A Phase 2 interventional study of Sirolimus 2mg Tablet in Metastatic dMMR Solid Cancer, Solid Tumor and Cancer, sponsored by Albert Einstein College of Medicine. Terminated at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2024-07-25.
Sponsored by Albert Einstein College of Medicine · Phase 2, Interventional, and Treatment
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).
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%.
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Exclusion Criteria:
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.
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.
Time frame: Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total
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.
Time frame: 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.
Time frame: 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.
Time frame: Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total
Patients were enrolled into the study from 11/16/2020 through 12/22/2021 at the Montefiore-Einstein Cancer Center.
| Milestone | Sirolimus |
|---|---|
| Started | 6 |
| Completed | 4 |
| Not completed | 2 |
| Withdrew: Death | 1 |
| Withdrew: Lost to follow-up | 1 |
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.
| Participants | Sirolimus |
|---|---|
| Objective Response Rate (ORR) | 1 |
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.
| months | Sirolimus |
|---|---|
| Progression Free Survival (PFS) | 3.5 (3.3 to 6.0) |
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.
| months | Sirolimus |
|---|---|
| Response Duration (RD) | 6.0 (6.0 to 6.0) |
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.
| months | Sirolimus |
|---|---|
| Overall Survival (OS) | 6.1 (3.7 to 6.9) |
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), the best OR will be determined based on RECIST criteria following review of imaging (CT-CAP or PET-CT) data. Tumor responses will be categorized based on RECIST v1.1 criteria as follows: Complete Response (CR): disappearance of all target tumors Partial Response (PR): ≥30% decrease in the sum of the longest diameters of target tumors Progressive Disease (PD): at least 20% increase in sum of diameters of target tumor (noting smallest sum on study); absolute increase of 5mm must be demonstrated Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD Inevaluable/Not Evaluable (NE): No imaging taken/no measurement performed
| Participants | Sirolimus |
|---|---|
| CR | 0 |
| PR | 1 |
| SD | 3 |
| PD | 1 |
| NE | 1 |
Collected over Approximately 24 weeks following initiation of treatment, up to 7 months total.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Sirolimus | 1/6 (16.7%) | 1/6 (16.7%) | 6/6 (100%) |
| Event | Sirolimus |
|---|---|
| Abdominal PainGastrointestinal disorders | 1/6 |
| VomitingGastrointestinal disorders | 1/6 |
| Event | Sirolimus |
|---|---|
| FatigueGeneral disorders | 3/6 |
| Back PainMusculoskeletal and connective tissue disorders | 3/6 |
| DiarrheaGastrointestinal disorders | 3/6 |
| AnorexiaMetabolism and nutrition disorders | 2/6 |
| Rash Maculo-papularSkin and subcutaneous tissue disorders | 2/6 |
| Edema LimbsGeneral disorders | 2/6 |
| AnemiaBlood and lymphatic system disorders | 2/6 |
| HoarsenessRespiratory, thoracic and mediastinal disorders | 1/6 |
| NeuropathyNervous system disorders | 1/6 |
| Abdominal PainGastrointestinal disorders | 1/6 |
6 baseline participants
| Age, Categorical(Participants) | Sirolimus |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 5 |
| >=65 years | 1 |
| Sex: Female, Male(Participants) | Sirolimus |
|---|---|
| Female | 4 |
| Male | 2 |
| Ethnicity (NIH/OMB)(Participants) | Sirolimus |
|---|---|
| Hispanic or Latino | 3 |
| Not Hispanic or Latino | 3 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Sirolimus |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 0 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 2 |
| White | 1 |
| More than one race | 3 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Sirolimus |
|---|---|
| United States | 6 |
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