Cabozantinib in Patients With KIF5B/RET Positive Advanced Non-Small Cell Lung Cancer

• progression-free survival (PFS) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  Progression-free (PFS) and overall survival (OS) will be calculated using Kaplan-Meyer estimators starting from the time of treatment initiation. For PFS, patients alive without evidence of progression at the end of the study will be censored at the time of the last available follow-up. For OS, patients alive at the end of the study will be censored at the time of the last available follow-up.
• overall survival (OS) [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  Progression-free (PFS) and overall survival (OS) will be calculated using Kaplan-Meyer estimators starting from the time of treatment initiation. For PFS, patients alive without evidence of progression at the end of the study will be censored at the time of the last available follow-up. For OS, patients alive at the end of the study will be censored at the time of the last available follow-up.
• safety [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  Observed toxicities will be individually tabulated according to CTCAE version 4.0 and summarized using descriptive statistics.

The purpose of this phase II study is to find out what effects cabozantinib (XL184) has, good and/or bad, in patients whose tumors have a gene called KIF5B/RET.

A phase II study looks at how effective a medication is at treating a specific type of cancer and collects information on the side effects of the study treatment.

KIF5B/RET is an abnormal gene that leads to lung cancer cell growth. Cabozantinib is an oral medicine that inhibits the effects of this gene. In addition, this drug interferes with other cell pathways that also cause cancer cells to grow, form new blood vessels, and spread to other organs of the body. The goal of using cabozantinib is to shrink your cancer and to prevent it from growing.

Cabozantinib has been studied and shown to cause cancer shrinkage in other cancers such as medullary thyroid cancer and prostate cancer. We thus have a good idea of what side-effects it causes and can anticipate them.

Inclusion Criteria:

A subject must fully meet all of the following criteria to be eligible for the study:

1. The subject has a pathologic diagnosis of non-small cell lung carcinoma that is metastatic or unresectable.
2. Documented presence of KIF5B/RET or related variant RET fusions.
3. The subject is ≥ 18 years old on the day of consent. The subject has a Karnofsky performance status of > 70%.

5. The subject has organ and marrow function and laboratory values as follows:

• Absolute neutrophil count (ANC) ≥ 1500/mm3 without colony stimulating factor support
• Platelets ≥ 100,000/mm3 Hemoglobin ≥ 9 g/dL
• Bilirubin ≤ 1.5 × the upper limit of normal (ULN). For subjects with known Gilbert's disease, bilirubin ≤ 3.0 mg/dL
• Serum albumin ≥ 2.8 g/dl
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used:

Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72) Female:

Multiply above result by 0.85

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

  ≤ 3.0 × ULN if no liver involvement, or ≤ 5 × ULN with liver involvement

• Lipase < 2.0 x the upper limit of normal (except for subjects with adenocarcinoma of the pancreas)
• Urine protein/creatinine ratio (UPCR) ≤ 1
• Serum phosphorus, magnesium, and potassium ≥ LLN
• 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 (eg, 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:

A subject who meets any of the following criteria is ineligible for the study:

1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment.
2. Prior treatment with cabozantinib

3. The subject has received radiation therapy:

   • to the thoracic cavity or gastrointestinal tract within 3 months of the first dose of study treatment.
   • to bone or brain metastasis 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
4. The subject has received prior treatment with a small molecule kinase inhibitor within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. Subjects on LHRH or GnRH agonists may be maintained on these agents.
5. The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
6. 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.
7. The subject has active brain metastases or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain scans are not required to confirm eligibility.)
8. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test results at screening ≥ 1.3 × the laboratory ULN.
9. The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted.

10. The subject has experienced any of the following within 3 months before the first dose of study treatment:

    • clinically-significant hematemesis or gastrointestinal bleeding
    • hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood c. any other signs indicative of pulmonary hemorrhage
11. The subject has radiographic evidence of cavitating pulmonary lesion(s)
12. The subject has tumor in contact with, invading or encasing major blood vessels
13. The subject has any evidence of an endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.

14. 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 > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment (BP must be controlled at screening)
      • 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
        • 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 GI mucosa
        • 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:

        • major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound healing complications
        • minor surgery within 1 month of the first dose of cabozantinib if there were no would healing complications or within 3 months of the first dose of cabozantinib if there were wound complications
        • in addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery
15. The subject is unable to swallow tablets
16. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before the first dose of cabozantinib. Note: if the initial QTcF is found to be >500 ms, two additional ECGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤ 500ms, the subject meets eligibility in this regard.
17. The subject is pregnant or breastfeeding.
18. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.
19. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
20. The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment