A Phase II Study of 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
The purpose of this phase II study is to find out what effects cabozantinib (XL184) has, good and/or bad, in patients whose tumors one of the following gene changes RET, ROS1, or NTRK fusion, or increased MET or AXL activity. 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. RET, ROS1, or NTRK fusion or increased MET or AXL activity gene leads to lung cancer cell growth. Cabozantinib is an oral medicine that inhibits of RET, ROS1, NTRK, MET, and AXL. 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 the 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.
∙ A subject must fully meet all of the following criteria to be eligible for the study:
• The subject has a pathologic diagnosis of non-small cell lung carcinoma that is metastatic or unresectable.
• Documented presence:
‣ Group A: KIF5B/RET or related variant RET fusions.
⁃ Group B: any of the following aberrations
‣ ii. NTRK fusion iii. MET overexpression, amplification, or mutation iv. AXL overexpression, amplification, or mutation
⁃ Group C: ROS1 fusion
⁃ GROUP D: RET-fusion post-progression on selective RET inhibitor
• The subject is ≥ 18 years old on the day of consent.
• Measurable Disease by RECIST1.1
• The subject has a Karnofsky performance status of \> 70%.
• 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 creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 30 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
⁃ Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (113.2 mg/mmol) creatinine or 24-hr urine protein of \< 1 g
⁃ Serum phosphorus, magnesium, and potassium ≥ 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 (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.