1/2 Dose-Escalation, Safety, Clinical Activity, Pharmacokinetic and Pharmacodynamic Study of the ERK1/2 Inhibitor BVD-523 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndromes

This study is being performed to assess the safety, tolerability, and preliminary clinical effects of BVD-523 given orally, twice daily for 21-day cycles, in patients with Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS).

Study Overview

Status

Completed

Intervention / Treatment

Detailed Description

The study is being performed to assess the safety and tolerability of BVD-523 given orally, twice daily for 21-day cycles.

Part 1 of the study will establish dose limiting toxicities (DLT), maximum tolerated dose (MTD), and the recommended Phase 2 dose (RP2D).

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 (RP2D). 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)

53

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

    • California
      • Los Angeles, California, United States, 90024
        • UCLA Medical Center
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Winship Cancer Institute of Emory University
    • New York
      • Buffalo, New York, United States, 14263
        • Roswell Park Cancer Institute
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Perelman Center for Advanced Medicine
    • Texas
      • Houston, Texas, United States, 77030
        • MD 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 to 100 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Have either of the following diagnoses:

    1. Morphologically confirmed acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL), including leukemia secondary to prior therapy or antecedent hematologic disorder (e.g., MDS or myeloproliferative disorders), who have failed to achieve CR or who have relapsed after prior therapy and are not candidates for potentially curative therapy
    2. Intermediate-2 or High-grade risk MDS (including chronic myelomonocytic leukemia (CMML))
  • Have received at least one prior therapy. Patients who are over age 65 and have not received therapy for AML are also eligible, if they are not candidates for induction chemotherapy
  • ECOG performance status of 0 to 2
  • Predicted life expectancy of ≥ 3 months
  • Adequate liver, renal and cardiac function

For Group 1 in Part 2 of the Study ONLY:

• Positive for RAS mutation at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory prior to study entry

Exclusion Criteria:

  • Concomitant malignancies except carcinoma in situ, basal or squamous cell skin carcinoma; low grade prostate cancer treated with prostatectomy more than 10 years ago; early stage melanoma treated with complete surgical excision more than 5 years ago; carcinoma in situ of cervix treated with cone procedure more than 8 years ago
  • Gastrointestinal condition which could impair absorption of study medication
  • Uncontrolled or severe intercurrent medical condition
  • Patients with rapidly increasing peripheral blood blast counts
  • Known uncontrolled central nervous system involvement
  • Any cancer-directed therapy within 28 days or 5 half-lives, whichever is shorter
  • Any concurrent or prior use of an investigational drug (including MEK inhibitors) within previous 28 days or 5 half-lives, whichever is shorter
  • Received chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Received chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last two weeks.
  • Ongoing anticoagulant therapy that cannot be held if necessary to permit bone marrow sampling.
  • Major surgery within 4 weeks prior to first dose
  • 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 drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of CYP3A4

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: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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
Number of Patients With Dose Limiting Toxicities
Time Frame: In the first 21 days of treatment
DLT defined using CTCAE v.4.03. All toxicities were considered to be related to BVD523 if not definitively explained by underlying disease, intercurrent illness, or con meds.
In the first 21 days of treatment
Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours
Time Frame: Samples will be collected on or about Day 22 of the protocol
The PK population consisted of patients who received at least one dose of BVD-523 and had evaluable PK data in plasma.
Samples will be collected on or about Day 22 of the protocol

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Evidence of Cancer Response in Bone Marrow Biopsies
Time Frame: Until patient discontinuation; ~24 months on average
Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Bone marrow assessments (aspiration or biopsy, cytogenetics) were collected prior to therapy on Day 1 and Day 22, every 2 cycles thereafter, as well as at the final study visit if discontinuation was not due to disease progression. Some patients were unable to have bone marrow assessments taken at any or all of the time points. Shown is best response across all time points. Less than partial remission/response (<PR), partial remission/response (PR), complete remission/response with incomplete platelet recovery (CRp), or complete remission/response (CR).
Until patient discontinuation; ~24 months on average
Duration of Disease Control in Patients That Respond
Time Frame: Until patient discontinuation; ~24 months on average
Assessments were made via bone marrow biopsies using the International Working Group 2003 and 2006 criteria for AML or MDS, respectively. Progression-free survival (PFS) and duration of response (DOR) of AML or MDS patients was assessed in patients treated with BVD-523 that achieved complete remission/response (CR) or complete remission/response with incomplete platelet recovery (CRp). <PR = less than partial remission/response. Shown is the duration (number of days) of CR or CRp response for the 2 patients in part 2 that obtained this level of response.
Until patient discontinuation; ~24 months on average

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses.
Time Frame: Patients will be evaluated at baseline and on or about Day 22 of the protocol
Multiple biomarkers intended to demonstrate inhibition of the molecular target, and mechanism of action were investigated from blood and/or bone marrow aspirate samples. Phosphorylation of ERK enzyme substrate proteins (e.g. RSK1 and RSK2 genes) were measured. Additional biomarkers, including PBMCs and/or DNA sequence analysis, were identified and measured as appropriate. Measurements were by ELISA. The pharmacodynamics (PD) population was defined as all patients who received at least one dose of study drug and had sufficient, valid PD samples to estimate key parameters for at least one of the days of sampling.
Patients will be evaluated at baseline and on or about Day 22 of the protocol

Collaborators and Investigators

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

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.

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

November 1, 2014

Primary Completion (Actual)

June 15, 2017

Study Completion (Actual)

June 15, 2017

Study Registration Dates

First Submitted

November 13, 2014

First Submitted That Met QC Criteria

November 18, 2014

First Posted (Estimate)

November 20, 2014

Study Record Updates

Last Update Posted (Actual)

January 29, 2019

Last Update Submitted That Met QC Criteria

January 9, 2019

Last Verified

January 1, 2019

More Information

Terms related to this study

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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