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

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ClinicalTrials.gov Identifier: NCT02296242
Recruitment Status : Completed
First Posted : November 20, 2014
Results First Posted : September 5, 2018
Last Update Posted : October 5, 2018
Sponsor:
Information provided by (Responsible Party):
BioMed Valley Discoveries, Inc

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Acute Myelogenous Leukemia Myelodysplastic Syndrome Drug: BVD-523 Phase 1 Phase 2

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  (Clinical Trial)
Actual Enrollment : 53 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : November 2014
Actual Primary Completion Date : June 15, 2017
Actual Study Completion Date : June 15, 2017


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




Primary Outcome Measures :
  1. 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.

  2. 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 ]
    Final PK data analysis and report are still in process as of 9/5/18.


Secondary Outcome Measures :
  1. 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).

  2. 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.


Other Outcome Measures:
  1. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02296242


Locations
United States, California
UCLA Medical Center
Los Angeles, California, United States, 90024
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
United States, Pennsylvania
Perelman Center for Advanced Medicine
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
BioMed Valley Discoveries, Inc
  Study Documents (Full-Text)

Documents provided by BioMed Valley Discoveries, Inc:
Study Protocol  [PDF] November 18, 2015
Statistical Analysis Plan  [PDF] December 21, 2017


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: BioMed Valley Discoveries, Inc
ClinicalTrials.gov Identifier: NCT02296242     History of Changes
Other Study ID Numbers: BVD-523-02
BVD-523-02 ( Other Identifier: BioMed Valley Discoveries, Inc. )
First Posted: November 20, 2014    Key Record Dates
Results First Posted: September 5, 2018
Last Update Posted: October 5, 2018
Last Verified: September 2018

Additional relevant MeSH terms:
Syndrome
Leukemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions