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

Study Overview
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Brief Summary
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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
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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), a 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%.

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

Conditions
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Metastatic dMMR Solid Cancer, Solid Tumor, Cancer, Metastatic Solid Tumor

Intervention / Treatment
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* Drug: Sirolimus 2Mg Tab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sirolimus<br>Participants will be instructed to take 2 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. | Drug: Sirolimus 2Mg Tab<br>* Sirolimus (oral) will be started at 2 mg daily. Sirolimus dosing will be titrated to meet serum trough levels of >8 ng/ml, assayed at 7 days after starting a new dose, by chromatography/nmass spectrometry. Once adequate serum levels are met (≥8 ng/ml), the same dosing will be continued until progression of disease as evidenced by imaging, or unacceptable toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | 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). | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) - median months | 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). | 6 months | 
| Response Duration (months) | 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). | 6 months | 
| Overall Survival (OS) - median months | 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). | 6 months |