Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Patients with BRAF mutated colorectal cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Patients with BRAF mutated melanoma who had progressed or were refractory to BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Patients with NRAS mutated melanoma, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Patients with MEK mutated cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Patients with BRAF mutated non-small cell lung cancer, not previously treated with BRAF and/or MEK inhibitors. Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

Total of all reporting groups

Patients received 10mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 20mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 40mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks

Patients received 75mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 150mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 300mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 750mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 900mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion was noted. Treatment cycles occurred consecutively without interruption, except when necessary to manage AEs. All dose-escalation decisions were based on Cycle 1 safety data and doses were not escalated unless the patients receiving the highest current dose had been observed for at least 3 weeks.

Patients received 600mg oral doses of BVD 523 b.i.d. for 21 days (a "Cycle"). Patients received doses of BVD-523 until disease progression, unacceptable toxicity, or another withdrawal criterion was met. Treatment cycles occurred consecutively without interruption except when necessary to manage AEs.

TOXICITY TO VARIOUS AGENTS