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.
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
