Atezolizumab in Combination with Carboplatin and Paclitaxel before Surgery in Treating Participants with Newly-Diagnosed Stage III-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
- STUDY ENTRY: Signed Informed Consent Form (ICF).
- STUDY ENTRY: Ability and willingness to comply with the requirements of the study protocol.
- STUDY ENTRY: No prior treatment for primary advanced (stage III or IV) epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
- STUDY ENTRY: 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.
- STUDY ENTRY: All patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray. Lymph nodes must be >= 15 mm in short axis when measured by CT or MRI.
- STUDY TREATMENT: Histology consistent with high-grade epithelial ovarian cancer (excluding mucinous carcinoma and clear cell carcinoma).
- STUDY TREATMENT: 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 may be adequate at the discretion of the investigator. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement of the investigator.
- STUDY TREATMENT: Absolute neutrophil count (ANC) >= 1500 cells/uL within 14 days prior to the first study treatment.
- STUDY TREATMENT: Lymphocyte count >= 300/uL within 14 days prior to the first study treatment.
- STUDY TREATMENT: Platelet count >= 100,000/uL within 14 days prior to the first study treatment.
- STUDY TREATMENT: Hemoglobin >= 9.0 g/dL within 14 days prior to the first study treatment.
- STUDY TREATMENT: Total bilirubin =< 1.5 × upper limit of normal (ULN) within 14 days prior to the first study treatment with the following exception: * Patients with known Gilbert's disease who have serum bilirubin level =< 3 × ULN may be enrolled.
- STUDY TREATMENT: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 × ULN within 14 days prior to the first study treatment with the following exception: * Patients with liver involvement: AST and/or ALT =< 5 × ULN.
- STUDY TREATMENT: Alkaline phosphatase =< 2.5 × ULN within 14 days prior to the first study treatment with the following exceptions: * Patients with documented liver involvement or bone metastases: alkaline phosphatase =< 5 ×ULN, or * Patients with isolated =< 5 x ULN with elevation AST, ALT, or bilirubin.
- STUDY TREATMENT: Creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation within 14 days prior to the first study treatment.
- STUDY TREATMENT: International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 × ULN within 14 days prior to the first study treatment. * This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose.
- STUDY TREATMENT: Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
- STUDY TREATMENT: Peripheral neuropathy less than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 1.
- STUDY TREATMENT: 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.
- STUDY TREATMENT: Patients who opt to receive bevacizumab must meet standard institutional treatment guidelines.
- GENERAL: Prior systemic chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancer.
- GENERAL: 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.
- GENERAL: Adverse events (AEs) from prior anticancer therapy that have not resolved to grade =< 1 except for alopecia.
- GENERAL: Bisphosphonate therapy for symptomatic hypercalcemia. * Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed.
- GENERAL: Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
- GENERAL: Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases.
- GENERAL: Pregnancy, lactation, or breastfeeding.
- GENERAL: Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.
- GENERAL: Inability to comply with study and follow-up procedures.
- GENERAL: 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, Sjogren’s syndrome, Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. * Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. * Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible. * Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: ** Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations. ** Rash must cover less than 10% of body surface area (BSA). ** Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%). ** No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids).
- GENERAL: 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. * History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- GENERAL: 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.
- GENERAL: History of human immunodeficiency virus (HIV) infection or active hepatitis B (chronic or acute) or hepatitis C infection. * Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA).
- GENERAL: Active tuberculosis.
- GENERAL: 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.
- GENERAL: Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1.
- GENERAL: Received oral or intravenous (IV) antibiotics within 2 weeks prior to cycle 1, day 1. * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
- GENERAL: 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. * Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to cycle 1, day 1 or at any time during the study.
- MEDICATION-RELATED: 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.
- MEDICATION-RELATED: 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.
- MEDICATION-RELATED: 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).
- MEDICATION-RELATED: 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. * Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
- MEDICATION-RELATED: History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- MEDICATION-RELATED: Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation.
I. To validate a safe dose of the combination of atezolizumab with weekly dose-dense paclitaxel and carboplatin when delivered over multiple cycles of neoadjuvant chemotherapy (NACT) with planned interval cytoreductive surgery (ICS) (henceforth referred to as NACT-ICS), followed by concurrent paclitaxel, carboplatin, and atezolizumab +/- bevacizumab, followed by maintenance atezolizumab +/- bevacizumab in women with advanced ovarian cancer, as measured by frequency and severity of adverse events by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.0.
I. To estimate objective response rate (ORR), pathologic complete response rate (pCR) at interval cytoreduction, progression-free survival (PFS), and overall survival (OS) in the study population.
I. To correlate clinical outcomes (in particular median PFS) with PD-L1 expression. (Primary translational)
II. To correlate clinical outcomes (in particular median PFS) with tumor-infiltrating lymphocyte subpopulations, immune checkpoint receptor profiles, gene expression profiles associated with immunoactivation, cytokine expression profiles, BRCA mutation status, and tumor mutation profile. (Secondary translational)
NACT-ICS: Patients receive atezolizumab intravenously (IV) over 30-90 minutes on day 1, carboplatin IV over 15-30 minutes on day 1, and paclitaxel IV over 60 minutes on days 1, 8, and 15. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo planned ICS within 6 weeks after completion of cycle 3. Within 6 weeks after ICS, patients receive atezolizumab IV on day 1, carboplatin IV on day 1, and paclitaxel IV on days 1, 8, and 15. Beginning cycle 5, patients may optionally receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: After completion of NACT-ICS, patients may receive atezolizumab IV over 30-90 minutes on day 1. Patients who previously began bevacizumab, will also receive bevacizumab IV over 30-90 minutes on day 1. Treatment repeat every 21 days for 16 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and then every 6 months for up to 3 years.
Trial Phase Phase I
Trial Type Treatment
Duke University Medical Center
Angeles Alvarez Secord
- Primary ID Pro00079313
- Secondary IDs NCI-2018-01063
- Clinicaltrials.gov ID NCT03394885