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Atezolizumab With Bevacizumab and Chemotherapy vs Bevacizumab and Chemotherapy in Early Relapse Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT03353831
Recruitment Status : Recruiting
First Posted : November 27, 2017
Last Update Posted : May 20, 2019
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
AGO Research GmbH

Brief Summary:
This is a phase III, randomized, partially blinded, multicenter trial to evaluate the efficacy and safety of atezolizumab plus bevacizumab and chemotherapy compared to placebo plus bevacizumab and chemotherapy in patients with recurrent ovarian-, fallopian tube, or primary peritoneal cancer with 1st or 2nd relapse within 6 months after platinum based chemotherapy or 3rd relapse.

Condition or disease Intervention/treatment Phase
Recurrent Ovarian Carcinoma Drug: Bevacizumab Drug: Atezolizumab Drug: Chemotherapy Drug: Placebos Phase 3

Detailed Description:

Approximately 664 patients will be randomized in a 1:1 ratio to the treatments as specified below:

Arm A: Chemotherapy + Bevacizumab + Placebo Arm B: Chemotherapy + Bevacizumab + Atezolizumab

Study treatment will continue until disease progression per RECIST v1.1, unacceptable toxicity, or patient or investigator decision to discontinue treatment. Atezolizumab/placebo, chemotherapy and bevacizumab may be discontinued for toxicity independently of each other in the absence of disease progression.

For each patient, chemotherapy (PLD or Paclitaxel weekly) will be selected by the investigator prior to randomization.

Recruitment to an individual chemotherapy cohort will be closed once 50% of patients are recruited to this cohort. In such case the remaining cohort will remain open for recruitment.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 664 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Atezolizumab in Combination With Bevacizumab and Chemotherapy Versus Bevacizumab and Chemotherapy in Recurrent Ovarian Cancer - a Randomized Phase III Trial
Actual Study Start Date : September 11, 2018
Estimated Primary Completion Date : July 1, 2021
Estimated Study Completion Date : July 1, 2022


Arm Intervention/treatment
Placebo Comparator: Arm A: Chemotherapy + Bevacizumab + Placebo
Chemotherapy: Paclitaxel 80 mg/m² d1, 8, 14, 22 q28 or pegylated liposomal doxorubicin 40 mg/m² q28 + Bevacizumab 10 mg/kg q14 + Placebos q14
Drug: Bevacizumab
Bevacizumab will be administered by intravenouse route at a dose of 10mg/kg q14 during the treatment period

Drug: Chemotherapy
Chemotherapy (Paclitaxel or PLD) will be administered by intravenous route at different doses during the treatment period q28

Drug: Placebos
Placebo will be administered by intravenous route q14 during the treatment period

Experimental: Arm B: Chemotherapy + Bevacizumab + Atezolizumab
Chemotherapy: Paclitaxel 80 mg/m² d1, 8, 14, 22 q28 or pegylated liposomal doxorubicin 40 mg/m² q28 + Bevacizumab 10 mg/kg q14 + Atezolizumab 840 mg q14
Drug: Bevacizumab
Bevacizumab will be administered by intravenouse route at a dose of 10mg/kg q14 during the treatment period

Drug: Atezolizumab
Atezolizumab will be administered by intravenous route at a dose of 840 mg q14 during the treatment period

Drug: Chemotherapy
Chemotherapy (Paclitaxel or PLD) will be administered by intravenous route at different doses during the treatment period q28




Primary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: time from randomization to death from any cause,assessed up to 40 months ]
    regular patient contacts during the trial regarding life status

  2. Progression-free survival [ Time Frame: time from randomization to progressive disease (PD) or death, whichever occurs earlier, assessed up to 40 months ]
    Progressive Disease is based on investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).


Secondary Outcome Measures :
  1. patient reported outcomes (QLQ and PRO-CTCAE) [ Time Frame: every 4 weeks during the first 3 months, then every 12 weeks until PD#1, assessed up to 40 months ]
    questionnaires to be completed by patients and collected frequently during the trial

  2. Objective Response Rate (ORR) [ Time Frame: time from randomization to progressive disease (PD) or death, whichever occurs earlier, assessed up to 40 months ]
    Both criteria are based on investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

  3. Duration of Response (DOR) [ Time Frame: time from randomization to progressive disease (PD) or death, whichever occurs earlier, assessed up to 40 months ]
    Both criteria are based on investigator assessment using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).


Other Outcome Measures:
  1. Time from randomization to first subsequent therapy (TFST) [ Time Frame: at every visit during the trial up to a maximum of 40 months ]
  2. Time from randomization to second subsequent therapy (TSST) [ Time Frame: at every visit during the trial up to a maximum of 40 months ]
  3. Analysis on LDH levels at baseline (normal vs. elevat-ed values) [ Time Frame: at Baseline ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with histologically diagnosed ovarian, fallopian tube, or primary peritoneal cancer
  2. Relapsed disease
  3. Patients with up to three prior therapies. In patients with 1 or 2 prior treatment lines, the treatment free interval after platinum has to be less than 6 months; in addition patients with three prior lines of chemotherapy who are not considered for platinum-containing chemotherapy lines are also eligible
  4. Measurable disease, evaluable disease in combination with GCIG CA-125 criteria, or histologically proven relapse/progression
  5. Patient agrees and is able to provide a recent tumor biopsy (not older than 3 months) or agrees and has a tumor lesion amenable for taking a new tumor biopsy.
  6. Availability of a representative archival FFPE tumor sample (preferable from primary diagnosis)
  7. Patient has not progressed on the chosen/planned chemotherapy (PLD or Paclitaxel) in any prior line
  8. Patients previously treated with bevacizumab are eligible, with the exclusion of those patients that has suspended bevacizumab for more than 2 subsequent cycles or permanently discontinued bevacizumab during their previous treatment due to toxicity.
  9. Females aged ≥ 18 years at signing at time of signing informed consent form
  10. Signed written informed consent and ability to comply with the study protocol, in the investigator's judgement
  11. Adequate hematological, renal and hepatic function within 28 days prior to first administration of study treatment:

    • Hemoglobin ≥ 9.0 g/dL
    • Absolute neutrophil count (ANC) ≥ 1.5 x 10xE^9/L
    • Platelet count ≥ 100 x 10xE^9/L
    • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
    • 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 case of liver metastases values must be ≤ 5 x ULN
    • Serum creatinine ≤ 1.5 x institutional ULN
    • Patient not receiving anticoagulant medication who has 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). If the patient is on oral anticoagulants, dose has to be stable for at least two weeks at the time of randomization
    • Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24-hours urine must demonstrate ≤ 1 g of protein in 24 hours.
  12. Patients must have adequately controlled blood pressure (BP), with a systolic BP of ≤ 140 mmHg and diastolic BP of ≤ 90 mmHg for eligibility. Patients must have a BP of ≤ 140/90 mmHg taken in the clinic setting by a medical professional within 2 weeks prior to starting study.
  13. Estimated life expectancy of at least 3 months
  14. ECOG performance status 0 - 1
  15. Negative urine or serum pregnancy test within 7 days of study treatment in women of childbearing potential (WOCBP), confirmed prior to treatment on day 1
  16. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 5 months after administration of the last dose of atezolizumab/placebo and 6 months after the last dose of bevacizumab, paclitaxel, or PLD, whichever is later.
  17. For countries where this will apply to: a patient will be eligible for randomization in this study only, if either affiliated to, or a beneficiary of a social security category.
  18. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, that include the completion of patient-reported outcomes questionnaires.

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. Malignancies other than ovarian cancer within 5 years prior to randomisation, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%) and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, ductal carcinoma in situ, or Stage I uterine cancer)
  4. More than three prior systemic anticancer regimens; maintenance therapies (e.g. with bevacizumab, olaparib or niraparib) are not calculated as separate line.
  5. Prior systemic anticancer therapy within 28 days before randomization (except bevacizumab: 20 days).
  6. Prior radiotherapy to the pelvis or the abdomen.
  7. 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 thera-py is permitted).
  8. Prior treatment with anti-CD137 or immune checkpoint blockade therapies, anti-PD1, or anti-PD-L1 therapeutic antibodies or anti-CTLA 4
  9. Prior randomization in AGO-OVAR 2.29.
  10. Treatment with systemic immunostimulatory agents (in-cluding 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 longer) prior to cycle 1, day 1.
  11. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophos-phamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor [TNF] agents) within 2 weeks prior to cycle 1, day 1, or anticipated requirement for systemic immunosuppressive medications during the trial.

    The use of inhaled corticosteroids for chronic obstruc-tive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.

  12. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have screening and subsequent tumor assessments performed using magnetic resonance imaging (MRI).
  13. 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 or within 5 months after the last dose of atezolizumab/placebo. Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccination
  14. Major surgery within 4 weeks of starting study treatment or patient who has not completely recovered from the effects of any major surgery. Core biopsy or other minor surgical procedure within 7 days prior to day 1, cycle 1 is permitted.
  15. Previous allogeneic bone marrow transplant or previous solid organ transplantation.
  16. Current treatment with anti-viral therapy for HBV.
  17. History of idiopathic pulmonary fibrosis (including pneumonitis), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evi-dence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) detected on screening chest CT scan is permitted
  18. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization
  19. History or evidence of thrombotic or hemorrhagic disorders within 6 months prior to randomization
  20. 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 sus-pected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in case of sus-pected spinal cord compression
  21. History of autoimmune disease, including but not limited to dermatomyositis, myasthenia gravis, myositis, auto-immune hepatitis, systemic lupus erythematosus, rheu-matoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guil-lain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Except patients with:

    • a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone
    • controlled type 1 diabetes mellitus on a stable insulin regimen

    Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

    • Rash must cover < 10% of body surface area
    • Disease is well controlled at baseline and requires only low-potency topical corticosteroids
    • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
  22. Any prior history of hypertensive crisis (CTCAE grade 4) or hypertensive encephalopathy.
  23. 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 re-solved 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.

  24. Persistent toxicities (≥ CTCAE grade 2) with the exception of alopecia, caused by previous cancer treatment. Neurotoxicity CTCAE grade 2 is permitted in case the patient is planned for PLD treatment.
  25. Severe infection requiring oral or IV antibiotics within 4 weeks prior to randomization, including but not limited to active tuberculosis or hospitalization for complications of infection, bacteremia, or severe pneumonia. Patients receiving prophylactic antibiotics (e.g., to prevent urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
  26. Current or recent (within 10 days prior randomization) chronic use of aspirin > 325 mg/day.
  27. Clinically significant (e.g. active) cardiovascular disease, including:

    • Myocardial infarction or unstable angina pectoris within ≤ 6 months of randomization
    • New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF)
    • Poorly controlled cardiac arrhythmia despite medica-tion (patients with rate controlled atrial fibrillation are eligible)
    • Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision)
    • Resting ECG with QTc >470 msec or family history of long QT syndrome
  28. For patients with PLD treatment: Left ventricular ejection fraction defined by ECHO below the institutional lower limit of normal
  29. Evidence of bleeding diathesis or significant coagulopathy (in the absence of anticoagulation).
  30. Non-healing wound, active ulcer or bone fracture.
  31. History of bowel obstruction (including subocclusive disease) related to underlying disease, a history of ab-dominal fistula, GI perforation, or intra-abdominal abscess, or evidence of deep infiltration of the bowel by pelvic examination or on computed tomography, or clinical symptoms of bowel obstruction.
  32. Patients with evidence of abdominal free air.
  33. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications
  34. Known hypersensitivity or allergy to drugs containing Chinese hamster (CHO) ovary cells or history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  35. Known hypersensitivity reaction or allergy to drugs chemically related to bevacizumab, paclitaxel, pegylated liposomal doxorubicin, or their excipients that contra-indicates the subject's participation.
  36. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. This includes also any psychiatric disorder that prohibits obtaining informed consent.
  37. Pregnancy, lactation, or intention to become pregnant during the study or within 5 months after the last dose of atezolizumab/placebo.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03353831


Contacts
Layout table for location contacts
Contact: Nadin Cron +49 201 95 98 12 ext 15 ncron@ago-ovar.de

  Show 60 Study Locations
Sponsors and Collaborators
AGO Research GmbH
Hoffmann-La Roche
Investigators
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Study Chair: Philipp Harter, MD, PhD Kliniken Essen-Mitte, Germany

Additional Information:
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Responsible Party: AGO Research GmbH
ClinicalTrials.gov Identifier: NCT03353831     History of Changes
Other Study ID Numbers: AGO-OVAR 2.29
First Posted: November 27, 2017    Key Record Dates
Last Update Posted: May 20, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AGO Research GmbH:
Recurrent Ovarian Cancer
Atezolizumab
Bevacizumab

Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Paclitaxel
Bevacizumab
Atezolizumab
Liposomal doxorubicin
Doxorubicin
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Angiogenesis Inhibitors
Angiogenesis Modulating Agents