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

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

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.

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.

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