Dose Escalation Study of ARQ 197 in Combination With Sorafenib in Adult Patients With Advanced Solid Tumors

The study is only enrolling patients in the expanded cohorts with hepatocellular carcinoma,
renal cell carcinoma, melanoma, non-small cell lung cancer, and breast cancer.

Enrollment of an initial patient cohort of 3 or 6 patients will follow the traditional "3 +
3" dose escalation scheme. These patients will be treated with ARQ 197 and sorafenib at
Dose Level 1 [ARQ 197 360 mg twice daily (bid) and sorafenib 200 mg bid]. Enrollment of
subsequent patient cohort(s) will depend on the safety and tolerability of the combination
treatment in the initial cohort. If < 33% patients treated at Dose Level 1 experience
dose-limiting toxicity(ies) by the end of first treatment cycle (4 weeks), then next cohort
of 6 patients will be enrolled and treated at Dose Level 2 (ARQ 197 360 mg bid and sorafenib
400 mg bid). If ≥ 33% patients treated at Dose Level 1 experience DLT(s) by the end of first
treatment cycle, the next cohort of 6 patients will be enrolled and treated at Dose Level 0
(ARQ 197 240 mg bid and sorafenib 200 mg bid).

Additional treatment cohorts may be enrolled to explore intermediate, higher or lower doses
of ARQ 197, as indicated by the tolerability, safety profile, and pharmacokinetic (PK)
profile.

Intra-patient dose-escalation from Dose Level 1 to Dose Level 2 may occur in patients
enrolled in Dose Level 1 after they complete at least 1 cycle of treatment without DLT and
other drug-related adverse event that, in the opinions of Investigator and Medical Monitor,
is serious and medically significant.

Once a safe and recommended dose level is determined, an expanded cohort (Expansion Cohort
1) of up to 20 patients with either unresectable hepatocellular carcinoma (HCC) or advanced
renal cell carcinoma (RCC), for whom sorafenib is indicated, will be enrolled and treated at
this dose level (expansion portion). At least 10 of the 20 patients in the expanded cohort
should be patients with unresectable HCC.

Under Amendment 1, an additional expansion cohort (Expansion Cohort 2) of up to 30 patients
with breast cancer, non-small cell lung cancer or melanoma will be enrolled and treated at
MTD/RP2D. Up to 10 patients may be enrolled for each tumor type.

Expansion Cohort 3 may be open to enroll patients with other tumor type(s) if newly
available preclinical data indicate that patients with the tumor type(s) may get benefit
from the combination therapy of ARQ 197 and sorafenib.