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

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