Sirolimus for the Treatment of Metastatic Mismatch Repair Deficient Solid Tumors after Progression on Immunotherapy

PRIMARY OBJECTIVE:

I. 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 mismatch repair deficiency (dMMR) solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment).

SECONDARY OBJECTIVES:

I. To assess potential tissue biomarkers (Akt, pAkt, FOXO3a, pFOXO3a, 8OxoG expression by immunohistochemistry, tumor mutational burden/gene mutations by next-generation sequencing), the effect of sirolimus treatment on these biomarkers, and possible correlation between these biomarkers and clinical response.

II. To evaluate other clinical end-points such as progression-free survival, response duration and overall survival of sirolimus in patients with metastatic dMMR solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment).

III. To evaluate tolerability and safety of sirolimus using Common Terminology Criteria for Adverse Events (CTCAE) grading scale.

OUTLINE:

Patients receive sirolimus orally (PO) daily on days 1-28 in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or positron emission tomography (PET)/CT after 8, 16, and 24 weeks of treatment. Patients may continue sirolimus treatment in the absence of disease progression or unacceptable toxicity if disease is controlled during imaging.