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

Phase 1

Completed

Conditions: Acute Myelogenous Leukemia
Myelodysplastic Syndrome

Interventions: Drug: BVD-523

Registration Number: NCT02296242

Lead Sponsor: 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).

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 53

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BVD-523	BVD-523	-

Primary Outcome Measures

Name	Time	Method
Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours	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.
Number of Patients With Dose Limiting Toxicities	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.

Secondary Outcome Measures

Name	Time	Method
Clinical Evidence of Cancer Response in Bone Marrow Biopsies	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	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.

Trial Locations

Locations (5): Perelman Center for Advanced Medicine
🇺🇸
Philadelphia, Pennsylvania, United States
MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
UCLA Medical Center
🇺🇸
Los Angeles, California, United States
Winship Cancer Institute of Emory University
🇺🇸
Atlanta, Georgia, United States
Roswell Park Cancer Institute
🇺🇸
Buffalo, New York, United States