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

NCT ID: NCT04393454

Last Updated: 2024-07-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 6 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-16
• Study Completion Date: 2023-05-16

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%.

Conditions

Metastatic dMMR Solid Cancer; Solid Tumor; Cancer; Metastatic Solid Tumor

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Sirolimus

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.

Group Type: EXPERIMENTAL

Sirolimus 2mg Tablet

Intervention Type: DRUG

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/mass 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.

Interventions

Sirolimus 2mg Tablet

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/mass 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Albert Einstein College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Chaoyuan Kuang, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Montefiore Medical Center

Locations

Montefiore Medical Center

The Bronx, New York, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2019-10724

Identifier Type: -

Identifier Source: org_study_id