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).

Study Overview

• Status: Terminated
• Conditions: Cancer; Solid Tumor; Metastatic Solid Tumor; Metastatic dMMR Solid Cancer
• Intervention / Treatment: Drug: Sirolimus 2mg Tablet

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%.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	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.	Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	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.	Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total
Response Duration (RD)	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.	Up to ~24 weeks from the time of tumor response, up to 7 months total
Overall Survival (OS)	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.	Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total

Collaborators and Investigators

• Sponsor: Albert Einstein College of Medicine
• Investigators: Principal Investigator: Chaoyuan Kuang, MD, PhD, Montefiore Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2020
• Primary Completion (Actual): May 16, 2023
• Study Completion (Actual): May 16, 2023

Study Registration Dates

• First Submitted: May 13, 2020
• First Submitted That Met QC Criteria: May 16, 2020
• First Posted (Actual): May 19, 2020

Study Record Updates

• Last Update Posted (Actual): July 25, 2024
• Last Update Submitted That Met QC Criteria: June 28, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 2019-10724

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes