Cancer, Metastatic dMMR Solid Cancer, Metastatic Solid Tumor, Solid Tumor
Conditions
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).
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%.
Interventions
DRUGSirolimus 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.
Sponsors
Albert Einstein College of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total | 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. |
| Progression Free Survival (PFS) | Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total | 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. |
| Response Duration (RD) | Up to ~24 weeks from the time of tumor response, up to 7 months total | 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. |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled into the study from 11/16/2020 through 12/22/2021 at the Montefiore-Einstein Cancer Center.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
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.
Time frame: Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sirolimus | Objective Response Rate (ORR) | 1 Participants |
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.
Time frame: Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total
Population: 2 patients were unable to be evaluated for OS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sirolimus | Overall Survival (OS) | 6.1 months |
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.
Time frame: Approximately 24 weeks after sirolimus initiation, up to approximately 7 months total
Population: Progression-free Survival (PFS) was unable to be assessed in 2 of the enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sirolimus | Progression Free Survival (PFS) | 3.5 months |
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.
Time frame: Up to ~24 weeks from the time of tumor response, up to 7 months total
Population: Response duration was only able to be evaluated in the one patient who showed a Partial Response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sirolimus | Response Duration (RD) | 6.0 months |
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
Time frame: Up to approximately 24 weeks after achieving therapeutic sirolimus levels, up to 7 months total
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sirolimus | Best Overall Response (OR) | SD | 3 Participants |
| Sirolimus | Best Overall Response (OR) | CR | 0 Participants |
| Sirolimus | Best Overall Response (OR) | PR | 1 Participants |
| Sirolimus | Best Overall Response (OR) | PD | 1 Participants |
| Sirolimus | Best Overall Response (OR) | NE | 1 Participants |