Efficacy & Safety of Olvi-Vec and Platinum-doublet + Bevacizumab Compared to Platinum-doublet + Bevacizumab in Platinum-Resistant/Refractory Ovarian Cancer (OnPrime, GOG-3076)

Study Overview
=================
Brief Summary
-----------------
The OnPrime study is a multi-center, randomized open-label phase 3 study evaluating the safety and efficacy of Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab compared to the Active Comparator Arm with platinum-doublet chemotherapy and bevacizumab in women diagnosed with platinum-resistant/refractory ovarian cancer (includes fallopian tube cancer and primary peritoneal cancer).

Detailed Description
-----------------
Olvi-Vec (olvimulogene nanivacirepvec, aka GL-ONC1, laboratory name: GLV-1h68) is an oncolytic vaccinia virus-based immunotherapy. This study is to test the hypothesis that the combination of Olvi-Vec followed by further chemotherapy is particularly effective against established tumors by virus-mediated immune activation and re-sensitization of tumor cells to chemotherapy. Participant population includes histologically confirmed non-resectable platinum-resistant/refractory ovarian cancer (PRROC). Determination of progression-free survival, safety and overall survival are key objectives. Participants randomized into the Experimental Arm will receive a single-cycle (2 infusions on two consecutive days) of Olvi-Vec through an intraperitoneal catheter. The catheter is then removed, and patients receive systemically administered platinum-doublet chemotherapy and bevacizumab. The control arm receives the same platinum-doublet chemotherapy and bevacizumab at the same dose and schedule. Biological samples will be obtained from some Experimental Arm participants for virus-shedding testing. Assessment of response to treatment in both arms will be by RECIST 1.1 and iRECIST. Maintenance/continued treatment with non-platinum chemotherapy and bevacizumab is dependent on a participant being clinically stable until confirmed progressive disease by iRECIST or can no longer tolerate therapy. Dr. Robert W. Holloway (AdventHealth Cancer Institute, Orlando, FL) will serve as the National Principal Investigator for this Phase 3 study in PRROC.

Official Title
-----------------
A Randomized Phase 3 Study Assessing the Efficacy and Safety of Olvi-Vec Followed by Platinum-doublet Chemotherapy and Bevacizumab Compared With Platinum-doublet Chemotherapy and Bevacizumab in Women With Platinum-Resistant/Refractory Ovarian Cancer (OnPrime, GOG-3076)

Conditions
-----------------
Platinum-resistant Ovarian Cancer, Platinum-refractory Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer, High-grade Serous Ovarian Cancer, Endometrioid Ovarian Cancer, Ovarian Clear Cell Carcinoma

Intervention / Treatment
-----------------
* Biological: olvimulogene nanivacirepvec
* Drug: Platinum chemotherapy: carboplatin (preferred) or cisplatin
* Drug: Non-platinum chemotherapy: Physician's Choice of gemcitabine, taxane (paclitaxel, docetaxel or nab-paclitaxel) or pegylated liposomal doxorubicin
* Drug: Bevacizumab (or biosimilar)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed (from prior treatment) non-resectable ovarian, fallopian tube or primary peritoneal cancer. High-grade serous [including malignant mixed Mullerian tumor (MMMT) with metastasis that contains high-grade epithelial carcinoma, FIGO grades 2 & 3 allowed], endometrioid, or clear-cell ovarian cancer. Performance status ECOG of 0 or 1. Life expectancy of at least 6 months. Received a minimum of 3 prior lines (including the 1st line) of systemic therapy with no maximal limit. Time from Last Platinum of 3-15 months since the last dose of platinum in the most recent platinum-based line of therapy (excluding using platinum as a radiosensitizer) until consent into this trial. Platinum-resistant or -refractory disease based on platinum-free interval (PFI) from the last dose of the most recent. platinum-based line of therapy (must have received a minimum of 2 doses of platinum in that line) to subsequent disease progression based on radiological assessment. Platinum-refractory: PFI of < 1 month (including disease progression while on platinum-based therapy). Platinum-resistant: PFI of 1-6 months. Received prior bevacizumab (or biosimilar) treatment. No contraindication to receive carboplatin, cisplatin or bevacizumab (or biosimilar). Have disease progression after last prior line of therapy based on radiological assessment prior to randomization. At least 1 measurable target lesion per RECIST 1.1 based on abdominal/pelvis imaging scan at screening. Evidence by CT and/or PET scans or physical exam of abdominal/pelvis region likely having disease in the peritoneal cavity (i.e., peritoneal carcinomatosis). Adequate renal, hepatic, bone marrow function, adequate coagulation tests, adequate immune function by lymphocyte count. Exclusion Criteria: Tumors of mucinous, low-grade serous, squamous cell, small cell neuroendocrine subtypes, MMMT tumors absent an epithelial component on recent biopsy, or non-epithelial ovarian cancers (e.g., germ cell tumors, Sex-cord tumors). Bowel obstruction within last 3 months prior to screening. Active urinary tract infection, pneumonia, other systemic infections. Active gastrointestinal bleeding. Known current central nervous system (CNS) metastasis. Inflammatory diseases of the bowel. History of HIV infection. Active hepatitis B virus or hepatitis C virus within 4 weeks prior to study. History of thromboembolic event within the prior 3 months. Contraindications for intraperitoneal (IP) catheter placement: Bowel obstruction with distended abdomen, rigid abdomen with bulky anterior wall carcinomatosis, abdominal wall hernia mesh that precludes laparoscopic entry to abdomen. Clinically significant cardiac disease at screening (New York Heart Association Class III/IV). Acute cerebrovascular event(s) such as cerebrovascular accident (CVA) or transient ischemic attack (TIA) in previous 6 months. Oxygen saturation <90%. Received prior virus-based gene therapy or therapy with cytolytic virus of any type. Receiving concurrent antiviral agent. Prior malignancy of other histology active within previous 3 years except for locally curable cancers apparently cured such as basal/squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of cervix or breast, any other stage I/II local malignancies. Received chemotherapy, radiotherapy, other anti-cancer biologic therapies within 4 weeks prior to planned treatment. Underwent surgery within 4 weeks, or have insufficient recovery from surgical-related trauma or wound healing, prior to first study treatment in either Arm. Receiving immunosuppressive therapy or steroids (except acute concurrent corticosteroid of no more than 20 mg per day for medical management with prednisolone equivalent. Symptomatic malignant ascites or pleural effusions defined as rapidly progressive ascites with abdominal distension and gastrointestinal dysfunction, pleural effusions with respiratory difficulties requiring frequent paracentesis > once every 14 days. Known hypersensitivity to gentamicin.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization (2:1) is either into the Experimental Arm which is Olvi-Vec followed by platinum-doublet chemotherapy and bevacizumab or into the Active Comparator Arm which is platinum-doublet chemotherapy and bevacizumab.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Olvi-Vec + Platinum-doublet & bevacizumab<br>Olvi-Vec: A total of 2 consecutive days of intraperitoneal catheter infusions in Week 0 Platinum-doublet & bevacizumab (or biosimilar) administered beginning in Week 4 (preferred), but no later than Week 5 | Biological: olvimulogene nanivacirepvec<br>* Olvi-Vec is an engineered oncolytic vaccinia virus<br>* Other names: GL-ONC1 and GLV-1h68;Drug: Platinum chemotherapy: carboplatin (preferred) or cisplatin<br>* Administered according to local practice<br>Drug: Non-platinum chemotherapy: Physician's Choice of gemcitabine, taxane (paclitaxel, docetaxel or nab-paclitaxel) or pegylated liposomal doxorubicin<br>* Administered according to local practice<br>Drug: Bevacizumab (or biosimilar)<br>* Administered according to local practice<br>|
| Active Comparator: Platinum-doublet & bevacizumab<br>Platinum-doublet & bevacizumab (or biosimilar) administered beginning in Week 0 | Drug: Platinum chemotherapy: carboplatin (preferred) or cisplatin<br>* Administered according to local practice<br>Drug: Non-platinum chemotherapy: Physician's Choice of gemcitabine, taxane (paclitaxel, docetaxel or nab-paclitaxel) or pegylated liposomal doxorubicin<br>* Administered according to local practice<br>Drug: Bevacizumab (or biosimilar)<br>* Administered according to local practice<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) by RECIST 1.1 in the Intention-to-Treat (ITT) population (all randomized participants regardless of whether they received any dose of treatment) | To assess progression-free survival from time of randomization until first documented disease progression based on radiological assessment or death from any cause. | From date of randomization up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent Adverse Events in the ITT population | Determine safety and tolerability of administering multiple doses of Olvi-Vec via intraperitoneal catheter in combination with platinum-doublet and bevacizumab (or biosimilar) as assessed by CTCAE v. 5.0 following initiation of study treatment until end of study participation. | From date of first study treatment until death or study completion; assessed up to 36 months | 
| Duration of Response (DOR) by RECIST 1.1 in the ITT population | Time from date of first response until the first date of progressive disease based on radiological assessment. | From date of randomization up to 12 months | 
| PFS by RECIST 1.1 in the modified ITT (mITT) population (participants who received at least 1 dose of treatment in either Arm) | Time from randomization to first documented disease progression based on radiological assessment or death from any cause. | From date of randomization up to 12 months | 
| PFS by iRECIST in the ITT population | Time from randomization to first documented disease progression with confirmatory imaging scan performed 4-8 weeks after unconfirmed disease progression or death from any cause. | From date of randomization up to 12 months | 
| Overall Response Rate (ORR) by RECIST 1.1 in the ITT population | Ratio of the sum of CR & PR divided by the number of ITT participants from start of treatment to confirmation of response. | From date of randomization up to 12 months | 
| Overall Survival in the ITT population | Time from randomization until date of death from any cause. | From date of randomization until death or study completion; assessed up to 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
viral therapy, olvimulogene nanivacirepvec, GL-ONC1, GLV-1h68, oncolytic virus, virotherapy, immunotherapy, immunochemotherapy, combination therapy, vaccinia virus, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, platinum resistant, platinum refractory, recurrent ovarian cancer