This phase II/III trial studies how well pegylated liposomal doxorubicin hydrochloride with atezolizumab and/or bevacizumab work in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has come back (recurrent). Chemotherapy drugs, such as pegylated liposomal doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. It is not yet known which combination will work better in treating patients with ovarian, fallopian tube, or primary peritoneal cancer.
PRIMARY OBJECTIVES: I. Estimate the probability of a dose limiting toxicity (DLT) following cycle 1 of experimental regimens (pegylated liposomal doxorubicin hydrochloride \[pegylated liposomal doxorubicin\] \[PLD\] and atezolizumab and PLD/bevacizumab and atezolizumab). (Safety lead-in) II. Estimate and compare the hazard of first progression or death (progression free survival \[PFS\]) of each experimental regimen relative to the reference regimen, PLD and bevacizumab. (Phase II study) III. Estimate and compare the hazard of death and the hazard of first progression or death (PFS) of the experimental regimen relative to the reference regimen. (Phase III) (24-FEB-2021) SECONDARY OBJECTIVES: I. Estimate and compare the probabilities of response (objective response rate \[ORR\], either partial or complete response) defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria on each study regimen. (Phase II study) (24-FEB-2021) II. Estimate the frequency and severity of adverse events as classified and graded with Common Terminology Criteria for Adverse Events (CTCAE) in those patients who initiate their randomly assigned study treatment. (Phase II study) (03/19/2018) III. Estimate and compare ORR in each treatment group. (Phase III study) IV. Estimate the frequency and severity of adverse events in those patients who initiate their randomly assigned study treatment. (Phase III study) V. Estimate and compare mean patient reported outcome scores (PROs) as measured by National Comprehensive Cancer Network (NCCN)-Functional Assessment of Cancer Therapy (FACT) ovarian symptom index (NFOSI)-18 disease-related symptoms (DRS). (Phase III study) VI. Estimate and compare the treatment groups on the basis of the PROs: treatment side effects (TSE), function/well-being (FWB), fatigue (Functional Assessment of Chronic Illness Therapy \[FACIT\]-fatigue subscale) and abdominal discomfort (FACT/Gynecologic Oncology Group \[GOG\]-abdominal discomfort \[AD\] subscale). (Phase III study) (10/16/2017) TRANSLATIONAL SCIENCE OBJECTIVES: I. To determine whether biomarker levels in pre-treatment tissue, and pre- or on-treatment peripheral blood, and stool specimens are associated with ORR, PFS and/or overall survival (OS). II. Estimate pre-treatment PD-L1 expression on tumor cells measured by quantitative immunohistochemistry (IHC), and determine whether it is associated with the duration of PFS or overall survival. (Integrated Biomarker) III. Analysis of T cell receptor (TCR) repertoires by deep sequencing of peripheral blood samples. (Exploratory Biomarkers \[10/16/2017\]) IV. Tumor "immunogenicity" as determined by the neo-antigen landscape and characterization of the tumor microenvironment using next-generation sequencing, including but not limited to whole exome sequencing and/or RNA sequencing. (Exploratory Biomarkers \[10/16/2017\]) V. Microbiome analysis via stool sampling. (Exploratory Biomarkers \[10/16/2017\]) VI. To determine whether changes in quantitative biomarker parameters after the first 6 and 12 weeks of therapy predict ORR, PFS and/or OS. OUTLINE: Patients will be randomized to 1 of 3 arms. ARM I: Patients receive pegylated liposomal doxorubicin hydrochloride intravenously (IV) over 60 minutes on day 1 and atezolizumab IV over 30-60 minutes on days 1 and 15. (Closed to accrual as of February 09, 2021) ARM II: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1, bevacizumab IV over 30-90 minutes on days 1 and 15, and atezolizumab IV over 30-60 minutes on days 1 and 15. Patients also undergo computed tomography (CT) on study. ARM III: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1 and bevacizumab IV over 30-90 minutes on days 1 and 15. Patients also undergo CT on study. In all arms, cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 2 years, and then every 6 months for up to 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
444
Given IV
Given IV
Undergo CT
Given IV
Ancillary studies
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
Alaska Women's Cancer Care
Anchorage, Alaska, United States
Incidence of Dose Limiting Toxicities (DLT) of Experimental Regimens
Will be graded using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0 (CTCAE version 5.0 will be used beginning April 1, 2018). DLT will be assessed.
Time frame: Up to 28 days
Progression Free Survival (PFS) (Phase II)
Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria and will include estimates of the hazard ratios and the corresponding confidence intervals for the experimental regimen relative to the reference regimen, as well as Kaplan-Meier estimates of the survivorship function for each treatment group. Progression is defined by a 20% increase in the sum of the longest diameter of target lesions and a 5 mm absolute increase from nadir, or an unequivocal increase in a non-target lesion, or the appearance of new lesions.
Time frame: From study enrollment to the investigator determined date of progression or death due to any cause, whichever occurs first, assessed up to 5 years
PFS (Phase III)
Will be assessed by RECIST v1.1 criteria and will include estimates of the hazard ratios and the corresponding confidence intervals for the experimental regimen relative to the reference regimen, as well as Kaplan-Meier estimates of the survivorship function for each treatment group. Progression is defined by a 20% increase in the sum of the longest diameter of target lesions and a 5 mm absolute increase from nadir, or an unequivocal increase in a non-target lesion, or the appearance of new lesions.
Time frame: From study enrollment to the investigator determined date of progression or death due to any cause, whichever occurs first, assessed up to 5 years.
Overall Survival (OS) (Phase III)
OS will be evaluated by Kaplan Meier methods. The median survival and confidence intervals will be reported.
Time frame: From study enrollment to the date of death regardless of the cause, assessed up to 5 years
Objective Response Rate (ORR) (Partial or Complete Response) (Phase II)
Will be assessed by RECIST v1.1 criteria. Will be tabulated by treatment group, and 95% confidence intervals presented using Wilson's Score Method. Treatment arms will be compared using a likelihood ratio chi-square test. Progression is defined by a 20% increase in the sum of the longest diameter of target lesions and a 5 mm absolute increase from nadir, or an unequivocal increase in a non-target lesion, or appearance of new lesions. For the definition of response: the responses are assessed as overall best response during the course of therapy. For partial response (PR), the sum of the longest diameters must decrease by at least 30%. For a complete response (CR), all evidence of disease must be gone and the CA125 levels must normalize. If a patient experiences a disease progression during treatment, this is classified as progressive disease (PD). If the patient neither progresses (PD) nor has a response (CR or PR), then the patient is classified as stable disease (SD).
Time frame: Up to 5 years
ORR (Partial or Complete Response) (Phase III)
Will be assessed by RECIST v1.1. Will be tabulated by treatment group, and 95% confidence intervals will be presented using Wilson's Score Method. Treatment arms will be compared using a likelihood ratio chi-square test. Progression is defined by a 20% increase in the sum of the longest diameter of target lesions and a 5 mm absolute increase from nadir, or an unequivocal increase in a non-target lesion, or the appearance of new lesions. For the definition of response: the responses are assessed as overall best response during the course of therapy. For partial response (PR), the sum of the longest diameters must decrease by at least 30%. For a complete response (CR), all evidence of disease must be gone and the CA125 levels must normalize. If a patient experiences a disease progression during treatment, this is classified as progressive disease (PD). If the patient neither progresses (PD) nor has a response (CR or PR), then the patient is classified as stable disease (SD).
Time frame: Up to 5 years
Number of Patients With a Grade 3 (or Higher) Adverse Event (Phase II)
CTCAE V5.0 was used to classify adverse events. This endpoint will tabulate the number of patients who reported at least one adverse event of a grade 3 (or higher).
Time frame: Up to 5 years
Number of Patients With a Grade 3 (or Higher) Adverse Event (Phase III)
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Anchorage Oncology Centre
Anchorage, Alaska, United States
Katmai Oncology Group
Anchorage, Alaska, United States
Providence Alaska Medical Center
Anchorage, Alaska, United States
Fairbanks Memorial Hospital
Fairbanks, Alaska, United States
CTCA at Western Regional Medical Center
Goodyear, Arizona, United States
...and 912 more locations
CTCAE V5.0 was used to classify adverse events. This endpoint will tabulate the number of patients who reported at least one adverse event of a grade 3 (or higher).
Time frame: Up to 5 years
Patient Reported Outcomes
Patient reported outcomes are measured with the NFOSI-18 Disease-related physical symptoms subscale (DRS-P). The DRS-P subscale comprises 9 items with each item ranging from 0 to 4. The total score of the DRS-P subscale ranges 0 - 36 with a larger score suggesting preferred/better health states.
Time frame: Up to 2 years