Avelumab and Talazoparib in Untreated Advanced Ovarian Cancer (JAVELIN OVARIAN PARP 100)

Study Description

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Brief Summary:

This is a Phase 3, randomized, open-label, multicenter study to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with the PARP inhibitor talazoparib in patients with previously untreated advanced ovarian cancer. Eligible patients must have previously untreated histologically confirmed Stage III IV epithelial ovarian, fallopian tube, or primary peritoneal cancer and must be candidates for bevacizumab in combination with platinum based chemotherapy.

Condition or disease	Intervention/treatment	Phase
Ovarian Cancer	Drug: Chemotherapy + avelumab followed by avelumab + talazoparib; Drug: Chemotherapy followed by talazoparib maintenance; Drug: Chemotherapy + bevacizumab followed by bevacizumab	Phase 3

Detailed Description:

This is a Phase 3, randomized, open-label, multicenter study to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with the PARP inhibitor talazoparib in patients with previously untreated advanced ovarian cancer. Eligible patients must have previously untreated histologically confirmed Stage III IV epithelial ovarian, fallopian tube, or primary peritoneal cancer and must be candidates for bevacizumab in combination with platinum based chemotherapy.

The primary purpose of the study is to demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging PFS in patients with advanced ovarian cancer.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	720 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB IN COMBINATION WITH CHEMOTHERAPY FOLLOWED BY MAINTENANCE THERAPY OF AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER (JAVELIN OVARIAN PARP100)
Actual Study Start Date :	July 19, 2018
Estimated Primary Completion Date :	February 9, 2022
Estimated Study Completion Date :	May 18, 2026

Arms and Interventions

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Arm	Intervention/treatment
Experimental: chemotherapy, avelumab and talazoparib; Platinum-based chemotherapy + avelumab followed by avelumab + talazoparib maintenance	Drug: Chemotherapy + avelumab followed by avelumab + talazoparib; Chemotherapy Period Paclitaxel Carboplatin Avelumab Maintenance Period Avelumab Talazoparib
Experimental: chemotherapy, and talazoparib; Platinum-based chemotherapy followed by talazoparib maintenance	Drug: Chemotherapy followed by talazoparib maintenance; Chemotherapy Period Paclitaxel Carboplatin Maintenance Period Talazoparib
Active Comparator: chemotherapy and bevacizumab; Platinum-based chemotherapy + bevacizumab followed by bevacizumab maintenance	Drug: Chemotherapy + bevacizumab followed by bevacizumab; Chemotherapy Period Paclitaxel Carboplatin Bevacizumab Maintenance Period Bevacizumab

Outcome Measures

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Primary Outcome Measures :

1. Progression-Free Survival (PFS) [ Time Frame: Baseline to measured progressive disease (up to approximately 41 months) ]
   The time from the date of randomization to the date of the first documentation of Progression of Disease or death due to any cause, whichever occurs first. Assessments to be completed by third-party blinded independent committee review.

Secondary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: Baseline to date of death from any cause (up to approximately 93 months) ]
   Overall survival (OS) is time from the date of randomization to the date of death due to any cause.
2. Euro Quality of Life (EQ-5D-5L) [ Time Frame: Every 3 weeks during chemotherapy period (up to 18 weeks), and every 6 weeks (up to 24 months) during maintenance and follow-up period (up to 3 years). ]
   Participant rated questionnaire to assess health related quality of life in terms of a single utility score. Health State Profile which has individualsrate their level of problems (none, slight, moderate, severe, or extreme/unable) in 5 areas (mobility, self care, usual activities, pain/discomfort, and anxiety/depression).
3. NFOSI-18 [ Time Frame: Day 1, 8, 15 of cycles 1,2,3 and D1 of cycles 4, 5, 6 in chemotherpy period (cycle is 21 days) and every 6 weeks (up to 24 months) during maintenance and follow-up period (up to 3 years). ]
   NFOSI-18 is an ovarian cancer-specific symptom index comprised of symptoms rated as highest priority by both oncology clinical experts and women with advanced ovarian cancer. DRS-P subscale include 9 physical symptoms/concerns (energy, pain, ill, stomach cramps, fatigue, constipation, stomach swelling, bowel control and sleep) and the disease related symptoms-emotional subscale include 1 emotional symptom/concern (worry condition will get worse). The treatment side effect subscale includes 5 items (nausea, hair loss, bothered by side effects, vomiting and skin problems). The functional well-being subscale includes 3 items (able to get around, enjoy life, and content with QoL).
4. ADA (Anti-Drug Antibodies) against Avelumab [ Time Frame: Every 3 weeks during 1st 4 cycles of chemotherapy ( cycle 21 days), day 1 and 29 during 1st cycle of maintenance (cycle 42 days) and every 12 weeks (up to 60 weeks). ]
   The percentage of participants with positive ADA and neutralizing antibodies will be summarized in treatment Arm A. All samples that are positive for ADA will also undergo characterization for Neutralizing Antibodies (NAb).
5. Progression Free Survival after the second line of therapy (PFS2) [ Time Frame: Baseline up to second progression up to approximately 41 months. ]
   Time from the date of randomization to the start of second subsequent treatment after first PD by Investigator assessment, or death from any cause, whichever occurs first.
6. Cmax - Talazoparib [ Time Frame: Pre-dose on Days 1, 15, and 29 of Cycle 1 (Cycle is 42 days) of maintenance treatment. ]
   Maximum Observed Plasma Concentration (Cmax)
7. Cmax - Avelumab [ Time Frame: Every 3 weeks during 1st 4 cycles of chemotherapy ( cycle 21 days), day 1 and 29 during 1st cycle of maintenance (cycle 42 days) and every 12 weeks (up to 60 weeks). ]
   Maximum Observed Plasma Concentration (Cmax).

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Histologically confirmed Stage III IV epithelial ovarian, fallopian tube, or primary peritoneal cancer including carcinosarcoma with high-grade serous component.
• Patients must be candidates for bevacizumab in combination with platinum based chemotherapy and previously untreated.

• Must have completed a primary surgical debulking procedure, or be candidates for neoadjuvant chemotherapy with planned interval debulking surgery.

  1. Patients who completed primary debulking must have had incompletely resected disease that is macroscopically/grossly visible and at least with lesions >1 mm and be randomized at a maximum of 8 weeks after surgery.

  2. For patients who are candidates for neoadjuvant chemotherapy, the diagnoses must have been confirmed by:

     • Core tissue (not fine-needle aspiration) biopsy is required for diagnosis.
     • Stage IIIC-IV documented via imaging or surgery (without attempt at cytoreduction).
     • Serum CA-125/CEA ratio >25. If the serum CA-125/CEA ratio is <25, then workup should be negative for the presence of a primary gastrointestinal or breast malignancy (<6 weeks before start of neoadjuvant treatment).
     • Randomization must occur within 8 weeks after diagnosis.
• Availability of an archival FFPE tumor tissue block or a minimum of 25 slides, together with an accompanying original H&E slide. If archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample must be obtained in accordance with local institutional practice for tumor biopsies. Tumor tissue must contain 40% or greater tumor nuclei per central laboratory assessment.
• ECOG performance status 0-1
• Age >=18 years (or >=20 years in Japan).
• Adequate bone marrow, hepatic, and renal function and blood coagulation

Exclusion Criteria:

• Non-epithelial tumors or ovarian tumors with low malignant potential (ie, borderline tumors) or mucinous tumors.
• Patients for whom intraperitoneal cytotoxic chemotherapy is planned.
• Prior exposure to immunotherapy with interleukin (IL)-2, interferon alpha (IFN-α), or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, excluding therapeutic anticancer vaccines.
• Prior treatment with a PARP inhibitor.
• Prior treatment with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab.
• Major surgery (other than debulking or exploratory surgery for ovarian cancer) for any reason within 4 weeks prior to randomization and/or incomplete recovery from surgery.
• Prior radiotherapy to any portion of the abdominal cavity or pelvis. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease.
• Prior targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their ovarian, peritoneal primary or fallopian tube carcinoma.
• Prior organ transplantation including allogenic stem cell transplantation.
• Diagnosis of Myelodysplastic Syndrome (MDS).
• Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.

Contacts and Locations

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Contacts

Contact: Pfizer CT.gov Call Center	1-800-718-1021	ClinicalTrials.gov_Inquiries@pfizer.com

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Sponsors and Collaborators

Pfizer

Investigators

Study Chair:	Bradley Monk, MD	Department of Obstetrics and Gynecology, University of Arizona College of Medicine - Phoenix
Study Chair:	Jonathan Ledermann, MD	UCL Cancer Institute at University College London
Study Director:	Pfizer CT.gov Call Center	Pfizer

More Information

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Additional Information:

To obtain contact information for a study center near you, click here. 

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT03642132 History of Changes
Other Study ID Numbers:	B9991030; 2017‐004456‐30 ( EudraCT Number ); B9991030 ( Other Identifier: Alias Study Number )
First Posted:	August 22, 2018
Last Update Posted:	February 19, 2019
Last Verified:	February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL:	https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

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

Keywords provided by Pfizer:

untreated epithelial ovarian cancer; fallopian tube carncer; primary peritoneal cancer

Additional relevant MeSH terms:

Ovarian Neoplasms; Neoplasms, Glandular and Epithelial; Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Urogenital Neoplasms; Endocrine System Diseases; Gonadal Disorders; Neoplasms by Histologic Type	Bevacizumab; Talazoparib; Antibodies, Monoclonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents; Immunologic Factors; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action