Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies

Phase 1

Completed

Brief Summary: This open-label, multi-center Phase 1/2 study will assess the safety, pharmacokinetics, and pharmacodynamics of escalating doses of BVD-523 in patients with advanced malignancies. The study also seeks to demonstrate target modulation and early signs of clinical response in select patient populations.

Detailed Description: The study is being performed to assess the safety and tolerability of BVD-523

In Part 1 of the study, an accelerated dose escalation plan will be used to establish dose limiting toxicities, maximum tolerated dose, and the recommended Phase 2 dose.

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. Patients may also be assessed pharmacodynamic measures in healthy or malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic measures.

Recruitment & Eligibility

Inclusion Criteria

Patients with metastatic or advanced-stage malignant tumor. Patients may have received up to 2 prior lines of chemotherapy for their metastatic disease
ECOG score of 0 or 1
Predicted life expectancy of ≥ 3 months
Adequate bone marrow, liver and renal function renal function
Adequate cardiac function
For women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal, or compliant with a contraceptive regimen during and for 3 months after the treatment period
For men: Must be surgically sterile, or compliant with a contraceptive regimen during and for 3 months after the treatment period
For Part 2 of the Study only, patients must have measurable disease by RECIST 1.1 and be in one of the the groups below. Patients in groups 1, 2, 4, 5 and 6 may not have been previously treated with BRAF and/or MEK inhibitors
- Group 1: Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers
- Group 2: Patients with BRAF mutated colorectal cancer
- Group 3: Patients with BRAF mutated melanoma who have progressed on, or are refractory to BRAF and/or MEK inhibitors
- Group 4: Patients with NRAS mutated melanoma
- Group 5: Patients with MEK mutated cancer
- Group 6: Patients with BRAF mutated non-small cell lung cancer
- Group 7: Patients with ERK mutated cancer

Exclusion Criteria

Gastrointestinal condition which could impair absorption of study medication
Uncontrolled or severe intercurrent medical condition
Known uncontrolled brain metastases. Stable brain metastases either treated or being treated with a stable dose of steroids/anticonvulsants
Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, etc.) within 28 days or 5 half-lives, whichever is shorter
Major surgery within 4 weeks prior to first dose
Any use of an investigational drug within 28 days or 5 half-lives (whichever is shorter) prior to the first dose of BVD-523.
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 any other investigational agent
Concomitant malignancies or previous malignancies with less than 2 years disease-free interval at the time of enrollment

Arm && Interventions

Group	Intervention	Description
BVD-523	BVD-523	-

Primary Outcome Measures

Name	Time	Method
Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT).	As indicated by safety and tolerability during study conduct; ~42 months	DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in: 1. ≥Grade 4 hematologic toxicity for \>1 day; 2. Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding; 3. ≥Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain and rash (these become DLTs if the adverse event (AE) persists despite adequate treatment), a doubling of aspartate transaminase (AST)/alanine transaminase (ALT) in patients with grade 2 ALT/AST at baseline; 4. A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for \> 7 days) due to BVD-523-related toxicity.

Secondary Outcome Measures

Name	Time	Method
Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam.	Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is completion. The best responses presented occurred at different time points for each patient.	At enrollment, all study patients had metastatic or advanced-stage malignant tumor for which no curative therapy was known to exist. Patients entering Part 2 additionally had to have measurable disease by RECIST version 1.1. Data shown is best response.
Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites.	Samples will be collected on day 1 and day 15 of Cycle 1	Data provided is for BVD-523.

Locations (9): Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Yale Cancer Center
🇺🇸
New Haven, Connecticut, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸
New York, New York, United States
Florida Cancer Specialists and Research Group (Sarah Cannon Research Institute)
🇺🇸
Sarasota, Florida, United States
Massachusetts General Hospital (MGH)
🇺🇸
Boston, Massachusetts, United States
UCLA Med-Hematology & Oncology
🇺🇸
Los Angeles, California, United States
Sarah Cannon Research Institute Hospital at Vanderbilt
🇺🇸
Nashville, Tennessee, United States
Vanderbilt-Ingram Cancer Center
🇺🇸
Nashville, Tennessee, United States
UT M.D Anderson Cancer Center
🇺🇸
Houston, Texas, United States