Safety and Efficacy of CRS-207 With Epacadostat in Platinum Resistant Ovarian, Fallopian or Peritoneal Cancer

Study Overview
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Brief Summary
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This 2-part, Phase 1/2 study will test investigational cancer drugs known as CRS-207, epacadostat (IDO), and pembrolizumab (pembro). The purpose of this study is to find out how safe it is to give the investigational drugs to women with platinum-resistant ovarian, fallopian tube, or peritoneal cancer and if it helps patients with these types of cancer live longer or can help shrink or slow the growth of cancer.

Official Title
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A Phase 1/2, Open-Label Safety and Efficacy Evaluation of CRS-207 in Combination With Epacadostat in Adults With Platinum-Resistant Ovarian, Fallopian, or Peritoneal Cancer

Conditions
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Platinum-resistant Ovarian Cancer, Platinum-resistant Fallopian Cancer, Platinum-resistant Peritoneal Cancer

Intervention / Treatment
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* Biological: CRS-207
* Drug: Epacadostat
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed disease Phase 1: Individuals with epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinomas who are considered to have platinum-resistant disease (progression within 6 months from completion of platinum-based chemotherapy). Phase 2: Individuals with epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinomas who are considered to have platinum-resistant disease (progression within 6 months from completion of a minimum of 4 platinum therapy cycles). Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Agree to provide core biopsies at baseline and at Cycle 2 Day 15 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Available archived tumor tissue for central analysis Adequate organ and marrow function Exclusion Criteria Platinum-refractory disease (progression during the first platinum-based chemotherapy) Major surgical procedure within 4 weeks prior to Study Day 1 Inaccessible tumors or for whom biopsy is contraindicated Clinically significant ascites Phase 2 only: Previous treatment with >3 chemotherapy regimens for locally advanced or metastatic disease Active bowel obstruction, or hospitalization for bowel obstruction within 2 months prior to screening Require parenteral nutrition Hospitalization within 2 weeks prior to screening Received any anticancer medication or therapy in the 21 days prior to study Day 1 Prior monoclonal antibody treatment within 4 weeks before study Day 1 History of listeriosis or previous treatment with a listeria-based immunotherapy Known allergy to both penicillin and sulfa antibiotics Any immunodeficiency disease or immune-compromised state Received prior immune checkpoint inhibitors (e.g., anti-CTLA-4, anti-PD-1, anti PDL-1) and any other antibody or drug specifically targeting T-cell costimulation or an IDO inhibitor Pregnant or breastfeeding Clinically significant heart disease Valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis History of any autoimmune disease which required systemic therapy in the past 2 years Diagnosed with another malignancy within the past 3 years Currently receiving therapy with a UDP-glucuronosyltransferase 1A9 inhibitor including diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid Receiving monoamine oxidase inhibitor (MAOIs) or a drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening Had prior serotonin syndrome Has implanted medical devices that pose high risks for colonization and cannot be easily removed

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: CRS-207<br>CRS-207 administered in 3-week cycles. * CRS-207 (1 x 10e9 colony forming units [CFU]) administered by intravenous (IV) infusion. For Cycle 1 through Cycle 6, CRS-207 will be administered on Day 1 of each cycle. After 6 cycles, CRS-207 will be administered on Day 1 once every 6 weeks (every other cycle). | Biological: CRS-207<br>* via IV infusion<br>* Other names: Live, attenuated double-deleted Listeria monocytogenes (LADD);|
| Experimental: Phase 1: CRS-207/IDO 100 mg<br>CRS-207 administered in 3-week cycles, IDO administered twice daily (BID). CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 1 of each cycle. After 6 cycles, CRS-207 administered on Day 1 once every 6 weeks (every other cycle). IDO (100 milligrams [mg]) administered by mouth (PO) BID, starting on Day 2 of the first CRS-207 treatment cycle. | Biological: CRS-207<br>* via IV infusion<br>* Other names: Live, attenuated double-deleted Listeria monocytogenes (LADD);Drug: Epacadostat<br>* PO BID<br>* Other names: IDO;|
| Experimental: Phase 1: CRS-207/IDO 300 mg<br>CRS-207 administered in 3-week cycles, IDO administered BID. CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 1 of each cycle. After 6 cycles, CRS-207 administered on Day 1 once every 6 weeks (every other cycle). IDO (300 mg) administered PO BID, starting on Day 2 of the first CRS-207 treatment cycle. | Biological: CRS-207<br>* via IV infusion<br>* Other names: Live, attenuated double-deleted Listeria monocytogenes (LADD);Drug: Epacadostat<br>* PO BID<br>* Other names: IDO;|
| Experimental: Phase 2: CRS-207/Pembro/IDO<br>CRS-207 and pembrolizumab (pembro) administered in 3-week cycles, IDO administered BID. CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 2 of each cycle. After 6 cycles, CRS-207 administered on Day 2 once every 6 weeks (every other cycle). Pembro (200 mg) administered by IV infusion on Day 1 in 3-week cycles. IDO (300 mg) administered PO BID, starting on Day 3 of the first CRS-207 treatment cycle. | Biological: CRS-207<br>* via IV infusion<br>* Other names: Live, attenuated double-deleted Listeria monocytogenes (LADD);Drug: Epacadostat<br>* PO BID<br>* Other names: IDO;Biological: Pembrolizumab<br>* via IV infusion<br>* Other names: Pembro;|
| Experimental: Phase 2: CRS-207/Pembro<br>CRS-207 and pembro administered in 3-week cycles. CRS-207 (1 x 10e9 CFU) administered by IV infusion. For Cycle 1 through Cycle 6, CRS-207 administered on Day 2 of each cycle. After 6 cycles, CRS-207 administered on Day 2 once every 6 weeks (every other cycle). Pembro (200 mg) administered by IV infusion on Day 1 in 3-week cycles. | Biological: CRS-207<br>* via IV infusion<br>* Other names: Live, attenuated double-deleted Listeria monocytogenes (LADD);Biological: Pembrolizumab<br>* via IV infusion<br>* Other names: Pembro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of Subjects Reporting Hematologic and/or Non-hematologic Dose-limiting Toxicity (DLT) | Count of subjects in the Phase 1 cohorts who reported a hematologic and/or non-hematologic DLT. Non-hematological DLTs are defined as follows, excluding the safety events specified for exemption in Section 5.3.1 of the study protocol: any treatment-emergent adverse event (TEAE) not attributable to disease or disease-related processes that occurs during the DLT observation period (Cycle 1) and is Grade 3 or higher according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4; any use of systemic steroids; and/or a study drug dose interruption lasting ≥ 7 days for an adverse event with an unclear relationship to study drug. Hematological DLTs are defined as: Grade 4 neutropenia lasting >7 days; Grade ≥3 febrile neutropenia; Grade 4 anemia; Grade 4 thrombocytopenia or ≥ Grade 3 thrombocytopenia lasting >7 days or associated with bleeding; and/or Dose delay >7 days secondary to myelosuppression. | Subjects followed for DLTs for 21 days following the first dose of CRS-207 (treatment Cycle 1 for CRS-207). | 
| Phase 1: Adverse Events (AEs) by CTCAE Grade 3 or Higher | Count of subjects in the Phase 1 cohorts with incidences of CTCAE Grade 3 or higher AEs. | Subjects followed from the start of study treatment until 30 days following the final dose of study drug, an average of 3 months. | 
| Phase 2: Adverse Events (AEs) | Count of subjects in the Phase 2 cohorts with incidences of AEs. | Subjects followed from the start of study treatment until 30 days following the final dose of study drug, an average of 2 months. | 
| Phase 2: Objective Response Rate (ORR) | ORR was evaluated for Phase 2 subjects based upon the best overall response (BOR) for individual study subjects. BOR was determined by the highest post-baseline qualitative response value for each assessed subject as measured by modified response evaluation criteria in solid tumors (mRECIST) and given the following hierarchy of overall response results: complete response (CR) > partial response (PR) > stable disease (SD) > progressive disease (PD) > not evaluable (NE). The protocol-specified ORR was defined as the percentage of evaluable subjects with a BOR of CR or PR; however, this percentage was not calculated per the final study Statistical Analysis Plan (SAP). Therefore, the number of evaluable subjects with BOR mRECIST values of CR, PR, SD, PD, and NE are provided for this outcome measure. | BOR was assessed from the first dose of study treatment until documented disease progression, initiation of a new cancer treatment, death, or study termination, whichever comes first, assessed up to 20 weeks. | 
| Phase 2: Progression Free Survival (PFS) | Number of weeks from the date of first dose of study treatment to the first date of objectively determined progressive disease (PD) or death from any cause, estimated using Kaplan-Meier (KM) methods with 95% confidence intervals (CIs). PD is determined by mRECIST. | Subjects followed for disease progression from first dose of study treatment until 30 days after last dose of study treatment or initiation of new cancer treatment, whichever comes first, assessed up to 20 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Objective Response Rate (ORR) by mRECIST | ORR was evaluated for Phase 1 subjects based upon the best overall response (BOR) for individual study subjects. BOR was determined by the highest post-baseline qualitative response value for each assessed subject as measured by modified response evaluation criteria in solid tumors (mRECIST), RECIST v1.1, and GCIG CA-125 criteria and given the following hierarchy of overall response results: complete response (CR) > partial response (PR) > stable disease (SD) > progressive disease (PD) > not evaluable (NE). The protocol-specified ORR was defined as the percentage of evaluable subjects with a BOR of CR or PR; however, this percentage was not calculated per the final study Statistical Analysis Plan (SAP). Therefore, the number of evaluable subjects with BOR mRECIST values of CR, PR, SD, PD, and NE are provided for this outcome measure. | BOR was assessed from the first dose of study treatment until documented disease progression, starting of a new cancer treatment, death, or study termination, whichever is earlier, assessed up to 100 weeks. | 
| Phase 1: Progression Free Survival (PFS) | Number of weeks from the date of first dose of study treatment to the first date of objectively determined progressive disease (PD) or death due to any cause, estimated using Kaplan-Meier (KM) methods with 95% confidence intervals (CIs). PD is determined by mRECIST, RECIST v1.1, and GCIG CA-125. | Subjects followed for disease progression from first dose of study treatment until 30 days after last dose of study treatment or initiation of new cancer treatment, whichever comes first, assessed up to 100 weeks | 
| Disease Control Rate (DCR) | The protocol-specified DCR was defined as the percentage of evaluable subjects with a BOR of CR or PR, or SD as determined by mRECIST, RECIST v1.1, and GCIG CA-125 criteria. | BOR was assessed from the first dose of study treatment until documented disease progression, starting of a new cancer treatment, death, or study termination, whichever comes first, assessed up to 100 weeks. | 
| Duration of Response (DOR) | Number of weeks from date of CR or PR designation until PD designation, as determined by mRECIST, RECIST v1.1 and GCIG CA-125 criteria. | Subjects followed for disease progression from date of CR or PR designation until documented disease progression or study termination, whichever comes first, assessed up to 100 weeks. | 
| Overall Survival (OS) | Number of weeks from the date of first dose of study treatment to the date of death from any cause, estimated using KM methods with 95% CIs for subjects in the SAF. Subjects without documentation of death at the time of analysis were censored as of the date the subject was last known to be alive. For subjects lost to follow up, the last visit or last contact date where the subject is documented to be alive will be used to estimate last known date alive. | OS was assessed from the first dose of study treatment until death or study termination, whichever comes first, assessed up to 100 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ovarian cancer, Fallopian cancer, Primary peritoneal cancer