Clinical trial NCT02891824: ATALANTE: Atezolizumab vs Placebo Phase III Study in Late Relapse Ovarian Cancer Treated With Chemotherapy+Bevacizumab
Official title: A Randomized, Double-blinded, Phase III Study of Atezolizumab Versus Placebo in Patients With Late Relapse of Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer Treated by Platinum-based Chemotherapy and Bevacizumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ovarian Cancer
Keywords: PD-L1
Atezolizumab
Randomized, double blinded
first or second late relapse
progressive non-mucinous epithelial ovarian cancer, primary peritoneal adenocarcinoma and / or fallopian-tube adenocarcinoma
progression-free survival
Lead sponsor: ARCAGY/ GINECO GROUP
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2016-09-08
Enrollment: 614
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a phase III, randomized, double-blinded, comparative, multi-centre study to assess the efficacy of atezolizumab in combination with platinum-based chemotherapy plus bevacizumab administered concurrent to chemotherapy and in maintenance, in patients presenting epithelial ovarian cancer (including patients with primary peritoneal and / or fallopian tube adenocarcinoma) who have platinum-sensitive relapse (platinum-free interval \> 6 months).

Detailed description: Approximately 600 patients will be randomized using an Interactive Voice Response System /Interactive web system (IVR/IWR system) in a 1:2 ratio to the treatments as specified below:

A. Arm A: Placebo + bevacizumab \& platinum-based chemotherapy.

The placebo arm will include one of 3 following regimens up to investigator choice (chosen prior to randomization)

1. Carboplatin (day1)combined with gemcitabine (day1 \& day8) and bevacizumab (day1) + placebo ( day1) x 6 cycles q3weeks followed by maintenance with bevacizumab ( day1) + placebo (day1) q3weeks until disease progression or
2. Carboplatin (d1) combined with paclitaxel (day1) and bevacizumab (day1) + placebo (d1) x 6 cycles every 3weeks followed by maintenance with bevacizumab (day1) + placebo (day1) q3weeks until disease progression or
3. Carboplatin (day1) combined with pegylated liposomal doxorubicin (PLD) (day1) and bevacizumab (day1 \& 15) + placebo ( day1\& 15) x 6 cycles every 4weeks followed by maintenance with bevacizumab (day1) + placebo (day1) q3weeks until disease progression.

B. Arm B: Atezolizumab + bevacizumab \& platinum-based chemotherapy

The atezolizumab arm will include one of 3 following regimens up to investigator choice (chosen prior to randomization)

1. Carboplatin (day1) combined with gemcitabine (day1 \& d8) and bevacizumab (day1) + atezolizumab ( day1) x 6 cycles q3weeks followed by maintenance with bevacizumab (day1) + atezolizumab (day1) q3w until disease progression or
2. Carboplatin (day1) combined with paclitaxel (day1) and bevacizumab ( day1) + atezolizumab (1200mg, d1) x 6 cycles every 3wk (day1) q3weeks until disease progression or
3. Carboplatin (day1) combined with pegylated liposomal doxorubicin (PLD) (day1) and bevacizumab (day1 \& 15) + atezolizumab (day1\& 15) x 6 cycles every 4weeks followed by maintenance with bevacizumab (day1) + atezolizumab ( day1) q3weeks until disease progression.

Before randomization to the study:

* A tumor biopsy should have been obtained and sent to the central laboratory
* PD-L1 status should be determined

Eligibility criteria: Inclusion Criteria:

1. Female Patients must be ≥18 years of age.
2. Signed informed consent and ability to comply with treatment and follow-up.
3. Patients with histologically confirmed progressive non-mucinous epithelial ovarian cancer, primary peritoneal adenocarcinoma and / or fallopian-tube adenocarcinoma
4. Patients with PD-L1 status determined for stratification on mandatory de novo biopsy sent to central laboratory as a formalin-fixed, paraffin-embedded (FFPE) sample.

   * Cell pellet from pleural effusion, or ascites or lavage are not acceptable.
   * For core needle biopsy specimens, at least three cores should be obtained. Biopsies must be obtained in a manner that minimizes risks. If the location of the tumor renders tumor biopsy medically unsafe or not feasible, patient eligibility should be discussed with the sponsor.
5. Patients whose disease has relapsed more than 6 months from the last dose of platinum before randomization:

   1. criterion for relapse can be according to RECIST v1.1, CA-125 (GCIG) or clinical symptoms
   2. the interval between last dose of platinum and entry in the study should be free of new anti-cancer treatment, with the exception of a maintenance therapy which is allowed up to 21 days before study entry.
6. Patients with one or 2 prior lines of chemotherapy. The last line of chemotherapy should have included platinum.
7. Availability at the study site of representative FFPE tumor sample from surgery during front line therapy, at best before chemotherapy
8. Patients must have normal organ and bone marrow function :

   1. Haemoglobin ≥ 10.0 g/dL.
   2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
   3. Platelet count ≥ 100 x 109/L.
   4. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
   5. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN.
   6. Serum creatinine ≤ 1.5 x institutional ULN,
   7. Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) ≤1.5 and an Activated ProThrombin Time (aPTT) ≤1.5 x ULN. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or APTT is within therapeutic limits (according to site medical standard) and if the patient is on a stable dose of anticoagulants for at least two weeks at the time of randomization.
   8. Urine dipstick for proteinuria \< 2+. If urine dipstick is ≥2+, 24-hours urine must demonstrate ≤1 g of protein in 24 hours.
   9. Normal blood pressure or adequately treated and controlled hypertension (systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90 mmHg).
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

For France only: In France, a subject will be eligible for randomization in this study only if either affiliated to, or a beneficiary of, a social security category

Exclusion Criteria:

1. Non-epithelial tumor origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).
2. Ovarian tumors of low malignant potential (e.g. borderline tumors)
3. Patients with synchronous primary endometrial cancer unless both of the following criteria are met:

   1. stage \< II,
   2. Less than 60 years old at the time of diagnosis of endometrial cancer with stage IA or IB grade 1 or 2, or stage IA grade 3 endometrioid adenocarcinoma OR ≥ 60 years old at the time of diagnosis of endometrial cancer with stage IA grade 1or 2 endometrioid adenocarcinoma.
   3. Patients with serous or clear cell adenocarcinoma or carcinosarcoma of the endometrium are not eligible.
4. Other malignancy within the last 5 years except cervix or breast in situ carcinoma, breast cancer ≥ 3 years free of disease and treatment, type I stage I endometrial cancer).
5. Patients receiving radiotherapy within 6 weeks prior to study treatment.
6. Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered from the effects of any major surgery. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1, Cycle 1
7. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
8. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted).
9. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA 4.
10. Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-α) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1
11. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[TNF\] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial

    1. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
    2. Prophylactic anti-emetic corticosteroids will be avoided if possible in patients treated with pegylated liposomal doxorubicin-carboplatin or gemcitabine-carboplatin regimen. The use of corticosteroids is allowed as premedication for paclitaxel-based regimen and/or premedication in case of carboplatin hypersensitivity.
12. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Are eligible patients with:

    1. a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone
    2. controlled Type 1 diabetes mellitus on a stable insulin regimen
13. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis. Radiation pneumonitis in the radiation field (fibrosis) detected on screening chest CT scan is permitted
14. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV). Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening) or hepatitis C.

    Patients with past hepatitis B virus (HBV) infection or 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 Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
15. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
16. Administration of a live, attenuated vaccine within 4 weeks prior to 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 (example approximately October to March in the Northern Hemisphere). Patients must not receive live, attenuated influenza
17. Current or recent (within 10 days prior to randomization) chronic use of aspirin \> 325 mg/day.
18. Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.
19. Inadequately controlled HTN (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications)
20. Clinically significant (e.g. active) cardiovascular disease, including:

    1. Myocardial infarction or unstable angina within ≤ 6 months of randomization,
    2. New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF),
    3. Poorly controlled cardiac arrhythmia despite medication (patients with rate controlled atrial fibrillation are eligible),
    4. Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living \[ADL\] requiring repair or revision)
21. Resting ECG with QTc \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
22. Left ventricular ejection fraction defined by MUGA/ECHO below the institutional lower limit of normal (only applicable for patients intended to be treated with pegylated liposomal doxorubicin).
23. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.
24. History or evidence of hemorrhagic disorders within 6 months prior to randomization.
25. Evidence of bleeding diathesis or significant coagulopathy (in the absence of coagulation).
26. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of suspected spinal cord compression.
27. History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
28. Significant traumatic injury during 4 weeks prior to randomization.
29. Non-healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no evidence of facial dehiscence or infection are eligible but require 3 weekly wound examinations.
30. History of VEGF therapy related abdominal fistula or gastrointestinal perforation.
31. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
32. Patients with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
33. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications.
34. Women of childbearing potential (\<2 years after last menstruation and not surgically sterile) not willing to use highly-effective means of contraception (Appendix 1) during the study and for 6 months after the last dose of study medication
35. Pregnant or lactating women.
36. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
37. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation.
38. Known hypersensitivity reaction or allergy to drugs chemically related to bevacizumab, carboplatin, gemcitabine, paclitaxel, pegylated liposomal doxorubicin, or their excipients that contraindicates the subject's participation

Primary outcomes:
measure: Efficacy: Progression free survival, where the date of progression is based on investigator assessment using the RECIST version 1.1
timeFrame: An average of 19 months
Secondary outcomes:
measure: Efficacy: Overall survival (OS)
timeFrame: To be assessed around 73 months
measure: Efficacy: Time from date randomization to second subsequent therapy or date of death (TSST) whichever come first
timeFrame: To be assessed around 73 months
measure: patient reported outcome variables
timeFrame: to be assessed 19 months
measure: Adverse events
timeFrame: to be assessed 19 months
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Krankenhaus der Barmherzigen Brüder Graz
city: Graz
country: Austria
facility: Medical University of Graz
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: Uz Leuven
city: Prague
country: Czechia
facility: General University Hospital in Prague
city: Angers
country: France
facility: ICO Paul Papin
city: Avignon
country: France
facility: Sainte-Catherine Institut du Cancer Avignon-Provence
city: Besançon
country: France
facility: CHRU Jean Minjoz
city: Bordeaux
country: France
facility: Clinique Tivoli
city: Bordeaux
country: France
facility: Institut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Grenoble
country: France
facility: Groupe Hospitalier Mutualiste de Grenoble
city: Grenoble
country: France
facility: Hôpital Michallon - Centre Hospitalier Universitaire de Grenoble
city: La Roche sur Yon
country: France
facility: Centre Hospitalier Départemental Les Oudairies
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Mont de Marsan
country: France
facility: Hôpital de Mont-de-Marsan
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Mougins
country: France
facility: Centre Azuréen de Cancérologie
city: Nancy
country: France
facility: ORACLE - Centre d'Oncologie de Gentilly
city: Nantes
country: France
facility: Hôpital Privé du Confluent, S.A.S.
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nimes
country: France
facility: CHU Nîmes - Institut de Cancérologie du Gard
city: Orléans
country: France
facility: Centre Hospitalier Régional d'Orléans
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses-Croix Saint Simon
city: Paris
country: France
facility: Groupe Hospitalier Saint-Joseph
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Hôpital Tenon
city: Paris
country: France
facility: Institut Curie - Hopital Claudius Régaud
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Plérin
country: France
facility: Centre CARIO - HPCA
city: Poitiers
country: France
facility: Hôpital de la Milétrie - Centre Hospitalier Universitaire de Poitiers - Pôle Régional de Cancérologie
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Saint-Cloud
country: France
facility: Hôpital René Huguenin, Institut Curie
city: Saint-Herblain
country: France
facility: ICO Centre René Gauducheau
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Strasbourg
country: France
facility: Institut de Cancérologie Strasbourg Europe (ICANS)
city: Toulouse
country: France
facility: Clinique Pasteur
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Vandoeuvre Les Nancy
country: France
facility: ICL Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy
city: Berlin
country: Germany
facility: Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Dusseldorf
country: Germany
facility: Universitatsklinikum Dusseldorf
city: Essen
country: Germany
facility: Kliniken Essen Mitte, Evang. Huyssens-Stiftung
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe
city: München
country: Germany
facility: Klinikum der Universität München - LMU, Campus Großhadern
city: München
country: Germany
facility: Klinikum rechts der Isar, Technischen Universität München
city: Offenbach
country: Germany
facility: Sana Klinikum Offenbach
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg
city: Tübingen
country: Germany
facility: Universitatsklinikum Tübingen
city: ULM
country: Germany
facility: Universitätsklinikum Ulm
city: Worms
country: Germany
facility: Klinikum Worms
city: Jerusalem
country: Israel
facility: Sharre Zedek Medical Centre
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clínic Barcelona
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcántara
city: Girona
country: Spain
facility: Hospital Universitari de Girona ICO Girona (Dr. Josep Trueta)
city: Madrid
country: Spain
facility: Hospital Universitario Clínico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Murcia
country: Spain
facility: Hospital Central Universitario Virgen de la Arrixaca
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
city: San Sebastián
country: Spain
facility: Hospital Universitario Donostia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Vigo
country: Spain
facility: Hospital Alvaro Cunqueiro
Study officials:
affiliation: GINECO - Institut de cancérologie Strasbourg Europe
name: Jean-Emmanuel KURTZ
role: PRINCIPAL_INVESTIGATOR
References: