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

Myelodysplastic Syndrome Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02296242
• Other study ID #: BVD-523-02
• Secondary ID: BVD-523-02
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 2014
• Est. completion date: June 15, 2017

Study information

• Verified date: January 2019
• Source: BioMed Valley Discoveries, Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: June 15, 2017
• Est. primary completion date: June 15, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• BVD-523
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle

Locations

Country	Name	City	State
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	MD Anderson Cancer Center	Houston	Texas
United States	UCLA Medical Center	Los Angeles	California
United States	Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
BioMed Valley Discoveries, Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacodynamic Results of Inhibition (%) of Molecular Target (ERK Pathway) Assessed by Blood and Tissue Analyses.	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
Primary	Number of Patients With Dose Limiting Toxicities	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
Primary	Steady-state Plasma Concentration of BVD-523 and Selected Metabolites Over 12 Hours	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	Clinical Evidence of Cancer Response in Bone Marrow Biopsies	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 (	Until patient discontinuation; ~24 months on average
Secondary	Duration of Disease Control in Patients That Respond	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).	Until patient discontinuation; ~24 months on average