Vemurafenib, Cetuximab, and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or That Cannot Be Removed by Surgery
Vemurafenib, Cetuximab, and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or That Cannot Be Removed by Surgery
This phase I trial studies the side effects and best dose of vemurafenib when given together
 with cetuximab and irinotecan hydrochloride in treating patients with solid tumors that have
 spread to other parts of the body or cannot be removed by surgery. Vemurafenib and irinotecan
 hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for
 cell growth. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's
 immune system attack the cancer, and may interfere with the ability of tumor cells to grow
 and spread. Giving vemurafenib with cetuximab and irinotecan hydrochloride may be a better
 treatment for solid tumors.
PRIMARY OBJECTIVES:

 I. To define the maximum tolerated dose (MTD) of vemurafenib when used in combination with
 cetuximab and irinotecan (irinotecan hydrochloride).

 II. To define the safety profile of this combination. III. To determine the antitumor
 activity of this combination specifically in patients with advanced solid malignancies with
 positive v-raf murine sarcoma viral oncogene homolog B (BRAF) (V600)/negative Kirsten rat
 sarcoma viral oncogene homolog (K-RAS) mutation. (Part II-expanded cohort) IV. To determine
 the antitumor activity of this combination in patients with metastatic colorectal cancer with
 positive BRAF (V600)/negative K-RAS mutation. (Part II-expanded cohort)

 SECONDARY OBJECTIVES:

 I. To evaluate clinical response signals of the combination. II. To assess the
 pharmacokinetic (PK) and pharmacodynamic (PD) profile of the combination.

 OUTLINE: This is a dose-escalation study of vemurafenib.

 Patients receive vemurafenib orally (PO) twice daily (BID) on days 1-14, cetuximab
 intravenously (IV) over 90 minutes, and irinotecan hydrochloride IV over 90 minutes on day 1.
 Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 days.
Inclusion Criteria:

 -  Patients must have histologically confirmed malignancy that is metastatic or
 unresectable

 -  Cancers with positive BRAF V600 mutation detected by a Clinical Laboratory Improvement
 Act (CLIA)-certified laboratory

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

 -  Life expectancy of greater than 3 months

 -  Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors
 (RECIST) 1.1 criteria

 -  Patients must have a K-RAS wild-type (WT) tumor

 -  Absolute neutrophils count >= 1500/mcl (within 14 days)

 -  Platelets >= 100000/mcl (within 14 days)

 -  Hemoglobin (Hb) >= 9 mg/dl (within 14 days)

 -  Total bilirubin =< 1.5 mg/dl (within 14 days)

 -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5 x upper limit of
 normal if liver metastases present; otherwise, then =< 2.5 x upper limit (within 14
 days)

 -  Estimated creatinine clearance by Cockcroft-Gault equation > 30 mL/min (within 14
 days)

 -  Current treatment may cause harm to the developing human fetus; for this reason women
 of child-bearing age must have a negative pregnancy test at screening and both women
 of child-bearing potential and men must agree to use adequate contraception (hormonal
 or barrier method of birth control; abstinence) prior to study entry and for the
 duration of study participation, and for 6 months after last dose; should a woman
 become pregnant or suspect she is pregnant while she or her partner is participating
 in this study, she should inform her treating physician immediately

 -  Signed informed consent approved by the Institutional Review Board prior to patient
 entry

 -  Expansion cohort: We propose a final expansion cohort for this study in a subset of
 interest utilizing the recommended dosing of combination; this cohort will include
 patients harboring characteristics that may predict response of combination or with
 clinical features that proved to derive most benefit of the study combination during
 preclinical studies; cancers with positive BRAF (V600) mutation detected by a
 CLIA-certified laboratory

 Exclusion Criteria:

 -  Patient receiving any concurrent chemotherapy

 -  Concurrent severe and/or uncontrolled medical disease including, but not limited to,
 ongoing or active infection requiring intravenous antibiotics, bowel obstruction

 -  Symptomatic congestive heart failure (New York Heart Association [NYHA] class III or
 IV), or unstable angina pectoris

 -  Patients who have had a myocardial infarction, transient ischemic attack, unstable
 angina, or cardiovascular symptoms (CVS) within 6 months before treatment

 -  Presence of symptomatic pleural and/or pericardial effusion not appropriately treated

 -  Prolonged corrected QT (QTc) interval (>= 450 msec) as calculated by Bazett's formula,
 or patients with a history of congenital long QT syndrome or uncorrectable electrolyte
 abnormalities

 -  Medical and/or psychiatric problems of sufficient severity to limit full compliance
 with the study or expose patients to undue risk

 -  Known anaphylactic or severe hypersensitivity to the study drugs or their analogs

 -  Patient has failed to recover from any prior surgery within 4 weeks of study entry

 -  Patient is pregnant, lactating, or breastfeeding

 -  Patient has had any treatment specific for tumor control within 3 weeks of dosing with
 investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given
 weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of
 biological targeted agents with half-lives and pharmacodynamic effects lasting less
 than 5 days

 -  Patient is not able to swallow oral medication

 -  Patients receiving any medications or substances that are strong inhibitors or
 inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) complex are
 ineligible

 -  Patients with known K-RAS mutant (codon 12 or 13) detected by a Food and Drug
 Administration (FDA)-approved test in a CLIA-certified laboratory

 -  Patients with BRAF WT cancers