A Randomized, Placebo-Controlled, Phase 1/2 Study Of ARQ 197 in Combination With Irinotecan and Cetuximab in Subjects With Metastatic Colorectal Cancer With Wild-type KRAS Who Have Received Front-Line Systemic Therapy
1. Subjects with surgically unresectable locally advanced or metastatic disease who have
received one prior line of chemotherapy. (The Phase 1 portion of the study will be
open for enrollment for subjects who received 1 or more prior therapies). Both
relapsed and refractory CRC are allowed.
2. All subjects must express the wild-type form of the gene KRAS.
3. Measurable disease according to RECIST (Response Evaluation Criteria In Solid Tumors)
criteria, Version 1.1.
4. Male or female >= to 18 years of age.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE,
Version 4.0, grade <= to 1.
7. Adequate bone marrow, liver, and renal functions, defined as:
- Hemoglobin >= to 9.0 g/dL (transfusion and/or growth factor support allowed).
- Absolute neutrophil count (ANC) >= to 1.5 x 10^9/L.
- Platelet count >= to 75 x 10^9/L.
- Serum creatinine <= to 1.5 x upper limit of normal (ULN) or creatinine clearance
>= to 60 mL/min.
- Alanine transaminase (ALT), aspartate transaminase (AST), and alkaline
phosphatase <= to 2.5 x ULN in subjects with no liver metastasis and <= to 5.0 x
ULN in subjects with liver metastasis.
- Total bilirubin <= to 1.5 x ULN (<= to 4 x ULN and direct bilirubin <= to 1.5 x
ULN is acceptable for subjects with Gilbert's syndrome).
8. 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.
9. All female subjects of childbearing potential must each have a negative pregnancy
test (serum or urine) result before initiating study treatment.
10. Subjects must be fully informed about their illness and the investigational nature of
the study protocol (including foreseeable risks and possible side effects) and must
sign and date an Independent Ethics Committee (IEC) or Institutional Review Board
(IRB)-approved informed consent form (ICF) (including HIPAA authorization, if
applicable) before performance of any study specific procedures or tests.
1. Prior therapy with an Epidermal Growth Factor Receptor (EGFR) inhibitor.
2. History of malignancy other than CRC, unless there is an exception that the
malignancy has been cured and no tumor-specific treatment for the malignancy has been
administered within the 5 years prior to initiation of study treatment (subjects with
a history of basal cell carcinoma or benign tumor of cervix can be enrolled if
diagnosis and treatment occurred less than 3 years prior to randomization).
3. Anticipation of need for a major surgical procedure or radiation therapy (RT) during
4. Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological
therapy, or any other investigational anticancer agent within 4 weeks prior to start
of study treatment.
5. 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
or higher according to NCI CTCAE, version 4.0, or uncontrolled hypertension.
- Myocardial infarction that occurred within 6 months prior to start of study
treatment (myocardial infarction that occurred greater than 6 months before the
start of study treatment is permitted).
6. Malabsorption syndrome, chronic diarrhea (lasting greater than 4 weeks), inflammatory
bowel disease, or partial bowel obstruction.
7. Known metastatic brain or meningeal tumors, unless the subject is greater than 6
months from definitive therapy, has a negative imaging study within 4 weeks of first
dose of study treatment, and is clinically stable (no concomitant therapy, including
supportive therapy with steroids or anticonvulsant medications) with respect to the
tumor at the time of first dose of study treatment.
8. Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis.
9. Pericardial or pleural effusion (eg, requiring drainage) or pericardial involvement
with the tumor. Subjects with minimal pleural effusion may be eligible upon request
by Investigator and approval by Sponsor.
10. Clinically significant active infection that requires antibiotic therapy.
11. Previous administration of ARQ 197.
12. Substance abuse or medical, psychological or social conditions that may, in the
opinion of the Investigator, interfere with the subject's participation in the
clinical trial or evaluation of the clinical trial results.
13. Any condition that is unstable or that could jeopardize the safety of the subject and
the subject's protocol compliance including known human immunodeficiency virus (HIV),
hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.
14. Inability to swallow oral medications.
15. Pregnant or nursing females.