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).
Brief Title
Study to Evaluate the Efficacy and Safety of Sirolimus in Subjects With Metastatic, Mismatch Repair Deficient Solid Tumors After Immunotherapy
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%.
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%.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Metastatic dMMR Solid Cancer
Solid Tumor
Cancer
Metastatic Solid Tumor
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.
* 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.
Inclusion 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
* 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
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
65 Years
Minimum Age
18 Years
NCT Id
NCT04393454
Org Class
Other
Org Full Name
Albert Einstein College of Medicine
Org Study Id
2019-10724
Overall Status
Terminated
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Phase II Study to Evaluate the Efficacy and Safety of Sirolimus in Subjects With Metastatic, Mismatch Repair Deficient Solid Tumors After Immunotherapy
Primary Outcomes
Outcome Description
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.
Outcome Measure
Objective Response Rate (ORR)
Outcome Time Frame
Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total
Outcome Measure
Progression Free Survival (PFS)
Outcome Description
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.
Outcome Time Frame
Up to ~24 weeks from the time of tumor response, up to 7 months total
Outcome Measure
Response Duration (RD)
Outcome Description
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.
Outcome Time Frame
Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total
Outcome Measure
Overall Survival (OS)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
65
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Ana Acuna-Villaorduna
Investigator Email
aacunavi@montefiore.org
Investigator Phone