Study to Evaluate the Efficacy and Safety of Sirolimus in Subjects With Metastatic, Mismatch Repair Deficient Solid Tumors After Immunotherapy

Phase II Study to Evaluate the Efficacy and Safety of Sirolimus in Subjects With Metastatic, Mismatch Repair Deficient Solid Tumors After Immunotherapy

To evaluate the efficacy of sirolimus by estimating the overall response rate (ORR) as assessed by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) in patients with metastatic dMMR solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment).

Despite recent therapeutic strategies, including immunotherapy, treatment alternatives for patients with metastatic mismatch-repair deficient (dMMR) solid tumors remain scarce. Pre-clinical data suggests that dMMR tumors are susceptible to rapamycin (sirolimus), an mTOR inhibitor. In these tumors, characterized by higher levels of oxidative stress, sirolimus can exert a cytotoxic effect, led by the failure to repair DNA damage by inhibition of antioxidant enzymes such as FOXO3a triggered by Akt hyperactivation.

This proposal presents a phase 2 clinical trial designed to evaluate the efficacy of sirolimus in patients with dMMR solid tumors after immunotherapy. The investigators hypothesize that sirolimus will increase the overall response rate (ORR) by 20%.

Inclusion Criteria:

• Metastatic solid cancer tumor after immunotherapy (either due to progression of disease or inability to tolerate treatment)
• dMMR by immunohistochemistry (IHC) defined as the loss of expression in any of the four major MMR proteins (MLH1, MSH2, MSH6 and PMS2) or by next- generation sequencing (NGS)
• Age older than 18 at the time of informed consent
• Eastern Cooperative Oncology Group performance status of 0-2
• ≥1 measurable lesion based on RECIST, version 1.1 (16)
• Absolute neutrophil count (ANC) ≥1,500 mm3
• Platelet count ≥75,000 mm3
• Hemoglobin ≥ 9 g/dl
• Aspartate aminotransferase (AST) ≤3.0 times the upper normal limit (UNL)
• Alanine aminotransferase (ALT) ≤3.0 times the upper normal limit (UNL) Bilirubin ≤1.5 times the UNL
• Serum creatinine ≤1.5 times the UNL

Exclusion Criteria:

• Received immunotherapy in the prior 21 days.
• Have not recovered from toxicities of prior treatments to at least grade 1.
• Symptomatic central nervous system (CNS) metastases
• Pregnancy or Breast-feeding.