Dose Escalation Study of ARQ 736 in Adult Subjects With Advanced Solid Tumors Harboring BRAF and/or NRAS Mutations

ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)

Status and phase

Completed

Phase 1

Conditions

Solid Tumor

Treatments

Drug: ARQ 736

Study type

Interventional

Funder types

Industry

Identifiers

NCT01225536

ARQ 736-101

Details and patient eligibility

About

This is an open-label, Phase 1, dose escalation study of oral ARQ 736 administered to subjects with advanced solid tumors harboring the mutation. The study is designed to explore the safety, tolerability, pharmacokinetics and pharmacodynamics of ARQ 736 and to define a recommended Phase 2 dose of ARQ 736.

Full description

Treatment will be initiated at a dose level of 450 mg twice daily (900 mg/daily). All cycles/cohorts of therapy will consist of the oral administration of ARQ 736 twice or four times a day, one hour prior to or two hours after the meal for 28 days continuously. Tumor assessments (CT scan or MRI) will be performed at Baseline, and every two cycles (every eight weeks) thereafter or as otherwise clinically indicated. For early assessment of evidence of biological activity of the tumor PET scan may be performed at Baseline and four weeks from the administration of the first dose of ARQ 736 (approximately Cycle 2 Day1).

Enrollment

24 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Signed written informed consent granted prior to initiation of any study-specific procedures
Male or female subjects of ≥ 18 years of age
All subjects must be positive for a BRAF and/or NRAS mutation
Histologically or cytologically confirmed locally advanced, inoperable or metastatic solid tumors
Failure to respond to at least one prior systemic therapy (including previous treatment with BRAF inhibitors) or to whom standard or curative therapy does not exist
Life expectancy of greater than three months
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
Measurable disease as defined by Response Evaluation Criteria in Solid Tumors
Hemoglobin (Hgb) ≥10 g/dl
Absolute neutrophil count (ANC) ≥1.5 x 10^9/L
Platelet count ≥100 x 10^9/L
Total bilirubin ≤1.5 × upper limit of normal (ULN)
Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × ULN (≤5 x ULN for subjects with liver metastases)
Serum creatinine ≤1.5 × ULN or creatinine clearance >60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
Left Ventricular Ejection Fraction (LVEF) ≥ the institutional lower limit normal (ILLN)
Male or female subjects of child-producing potential must agree to use double-barrier contraceptive measures, oral contraception or avoidance of intercourse during the study and for 30 days after the last dose of ARQ 736
Females of childbearing potential must have a negative serum pregnancy test within seven days prior to the first dose of ARQ 736
Must agree to have tumor and/or skin (nevi) biopsy at baseline and on Day 15 or Day 22 of Cycle 1. Tumor biopsy will be done if the subject has a lesion for which in the Investigator's opinion a non- or minimally invasive tumor biopsy may be performed. If tumor biopsy is not available, skin (nevi) biopsy should be performed.

Exclusion criteria

Anti-cancer chemotherapy, immunotherapy, or investigational agents within four weeks of the first dose of ARQ 736
Major surgery or radiotherapy within two weeks of the first dose of ARQ 736
Brain metastases that are progressing or have been documented to be stable for less than six weeks, or for which systemic corticosteroids are required
History of allergic reactions attributed to compounds of similar chemical or biologic composition as ARQ 736
Unable or unwilling to swallow the complete daily dose of ARQ 736
Significant gastrointestinal disorder(s), in the opinion of the Investigator, (e.g., Crohn's disease, ulcerative colitis, extensive gastric resection)
History of myocardial infarction (MI) within 6 months of the administration of the first dose of ARQ 736 (MI occurring > 6 months of the first dose of ARQ 736 will be permitted)
History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification within 6 months of the administration of the first dose of ARQ 736
Previous malignancy within 2 years of the first dose of ARQ 736, except carcinoma in-situ of the cervix
Concurrent uncontrolled illness, including but not limited to:
Ongoing or active infection, including human immunodeficiency virus (HIV) infection or bleeding
Psychiatric illness/substance abuse/social situation that would limit compliance with study requirements
Blood transfusion within five days prior to blood draw being used to confirm eligibility