A phase II study of the anti-PDL1 antibody atezolizumab, bevacizumab and acetylsalicylic acid to investigate safety and efficacy of this combination in recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal adenocarcinoma
PFS-6months rate is 30% for patients from the target population treated with bevacizumab alone and consider a treatment option worthwhile, if an increase to 50% is observed. We will also consider all arms where the PFS-6month is <5% different (=indifference region) from the arm with the best observed activity, as sufficiently ‘similar’ and worthwhile for further evaluation.
The primary objective of the study is to evaluate the efficacy and safety of 5 different treatments involving atezolizumab, bevacizumab and/or acetylsalicylic acid/placebo in advanced recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer patients in order to select the optimal treatments for further development in phase III.
The secondary objectives of the study are to:
- assess the biological activity and immunological effects of each treatment in the tumor microenvironment and in the peripheral blood
- assess the effect of treatment on disease control and overall survival
Recurrent, histologically proven, platinum-resistant, epithelial ovarian cancer, fallopian tube and primary peritoneal cancer in advanced or metastatic stage. Histological diagnosis by image guided biopsy, laparoscopy or laparotomy. Tumors diagnosed on cytology only and borderline tumors (i.e. low malignant potential) are excluded.
- Platinum-resistant cancer is defined as disease that responded to platinum-based chemotherapy but with documented recurrence within six months of completing this therapy
- At least one lesion accessible to biopsy without putting patient at risk
- Prior systemic (chemotherapy, hormonal therapy, biologic agents, and/or vaccines) or radiation treatment is allowed under following conditions:
- No prior treatment with Hyperthermic intraperitoneal chemotherapy (HIPEC)
- Systemic anti-tumoral treatment: wash-out period of 21 days prior to the first study treatment
- Any number of platinum-based chemotherapy lines are allowed but a maximum of 2 previous non-platinum containing lines
- Prior treatment with bevacizumab or other targeted agents against VEGF or VEGF receptor is allowed, but at least 18 weeks must have elapsed since their last administration
- Patients with ≤ 2 previous treatment lines must have been previously exposed to bevacizumab or other targeted agents against VEGF or VEGF receptor
- No current, recent (within 4 weeks of randomization), or planned participation in an experimental drug study
- Recovery from any toxic effects of prior therapy to ≤ Grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.0) except fatigue or alopecia.
- Radiation therapy: recovery period of 14 days prior to the first study treatment; exception: single fraction radiotherapy with the indication of pain control and no prior radiation to the pelvis. Age ≥18 years
- WHO PS: 0-2 for patients having received no more than two previous lines of therapy. WHO PS: 0-1 for patients having received >2 previous lines of therapy
- Life expectancy of ≥ 12 weeks
- Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to randomization:
- WBC counts 2.5 x 10^9/L and 15.0 x 10^9/L and ANC 1.5 x 10^9/L cells/L (without granulocyte colony-stimulating factor support within 2 weeks prior to randomization), Lymphocyte count 0.5 x 10^9/L , Platelet count 100 x 10^9/L (without requiring transfusion within 1 week prior to randomization), Hemoglobin 9.0 g/dL (Patients may be transfused to meet the hemoglobin criterion)
- AST, ALT, and alkaline phosphatase 2.5 x ULN, with the following exceptions:
Patients with documented liver metastases: AST and ALT 5 x ULN
- Patients with documented liver or bone metastases: alkaline phosphatase 5 x ULN
- Serum total bilirubin 1.5 ULN
Patients with suspicion of Gilbert disease who have serum bilirubin level 3 x ULN may be enrolled.
- Adequate synthetic liver function with PT or INR and aPTT 1.5 x ULN and serum albumin 25 g/l
- Creatinine clearance 40 ml/min on the basis of the Chronic Kidney Disease Epidemiology Collaboration formula
- Estimated glomerular filtration rate 141 min(SCr/k,1) max(SCr/k,1) 1.209 0.993 Age 1.018 [1.159 if Black] where SCr is serum creatinine (mg/dL), k 0.7, is 0.329 for females, min is the minimum of SCr/k or 1, and max is the maximum of SCr/k or 1.
- Women of childbearing potential (WOCP: defined as a sexually mature woman who 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally post-menopausal (amenorrhoea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)) must:
Have a negative serum pregnancy test within 7 days prior to randomization.
- Agree to remain sexually abstinent, have a partner who is sterile (i.e., vasectomy), or use two medically effective methods of contraception during dosing and through 6 months after last study treatment. An effective method is the combination of the following (a+b): a. Hormonal method eg, birth control pills; b. Placement of an intrauterine device (IUD) or intrauterine system (fUS), barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/ gel/film/ cream/vaginal suppository. This requirement should be followed from screening through 6 months after last study treatment.
- During treatment: Patient should agree to urine pregnancy test to be performed before each treatment;
- Agree to discontinue treatment in case of pregnancy or positive pregnancy test.
- Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
Uncontrolled hypercalcemia [1.5 mmol/L (4.8 mg/dL) ionized calcium, or Total Ca 3 mmol/L (12 mg/dL) or corrected serum calcium ULN] or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
- Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible.
- Symptomatic brain or leptomeningeal disease; any brain metastases must be stable for at least 6 months
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
- Significant cardiovascular disease, such as:
- Inadequately controlled hypertension (defined as systolic blood pressure 150 mm Hg and/or diastolic blood pressure 100 mm Hg despite intensive medical management) or prior history of hypertensive crisis or hypertensive encephalopathy. Anti-hypertensive therapy is allowed.
- New York Heart Association Class II or greater congestive heart failure and history of myocardial infarction or unstable angina within 6 months prior to randomization.
- Significant vascular disease including stroke, transient ischemic attack, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis within 6 months prior to randomization.
Use of acetylsalicylic acid, NSAIDs or other COX-2 inhibitors that cannot be stopped at baseline and for the whole duration of the study. Occasional use (i.e. no more than 5 times/doses per (calendar) month) is allowed.
- Hypersensitivity to the active ingredient acetylsalicylic acid or any of the excipients, hypersensitivity to Chinese hamster ovary (CHO) cell products or other recombinant human or humanised antibodies or fusion proteins.
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) and current or recent (within 10 days prior to randomization) use of dipyridamole, ticlopidine, clopidogrel, cilostazol, prasugrel, or ticagrelor; or use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
- Prophylactic anticoagulation for the patency of venous access devices is allowed, provided the activity of the agent results in PT or an INR 1.5 ULN and aPTT is within normal limits within 1 week prior to randomization.
- Prophylactic or therapeutic use of low molecular-weight heparin (e.g., enoxaparin) is allowed.
Obvious signs of, or risks for gastrointestinal fistula formation or perforation, such as
- History of bowel obstruction, including sub- occlusive disease, related to the underlying disease and history of abdominal fistula, tracheoesophageal fistula, gastrointestinal perforation or intra-abdominal abscess.
- Clinical symptoms of recent bowel obstruction or paralytic ileus, but excluding postoperative (within 4 weeks after abdominal surgery), or evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan
- Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture. Surgery (including open but not core biopsy) within 4 weeks prior to randomization, or anticipation of the need for major surgery during study treatment
- Proteinuria as demonstrated by urine dipstick ≥ 2+ or > 1.0 g of protein in a 24-hour urine collection (All patients with 2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein and will become eligible if ≤ 1.0 g of protein detected) within 2 weeks of randomization.
- History of inflammatory bowel disease or any autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis
- Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study.
Patients with controlled Type I diabetes mellitus on a stable insulin regimen are eligible
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- History of radiation pneumonitis/fibrosis in the radiation field is permitted.
- Signs or symptoms of infection or therapeutic use of antibiotics (except prophylactic antibiotics) within 2 weeks prior to randomization and no severe infections within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- HIV (test to be performed within 14 days of randomization)
- Active or chronic hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening), or hepatitis C
- Patients with past/resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. HBV DNA must be obtained in patients with positive hepatitis B core antibody prior to randomization.
- Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
Active tuberculosis (all patients will have tuberculin skin test or IGRA done locally prior to inclusion to study)
- Conditions leading to immune suppression or stimulation of the immune system, such as:
- Prior treatment with CD137 agonists, antiPD-1, or antiPD-L1 therapeutic antibody or pathway-targeting agents
- Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided at least 5 half-lives (approximately 75 days) have elapsed since the last dose of anti-CTLA-4 and there was no history of severe immune-mediated adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 or 4)
- Treatment with systemic immunostimulatory agents (including but not limited to IFN-, IL-2) for any reason within 6 weeks or five half-lives of the drug, whichever is shorter, prior to randomization.
- Prior allogeneic stem cell or solid organ transplant.
Treatment with systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization.
- Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) or physiologic replacement doses (i.e., prednisone 57.5 mg/day) for adrenal insufficiency may be enrolled in the study.
- The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed
- Malignancies other than ovarian cancer within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death, treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, ductal carcinoma in situ treated surgically with curative intent, and non-muscle invasive urothelial cell carcinoma).
- Breast feeding during dosing and through 6 months after last study treatment.
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
This is a randomized phase II study, aimed at evaluating different atezolizmab/bevacizumab-based strategies using progression free survival rates at 6 months (PFS-6) to select the best combination(s) to recommend for a phase III study, where it will be compared to a standard of care.
Randomization occurs after verification of the eligibility criteria and informed consent. Patients are randomized centrally to one of the 5 treatment options and will be stratified for the following factors:
- Number of previous treatment lines
Randomized treatment Cross over treatment
Arm 1: Bevacizumab 15 mg/kg in 30 min. i.v. on Day 1 of every 21-day cycle
Atezolizumab 1200 mg (fixed dose) in 30 min i.v. (first administration of Atezolizumab in 60 min on Day 1 of every 21-day cycle + Bevacizumab 15 mg/kg in 30 min.* i.v. on Day 1 of every 21-day cycle
Arm 2: Atezolizumab 1200 mg (fixed dose) in 30 min i.v. (first administration of Atezolizumab in 60 min) on Day 1 of every 21-day cycle + placebo 320 mg (oral once daily) continuously
Arm 3: Atezolizumab 1200 mg (fixed dose) in 30 min i.v. (first administration of Atezolizumab in 60 min) on Day 1 of every 21-day cycle + ASA 320 mg (oral once daily) continuously
Arm 4: Atezolizumab 1200 mg (fixed dose) in 30 min i.v. (first administration of Atezolizumab in 60 min) on Day 1 of every 21-day cycle + Bevacizumab 15 mg/kg in 30 min. i.v. on Day 1 of every 21-day cycle + placebo 320 mg (oral once daily) continuously.
None (patients will not receive further study treatment, but be treated as considered most appropriate by the treating physician according to clinical practice. Patients will remain on study and be followed up as described).
Arm 5: Atezolizumab 1200 mg (fixed dose) in 30 min i.v. (first administration of Atezolizumab in 60 min) on Day 1 of every 21-day cycle + Bevacizumab 15 mg/kg in 30 min. i.v. on Day 1 of every 3-week cycle + ASA 320 mg (oral once daily) continuously.
Nelleke Ottevanger: email@example.com
Vermelding in trialregister, bv
Nederlands trialregister: www.trialregister.nl
Trialregister (Engels): https://www.clinicaltrials.gov
26 juni 2019