Cabozantinib-s-malate in Treating Patients with Non-small Cell Lung Cancer That Is Metastatic or Cannot Be Removed by Surgery

Status: Active

Description

This phase II trial studies how well cabozantinib-s-malate works in treating patients with non-small cell lung cancer that has spread to other parts of the body (metastatic) 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.

Eligibility Criteria

Inclusion Criteria

  • The subject has a pathologic diagnosis of non-small cell lung carcinoma that is metastatic or unresectable
  • Documented presence * GROUP A: kinesin family member 5B (KIF5B)-RET or related variant RET fusions * GROUP B: any of the following aberrations ** NTRK fusion ** MET overexpression, amplification, or mutation ** AXL overexpression, amplification, or mutation * GROUP C: ROS1 fusion
  • The subject has a Karnofsky performance status of > 70%
  • Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Bilirubin =< 1.5 x the upper limit of normal (ULN); for subjects with known Gilbert's disease, bilirubin =< 3.0 mg/dL
  • Serum creatinine =< 1.5 x ULN, or creatinine clearance (CrCl) >= 30 mL/min; for creatinine clearance estimation, the Cockcroft and Gault equation should be used
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN if no liver involvement, or =< 5 x ULN with liver involvement
  • Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (113.2 mg/mmol) creatinine or 24-hour (hr) urine protein of < 1 g
  • Serum phosphorus, magnesium, and potassium >= lower limit of normal (LLN) after adequate supplementation if necessary
  • The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document
  • 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; women of childbearing potential must have a negative pregnancy test at screening
  • 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 reason

Exclusion Criteria

  • Any type of systemic anticancer agent (including investigational) within 3 weeks of first dose of study treatment, or within 5 half-lives of the agent whichever is shorter; subjects on luteinizing-hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists may be maintained on these agents
  • Prior treatment with cabozantinib
  • Radiation therapy for bone or brain metastasis within 2 weeks, any other external radiation therapy within 4 weeks of first dose of study drug; systemic treatment with radionuclides within 4 weeks; subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
  • The subject has not recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
  • Known uncontrolled symptomatic brain metastases or cranial epidural disease; subjects previously treated and on stable dose of corticosteroids and/or anticonvulsants for > 10 days, or not requiring such medications, are eligible; baseline brain scans are not required to confirm eligibility
  • The subject requires concomitant treatment, in therapeutic doses, unless deemed clinically unsafe to discontinue, with anticoagulants such as warfarin or warfarin-related agents, unfractionated heparin, thrombin or factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 100 mg/day), low-dose warfarin (=< 1 mg/day) are permitted; both prophylactic and/or treatment dose low molecular weight (fractionated) heparin (LMWH) are permitted and are the preferred agents to administer
  • The subject has experienced any of the following within 3 months before the first dose of study treatment: * Clinically-significant hematemesis or gastrointestinal bleeding * Clinically-significant hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood * Any other signs indicative of pulmonary hemorrhage
  • The subject has radiographic evidence of cavitating pulmonary lesion(s)
  • The subject has tumor invading major blood vessels
  • The subject has any evidence of an endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
  • The subject has 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 * Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) >= 150 mm Hg systolic, or >= 90 mm Hg diastolic despite optimal antihypertensive treatment (Note: if there is any BP measurement that is performed within the screening period that is < 150 mm Hg systolic and < 90 mm Hg diastolic, then BP does not meet definition of sustained) * Any congenital history of long QT syndrome * Any of the following within 6 months before the first dose of study treatment: ** Unstable angina pectoris ** Clinically-significant cardiac arrhythmias ** Stroke (including transient ischemic attack [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 before the first dose of study treatment ** Intra-abdominal tumor/metastases invading gastrointestinal (GI) mucosa (malignant abdominal ascites does not constitute mucosal invasion) ** Active peptic ulcer disease ** 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 before the first dose of study treatment: ** History of 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 to initiating treatment with cabozantinib even if the abscess occurred more than 6 months ago
  • GI surgery (particularly when associated with delayed or incomplete healing) within 28 days; Note: complete healing following abdominal surgery must be confirmed prior to initiating treatment with cabozantinib even if surgery occurred more than 28 days ago
  • Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus
  • Other clinically significant disorders such as: * Active infection requiring systemic treatment within 28 days before the first dose of study treatment * Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment * History of organ transplant * Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment * Major surgery (e.g., thoracotomy, removal or biopsy of brain metastasis) within 3 months before week 1 day 1; complete wound healing from major surgery must have occurred 1 month before week 1 day 1 and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before week 1 day 1; subjects with clinically relevant ongoing complications from prior surgery are not eligible
  • The subject is unable to swallow tablets
  • The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 14 days before week 1 day 1
  • The subject is pregnant or breastfeeding
  • The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation
  • The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
  • Uncontrolled concurrent malignancy that would limit assessment of efficacy of cabozantinib

Locations & Contacts

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Alexander Edward Dela C. Drilon
Phone: 646-888-4206
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Alexander Edward Dela C. Drilon
Phone: 646-888-4206
Montvale
Memorial Sloan Kettering Bergen
Status: Active
Contact: Alexander Edward Dela C. Drilon
Phone: 646-888-4206

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Alexander Edward Dela C. Drilon
Phone: 646-888-4206
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Alexander Edward Dela C. Drilon
Phone: 646-888-4206
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Alexander Edward Dela C. Drilon
Phone: 646-888-4206
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Alexander Edward Dela C. Drilon
Phone: 646-888-4206

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria to cabozantinib (cabozantinib-s-malate) in patients with advanced non-small cell lung cancer (NSCLC) whose tumor test positive for a rearranged during transfection proto-oncogene (RET) fusion. (Group A)

II. To determine the objective response rate (ORR) by RECIST v1.1 criteria to cabozantinib in patients with advanced NSCLC whose tumors test positive for a neurotrophic tyrosine receptor kinase (NTRK) fusion or MET proto-oncogene, receptor tyrosine kinase (MET) or AXL receptor tyrosine kinase (AXL) overexpression, amplification, or mutation. (Group B)

III. To determine the objective response rate (ORR) by RECIST v1.1 criteria to cabozantinib in patients with advanced NSCLC whose tumors test positive for a ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion. (Group C)

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS) and overall survival (OS) of patients with RET fusion-positive NSCLCs who were treated with cabozantinib. (Group A)

II. To evaluate ORR at 12 weeks, safety of cabozantinib in patients with RET fusion-positive NSCLCs. (Group A)

III. To evaluate ORR at 12 weeks, progression-free survival (PFS) and overall survival (OS) of patients with advanced NSCLCs whose tumors test positive for a NTRK fusion or MET or AXL overexpression or amplification who were treated with cabozantinib. (Group B)

IV. To evaluate the safety of cabozantinib in patients advanced NSCLCs with a NTRK fusion or MET or AXL overexpression, amplification, or mutation. (Group B)

V. To evaluate ORR at 12 weeks, progression-free survival (PFS) and overall survival (OS) of patients with RET fusion-positive NSCLCs who were treated with cabozantinib. (Group C)

VI. To evaluate the safety of cabozantinib in patients with ROS1 fusion-positive NSCLCs. (Group C)

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who continue to benefit from treatment based on the investigator's assessment may continue to receive cabozantinib-s-malate after evidence of radiographic progression via RECIST v1.1.

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

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Alexander Edward Dela C. Drilon

Trial IDs

Primary ID 12-097
Secondary IDs NCI-2012-01187
Clinicaltrials.gov ID NCT01639508