Durvalumab in Combination With Tremelimumab 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. 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 75 mg Q4W (equivalent to 1 mg/kg Q4W) intravenously for 7 doses then every 12
weeks for 2 doses. 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