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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: BVD-523


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BVD-523<br> | Drug: BVD-523<br>* Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). | DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in: ≥Grade 4 hematologic toxicity for >1 day; Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding; ≥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; 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. | As indicated by safety and tolerability during study conduct;  42 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. | Data provided is for BVD-523. | Samples will be collected on day 1 and day 15 of Cycle 1 | 
| Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. | 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. | 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. |