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

Phase 2

Terminated

Conditions: Metastatic dMMR Solid Cancer
Solid Tumor
Cancer
Metastatic Solid Tumor

Brief Summary: 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).

Detailed Description: 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%.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Sirolimus	Sirolimus 2mg Tablet	Participants will be instructed to take 2 milligrams (mg) every day for 28 days (1 cycle). They will be evaluated in the oncology clinic every 2 weeks to make sure they are tolerating the medication well.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total	To evaluate the efficacy of sirolimus in patients with metastatic mismatch repair deficient (dMMR) solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment), ORR will be determined. For this study ORR will be defined as the percentage of patients who achieve either a complete response (CR = disappearance of all target tumors); or a partial response (PR = ≥30% decrease in the sum of the longest diameters of target tumors) based on Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) following review of imaging (CT-CAP or PET-CT) data.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total	PFS, the duration of time from treatment initiation to progression of known metastases or new metastatic site, or death from any cause after a timeframe of 24 weeks, will be determined following treatment with sirolimus in patients with metastatic mismatch repair deficient (dMMR) solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment). Group median number of months will be reported.
Response Duration (RD)	Up to ~24 weeks from the time of tumor response, up to 7 months total	RD, defined as the duration of time from documentation of tumor response until the time of disease progression will be determined following treatment with sirolimus in patients with metastatic mismatch repair deficient (dMMR) solid cancer after immunotherapy (either due to disease progression or to inability to tolerate treatment). Group median number of months will be reported.
Overall Survival (OS)	Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total	Overall Survival, the duration of time from the start of treatment initiation for patients diagnosed with metastatic mismatch repair deficient (dMMR) solid cancer after immunotherapy (either due to disease progression or inability to tolerate treatment) to death from any cause, will be determined. Group median number of months will be reported.