| Eligibility |
Inclusion Criteria:Subjects must satisfy all of the following criteria to be included in
the study:
1. Subjects with surgically unresectable locally advanced or metastatic disease who have
received = 1 prior line of systemic therapies for advanced or metastatic disease. The
last treatment regimen must include EGFR inhibitor (cetuximab or panitumumab) on which
the patient had a best response as CR or PR or SD, and must have either progressed on
or after EGFR inhibitor based therapy within 3 months before enrollment. Subjects must
have radiologically documented disease progression prior to enrollment.
2. All subjects must express the wild-type form of the gene KRAS. Previously existing
KRAS mutation status from an accredited local laboratory will be accepted.
3. Fresh tumor biopsy tissue must be available for molecular sequencing and biomarker
expression in >70% of patients. If prior radiotherapy, tissue biopsy must be outside
radiotherapy field. In a minor percentage of patients (<30%) archival tumor tissue
could be considered acceptable for molecular sequencing and biomarker expression.
4. Patients must be MET High testing by IHC (IHC 2+ or 3+ in =50% of tumor cells)
analyzed by Ventana Test Kit.
5. Measurable disease according to RECIST criteria, Version 1.1.
6. Male or female = 18 years of age.
7. Eastern Cooperative Oncology Group (ECOG) performance status of = 2.
8. Resolution of any toxic effects of prior therapy to NCI CTCAE, Version 4.0, grade = 1
(with the exception of alopecia and grade = 2 neuropathy).
9. Adequate bone marrow, liver, and renal functions, defined as: Hemoglobin = 9.0 g/dL
(transfusion and/or growth factor support allowed).
Absolute neutrophil count (ANC) = 1.5 × 109/L. Platelet count = 75 × 109/L. Serum
creatinine = 1.5 × upper limit of normal (ULN) or creatinine clearance = 60 mL/min.
Alanine transaminase (ALT), and aspartate transaminase (AST) = 2.5 x ULN in subjects
with no liver metastasis and = 5.0 x ULN in subjects with liver metastasis. Total
bilirubin = 1.5 x ULN (= 4 x ULN and direct bilirubin = 1.5 x ULN is acceptable for
subjects with Gilbert's syndrome).
10. 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. 11. All female
subjects of childbearing potential must each have a negative pregnancy test (serum or
urine) result before initiating study treatment.
12. 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 IEC- or IRB-approved ICF (including HIPAA authorization, if applicable) before
performance of any study-specific procedures or tests.
Exclusion Criteria:
Subjects who meet any of the following criteria will be disqualified from entering the
study:
1. 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 3 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 < 3 years prior to enrollment).
2. Anticipation of need for a major surgical procedure or radiation therapy (RT) during
the study.
3. Treatment with chemotherapy, radiotherapy, surgery, immunotherapy, biological therapy,
or any other investigational anticancer agent within 3 weeks prior to start of study
treatment.
4. 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 (subjects with asymptomatic bradycardia and hear rate
above 50 bpm are allowed) 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 > 6 months prior the start of study treatment is permitted).
5. Malabsorption syndrome, chronic diarrhea (lasting > 4 weeks), inflammatory bowel
disease, or partial bowel obstruction.
6. Known metastatic brain or meningeal tumors, unless the subject is > 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.
7. Uncontrolled seizure disorder, spinal cord compression, or carcinomatous meningitis.
8. Pericardial or pleural effusion (requiring drainage) or pericardial involvement with
the tumor. Subjects with minimal pleural effusion may be eligible upon request by
Investigator and approval by Sponsor.
9. Clinically significant active infection that requires antibiotic therapy.
10. Previous administration of any MET inhibitor (including tivantinib) or EGFR inhibitor
(except cetuximab or panitumumab).
11. 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.
12. Any condition that is unstable or that could jeopardize the safety of the subject and
the subject's protocol compliance.
13. Inability to swallow oral medications.
14. Pregnant or nursing females.
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