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

• ClinicalTrials.gov Identifier: NCT02575807
• Recruitment Status: Terminated
• First Posted: October 15, 2015
• Results First Posted: April 4, 2019
• Last Update Posted: April 4, 2019
• Sponsor: Aduro Biotech, Inc.
• Collaborator: Incyte Corporation
• Information provided by (Responsible Party): Aduro Biotech, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Platinum-resistant Ovarian Cancer; Platinum-resistant Fallopian Cancer; Platinum-resistant Peritoneal Cancer	Biological: CRS-207; Drug: Epacadostat; Biological: Pembrolizumab	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 8, 2016
• Actual Primary Completion Date: April 26, 2018
• Actual Study Completion Date: May 8, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1: CRS-207; 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; via IV infusion; Other Name: Live, attenuated double-deleted Listeria monocytogenes (LADD)
Experimental: Phase 1: CRS-207/IDO 100 mg; 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; via IV infusion; Other Name: Live, attenuated double-deleted Listeria monocytogenes (LADD); Drug: Epacadostat; PO BID; Other Names: INCB024360; IDO
Experimental: Phase 1: CRS-207/IDO 300 mg; 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; via IV infusion; Other Name: Live, attenuated double-deleted Listeria monocytogenes (LADD); Drug: Epacadostat; PO BID; Other Names: INCB024360; IDO
Experimental: Phase 2: CRS-207/Pembro/IDO; 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; via IV infusion; Other Name: Live, attenuated double-deleted Listeria monocytogenes (LADD); Drug: Epacadostat; PO BID; Other Names: INCB024360; IDO; Biological: Pembrolizumab; via IV infusion; Other Names: Keytruda®; Pembro
Experimental: Phase 2: CRS-207/Pembro; 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; via IV infusion; Other Name: Live, attenuated double-deleted Listeria monocytogenes (LADD); Biological: Pembrolizumab; via IV infusion; Other Names: Keytruda®; Pembro

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Number of Subjects Reporting Hematologic and/or Non-hematologic Dose-limiting Toxicity (DLT) [ Time Frame: Subjects followed for DLTs for 21 days following the first dose of CRS-207 (treatment Cycle 1 for CRS-207). ]

   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.
2. Phase 1: Adverse Events (AEs) by CTCAE Grade 3 or Higher [ Time Frame: Subjects followed from the start of study treatment until 30 days following the final dose of study drug, an average of 3 months. ]
   Count of subjects in the Phase 1 cohorts with incidences of CTCAE Grade 3 or higher AEs.
3. Phase 2: Adverse Events (AEs) [ Time Frame: Subjects followed from the start of study treatment until 30 days following the final dose of study drug, an average of 2 months. ]
   Count of subjects in the Phase 2 cohorts with incidences of AEs.
4. Phase 2: Objective Response Rate (ORR) [ Time Frame: 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. ]
   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.
5. Phase 2: Progression Free Survival (PFS) [ Time Frame: 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. ]
   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.

Secondary Outcome Measures :

1. Phase 1: Objective Response Rate (ORR) by mRECIST [ Time Frame: 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. ]
   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.
2. Phase 1: Progression Free Survival (PFS) [ Time Frame: 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 ]
   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.
3. Disease Control Rate (DCR) [ Time Frame: 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. ]
   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.
4. Duration of Response (DOR) [ Time Frame: 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. ]
   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.
5. Overall Survival (OS) [ Time Frame: OS was assessed from the first dose of study treatment until death or study termination, whichever comes first, assessed up to 100 weeks. ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. 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).
2. Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
3. Agree to provide core biopsies at baseline and at Cycle 2 Day 15
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Available archived tumor tissue for central analysis
6. Adequate organ and marrow function

Exclusion Criteria

1. Platinum-refractory disease (progression during the first platinum-based chemotherapy)
2. Major surgical procedure within 4 weeks prior to Study Day 1
3. Inaccessible tumors or for whom biopsy is contraindicated
4. Clinically significant ascites
5. Phase 2 only: Previous treatment with >3 chemotherapy regimens for locally advanced or metastatic disease
6. Active bowel obstruction, or hospitalization for bowel obstruction within 2 months prior to screening
7. Require parenteral nutrition
8. Hospitalization within 2 weeks prior to screening
9. Received any anticancer medication or therapy in the 21 days prior to study Day 1
10. Prior monoclonal antibody treatment within 4 weeks before study Day 1
11. History of listeriosis or previous treatment with a listeria-based immunotherapy
12. Known allergy to both penicillin and sulfa antibiotics
13. Any immunodeficiency disease or immune-compromised state
14. 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
15. Pregnant or breastfeeding
16. Clinically significant heart disease
17. Valvular heart disease that requires antibiotic prophylaxis for prevention of endocarditis
18. History of any autoimmune disease which required systemic therapy in the past 2 years
19. Diagnosed with another malignancy within the past 3 years
20. Currently receiving therapy with a UDP-glucuronosyltransferase 1A9 inhibitor including diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid
21. Receiving monoamine oxidase inhibitor (MAOIs) or a drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening
22. Had prior serotonin syndrome
23. Has implanted medical devices that pose high risks for colonization and cannot be easily removed

Contacts and Locations

Locations

United States, Arizona

Scottsdale Healthcare Hospitals DBA HonorHealth

Scottsdale, Arizona, United States, 85258

United States, California

Stanford Cancer Center

Stanford, California, United States, 94305

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60611

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Pennsylvania

University of Pennsylvania Health System

Philadelphia, Pennsylvania, United States, 19104

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States, 19111

United States, Virginia

University of Virginia Health System

Charlottesville, Virginia, United States, 22903

United States, Washington

Virginia Mason Medical Center

Seattle, Washington, United States, 98101

Canada, Ontario

Princess Margaret Cancer Centre

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

CHUM - Centre Hospitalier de l'Université de Montréal

Montréal, Quebec, Canada, H2X 0A9

Sponsors and Collaborators

Aduro Biotech, Inc.

Incyte Corporation

  Study Documents (Full-Text)

Documents provided by Aduro Biotech, Inc.:

Study Protocol  [PDF] February 18, 2017

Statistical Analysis Plan  [PDF] May 3, 2018

More Information

• Responsible Party: Aduro Biotech, Inc.
• ClinicalTrials.gov Identifier: NCT02575807
• Other Study ID Numbers: ADU-CL-11
• First Posted: October 15, 2015
• Results First Posted: April 4, 2019
• Last Update Posted: April 4, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Aduro Biotech, Inc.:

Ovarian cancer; Fallopian cancer; Primary peritoneal cancer

Additional relevant MeSH terms:

Ovarian Neoplasms; Peritoneal Neoplasms; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Abdominal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Peritoneal Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents