Atezolizumab With Neoadjuvant Chemotherapy for Patients With Newly-Diagnosed Advanced-Stage Ovarian Cancer (AdORN)

Atezolizumab in Combination With Neoadjuvant Chemotherapy and Interval Cytoreductive Surgery for Patients With Newly-Diagnosed Advanced-Stage Epithelial Ovarian Cancer

The main purpose of this study is to validate a safe dose of atezolizumab with dose-dense paclitaxel and carboplatin when utilized with neoadjuvant chemotherapy and interval cytoreductive surgery followed by maintenance atezolizumab in women with advanced ovarian cancer.

Study Overview

• Status: Completed
• Conditions: Ovarian Neoplasms; Ovarian Cancer
• Intervention / Treatment: Drug: Atezolizumab; Drug: Carboplatin; Drug: Paclitaxel; Drug: Bevacizumab

Detailed Description

This is a Phase IB non-randomized, single-arm, open-label study of atezolizumab in combination with primary NACT-ICS in patients with advanced-stage epithelial ovarian cancer. The target population is women with previously untreated epithelial ovarian cancer (including fallopian tube and primary peritoneal cancer) with advanced stage (FIGO III-IV) disease suitable for NACT and ICS. The following regimen will be administered every 3 weeks for 3 cycles prior to ICS, then for 3 cycles following ICS:

• Carboplatin AUC = 5 or 6 IV, D1 of each cycle
• Paclitaxel 70 to 80mg/m2 IV, over one hour, on D1, 8, 15 of each cycle
• Atezolizumab 1200mg IV D1 of each cycle of chemotherapy and will be continued as maintenance therapy every 3 weeks until there is a lack of clinical benefit, unacceptable toxicity, or a total duration of 18 months.
• Bevacizumab (15 mg/kg IV every 3 weeks) may be added at cycle 5 of chemotherapy as per FDA approval. Those who opt for bevacizumab will receive chemotherapy, atezolizumab, and bevacizumab for cycles 5 and 6 followed by atezolizumab and bevacizumab maintenance. Maintenance bevacizumab will be given for a total duration of 16 cycles. Patients who have completed chemotherapy may opt for bevacizumab in the maintenance setting only if the amendment to add bevacizumab was not approved before after they started maintenance therapy.
• Upon completion of concurrent chemotherapy and atezolizumab therapy, patients will commence maintenance treatment with atezolizumab + bevacizumab for a total of up 16 cycles of maintenance therapy (22 total cycles of atezolizumab, and 18 total cycles of bevacizumab).

Each cycle is 21 days in duration and will be administered in the outpatient setting. Limited individualized flexibility in dose assignment (as noted) is permitted per physician discretion in regards to advanced-stage disease, nutritional status, ascites, non-physiologic creatinine measurements, and other comorbidities.

Three cycles of NACT with atezolizumab will be administered every 3 weeks prior to ICS (occurring between cycles 3 and 4) followed by 3 additional cycles (cycles 4-6) of chemotherapy with atezolizumab. Surgery must be performed after the third course of chemotherapy as soon as nadir counts permit, but preferably within six weeks after the completion of the third chemotherapy cycle. Fourth cycle of chemotherapy is to be administered as soon as possible, but preferably no more than six weeks after ICS.

Safety monitoring, including assessment for irAEs, will occur at each cycle and for 90 days after the last administration of atezolizumab or until start of next anti-cancer regimen, whichever occurs first. Image assessment by CT scan or MRI will be performed at baseline, prior to ICS to assess response, after completion of 6 cycles of chemotherapy with atezolizumab to assess response at end of chemotherapy treatment, and as clinically indicated during the maintenance phase and after completion of study treatment to assess PFS. Disease progression/recurrence will be defined per RECIST criteria and will not include isolated asymptomatic progression on the basis of CA125 levels. Immune function analysis will be performed on blood and tumor samples obtained at two time points: 1. confirmatory biopsy prior to start of therapy and 2. ICS.

It is estimated that 40 patients will be enrolled at an accrual rate of 3-5 patients/month and followed for a median of 3 years.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Signed Informed Consent Form (ICF)
• Ability and willingness to comply with the requirements of the study protocol
• Age ≥ 18 years
• No prior treatment for primary advanced (stage III or IV) epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
• Confirmation of diagnosis (by surgical excisional/incisional biopsy or imaging-guided core biopsy), and patients for whom the plan of management will include NACT followed by ICS. The decision to proceed with NACT will be at the treating physician's discretion and include patients with advanced stage disease considered at low likelihood for optimal cytoreduction with primary debulking surgery.
• All patients must have measurable disease per RECIST v1.1

Patients must meet the following criteria prior to initiation of study treatment:

• Histology consistent with high-grade epithelial ovarian cancer (excluding mucinous carcinoma, clear cell carcinoma, and carcinosarcoma)
• An adequate pre-treatment tumor biopsy is required to confirm histologic diagnosis. Acceptable options include laparoscopic biopsy or image-guided core needle biopsy (minimum of two cores). Fine needle aspiration (FNA) biopsy or cytology from ascites is not adequate.
• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2 (see Appendix 6)
• Peripheral neuropathy less than or equal to CTCAE Grade 1
• For female patients of childbearing potential, agreement (by patient) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use at least until ICS or if ICS is not performed then 90 days post last dose of atezolizumab

Exclusion Criteria:

• Mucinous, low-grade histology, clear cell carcinoma, or carcinosarcoma
• Prior systemic chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer.
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years. (Exceptions include basal cell or squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.)
• AEs from prior anticancer therapy that have not resolved to Grade ≤ 1 except for alopecia
• Bisphosphonate therapy for symptomatic hypercalcemia
• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
• Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases
• Pregnancy, lactation, or breastfeeding
• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
• Inability to comply with study and follow-up procedures
• History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection
• Active tuberculosis
• Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
• Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study
• Prior history of treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA4 or any other antibodies targeting co-stimulation or checkpoint pathways
• Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN] alpha or interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1
• Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within five half lives of the investigational product, whichever is longer)
• Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
• Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Atezolizumab, Carboplatin, Paclitaxel (+Optional Bevacizumab); Atezolizumab administered over 90 (± 15) minutes (for the first infusion, shortening to 60 (± 15) minutes and 30 ± 15) minutes for subsequent infusions as described below) followed by; Paclitaxel 70-80mg/m2 IV administered over approximately one hour followed by; Carboplatin IV administered over 15-30 minutes to achieve an initial target AUC of 5-6 mg/mL/Min (Calvert formula dosing).; (Optional, Physician choice) Bevacizumab IV maintenance administered starting at cycle 5 of chemotherapy over 30-90 minutes. For those who receive bevacizumab, it will be given for a total duration of 16 cycles

Drug: Atezolizumab; 1200mg IV q3weeks; Other Names: Tecentriq; Drug: Carboplatin; 5-6mg/ML IV q3 weeks; Other Names: Paraplatin; Drug: Paclitaxel; 70-80 mg/m2 IV q1 week; Other Names: Taxol; Drug: Bevacizumab; 15 mg/kg IV q3 weeks; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Incidence of Post Chemotherapy Surgical Debulking	The number of subjects able to undergo interval cytoreductive surgery will be utilized as a measure of safety regarding the initial dosing of atezolizumab.	9 weeks
Safety: Incidence of Treatment Emergent Adverse Events	The number of adverse events experienced while receiving study drugs will be utilized to assess safety of atezolizumab.	18 months
Safety: Dose Intensity	Percentage of planned doses of atezolizumab received at each cycle (21 day period) will be utilized as a measure of safety and tolerability for each subject.	Cycles 1-6,18 months total
Safety: Incidence of Dose Modifications	The number of dose modifications for atezolizumab at each cycle (21 day period) will be utilized as a measure of safety and tolerability for each subject. Dose modifications are defined as doses delayed, doses discontinued, or doses held.	Cycles 1-6,18 months total

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Complete or Partial Response as Measured by RECIST (Response Evaluation Criteria in Solid Tumors)	RECIST criteria will be utilized for subjects over the course of the study to measure their response to study drugs. A Complete Response (disappearance of all tumor lesions) or Partial Response (reduction of greater than 30% in total tumor size) is considered a response.	18 months
Number of Participants With Pathologic Complete Remission	Cytoreduction pathologic complete remission will be measured using RECIST (Response Evaluation Criteria in Solid Tumors) and immune-related response criteria.	9 weeks
Progression Free Survival Rate	All patients will be evaluated for progression free survival from the date of first treatment to the date of first observation of progressive disease or death due to any cause or will be stopped at date of last follow-up for those still alive without disease progression. 18-month progression free survival rate as estimated by Kaplan-Meier method.	18 months
Overall Survival Rate	All patients will be evaluated for overall survival from the date of first treatment on protocol to the date of death due to any cause and will be stopped at date of last follow-up for those still alive.18-month overall survival rate as estimated by Kaplan-Meier method.	18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Translational: PD-L1 Expression	Analyzing changes in PD-L1 expression measured based on: immunohistochemistry after treatment with atezolizumab, association with BRCA mutation status, tumor mutation profile (next generation sequencing), and progression free survival.	18 months
Translational: Tumor Infiltrating Lymphocytes	Analyzing changes in tumor infiltrating lymphocytes expression based on: immunohistochemistry after treatment with atezolizumab, association with BRCA mutation status, tumor mutation profile (next generation sequencing) and progression free survival.	18 months
Translational: Immune Checkpoint Receptors	Analyzing changes in immune checkpoint receptor expression based on: flow cytometry after treatment with atezolizumab, association with BRCA mutation status, tumor mutation profile (next generation sequencing) and progression free survival.	18 months
Translational: Fold Change in Cytokine Expression	Analyzing changes in cytokine expression based on: ELISA (enzyme-linked immunosorbent assay) after treatment with atezolizumab, association with BRCA mutation status, tumor mutation profile (next generation sequencing) and progression free survival.	Baseline, 18 months
Translational: Gene Expression Profiles	Analyzing changes in gene expression profiles based on: RNA sequencing after treatment with atezolizumab, association with BRCA mutation status, tumor mutation profile (next generation sequencing) and progression free survival.	18 months

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Johns Hopkins University; Genentech, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2018
• Primary Completion (Actual): July 20, 2020
• Study Completion (Actual): July 20, 2020

Study Registration Dates

• First Submitted: November 29, 2017
• First Submitted That Met QC Criteria: January 3, 2018
• First Posted (Actual): January 9, 2018

Study Record Updates

• Last Update Posted (Actual): August 12, 2021
• Last Update Submitted That Met QC Criteria: August 10, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Carboplatin; Paclitaxel; Bevacizumab; Atezolizumab
• Other Study ID Numbers: Pro00079313

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No