Cabozantinib-S-Malate and Panitumumab in Treating Patients with Colorectal Cancer That is Metastatic or Cannot Be Removed by Surgery

Status: Active

Description

This phase Ib / II trial studies the safety and best dose of cabozantinib-s-malate when given together with panitumumab in treating patients with colorectal cancer that has spread to other parts of the body or cannot be removed by surgery. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Panitumumab is a monoclonal antibody that blocks the ability of tumor cells to grow and spread. Giving cabozantinib-s-malate with panitumumab may work better in treating patients with colorectal cancer.

Eligibility Criteria

Inclusion Criteria

  • PROSPECTIVE SCREENING ELIGIBILITY CRITERIA:
  • Histologically and/or cytologically confirmed and radiographically measurable KRAS and NRAS 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
  • Prior treatment with anti-epidermal growth factor receptor (EGFR) therapy (either panitumumab or cetuximab)
  • At least one site of disease that is measurable by Response Evaluation Criteria in Solid Tumors (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
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Life expectancy greater than 3 months
  • Capable of understanding and complying with the protocol requirements and has signed the informed consent document
  • INCLUSION CRITERIA:
  • For the Monotherapy MET Amplified cohort only: MET amplification by prospective screening assay from peripheral blood; the amplification score must be “strongly positive” (++ or +++), which is defined as amplification present at a level that is observed in the upper 50th percentile of samples with amplifications
  • Histologically and/or cytologically confirmed and radiographically measurable KRAS and NRAS 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, subjects must have received prior treatment with anti-EGFR therapy (either panitumumab or cetuximab)
  • 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
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy > 3 months
  • Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) at the time of the serum pregnancy test (women of childbearing potential only); 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)
  • Women of childbearing potential must have a negative pregnancy test within 7 days before the first dose of study treatment; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible treatment
  • Absolute neutrophil count >= 1,500/ul without colony stimulating factor support
  • Platelets >= 100,000/ul
  • Hemoglobin >= 9 g/dL
  • AST/ALT =< 3 X upper limit of normal (ULN)
  • Total bilirubin =< 1.5 X ULN
  • Serum albumin >= 2.8 g/dL
  • Lipase < 2 X the upper limit of normal (ULN) and no radiologic or clinical evidence of pancreatitis
  • Creatinine clearance (CrCl) >= 50 mL/min; for creatinine clearance estimation, the Cockcroft and Gault equation should be used
  • Urine protein/creatinine ratio (UPCR) =< 1
  • Serum phosphorus >= lower limit of normal (LLN)
  • Calcium >= LLN
  • Magnesium >= LLN
  • Potassium >= LLN

Exclusion Criteria

  • EXCLUSION CRITERIA:
  • Presence of or known history of brain/central nervous system (CNS) tumor or metastases
  • KRAS or NRAS mutation detected in tumor specimen
  • Concurrent severe and/or uncontrolled medical conditions which may compromise participation in the study, including impaired heart function or clinically significant heart disease
  • Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin, and factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel); Note: low-dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparins (LMWH) are permitted; anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen
  • Previously experienced any of the following: * Clinically significant gastrointestinal bleeding within 6 months * Hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood within the last 3 months * Any other signs indicative of pulmonary hemorrhage within 3 months
  • Radiographic evidence of cavitating pulmonary lesion(s)
  • Tumor in contact with, invading or encasing any major blood vessels found on radiology report
  • Evidence of endotracheal or endobronchial tumor
  • Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: * Cardiovascular disorders including: ** Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening ** Any history of congenital long QT syndrome ** Any of the following within the last 6 months: *** Unstable angina pectoris *** Clinically-significant cardiac arrhythmias *** Stroke (including TIA, or other ischemic event) *** Myocardial infarction *** Thromboembolic event requiring therapeutic anticoagulation; Note: subjects with a venous filter (e.g., vena cava filter) are not eligible for this study * Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: ** Any of the following within 28 days: *** Active peptic ulcer disease *** Active inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis *** Malabsorption syndrome ** Any of the following within 6 months: *** Abdominal fistula *** Gastrointestinal perforation *** Bowel obstruction or gastric outlet obstruction *** Intra-abdominal abscess; Note: complete resolution of an intra-abdominal abscess must be confirmed prior even if the abscess occurred more than 6 months ago * Other disorders associated with a high risk of fistula formation or wound healing complications, including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months * History of chronic pancreatitis
  • History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan
  • Unable to swallow tablets
  • Evidence within the last 2 years of another malignancy which required systemic treatment
  • Known history of human immunodeficiency virus (HIV) seropositivity, acute or chronic active hepatitis B or C infection, or other serious chronic infection requiring ongoing treatment
  • Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment
  • Prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment
  • For Combination Dose Finding and Combination Expansion cohorts only: history of hypersensitivity reactions/anaphylaxis attributed to humanized and/or chimeric monoclonal antibodies or other such proteins; hypersensitivity reactions that are clearly related to cetuximab may be permitted at the discretion of the lead principal investigator (PI)
  • For Combination Expansion cohort only: prior treatment with cetuximab or panitumumab
  • Radionuclide treatment, including yttrium-90 treatment, within 6 weeks of the first dose of study treatment
  • Radiation therapy: * To the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study treatment or has ongoing complications or is without complete recovery and healing from prior radiation therapy * To bone metastases within 14 days of the first dose of study treatment * To any other site(s) within 28 days of the first dose of study treatment
  • Any other type of investigational agent within 28 days before the first dose of study treatment
  • Not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia, oxaliplatin-related neuropathy, asymptomatic electrolyte abnormalities =< grade 2, and other non-clinically significant adverse events
  • Presence of or known history of brain/CNS tumor or metastases
  • KRAS or NRAS mutation detected in tumor tissue specimen
  • Prothrombin time (PT) or partial thromboplastin time (PTT) test >= 1.3 x laboratory upper limit of normal (ULN) within 7 days before the first dose of study treatment
  • Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin, and factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel); note: low-dose aspirin for cardioprotection (per local applicable guidelines) and low dose, low molecular weight heparins (LMWH) are permitted; anticoagulation with therapeutic doses of LMWH is allowed in subjects without radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, and who have had no complications from a thromboembolic event or the anticoagulation regimen
  • Chronic concomitant treatment of strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers or CYP3A4 inhibitors
  • Previously experienced any of the following: * Clinically significant gastrointestinal bleeding within 6 months before the first dose of study treatment * Hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first dose of study treatment * Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
  • The subject is unable to swallow tablets
  • Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before start of treatment; Note: at baseline (i.e. screening), three ECGs to be obtained within 30 minutes but approximately 2 to 3 minutes apart (i.e. triplicate); if the average of the three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
  • Pregnant or breastfeeding
  • For the Combination Dose Finding and Combination Expansion cohorts only: previously identified allergy or hypersensitivity to components of the study treatment formulation or panitumumab
  • Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
  • Evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment
  • Known history of HIV seropositivity, hepatitis C virus, acute or chronic active hepatitis B infection, or other serious chronic infection requiring ongoing treatment

Locations & Contacts

North Carolina

Burlington
Cone Health Cancer Center at Alamance Regional
Status: Active
Contact: Rachel Ann Orr
Email: rachel.orr@duke.edu
Durham
Duke University Medical Center
Status: Active
Contact: Abigail Brunner McLeod
Phone: 919-681-1861
Email: abby.brunner@duke.edu
Henderson
Maria Parham Hospital
Status: Active
Contact: Rachel Ciancetta
Email: rachel.ciancetta@duke.edu
Laurinburg
Scotland Memorial Hospital-Laurinburg Cancer Center
Status: Active
Contact: Rachel Ciancetta
Email: rachel.ciancetta@duke.edu
Lumberton
Southeastern Regional Medical Center
Status: Active
Contact: Rachel Ciancetta
Email: rachel.ciancetta@duke.edu
Smithfield
Johnston Memorial Hospital
Status: Active
Contact: Rachel Ciancetta
Email: rachel.ciancetta@duke.edu

South Carolina

West Columbia
Lexington Medical Center
Status: Active
Contact: Rachel Ann Orr
Email: rachel.orr@duke.edu

Virginia

Norfolk
Virginia Oncology Associates - Lake Wright
Status: Active
Contact: Rachel Ann Orr
Email: rachel.orr@duke.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD) and recommended phase II dose (RPTD) of combination treatment with cabozantinib (cabozantinib-s-malate) and panitumumab.

II. To identify the objective response rate (ORR) of cabozantinib and panitumumab in patients with mesenchymal–epithelial transition (MET) amplified metastatic colorectal cancer.

III. To identify the objective response rate (ORR) of cabozantinib monotherapy in patients with MET amplified metastatic colorectal cancer.

SECONDARY OBJECTIVES:

I. To describe the non-dose limiting toxicities of cabozantinib and panitumumab.

II. To describe the clinical activity (ORR, progression-free survival [PFS], overall survival [OS]) of cabozantinib and panitumumab.

III. To describe the safety and tolerability of cabozantinib monotherapy in patients with MET amplified colorectal cancer.

IV. To describe the clinical activity (PFS, OS) of cabozantinib monotherapy in patients with MET amplified colorectal cancer.

TERTIARY OBJECTIVES:

I. To explore any correlation between tissue and blood based biomarkers and clinical outcomes.

II. To determine whether the combination of cabozantinib and panitumumab prevents the emergence of MET amplified cell-free tumor deoxyribonucleic acid (DNA) in peripheral blood.

III. To determine whether cabozantinib monotherapy eliminates MET amplified cell-free tumor DNA from the peripheral blood of subjects with MET amplified metastatic colorectal cancer (CRC).

OUTLINE: This is a phase Ib, dose-escalation study of cabozantinib-s-malate followed by a phase II study.

DOSE FINDING COHORT: Patients receive cabozantinib-s-malate orally (PO) daily on days 1-28 and panitumumab intravenously (IV) over 30-60 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

DOSE EXPANSION COHORT: Patients receive cabozantinib-s-malate PO daily on days 1-28 (days 1-42 of course 1) and panitumumab IV over 30-60 minutes on days 1 and 15 (days 15 and 29 of course 1). Courses repeat every 28 days (42 days for course 1) in the absence of disease progression or unacceptable toxicity

MONOTHERAPY COHORT: Patients receive cabozantinib-s-malate PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 18 months.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Duke University Medical Center

Principal Investigator
John Howard Strickler

Trial IDs

Primary ID Pro00049983
Secondary IDs NCI-2014-01160
Clinicaltrials.gov ID NCT02008383