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Following discussion with the Cancer Center the PI elected to terminate the study.
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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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sirolimus | Experimental | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sirolimus 2mg Tablet | 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. |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Chaoyuan Kuang, MD, PhD | Montefiore Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Montefiore Medical Center | The Bronx | New York | 10461 | United States |
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Patients were enrolled into the study from 11/16/2020 through 12/22/2021 at the Montefiore-Einstein Cancer Center.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. Sirolimus 2 milligram (mg) 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 3, 2023 |
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| 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 |
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| NOT COMPLETED |
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6 baseline participants
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. Sirolimus 2 milligram (mg) 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. |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | One patient had Stable Disease (SD), but was unable to be analyzed for ORR due to being clinical 'Progression of Disease' (POD) on study. Patient stopped study treatment due to toxicity. As such, only 5 patients were able to evaluated for ORR. | Posted | Count of Participants | Participants | Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total |
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| Secondary | 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. | Progression-free Survival (PFS) was unable to be assessed in 2 of the enrolled patients. | Posted | Median | Full Range | months | Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total |
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| Secondary | 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. | Response duration was only able to be evaluated in the one patient who showed a Partial Response | Posted | Median | Full Range | months | Up to ~24 weeks from the time of tumor response, up to 7 months total |
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| Secondary | 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. | 2 patients were unable to be evaluated for OS. | Posted | Median | Full Range | months | Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total |
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| Post-Hoc | Best Overall Response (OR) | 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 | Posted | Count of Participants | Participants | Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total |
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Approximately 24 weeks following initiation of treatment, up to 7 months total.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. Sirolimus 2 milligram (mg) 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. | 1 | 6 | 1 | 6 | 6 | 6 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal Pain | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | Hospitalized, Grade 3 |
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| Vomiting | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | Hospitalized, Grade 3 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | General disorders | CTCAE (4.0) | Non-systematic Assessment | All Grade 1 |
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| Hoarseness | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Non-systematic Assessment | Verbatim Term: Hoarse Voice. Grade 1 |
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| Anorexia | Metabolism and nutrition disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| Neuropathy | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment | Verbatim Term. Grade 1 |
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| Back Pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Non-systematic Assessment | One with intermittent back pain. Other with left, lateral back pain. Other unspecified. All Grade 1 |
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| Abdominal Pain | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | Intermittent. Grade 1 |
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| Dysuria | Renal and urinary disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| Diarrhea | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | 1 intermittent. All Grade 1 |
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| Hypertension | Cardiac disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 3 |
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| Rash Maculo-papular | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Non-systematic Assessment | Both Grade 1 |
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| Mucositis, Oral | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| Acute Kidney Injury | Renal and urinary disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| Headaches | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment | Intermittent, Grade 1 |
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| Weight Loss | Investigations | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| Pain | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Non-systematic Assessment | Verbatim Term: Knee Pain |
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| Edema Limbs | General disorders | CTCAE (4.0) | Non-systematic Assessment | Verbatim Term: Bilateral, Lower Extremity Edema |
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| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| Hypokalemia | Metabolism and nutrition disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| Urinary Tract Infection | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment | Grade 1 |
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| COVID Infection | Infections and infestations | CTCAE (4.0) | Non-systematic Assessment | Verbatim Term. Grade 1 |
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| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment | Both Grade 3 |
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| Hyperglycemia | Metabolism and nutrition disorders | CTCAE (4.0) | Non-systematic Assessment | Grade 3 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Chaoyuan Kuang | Albert Einstein College of Medicine | 718-430-3516 | chaoyuan.kuang@einsteinmed.edu |
| Jun 24, 2024 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D009369 | Neoplasms |
| D009362 | Neoplasm Metastasis |
| ID | Term |
|---|---|
| D009385 | Neoplastic Processes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D013607 | Tablets |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
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| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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