Durvalumab in Combination With Tremelimumab in Subjects With Advanced Rare Solid Tumors

A Phase II Study of Durvalumab (MEDI4736) (Anti-PD-L1 Antibody) in Combination With Tremelimumab (Anti-CTLA-4 Antibody) in Subjects With Advanced Rare Solid Tumors

This is an investigator initiated single institution, open-label study to evaluate the antitumor activity, safety, and tolerability of durvalumab in combination with tremelimumab in subjects with select advanced rare solid tumors.

This is an investigator initiated single institution, open-label study to evaluate the antitumor activity, safety, and tolerability of durvalumab in combination with tremelimumab in subjects with select advanced rare solid tumors. The dose-exploration phase, conducted across a range of tumor types, has been completed. The dose-expansion phase is ongoing and includes certain soft tissue sarcomas, neuroendocrine tumors and thymic carcinoma. Therefore, subjects diagnosed with any of those rare tumors are excluded from this trial. Given the safety and tolerability data in the previous and ongoing studies (Study D4190C00010 and D4190C00006), the selected dose for evaluation in all subjects enrolled in this trial is as follows:

Durvalumab, 1500 mg Q4W (equivalent to 20 mg/kg Q4W) intravenously for 13 doses and Tremelimumab 300 mg intravenously as a single dose on cycle 1 day 1 only. Weight-based dosing should be utilized for patients <30 kg: durvalumab 20 mg/kg and tremelimumab 1 mg/kg. Tremelimumab will be administered first and the infusion duration will be approximately 1 hour. The durvalumab infusion will start approximately 1 hour after the end of the tremelimumab infusion and the infusion will be administered over approximately 1 hour.

The project Surveillance of Rare Cancers in Europe (RARECARE) collected data on cancers from 89 population-based cancer registries in 21 European countries, making it possible to study the epidemiology of these cancers as a whole in a large and heterogeneous population. Working from this database and the literature, a RARECARE working group produced a new list of cancers and developed a new definition of rare cancers (incidence < 6/100,000/year). This definition and working list are adopted for this rare tumor immunotherapy study.

Inclusion Criteria:

• Diagnosis of a rare advanced solid malignancy meeting EORTC criteria.
• Subjects must have failed or been ineligible to receive standard treatment options if available.
• Subjects must be amenable to biopsy of a tumor site or have recent (< 2 years) archival material available.
• ECOG performance status of 0 to 2.
• Life expectancy > 3 months.
• Adequate normal organ and marrow function including: hemoglobin > 9.0 g/dl; ANC > 1500 per mm3; platelet count > 100,000 per mm3; bilirubin < 1.5 x ULN; ALT/AST < 2.5 x ULN unless liver metastases present in which case must be < 5 x ULN; creatinine clearance > 40 ml/min by Cockcroft-Gault or 24 hour urine collection

Exclusion Criteria:

• Previous treatment with durvalumab or tremelimumab.
• Prior treatment with any checkpoint inhibitor (including anti-CTLA-4, anti-PD-1 and anti-PD-L1).
• Rare malignancies under investigation in other studies including thymic carcinoma, certain sarcomas, and neuroendocrine tumors.
• Untreated central nervous system metastatic disease.
• Active or documented autoimmune disease within previous 2 years.
• Uncontrolled psoriasis.
• Prior chemotherapy within 28 days of the first dose of durvalumab or tremelimumab.
• Steroid exposure within 28 days of the first dose of durvalumab or tremelimumab with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid