Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell Lung Cancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or AXL Activity

Exclusion Criteria

• •1. 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 LHRH or GnRH agonists may be maintained on these agents.
• •2. Prior treatment with cabozantinib
• •4. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
• •5. 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.
• •6. 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 (eg, 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.
• •7. 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 (2.5ml) of red blood c. any other signs indicative of pulmonary hemorrhage
• •8. The subject has radiographic evidence of cavitating pulmonary lesion(s)
• •9. The subject has tumor in contact with invading major blood vessels
• •10. The subject has any evidence of an endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.
• •11. 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 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 TIA, or other ischemic event) myocardial infarction
• •* 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 treatmentF
• •* intra-abdominal tumor/metastases invading 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 that 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 that 28 days ago.
• •* Other disorders associated with a high risk of fistula formation including 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
• •* history of major surgery as follows:
• •12. The subject is unable to swallow tablets
• •13. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms 14 days before Week 1 Day 1
• •14. The subject is pregnant or breastfeeding.
• •15. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.
• •16. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
• •17. Uncontrolled concurrent malignancy that would limit assessment of efficacy of cabozantinib.