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

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ClinicalTrials.gov Identifier: NCT04393454
Recruitment Status : Recruiting
First Posted : May 19, 2020
Last Update Posted : June 6, 2022
Sponsor:
Information provided by (Responsible Party):
Albert Einstein College of Medicine

Study Description
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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).

Condition or disease Intervention/treatment Phase
Metastatic dMMR Solid Cancer Solid Tumor Cancer Metastatic Solid Tumor Drug: Sirolimus 2Mg Tab Phase 2

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), 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%.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study to Evaluate the Efficacy and Safety of Sirolimus in Subjects With Metastatic, Mismatch Repair Deficient Solid Tumors After Immunotherapy
Actual Study Start Date : June 3, 2020
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Arms and Interventions
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Arm Intervention/treatment
Experimental: Sirolimus
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
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.


Outcome Measures
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Primary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 6 months ]
    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).


Secondary Outcome Measures :
  1. Progression Free Survival (PFS) - median months [ Time Frame: 6 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).

  2. Response Duration (months) [ Time Frame: 6 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).

  3. Overall Survival (OS) - median months [ Time Frame: 6 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).


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04393454


Contacts
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Contact: Sanjay Goel, MD 718-405-8404 SGOEL@montefiore.org

Locations
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United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10461
Contact: Sanjay Goel, MD    718-405-8404    SGOEL@montefiore.org   
Sponsors and Collaborators
Albert Einstein College of Medicine
Investigators
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Principal Investigator: Sanjay Goel, MD Montefiore Medical Center
More Information
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Responsible Party: Albert Einstein College of Medicine
ClinicalTrials.gov Identifier: NCT04393454    
Other Study ID Numbers: 2019-10724
First Posted: May 19, 2020    Key Record Dates
Last Update Posted: June 6, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Neoplasms
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
 Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs