Colorectal Cancer
Conditions
Keywords
Colorectal cancer, Panitumumab, Cabozantinib
Brief summary
There will be three parts to this phase I study: 1) the Combination Dose Finding cohort; 2) the Combination Expansion cohort; and 3) the Monotherapy MET Amplified cohort. In the Combination Dose Finding cohort and the Combination Expansion cohort, we will combine cabozantinib and panitumumab in patients with KRAS wild-type metastatic colorectal cancer (CRC). In the Monotherapy MET Amplified cohort, we will screen at least 50 patients for MET gene amplification (MET amplification). Patients with MET amplification will receive cabozantinib only (monotherapy). The primary objective of this open-label phase Ib trial are: 1. To determine the maximum tolerated dose and the recommended phase II dose for the combination of cabozantinib and panitumumab in patients with KRAS wild-type metastatic colorectal cancer and 2. To identify the objective response rate (ORR) of cabozantinib monotherapy in patients with prospectively identified MET amplified metastatic colorectal cancer. The secondary objectives are: 1. To describe the non-dose limiting toxicities of cabozantinib and panitumumab. 2. To describe the clinical activity (ORR, PFS, OS) of cabozantinib and panitumumab. 3. To describe the safety and tolerability of cabozantinib monotherapy in patients with MET amplified colorectal cancer. 4. To describe the clinical activity (PFS, OS) of cabozantinib monotherapy in patients with MET amplified colorectal cancer.
Interventions
BIOLOGICALPanitumumab
The FDA approved dose for panitumumab is 6mg/kg IV, every two weeks. This is the dose and schedule that will be used in this study.
DRUGCabozantinib
There will be three parts to this phase I study: 1) the Combination Dose Finding cohort; 2) the Combination Expansion cohort; and 3) the Monotherapy MET Amplified cohort. Cabozantinib will start at a dose of 60 mg daily with reductions to 40 and 20 mg daily possible in the dose finding cohort. The combination expansion cohort dose will determined by the dose finding cohort. The Monotherapy MET Amplified cohort will recieve 60 mg Cabozantinib daily.
Sponsors
Exelixis
John Strickler, M.D.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
MET Amplification Screening Test Inclusion Criteria: 1. Histologically and/or cytologically confirmed and radiographically measurable KRAS wild-type adenocarcinoma of the colon or rectum that is metastatic and/ or unresectable. Subjects must have been treated with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan and bevacizumab or have contraindication to such treatment. 2. Prior treatment with anti-EGFR therapy (either panitumumab or cetuximab). 3. At least one site of disease that is measurable by RECIST (version 1.1) criteria that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation. 4. Age ≥ 18 years. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 6. Life expectancy greater than 3 months. 7. Capable of understanding and complying with the protocol requirements and has signed the informed consent document. 8. Adequate organ and marrow function as defined below: Absolute neutrophil count ≥ 1,000/μl without colony stimulating factor support Platelets ≥ 75,000/μl Hemoglobin ≥ 8 g/dL AST/ALT ≤ 3 X upper limit of normal (ULN) Total bilirubin ≤ 1.5 X upper limit of normal (ULN) Serum albumin ≥ 2.5 g/dL MET Amplification Screening Test
Exclusion criteria
1. Presence of or known history of brain/ CNS tumor or metastases. 2. KRAS exon 2 (codons 12 or 13) mutation detected in tumor tissue specimen. 3. Concurrent severe and/or uncontrolled medical conditions which may compromise participation in the study, including impaired heart function or clinically significant heart disease. 4. Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic LMWH are permitted. 5. Previously experienced any of the following: 1. clinically significant gastrointestinal bleeding within the last 6 months 2. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within the last 3 months 3. any other signs indicative of pulmonary hemorrhage within the last 3 months 6. Radiographic evidence of cavitating pulmonary lesion(s). 7. Tumor in contact with, invading or encasing any major blood vessels. 8. Evidence of endotracheal or endobronchial tumor. 9. Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: 1. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening ii. Any history of congenital long QT syndrome iii. Any of the following within the last 6 months: 1. unstable angina pectoris 2. clinically-significant cardiac arrhythmias 3. stroke (including TIA, or other ischemic event) 4. myocardial infarction 5. thromboembolic event requiring therapeutic anticoagulation Note: Subjects with a venous filter (e.g., vena cava filter) are not eligible for this study. b. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: i. Any of the following within the last 28 days: <!-- --> 1. active peptic ulcer disease 2. active inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis 3. malabsorption syndrome ii. Any of the following within the last 6 months: 1. abdominal fistula 2. gastrointestinal perforation 3. bowel obstruction or gastric outlet obstruction 4. intra-abdominal abscess Note: Complete resolution of an intra-abdominal abscess must be confirmed prior even if the abscess occurred more that 6 months ago. c. Other disorders associated with a high risk of fistula formation or wound healing complications, including percutaneous endoscopic gastrostomy (PEG) tube placement within the last 3 months. d. History of chronic pancreatitis. 10\. Unable to swallow tablets. 11\. Evidence within the last 2 years of another malignancy which required systemic treatment. 12\. Known history of HIV seropositivity, hepatitis C virus, acute or chronic active hepatitis B infection, or other serious chronic infection requiring ongoing treatment. Main Study Inclusion Criteria: 1. For the Monotherapy MET Amplified cohort only: MET gene amplification by prospective screening assay from peripheral blood. 2. Histologically and/or cytologically confirmed and radiographically measurable KRAS wild-type adenocarcinoma of the colon or rectum that is metastatic and/ or unresectable. Subjects must have been treated with a fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan and bevacizumab or have contraindication to such treatment. In addition, for the monotherapy MET Amplified cohort, must have received prior treatment with anti-EGFR therapy (either panitumumab or cetuximab). 3. At least one site of disease that is measurable by RECIST (version 1.1) criteria that has not been previously irradiated; if the patient has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation. 4. Age ≥ 18 years. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Life expectancy greater than 3 months. 7. Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s). 8. Women of childbearing potential must have a negative pregnancy test within 7 days before the first dose of study treatment. 9. Capable of understanding and complying with the protocol requirements and has signed the informed consent document. 10. Adequate organ and marrow function as defined by protocol. Main Study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Recommended phase II dose (RPTD) for the combination of cabozantinib and panitumumab | RPTD for the study will be determined at the completion of Phase I dose escalation cohort; estimated as 1 year |
| Objective response rate (ORR) of cabozantinib monotherapy in patients with prospectively identified MET amplified metastatic colorectal cancer | Approximately every 8 weeks and/or restaging |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival associated with the cabozantinib and panitumumab regimen | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | — |
| Overall survival associated with the cabozantinib and panitumumab regimen | From date of randomization until the date of death from any cause assessed up to 60 months | — |
| Non-dose limiting toxicities of cabozantinib and panitumumab. | Continuous, every 4 weeks minimum until end of study estimated at 4 years | Adverse events will be recorded |
| Overall survival associated with cabozantinib monotherapy in patients with MET amplified colorectal cancer | From date of randomization until the date of death from any cause assessed up to 60 months | — |
| To describe the safety and tolerability of cabozantinib monotherapy in patients with MET amplified colorectal cancer | Continuous, every 4 weeks minimum until end of study estimated at 4 years | Adverse events will be recorded |
| Progression free survival associated with cabozantinib monotherapy in patients with MET amplified colorectal cancer | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months | — |
| Response rate of cabozantinib and panitumumab | approximately every 8 weeks and/or restaging | Response is assessed at restaging, approximately every 8 weeks. |
Countries
United States
Outcome results
None listed