A091201: RANDOMIZED PHASE II STUDY COMPARING THE MET INHIBITOR CABOZANTINIB TO TEMOZOLOMIDE/DACARBAZINE IN OCULAR MELANOMA
This is a one-stage phase ii clinical trial design was chosen to examine the difference in progression free survival rate at 4 months (PFS4) between Cabozantinib and Temozolomide (or Dacarbazine).
Patients will be randomized in a 2:1 ratio (cabozantinib: temozolomide /DTiC) to the study interventions.
Cabozantinib, 60 mg Po once daily, days 1-28 of a 28-day cycle
Temozolomide, 150 mg/m2 Po Daily on days 1-5 of a 28-day cycle
Dacarbazine, 1000 mg/m2/day iV on day 1 of a 21-day cycle
To assess whether cabozantinib can improve the 4-month progression-free survival (PFS) rate in patients with uveal melanoma from 15%, that is achievable with temozolomide, to 40% with cabozantinib.
1. Histologically or cytologically confirmed uveal melanoma that is metastatic or unresectable
2. Measureable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >=20 mm with conventional techniques or as >=10 mm with spiral CT scan or MRI.
3. Prior therapies allowed, except for those treatments directed toward, or with activity against, c-Met or VEGF/R, and the chemotherapy agents temozolomide and dacarbazine.
4. Age >= 18 year of age.
5. ECOG performance status <= 1 (Karnofsky >= 70%)
6. A corrected QT interval calculated by the Fridericia formula (QTcF) <=500 ms within 28 days before randomization.
7. Recovered to baseline or CTCAE <= Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
8. No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, temozolomide and dacarbazine.
9. Initial Laboratory Values
- Normal organ and marrow function as defined below:
- Absolute neutrophil count: >= 1,500/mcL
- Platelets: >= 100,000/mcL
- Total bilirubin: <= 1.5 x ULN
- AST (SGOT)/ALT (SGPT)*: <= 5.0xinstitutional upper limit of normal
- AST (SGOT)/ALT (SGPT)**: <= 2.5xinstitutional upper limit of normal
- Serum creatinine: <= 1.5 x ULN, OR
- Calculated creatinine clearance: >= 30 mL/minute
- Hemoglobin: >= 9 g/dL
- Serum albumin: >= 2.8g/dL
- Urine protein/creatinine ratio (UPCR)***: <= 1
- TSH: Within normal limits (WNL)****
- Prothrombin time (PT)/International Normalized Ratio (INR) must be >=1.2 x the laboratory ULN within 7 days before the first dose of study treatment.
* For patients with liver metastases.
** For patients without liver metastases.
*** See Appendix II for information regarding the calculation of UPC ratio. If UPC >= 1, then a 24-hour urine protein must be assessed. Eligible patients must have a 24-hour urine protein value < 1 g/
**** Supplementation is acceptable to achieve a TSH WNL.