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

• 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: BioMed Valley Discoveries, Inc
• Information provided by (Responsible Party): BioMed Valley Discoveries, Inc

Study Description

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 Design

• 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

Arms and Interventions

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

Outcome Measures

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 ]
   The PK population consisted of patients who received at least one dose of BVD-523 and had evaluable PK data in plasma.

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.

Eligibility Criteria

• 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

Contacts and Locations

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• 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
• Results First Posted: September 5, 2018
• Last Update Posted: January 29, 2019
• Last Verified: January 2019

Additional relevant MeSH terms:

Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions