Platinum-based Chemotherapy With Atezolizumab and Niraparib in Patients With Recurrent Ovarian Cancer

NCT ID: NCT03598270

Last Updated: 2024-08-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 417 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-21
• Study Completion Date: 2024-08-05

Brief Summary

Atezolizumab in this study is expected to have a positive benefit-risk profile for the treatment of patients with platinum-sensitive relapse of ovarian cancer. Of interest, atezolizumab is being investigated also in combination with platinum-based doublet chemotherapy in second line (2L)/ third line (3L) platinum-sensitive recurrent ovarian cancer patients in ATALANTE (NCT02891824), which also includes bevacizumab in the combination. The study is proceeding as expected after >100 patients enrolled and under independent Data Monitoring Committee (IDMC) supervision.

Platinum-containing therapy is considered the treatment of choice for patients with platinum-sensitive relapse. However the duration of response and the prolongation of the progression free interval with chemotherapy are usually brief, among other because these chemotherapy regimens cannot be continued until progression as they are associated with neurological, renal and hematological toxicity and cannot generally be tolerated for more than about 6 to 9 cycles.

Niraparib received FDA approval in March 2017 as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. Recently, the European Medicines Agency (EMA) has also approved niraparib as maintenance monotherapy. Despite the progress brought about by niraparib, there is a need for a more effective treatment to extend the progression free interval in this patient population. The combination with immune checkpoint inhibitors such as anti-death protein 1 (anti-PD1) or anti-death protein ligand 1 (anti-PD-L1) has a compelling rationale to this aim, especially under the light of the emerging clinical data of this combination.

The use of atezolizumab concurrent to platinum-containing chemotherapy followed by niraparib as maintenance therapy after completion of chemotherapy, as per normal clinical practice, may provide further benefit to patients in terms of prolonging the progression free interval and increasing the interval between lines of chemotherapy, hence delaying further hospitalization and the cumulative toxicities associated with chemotherapy. Additionally, preliminary studies with atezolizumab suggest an acceptable tolerability profile for long term clinical use in recurrent ovarian cancer patients and other indications.

Conditions

Recurrent Ovarian Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Arm A (Control Arm)

Placebo of atezolizumab in combination with one of the platinum based regimens below (investigator's choice) followed by maintenance niraparib with placebo:

• Carboplatin (AUC = 5, d1) plus paclitaxel and placebo every 3 weeks. Non-progressing patients will be switched to maintenance niraparib in combination with placebo every 3 weeks
• Carboplatin (AUC = 4, d1) plus gemcitabine and placebo every 3 weeks. Non-progressing patients will be switched to maintenance niraparib in combination with placebo every 3 weeks.
• Carboplatin (AUC = 5, d1) plus pegylated liposomal doxorubicin (PLD) and placebo every 4 weeks. Non-progressing patients will be switched to maintenance niraparib in combination with placebo every 3 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Volume equivalent to 1200 mg of atezolizumab drug product. Intravenous Day 1

Carboplatin

Intervention Type: DRUG

Intravenous. Day 1

Paclitaxel

Intervention Type: DRUG

175 mg/m². Intravenous. Day 1

Niraparib

Intervention Type: DRUG

200 mg or 300 mg. Oral. From day 1 to 21

Gemcitabine

Intervention Type: DRUG

1000 mg/m². Intravenous. Day 1 and day 8.

Pegylated liposomal doxorubicin (PLD)

Intervention Type: DRUG

30 mg/m². Intravenous. Day 1

Arm B (experimental arm)

Atezolizumab in combination with one of the platinum based regimens below (investigator's choice) followed by maintenance niraparib with atezolizumab:

• Carboplatin (AUC = 5, d1) plus paclitaxel and atezolizumab every 3 weeks. Non-progressing patients will be switched to maintenance niraparib in combination with atezolizumab every 3 weeks.
• Carboplatin (AUC = 4, d1) plus gemcitabine and atezolizumab every 3 weeks. Non-progressing patients will be switched to maintenance niraparib in combination with atezolizumab every 3 weeks.
• Carboplatin (AUC = 5, d1) plus pegylated liposomal doxorubicin (PLD) and atezolizumab every 4 weeks. Non-progressing patients will be switched to maintenance niraparib in combination with atezolizumab every 3 weeks.

Group Type: EXPERIMENTAL

Carboplatin

Intervention Type: DRUG

Intravenous. Day 1

Paclitaxel

Intervention Type: DRUG

175 mg/m². Intravenous. Day 1

Niraparib

Intervention Type: DRUG

200 mg or 300 mg. Oral. From day 1 to 21

Gemcitabine

Intervention Type: DRUG

1000 mg/m². Intravenous. Day 1 and day 8.

Pegylated liposomal doxorubicin (PLD)

Intervention Type: DRUG

30 mg/m². Intravenous. Day 1

Atezolizumab

Intervention Type: DRUG

1200 mg. Intravenous. Day 1

Interventions

Placebo

Volume equivalent to 1200 mg of atezolizumab drug product. Intravenous Day 1

Intervention Type: DRUG

Carboplatin

Intravenous. Day 1

Intervention Type: DRUG

Paclitaxel

175 mg/m². Intravenous. Day 1

Intervention Type: DRUG

Niraparib

200 mg or 300 mg. Oral. From day 1 to 21

Intervention Type: DRUG

Gemcitabine

1000 mg/m². Intravenous. Day 1 and day 8.

Intervention Type: DRUG

Pegylated liposomal doxorubicin (PLD)

30 mg/m². Intravenous. Day 1

Intervention Type: DRUG

Atezolizumab

1200 mg. Intravenous. Day 1

Intervention Type: DRUG

Other Intervention Names

Placebo of Atezolizumab; Tecentriq

Eligibility Criteria

Inclusion Criteria

1. Patients ≥ 18 years old

2. Life expectancy ≥3 months

3. Signed informed consent and ability to comply with treatment and follow-up

4. Histologically confirmed diagnosis (cytology alone excluded) of high- grade serous or endometrioid ovarian, primary peritoneal or tubal carcinoma.

5. Breast Cancer (BRCA) mutational status is known (germline or somatic)

6. Relapsed disease more than 6 months after the last platinum dose

7. No more than 2 prior lines of chemotherapy are allowed, and the last one must contain a platinum-based regimen

8. At least one measurable lesion to assess response by RECIST v1.1 criteria.

9. Mandatory de novo tumor biopsy (collected within 3 months prior to randomization) sent to HistoGene X as a formalin-fixed, paraffin-embedded (FFPE) sample for PD-L1 status determination for randomization. The inclusion of patients with non informative tissue PD-L1 status will be capped to 10% of the whole study population:

• If the mandatory de novo biopsy is technically not possible or failed to produce enough representative tumor tissue, an FFPE sample from archival tissue may be acceptable after approval of the sponsor.
• Bone metastases, fine needle aspiration, brushing, cCell pellet from pleural effusion, or ascites or lavage are not acceptable.

10. Two additional tumour samples are needed: Archival tumor sample must be available for exploratory PD-L1 testing in archival tissue and archival or "de novo" tissue sample for biomarkers must also be available.

11. Performance status determined by Eastern Cooperative Oncology Group (ECOG) score of 0-1

12. Normal organ and bone marrow function:

• Haemoglobin ≥10.0 g/dL
• Absolute neutrophil count (ANC) ≥1.5 x 109/L
• Lymphocyte count ≥0.5 × 109/L
• Platelet count ≥100 x 109/L
• Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)
• Serum albumin ≥2.5 g/dL
• Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤2.5 x ULN, unless liver metastases are present in which case they must be ≤5 x ULN
• Serum creatinine ≤1.5 x institutional ULN or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation
• Patients not receiving anticoagulant medication must have an International Normalized Ratio (INR) ≤1.5 and an Activated ProThrombin Time (aPTT) ≤1.5 x ULN.

13. Negative Test Results for Hepatitis.

14. Toxicities related to previous treatments must be recovered to < grade 2

15. Female participants must be postmenopausal or surgically sterile or otherwise have a negative serum pregnancy test within 7 days of the first study treatment and agree to abstain from heterosexual intercourse or use single or combined contraceptive methods.

16. Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment.

17. Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.

Exclusion Criteria

1. Non-epithelial tumor of the ovary, the fallopian tube or the peritoneum.

2. Ovarian tumors of low malignant potential or low grade

3. Other malignancy within the last 5 years except curatively treated non-melanoma skin cancer, in situ cancer of the cervix and ductal carcinoma in situ (DCIS)

4. Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered (Grade ≥ 2) from the effects of any major surgery at randomization

5. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1, Cycle 1

6. Administration of other chemotherapy drugs, anticancer therapy or anti-neoplastic hormonal therapy, or treatment with other investigational agents or devices within 28 days prior to randomization, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, or anticipation to do it during the trial treatment period (non-investigational hormonal replacement therapy is permitted)

7. Palliative radiotherapy (e.g., for pain or bleeding) within 6 weeks prior to randomization or patients who have not completely recovered (Grade ≥ 2) from the effects of previous radiotherapy

8. Current or recent (within 10 days prior to randomization) chronic use of aspirin (>325 mg/day) or clopidogrel (>75 mg/day)

9. Clinically significant (e.g. active) cardiovascular disease

10. Resting ECG with corrected QT interval (QTc) >470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome

11. Left ventricular ejection fraction defined by multigated acquisition/echocardiogram (MUGA/ECHO) below the institutional lower limit of normal

12. 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

13. History or evidence upon neurological examination of central nervous system (CNS) disorders (e.g. uncontrolled epileptic seizures) unless adequately treated with standard medical therapy

14. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease

15. Uncontrolled tumor-related pain

16. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed

17. Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab

18. 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

19. Pregnant or lactating women

20. Simultaneously receiving therapy in any interventional clinical trial

21. Prior treatment with CD137 agonists or immune checkpoint stimulating or blockade therapies, such as anti-PD1, anti-PDL1 or anti-CTLA4 therapeutic antibodies

22. 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

23. 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

24. 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

25. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis

26. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV)

27. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1

28. Active tuberculosis

29. Administration of a live, attenuated vaccine (including against influenza) within 4 weeks prior to Cycle 1, Day 1 or anticipation that it will be administered at any time during the treatment period of the study or within 5 months after the final dose of atezolizumab.

30. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

31. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation or allergy to any of the other drugs included in the protocol or their solvents (including to Cremophor®)

32. Patient has received prior treatment with a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor in the recurrent setting or has participated in a study where any treatment arm included administration of a PARP inhibitor in the recurrent setting, unless the patient is unblinded and there is evidence of not having received a PARP inhibitor. Patients that received PARP inhibitor as front line are eligible for the study. The duration of exposure to PARPi following front line therapy needs to be ≥18 months for BRCA mutated patients and ≥ 12 months for BRCA wild type patients.

33. Patient has had any known ≥Grade 3 hematological toxicity anemia, neutropenia or thrombocytopenia due to prior cancer chemotherapy that persisted >4 weeks and was related to the most recent treatment

34. Patient has any known history or current diagnosis of Myelodysplasic syndrome (MDS) or Anaplastic Myeloid Leukemia (AML)

35. Previous allogeneic bone marrow transplant or previous solid organ transplantation

36. Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation for the full duration of the study treatment

37. Participant has any known hypersensitivity to niraparib components or excipients

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

AGO Study Group

OTHER

Sponsor Role: collaborator

Belgian Gynaecological Oncology Group

OTHER

Sponsor Role: collaborator

ARCAGY/ GINECO GROUP

OTHER

Sponsor Role: collaborator

Israeli Society of Gynecologic Oncology

OTHER

Sponsor Role: collaborator

MaNGO

UNKNOWN

Sponsor Role: collaborator

Apices Soluciones S.L.

INDUSTRY

Sponsor Role: collaborator

Grupo Español de Investigación en Cáncer de Ovario

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antonio González Martín, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Clinica Universitaria de Navarra

Locations

Grand Hôpital de Charleroi

Charleroi, , Belgium

UZ Leuven

Leuven, , Belgium

CHU de Liège, site Sart Tilman

Liège, , Belgium

CHU Ambroise Paré

Mons, , Belgium

CHU UCL Namur site St. Elisabeth

Namur, , Belgium

ICO - Paul Paupin - ANGERS

Angers, , France

CHU Besançon

Besançon, , France

Institut Bergonié

Bordeaux, , France

Centre François Baclesse

Caen, , France

Centre Jean Perrin

Clermont-Ferrand, , France

Centre Léon Bérard

Lyon, , France

Institut Paoli Calmettes

Marseille, , France

ICM Val d'Aurelle

Montpellier, , France

Centre Antoine Lacassagne

Nice, , France

ONCOGARD - Institut de Cancérologie du Gard

Nîmes, , France

Hôpital Cochin

Paris, , France

Hôpital Européen Georges Pompidou

Paris, , France

Groupe Hospitalier Diaconesses-Croix Saint Simon

Paris, , France

Hôpital Tenon

Paris, , France

HPCA Cario

Plérin, , France

Institut Curie - Hopital Claudius Régaud

Saint-Cloud, , France

Institut Curie - Hôpital René Huguenin- SAINT CLOUD

Saint-Cloud, , France

ICO Centre René Gauducheau

Saint-Herblain, , France

Institut de Cancérologie de Lorraine

Vandœuvre-lès-Nancy, , France

Gustave Roussy

Villejuif, , France

Hochtaunus-Kliniken

Bad Homburg, , Germany

Universitätsklinikum Carl Gustav Carus Dresden

Dresden, , Germany

Kliniken Essen-Mitte

Essen, , Germany

Mammazentrum Hamburg am Krankenhaus Jerusalem

Hamburg, , Germany

Diakovere Krankenhaus

Hanover, , Germany

Klinikum Kulmbach

Kulmbach, , Germany

Universitätsklinikum Mannheim

Mannheim, , Germany

Universitätsklinikum Münster

Münster, , Germany

MVZ Nordhausen

Nordhausen, , Germany

Klinikum Oldenburg AöR

Oldenburg, , Germany

ROMed Klinikum Rosenheim

Rosenheim, , Germany

Universitätsklinikum Tübingen

Tübingen, , Germany

Universitätsfrauenklinik Ulm

Ulm, , Germany

HELIOS Dr. Horst Schmidt Kliniken Wiesbaden

Wiesbaden, , Germany

Spedali Civili

Brescia, , Italy

Asst Lecco

Lecco, , Italy

Istituto Europeo di Oncologia

Milan, , Italy

I.R.C.C.S. Istituto Oncologico Veneto

Padua, , Italy

Arcispedale Santa Maria Nuova

Reggio Emilia, , Italy

AO Città della Salute e della Scienza- Ospedale Sant'Anna

Torino, , Italy

Ospedale Mauriziano Umberto I

Torino, , Italy

Hospital de Sabadell

Sabadell, Barcelona, Spain

Clinica Universidad de Navarra

Pamplona, Navarre, Spain

Complejo Hospitalario Universitario de A Coruña

A Coruña, , Spain

ICO Badalona

Badalona, , Spain

H. Clínic Barcelona

Barcelona, , Spain

Hospital de la Santa Creu i Sant Pau

Barcelona, , Spain

Hospital de la Vall d'Hebron

Barcelona, , Spain

H Reina Sofía Cordoba

Córdoba, , Spain

ICO Girona

Girona, , Spain

ICO Hospitalet

Hospitalet Del Llobregat, , Spain

Hospital de León

León, , Spain

Clinica Universitaria de Navarra

Madrid, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

Hospital Gregorio Marañon

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario Fundación Jiménez Díaz

Madrid, , Spain

Hospital Universitario La Paz

Madrid, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

Complejo Hospitalario Regional de Málaga

Málaga, , Spain

H Morales Meseguer

Murcia, , Spain

Hospital Son Llatzer

Palma de Mallorca, , Spain

Hospital Virgen del Rocio

Seville, , Spain

H La Fe de Valencia

Valencia, , Spain

Hospital Clínico Universitario de Valencia

Valencia, , Spain

Hospital Universitario Miguel Servet

Zaragoza, , Spain

Countries

Belgium; France; Germany; Italy; Spain

References

Gonzalez-Martin A, Rubio MJ, Heitz F, Depont Christensen R, Colombo N, Van Gorp T, Romeo M, Ray-Coquard I, Gaba L, Leary A, De Sande LM, Lebreton C, Redondo A, Fabbro M, Barretina Ginesta MP, Follana P, Perez-Fidalgo JA, Rodrigues M, Santaballa A, Sabatier R, Bermejo-Perez MJ, Lotz JP, Pardo B, Marquina G, Sanchez-Lorenzo L, Quindos M, Estevez-Garcia P, Guerra Alia E, Manso L, Casado V, Kommoss S, Tognon G, Henry S, Bruchim I, Oaknin A, Selle F. Atezolizumab Combined With Platinum and Maintenance Niraparib for Recurrent Ovarian Cancer With a Platinum-Free Interval >6 Months: ENGOT-OV41/GEICO 69-O/ANITA Phase III Trial. J Clin Oncol. 2024 Dec 20;42(36):4294-4304. doi: 10.1200/JCO.24.00668. Epub 2024 Sep 18.

Reference Type: DERIVED

PMID: 39292975 (View on PubMed)

Gonzalez Martin A, Sanchez Lorenzo L, Colombo N, dePont Christensen R, Heitz F, Meirovitz M, Selle F, van Gorp T, Alvarez N, Sanchez J, Marques C. A phase III, randomized, double blinded trial of platinum based chemotherapy with or without atezolizumab followed by niraparib maintenance with or without atezolizumab in patients with recurrent ovarian, tubal, or peritoneal cancer and platinum treatment free interval of more than 6 months: ENGOT-Ov41/GEICO 69-O/ANITA Trial. Int J Gynecol Cancer. 2021 Apr;31(4):617-622. doi: 10.1136/ijgc-2020-001633. Epub 2020 Dec 14.

Reference Type: DERIVED

PMID: 33318079 (View on PubMed)

Other Identifiers

2018-000366-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ENGOT-Ov41

Identifier Type: OTHER

Identifier Source: secondary_id

GEICO 69-O

Identifier Type: OTHER

Identifier Source: secondary_id

ENGOT-Ov41/GEICO 69-O/ANITA

Identifier Type: -

Identifier Source: org_study_id