A Randomized Phase II Trial of Cabozantinib Combined With PD-1 and CTLA-4 Inhibition in Metastatic Soft Tissue Sarcoma
The hypothesis of this study is that the response rate of soft tissue sarcoma will be improved with the addition of PD-1 and CTLA-4 inhibition to cabozantinib, and that cabozantinib priming will increase the response to nivolumab and ipilimumab.
• Histologically or cytologically confirmed soft tissue sarcoma that is metastatic or unresectable.
• Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
• Refractory to at least one and no more than two lines of therapy, with progression on last line of therapy. Neoadjuvant or adjuvant therapy completed more than one year prior does not count towards these two lines of therapy. Individuals with alveolar soft part sarcoma may enroll without being refractory to at least one line of chemotherapy. Any inappropriate therapies (ie hormonal therapies) should be discussed with the PI to determine if they are to be counted toward the two lines of therapy.
• At least 18 years of age.
• ECOG performance status ≤ 1
• Normal bone marrow and organ function as defined below:
‣ Absolute neutrophil count ≥ 1,500/mm3 without granulocyte colony-stimulating factor support
⁃ White blood cell count ≥ 2,000/mm3
⁃ Platelets ≥ 100,000/mm3 without transfusion
⁃ Hemoglobin ≥ 9.0 g/dL
⁃ Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease, ≤ 3.0 x IULN)
⁃ AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN; ALP ≤ 5.0 x IULN with documented bone metastases
⁃ Serum albumin ≥ 2.8 g/dl.
⁃ Serum creatinine ≤ 1.5x IULN or calculated creatinine clearance ≥ 40 mL/min by MDRD
⁃ Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
⁃ PT/INR or PTT \< 1.3 x IULN (within 7 days before first dose of study treatment, if not receiving any anticoagulation therapy)
• Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG within 14 days before the first dose of study treatment).
• Lesion amenable to biopsy for assessment of PD-L1 expression if no archival tissue is available
• Recover to baseline or ≤ grade 1 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy.
• The effects of cabozantinib on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 5 months after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and for at least 7 months after the last dose of study treatment.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).