A Study to Investigate ONCOS-102 in Combination With Durvalumab in Subjects With Advanced Peritoneal Malignancies

Study Overview
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Brief Summary
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This is a two-part Phase 1/2 dose escalation and dose expansion study of an Adenovirus Vector (Ad5/3-D24-GMCSF), Expressing GM-CSF (GM-CSF-encoding adenovirus), ONCOS-102, in combination with anti-programmed death ligand-1 (PD-L1) antibody, durvalumab, in adult subjects with peritoneal disease who have failed prior standard chemotherapy and have histologically confirmed epithelial ovarian cancer or metastatic colorectal cancer.

Detailed Description
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ONCOS-102 will be administered intraperitoneally (IP) at weekly intervals for 6 weeks. A bolus dose of 300 mg cyclophosphamide (CPO) will be administered intravenously (IV) 1 to 3 days before the first infusion of ONCOS-102. Durvalumab will be administered by IV infusion once every four weeks (Q4W) for a total of 12 four-week cycles. Phase 1 of the study is a dose escalation phase, which will use a 3+3 design to evaluate the safety of ONCOS-102 monotherapy before initiation of durvalumab and to identify the recommended combination dose (RCD) of a fixed dose of durvalumab (1500 mg) + ONCOS-102 at 2 dose levels (1 x 10^11 viral particles (VPs) and 3 x 10^11 VPs). Subjects treated at the RCD of 3 x 10^11 VPs ONCOS-102 will be included in the Phase 2 expansion cohort based on their tumor diagnosis. Phase 2 of the study is the dose expansion phase, which will further explore the safety and anti-tumor activity for the RCD in 2 expansion cohorts with peritoneal disease: Epithelial ovarian cancer Metastatic colorectal cancer Simon's 2-Stage MINIMAX Design will be used in Phase 2 for Expansion Cohorts 1 and 2. In the first stage, 18 subjects will be enrolled in Cohort 1 and 13 subjects in Cohort 2 (including the 6 subjects at the RCD from the dose escalation phase). If 5 or more subjects in Cohort 1, or one or more subjects in Cohort 2, demonstrate clinical benefit (defined as percentage of subjects who are not in progression at end of Week 24), 15 additional subjects will be enrolled in Stage 2 of Cohort 1, and 14 additional subjects will be enrolled in Stage 2 of Cohort 2. The primary endpoint is the percentage of subjects who are not in progression at the end of Week 24 as measured by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

Official Title
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A Phase 1/2 Dose Escalation Study With Expansion Cohorts to Investigate the Safety, Biologic and Anti-tumor Activity of ONCOS-102 in Combination With Durvalumab in Subjects With Advanced Peritoneal Malignancies

Conditions
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Colorectal Cancer, Ovarian Cancer, Appendiceal Cancer

Intervention / Treatment
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* Biological: ONCOS-102
* Drug: Durvalumab
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with peritoneal disease who have failed prior standard chemotherapy and have histologic confirmation of epithelial ovarian cancer or metastatic colorectal cancer (CRC) including cancer originating from the appendix. Subject is willing to undergo a core needle biopsy during screening and Cycle 2, Study Week 5. Archival tumor samples are requested but are not required for eligibility. Previously treated for advanced cancer with no additional therapy options available known to prolong survival. Laboratory parameters for vital functions should be in the normal range or not clinically significant. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1. Exclusion Criteria: Treatment with an investigational agent within 4 weeks of starting study treatment or prior treatment with a checkpoint inhibitor (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], programmed cell death protein 1 [PD-1] or programmed death ligand 1 [PD-L1] antibodies). Subject has known active central nervous system metastasis, glioma and nervous system malignancies including carcinomatous meningitis. Subjects with asymptomatic brain metastases or spinal cord compression who have been treated, are considered stable, and who have not received corticosteroids or anticonvulsants for at least 28 days prior to screening may be included. Subject has other active malignancy. Known immunodeficiency or known to have evidence of acute or chronic human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C or other uncontrolled inter-current illnesses. Ongoing bowel perforation or presence of bowel fistula or abscess or history of small or large bowel obstruction within 3 months of registration, including subjects with palliative gastric drainage catheters. Subjects with palliative diverting ileostomy or colostomy are allowed if they have been symptom-free for more than 3 months. Subjects with clinically significant cardiovascular disease, history of organ transplant or allogeneic bone marrow transplant, active known or history of autoimmune disease that might recur or major surgery within 28 days prior to the first dose or still recovering from prior surgery.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The Phase 1 cohorts were enrolled sequentially. In Phase 2, the two expansion cohorts are enrolled in parallel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: ONCOS-102 Dose Escalation<br>ONCOS-102, 1 x 10^11 viral particles (VPs) monotherapy for 6 weeks, followed by durvalumab 1500 mg starting on Day 71. A bolus dose of 300 mg cyclophosphamide (CPO) was administered intravenously (IV) 1 to 3 days before the first infusion of ONCOS-102. ONCOS-102 was infused intraperitoneally (IP) in a total volume of 500 mL saline (0.9 mg/mL sodium chloride [NaCl] in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1. Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose every 4 weeks (Q4W) for 10 cycles, starting on Day 71. Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better. | Biological: ONCOS-102<br>* ONCOS-102 was administered by intraperitoneal infusion at weekly intervals for 6 weeks.<br>* Other names: Adenovirus Vector (Ad5/3-D24-GMCSF), Expressing GM-CSF (GM-CSF-encoding adenovirus);Drug: Durvalumab<br>* Durvalumab was administered by IV infusion once every four weeks for a total of 10 (Cohort A) or 12 four-week cycles.<br>* Other names: Imfinzi®;Drug: Cyclophosphamide<br>* A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.<br>* Other names: Cytoxan®;|
| Experimental: Cohort B: ONCOS-102 Dose Escalation<br>ONCOS-102, 1 x 10^11 VPs + durvalumab 1500 mg starting on Day 15. A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102. ONCOS-102 was infused IP in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1. Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose Q4W for 12 cycles, starting on Day 15. Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better. | Biological: ONCOS-102<br>* ONCOS-102 was administered by intraperitoneal infusion at weekly intervals for 6 weeks.<br>* Other names: Adenovirus Vector (Ad5/3-D24-GMCSF), Expressing GM-CSF (GM-CSF-encoding adenovirus);Drug: Durvalumab<br>* Durvalumab was administered by IV infusion once every four weeks for a total of 10 (Cohort A) or 12 four-week cycles.<br>* Other names: Imfinzi®;Drug: Cyclophosphamide<br>* A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.<br>* Other names: Cytoxan®;|
| Experimental: Cohort 1: Epithelial Ovarian Cancer<br>ONCOS-102, 3 x 10^11 VPs + durvalumab 1500 mg starting on Day 15. A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102. ONCOS-102 was infused IP in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1. Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose Q4W for 12 cycles, starting on Day 15. Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better. | Biological: ONCOS-102<br>* ONCOS-102 was administered by intraperitoneal infusion at weekly intervals for 6 weeks.<br>* Other names: Adenovirus Vector (Ad5/3-D24-GMCSF), Expressing GM-CSF (GM-CSF-encoding adenovirus);Drug: Durvalumab<br>* Durvalumab was administered by IV infusion once every four weeks for a total of 10 (Cohort A) or 12 four-week cycles.<br>* Other names: Imfinzi®;Drug: Cyclophosphamide<br>* A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.<br>* Other names: Cytoxan®;|
| Experimental: Cohort 2: Metastatic Colorectal Cancer<br>ONCOS-102, 3 x 10^11 VPs + durvalumab 1500 mg starting on Day 15. A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102. ONCOS-102 was infused IP in a total volume of 500 mL saline (0.9 mg/mL NaCl in water for injection) by gravity feed or per institutional procedures for IP infusions. ONCOS-102 was to be administered weekly for a total of 6 weeks, starting on Day 1. Durvalumab was administered as an intravenous (IV) infusion at a fixed dose of 1500 mg in either 0.9% (w/v) saline or dextrose Q4W for 12 cycles, starting on Day 15. Optional durvalumab treatment extension beyond the initial 12-cycle treatment period was allowed for subjects who complete the 12-cycle treatment period with Stable Disease or better. | Biological: ONCOS-102<br>* ONCOS-102 was administered by intraperitoneal infusion at weekly intervals for 6 weeks.<br>* Other names: Adenovirus Vector (Ad5/3-D24-GMCSF), Expressing GM-CSF (GM-CSF-encoding adenovirus);Drug: Durvalumab<br>* Durvalumab was administered by IV infusion once every four weeks for a total of 10 (Cohort A) or 12 four-week cycles.<br>* Other names: Imfinzi®;Drug: Cyclophosphamide<br>* A bolus dose of 300 mg cyclophosphamide (CPO) was administered IV 1 to 3 days before the first infusion of ONCOS-102.<br>* Other names: Cytoxan®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Dose Limiting Toxicities (DLTs) | All Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 19.0 and classified by MedDRA system organ class (SOC) and preferred term. The severity of AEs was assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. Adverse events (AEs) were reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent was signed through 90 days after the last dose of study treatment. TEAEs are those that occurred or worsened after administration of the first dose of study treatment. Deaths within the AE Reporting Period included all deaths that occurred during the study treatment period, or up to 90 days after the administration of the last dose of study drug or initiation of a new treatment. | up to 31 months (90 days after the last dose of study medication). | 
| Progression-free Survival (PFS) at Week 24 as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up starting 8 weeks after the last disease assessment. Per RECIST 1.1, target lesions were categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; PD: ≥ 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria. PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression does not occur. Per RECIST 1.1, progressive disease (PD) is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions or the development of new lesions. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival (PFS) as Measured by Response Evaluation in Solid Tumors 1.1 (RECIST 1.1) Using Kaplan-Meier Method | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up starting 8 weeks after the last disease assessment. Per RECIST 1.1, target lesions were categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; PD: ≥ 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria. PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression does not occur. Per RECIST 1.1, progressive disease (PD) is defined as a ≥ 20% increase in the sum of the longest diameter of target lesions or the development of new lesions. | Up to 29 months | 
| Objective Response Rate as Measured by as Measured by Response Evaluation in Solid Tumors 1.1 (RECIST 1.1) | Tumor responses were evaluated using appropriate imaging and categorized according to RECIST 1.1 at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up starting 8 weeks after the last disease assessment. Per RECIST 1.1, target lesions were categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; PD: ≥ 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria. | Up to 15 months | 
| Progression-free Survival (PFS) at Week 24 as Measured by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up starting 8 weeks after the last disease assessment. Per irRECIST, measurable lesions were categorized as follows: immune-related complete response (irCR): Complete disappearance of all target lesions; immune-related partial response (irPR): ≥ 30% decrease from baseline in the Total Measurable Tumor Burden (TMTB); immune-related progressive disease (irPD): ≥ 20% increase from nadir in TMTB; immune-related stable disease (irSD): not meeting above criteria. PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression does not occur. Per irRECIST, irPD is defined as a ≥ 20% increase from nadir in the TMTB. | Up to 24 Weeks | 
| Median Progression-free Survival (PFS) by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) as Estimated Using the Kaplan-Meier Method | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5,7, 9, and 11 during study treatment, and during on-study follow-up starting 8 weeks after the last disease assessment. Per irRECIST, measurable lesions were categorized as follows: immune-related complete response (irCR): Complete disappearance of all target lesions; immune-related partial response (irPR): ≥ 30% decrease from baseline in the total measurable tumor burden (TMTB); immune-related progressive disease (irPD): ≥ 20% increase from nadir in TMTB; immune-related stable disease (irSD): not meeting above criteria. PFS was measured from the date of the first dose of study treatment to the date of earliest disease progression or to the date of death, if disease progression does not occur. Per irRECIST, irPD is defined as a ≥ 20% increase from nadir in the TMTB. | Up to 39 months | 
| Objective Response Rate as Measured by Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) | Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), at cycles 3, 5, 7, 9, and 11 during study treatment, and during on-study follow-up starting 8 weeks after the last disease assessment. Per irRECIST, measurable lesions were categorized as follows: immune-related complete response (irCR): Complete disappearance of all target lesions; immune-related partial response (irPR): ≥ 30% decrease from baseline in the total measurable tumor burden (TMTB); immune-related progressive disease (irPD): ≥ 20% increase from nadir in TMTB; immune-related stable disease (irSD): not meeting above criteria. | Up to 15 months | 
| Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method | After completion of treatment, all subjects were followed for survival every 6 months up to 3 years following initiation of study treatment or until June 25, 2022 when all post-study follow-up was completed. OS was measured from the date of the first dose of study treatment to the date of death or last follow-up (June 25, 2022 when the last follow-up data was collected or earlier). Subjects lost to follow-up are censored on the date when they were last known to be alive. | Up to 39 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncos-102, Durvalumab, Peritoneal, Cyclophosphamide