Nilotinib and Cetuximab in Treating Patients With Solid Tumors That Can Be Treated With Cetuximab
This phase I trial studies the side effects and the best dose of nilotinib when given together with cetuximab in treating patients with solid tumors that can be treated with cetuximab. Nilotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving nilotinib and cetuximab may be an effective treatment for solid tumors.
Inclusion Criteria
- Recurrent and/or metastatic Kras wildtype colorectal cancer or squamous cell carcinoma of the head and neck
- Ability to swallow medication capsules by mouth (which may include taking nilotinib mixed in apple sauce)
- A tumor lesion that can be readily biopsied using a core needle via clinical exam or imaging-guidance
- At least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
- Able to provide informed consent
- Previous therapy: * Patients must have progressed after standard therapy for metastatic/recurrent disease; this must have included irinotecan and oxaliplatin-containing regimens for patients with colorectal cancer (CRC) and platinum-containing regimens for patients with head and neck squamous cell carcinoma (H&NSCC) * Patients may have received cetuximab or panitumumab previously
- Hemoglobin >= 8.0 gm/dL
- Absolute neutrophil count (ANC) >= 1500 cells/mm^3
- Platelet count >= 100,000 /mm^3
- Creatinine within institutional normal limits or glomerular filtration rate (GFR) > 60 mL/min/m^2 (calculated by the Cockcroft-Gault equation)
- Total bilirubin =< 1.5 times upper limit of normal (ULN)
- Aspartate transaminase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times the ULN except in patients with hepatic metastases for whom AST and ALT must be < 5.0 times the ULN.
- Life expectancy of greater than 3 months
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Normal left ventricular ejection fraction, as defined by ejection fraction (EF) >= 50%
Exclusion Criteria
- Chemotherapy or surgery within 4 weeks prior to treatment start
- Radiation treatment within 3 weeks prior to treatment start
- Prior therapy with an Abelson murine leukemia viral oncogene homolog (ABL) kinase inhibitor such as nilotinib, ponatinib, dasatinib, or imatinib
- Untreated brain metastases or neurologically unstable central nervous system (CNS) metastases (CNS metastases will be considered stable if there are no new nor enlarging lesions for one month, and the patient remains off steroids and anti-epileptics for the same time period)
- Any severe or uncontrolled medical condition or other condition that could affect participation in this study, including but not limited to: unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, uncontrolled hypertension, or myocardial infarction ≤ 6 months prior to study entry
- Diarrhea > grade 1 at baseline
- Patients currently receiving treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors and treatment cannot be either discontinued or switched to a different medication prior to starting study drug
- Patients currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
- Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery)
- Acute or chronic pancreatic disease
- Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required)
- Another primary malignant disease, which requires systemic treatment (chemotherapy or radiation)
- Acute or chronic liver disease or severe renal disease considered unrelated to the cancer
- History of significant congenital or acquired bleeding disorder unrelated to cancer
- Major surgery within 4 weeks prior to day 1 of the study or who have not recovered from prior surgery
- Treatment with other investigational agents within 30 days of day 1
- Impaired cardiac function including any one of the following: * Inability to monitor the QT interval on electrocardiogram (ECG) * Congenital long QT syndrome or a known family history of long QT syndrome * Clinically significant resting brachycardia (< 50 beats per minute) * QTc > 450 msec on baseline ECG; if QTc > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc * Myocardial infarction within 12 months prior to starting study * Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension) * History of or presence of clinically significant ventricular or atrial tachyarrhythmias
- Female patients who are pregnant, breast feeding, or of childbearing potential without a negative pregnancy test prior to baseline; male or female patients of childbearing potential unwilling to use contraceptive precautions throughout the trial and 3 months following discontinuation of study drug; post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential; women of childbearing potential must have a negative serum pregnancy test prior to the first dose of nilotinib
- Patients unwilling or unable to comply with the protocol, or provide informed consent
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01871311.
PRIMARY OBJECTIVES:
I. To determine the safety, toxicity, and maximum tolerated dose of the combination of cetuximab and nilotinib in the treatment of patients with solid tumors who can be treated with cetuximab.
SECONDARY OBJECTIVES:
I. To assess the clinical benefit in treated patients in order to make initial assessment of activity of this drug regimen.
II. To evaluate the response rate in an expansion cohort (n=10) of patients with metastatic/recurrent info v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras) wildtype colorectal cancer.
III. To examine epidermal growth factor receptor (EGFR) pathway activation in tumor biopsy specimens before and after starting therapy.
IV. To estimate the effect of cetuximab and nilotinib on antibody‐dependent cell‐mediated toxicity, measured by the induction of host‐produced anti‐EGFR antibodies that do not cross‐react with the cetuximab binding site.
V. To explore the possible associations between genetic polymorphisms in info ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2), ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1), cytochrome P450 3A4 (CYP3A4), cytochrome P450 3A5 (CYP3A5), EGFR, and Fcγ with the toxicities experienced from treatment with cetuximab and nilotinib.
OUTLINE: This is a dose-escalation study of nilotinib.
Patients receive cetuximab intravenously (IV) on days 1, 8, 15, and 22 and nilotinib orally (PO) once daily (QD) or twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationMedStar Georgetown University Hospital
Principal InvestigatorJohn Frederick Deeken
- Primary ID2013-0039
- Secondary IDsNCI-2013-01168
- ClinicalTrials.gov IDNCT01871311