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

This is an open-label, dose-escalation/de-escalation study of ARQ 197 administered orally in combination with gemcitabine. The study is designed to determine the safety, tolerability and maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of ARQ 197 when administered in combination with gemcitabine to patients with advanced solid tumors.

Enrollment of an initial cohort of 3 or 6 patients will follow the traditional "3 + 3" dose escalation scheme. These patients will be treated with ARQ 197 and gemcitabine. ARQ 197 will be administered by mouth BID continuously. Gemcitabine will be administered by intravenous infusion over 30 minutes once weekly for 3 consecutive weeks followed by a week of rest. The dosing schedules of ARQ 197 and gemcitabine will be as described below.

ARQ 197 will be administered per the following cohorts, starting from week 1 of treatment.

Cohort------ARQ 197 (mg BID)

0-----------120, continuously

1-----------240, continuously

A-----------120 (repeated treatments of 2 weeks followed by a 1 week pause)

B-----------240 (repeated treatments of 2 weeks followed by a 1 week pause)

C-----------360 (repeated treatments of 2 weeks followed by a 1 week pause)

D-----------360 (repeated treatments of 3 weeks followed by a 1 week pause)

E-----------360, continuously

In case of DLT, intermediate dosing cohorts will be explored, administering ARQ 197 for 5 days instead of 7 during the weeks of ARQ 197 administration.

For cohorts 0 and 1, gemcitabine is administered at the dose of 1000mg/sqm from week 1 of treatment, 4 weeks in a row for the first month, then for 3 consecutive weeks followed by a week of pause. For all other cohorts, gemcitabine will be administered starting from week 2 of treatment at the dose of 1000mg/sqm, for 3 consecutive weeks followed by a week of pause.

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.

Once a safe and recommended dose level is determined, an Expanded Cohort of up to 60 patients with non-resectable cholangiocarcinoma (10 patients), breast carcinoma (10 patients), ovarian carcinoma (10 patients), endometrial carcinoma and carcinoma of the cervix (10 patients in total, at least five with endometrial carcinoma). Each group of 10 patients may enroll up to three patients who received at least 5-week gemcitabine treatment. The cohort will also include up to 20 patients with pancreatic carcinoma (up to five out of 20 patients may have received at least 5-week gemcitabine treatment).

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent granted prior to initiation of any study-specific screening procedures, given with the understanding that the patient has the right to withdraw from the study at any time, without prejudice
* 18 year of age or older
* Histologically or cytologically confirmed locally advanced, inoperable or metastatic primary solid tumors
* Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1
* Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) or ≤ 5 x ULN with metastatic liver disease
* Hemoglobin ≥ 10 g/dl (or ≥ 9 g/dl for expanded cohort)
* Total bilirubin ≤ 1.5 x ULN
* Serum creatinine ≤ 1.5 x ULN
* Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
* Platelets ≥ 100 x 10\^9/L
* Women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug
* Male and female subjects of child-bearing potential must agree to use double-barrier contraceptive measures, oral contraception, or avoidance of intercourse during the study and for 90 days after last investigational drug dose received

Exclusion Criteria:

* Other cancer within the last three years, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri or basal or squamous cell carcinoma of the skin
* Previous anti-cancer chemotherapy, radiotherapy, major surgery, immunotherapy or investigational agents within 4 weeks prior to the first day of study defined treatment
* History of cardiac disease: congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); previously diagnosed bradycardia or other cardiac arrhythmia defined as ≥ Grade 2 according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) (version 3.0), or uncontrolled hypertension; myocardial infarction occurred within 6 months prior to study entry (myocardial infarction occurred \> 6 months prior to study entry is permitted)
* Active clinically serious infections defined as ≥ Grade 2 according to NCI CTCAE, version 3.0
* Substance abuse, medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the patient's participation in the study or evaluation of the study results
* Any condition that is unstable or which could jeopardize the safety of the patient and his/her protocol compliance
* Known human immunodeficiency virus (HIV) infection
* Pregnancy or breast-feeding
* Inability to swallow oral medications
* Significant gastrointestinal disorder, in the opinion of the Investigator, could interfere with the absorption of ARQ 197 and/or gemcitabine (e.g. significant, uncontrolled inflammatory bowel disease or extensive small bowel resection)
* Central nervous system metastases