A Phase Ib/IIa Clinical Trial to Evaluate the Safety and Activity of Oregovomab and Nivolumab as a Combinatorial Immunotherapy Strategy in Patients With Recurrent Epithelial Cancer of Ovarian, Tubal or Peritoneal Origin
Overview
- Phase
- Phase 1
- Intervention
- Nivolumab
- Conditions
- Epithelial Ovarian Cancer
- Sponsor
- National Cancer Centre, Singapore
- Enrollment
- 13
- Locations
- 1
- Primary Endpoint
- Number of incidences and severity of Adverse Events (AE) and Serious AEs that are treatment-related, graded based on the CTCAE v4.03
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
The purpose of this study is to characterize the safety and tolerability, identify a recommended dose for expansion (RDE) / recommended phase II dose (RP2D), pharmacodynamics, and antitumor activity of Oregovomab vaccination in combination with Nivolumab as a novel combinatorial immunotherapeutic strategy in in female patients with recurrent epithelial ovarian cancer (EOC) who progressed after two or more prior lines of cytotoxic chemotherapy.
Detailed Description
This study tests the hypothesis that the combination of Oregovomab and Nivolumab will improve intracellular Cancer Antigen (CA) 125 antigen processing and elicit a stronger systemic CA 125-specific T cell response; in a manner that is synergistic, safe, and clinically efficacious in patients with relapsed EOC. This is an open-label, single-arm, phase Ib/IIa, single-center study with dose finding and dose expansion parts. In the phase Ib part, clinically recommended doses as monotherapy for Oregovomab (IV 2 mg Q4W, dose level 1) and Nivolumab (IV 240 mg Q2W) will be the starting doses for their combined use. A modified "3+3" dose finding design will be employed, with 2 lower dosages of Oregovomab (dose level -1 at 1 mg Q4W; level -2 at 0.5 mg Q4W) specified in case of excessive toxicity (defined as ≥ 2 dose limiting toxicities (DLTs) out of first 3 patients, or all 6 patients) encountered at dose level 1. Three patients will be initially enrolled into dose level 1. If 0 or 1 DLT is observed, another 3 patients will be enrolled into the same dose level; otherwise de-escalate and enroll 3 patients at dose level -1. If ≤ 1 DLT is observed among the 6 patients, dose level 1 will be the RDE/RP2D of Oregovomab to be combined with Nivolumab. Likewise, in the event of de-escalation, if 0 or 1 DLT is observed at a lower dose level, a further 3 patients will be enrolled for that level; if ≤ 1 DLT is observed out of the 6 patients, that dose level will be the RDE/RP2D. A minimum of 6 and a maximum of 18 patients will be enrolled in the dose finding part. Approximately 14 patients are to enroll in the dose expansion part wherein they will receive Oregovomab at RDE/RP2D, combined with Nivolumab. In total, 20 patients from the dose finding and dose expansion cohorts will be treated at RDE/RP2D, and be included in the phase IIa study population. Patients will be followed up for survival and post-progression treatment(s) over a duration of up to 36 months from the time of treatment initiation (i.e., Week 0 until up to 36 months).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed Written Informed Consent
- •Able to understand and voluntarily sign the Informed Consent Form (ICF). Written informed consent must be obtained before any study specific procedures that are not part of standard of care.
- •Willing and able to comply with scheduled visits, treatment schedule, laboratory test, and other protocol requirements
- •Age and Target Population
- •Age ≥ 21 years old
- •Histologically and/or cytologically confirmed diagnosis of epithelial ovarian carcinoma (serous, clear cell, endometrioid, mucinous, mixed, and others), fallopian tube and primary peritoneal carcinoma
- •Serum CA 125 level at enrollment must be at least twice the upper limit of normal (ULN) using local laboratory ranges
- •Objective evidence of disease recurrence following initial curative-intent treatment, and of progression after at least 2 prior lines of cytotoxic chemotherapy (including platinum and taxane) for advanced stage disease. Patients may have received prior treatment with Bevacizumab.
- •Presence of:
- •(a) measurable disease as defined by RECIST v1.1 AND a pre-treatment serum CA 125 level ≥ 2 x ULN on 1 occasion, OR (b) non-measurable but evaluable disease such as ascites and pleural effusions attributable to disease or radiologic abnormalities that do not meet RECIST v1.1 criteria AND a pre-treatment serum CA 125 level ≥ 2 x ULN on 2 occasions at least 1 week apart, OR (c) non-evaluable, non-measurable disease as defined by RECIST v1.1 AND pre-treatment CA 125 level ≥ 2 x ULN on 2 occasions at least 1 week apart
Exclusion Criteria
- •Cancer-specific Exclusions
- •Non-epithelial ovarian tumors, including malignant mixed Müllerian tumors (carcinosarcoma), or ovarian tumors with low malignant potential (i.e., borderline tumors).
- •Active symptomatic central nervous system (CNS) metastases. Patients with previous CNS metastases are eligible provided that they underwent CNS irradiation, are asymptomatic, do not require treatment with radiation therapy or anticonvulsants, and have stable disease at the screening tumor assessment. In addition, these patients must have been either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisolone (or equivalent).
- •Spinal cord compression not definitively treated with surgery and/or radiation. Patients with previously diagnosed and treated spinal cord compression are eligible provided that they have stable disease at the screening tumor assessment. In addition, these patients must have been either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisolone (or equivalent).
- •Leptomeningeal carcinomatosis
- •Uncontrolled pleural effusion(s), pericardial effusion, or ascites requiring recurrent drainage procedures
- •o Patients with functioning pleural and/or peritoneal drainage catheters/devices in situ at time of study entry may be eligible.
- •Previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 2 years before study entry AND no additional therapy is required, or anticipated to be required, during the study period.
- •General Medical Exclusions
- •Pregnant or lactating women
Arms & Interventions
Nivolumab and Oregovomab
Intervention: Nivolumab
Nivolumab and Oregovomab
Intervention: Oregovomab
Outcomes
Primary Outcomes
Number of incidences and severity of Adverse Events (AE) and Serious AEs that are treatment-related, graded based on the CTCAE v4.03
Time Frame: 4 weeks from the start of treatment
Overall response rate (ORR) as per Gynecological Cancer Intergroup (GCIG) criteria
Time Frame: Time from date of start of treatment until best overall response of CR or PR, up to 3 years
The proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR)
Progression-free survival (PFS) as per GCIG criteria
Time Frame: Time from date of start of treatment to the date of the first documented progression or death due to any cause, up to 3 years
Secondary Outcomes
- ORR as per immune-related response criteria (irRC)(Time from date of start of treatment until best overall response of CR or PR, up to 3 years)
- Disease control rate (DCR) as per GCIG criteria and irRC(Time from date of start of treatment until best overall response of CR, PR or SD, up to 3 years)
- ORR in EOC subtypes(Time from date of start of treatment until best overall response of CR or PR, up to 3 years)
- Overall survival (OS) as per GCIG criteria(Time from date of start of treatment to date of death due to any cause, up to 3 years)