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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 : January 29, 2019
Sponsor:
Information provided by (Responsible Party):
BioMed Valley Discoveries, Inc

Tracking Information
First Submitted Date  ICMJE November 13, 2014
First Posted Date  ICMJE November 20, 2014
Results First Submitted Date  ICMJE June 28, 2018
Results First Posted Date  ICMJE September 5, 2018
Last Update Posted Date January 29, 2019
Study Start Date  ICMJE November 2014
Actual Primary Completion Date June 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 3, 2018)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 18, 2014)
  • Number of Patients With Dose Limiting Toxicities [ Time Frame: 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 ]
Change History Complete list of historical versions of study NCT02296242 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2018)
  • 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).
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2014)
  • Clinical Evidence of Cancer Response in Bone Marrow Biopsies [ Time Frame: Until patient discontinuation; ~24 months on average ]
    Assessments will be made according to International Working Group 2003 and 2006 criteria for AML or MDS
  • Duration of Disease Control in Patients That Respond [ Time Frame: Until patient discontinuation; ~24 months on average ]
    Progression-free survival (PFS) and duration of response (DOR) of AML or MDS patients will be assessed in patients treated with BVD-523 that achieve CR/CRp.
Current Other Pre-specified Outcome Measures
 (submitted: August 6, 2018)
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.
Original Other Pre-specified Outcome Measures
 (submitted: November 18, 2014)
Pharmacodynamic response assessed by blood and tissue analyses. [ Time Frame: Patients will be evaluated at baseline and on or about Day 22 of the protocol ]
Phosphorylation of ERK enzyme substrate proteins (e.g. RSK1 and RSK2 genes) will be measured
 
Descriptive Information
Brief Title  ICMJE Phase 1/2 Study of the ERK1/2 Inhibitor BVD-523 in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndromes
Official Title  ICMJE 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
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).
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myelogenous Leukemia
  • Myelodysplastic Syndrome
Intervention  ICMJE Drug: BVD-523
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle
Study Arms  ICMJE Experimental: BVD-523
Intervention: Drug: BVD-523
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 Completed
Actual Enrollment  ICMJE
 (submitted: July 11, 2017)
53
Original Estimated Enrollment  ICMJE
 (submitted: November 18, 2014)
60
Actual Study Completion Date  ICMJE June 15, 2017
Actual Primary Completion Date June 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (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 NCT02296242
Other Study ID Numbers  ICMJE BVD-523-02
BVD-523-02 ( Other Identifier: BioMed Valley Discoveries, Inc. )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party BioMed Valley Discoveries, Inc
Study Sponsor  ICMJE BioMed Valley Discoveries, Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account BioMed Valley Discoveries, Inc
Verification Date January 2019

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