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

Recurrent Ovarian Carcinoma Clinical Trial

— ANITA  

Official title:

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 (TFIp) >6 Months

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03598270
• Other study ID #: ENGOT-Ov41/GEICO 69-O/ANITA
• Secondary ID: 2018-000366-11EN
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 21, 2018
• Est. completion date: January 2024

Study information

• Verified date: December 2023
• Source: Grupo Español de Investigación en Cáncer de Ovario
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 414
• Est. completion date: January 2024
• Est. primary completion date: January 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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-a) 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

Related Conditions & MeSH terms

• Recurrence
• Recurrent Ovarian Carcinoma

Intervention

Drug:
• Placebo
Volume equivalent to 1200 mg of atezolizumab drug product. Intravenous Day 1
• Carboplatin
Intravenous. Day 1
• Paclitaxel
175 mg/m². Intravenous. Day 1
• Niraparib
200 mg or 300 mg. Oral. From day 1 to 21
• Gemcitabine
1000 mg/m². Intravenous. Day 1 and day 8.
• Pegylated liposomal doxorubicin (PLD)
30 mg/m². Intravenous. Day 1
• Atezolizumab
1200 mg. Intravenous. Day 1

Locations

Country	Name	City	State
Belgium	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
France	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	Groupe Hospitalier Diaconesses-Croix Saint Simon	Paris
France	Hôpital Cochin	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital Tenon	Paris
France	HPCA Cario	Plérin Cedex
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
Germany	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	Hannover
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
Italy	Spedali Civili	Brescia
Italy	Asst Lecco	Lecco
Italy	Istituto Europeo di Oncologia	Milano
Italy	I.R.C.C.S. Istituto Oncologico Veneto	Padova
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
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	Cordoba
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	Clinica Universidad de Navarra	Pamplona	Navarra
Spain	Hospital de Sabadell	Sabadell	Barcelona
Spain	Hospital Virgen del Rocio	Sevilla
Spain	H La Fe de Valencia	Valencia
Spain	Hospital Clínico Universitario de Valencia	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza

Sponsors (9)

Lead Sponsor	Collaborator
Grupo Español de Investigación en Cáncer de Ovario	AGO Study Group, Apices Soluciones S.L., ARCAGY/ GINECO GROUP, Belgian Gynaecological Oncology Group, GlaxoSmithKline, Hoffmann-La Roche, Israeli Society of Gynecologic Oncology, MaNGO

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Evaluate PROs of disease associated with atezolizumab versus placebo	Mean and mean changes from the baseline score in disease by cycle and between treatment arms as assessed by scale of european organization for research and treatment of cancer quality of life questionnaire core-30 (EORTC QLQ-C30)	60 months
Other	Evaluate PROs of disease associated with atezolizumab versus placebo	Mean and mean changes from the baseline score in disease by cycle and between treatment arms as assessed by scale quality of life questionnaire ovarian 28 (QLQ-OV28)	60 months
Other	Evaluate treatment-related symptoms associated with atezolizumab versus placebo	Mean and mean changes from the baseline score in treatment-related symptoms by cycle and between treatment arms as assessed by all symptom item scale of EORTC QLQ-C30.	60 months
Other	Evaluate treatment-related symptoms associated with atezolizumab versus placebo	Mean and mean changes from the baseline score in treatment-related symptoms by cycle and between treatment arms as assessed by all symptom item scale of EORTC QLQ-OV28	60 months
Other	Treatment burden	Any treatment burden patients may experience in association with atezolizumab versus placebo, as measured by a single item (from GP5: "I am bothered by side effects of treatment") from the physical wellbeing subscale of the Functional Assessment of Cancer Therapy - General (FACT-G) Quality of Life instrument	60 months
Other	Patients' health utility	Evaluate and compare between treatment arms patients' health utility as measured by European Quality of Life Visual Analogue Scale (EQ-VAS) to generate utility scores for use in economic models for reimbursement	60 months
Other	Patients' health utility	Evaluate and compare between treatment arms patients' health utility as measured by EuroQoL 5 Dimension to generate utility scores for use in economic models for reimbursement	60 months
Other	Patients' health utility	Evaluate and compare between treatment arms patients' health utility as measured by 5 Level Questionnaire (EQ-5D-5L) to generate utility scores for use in economic models for reimbursement	60 months
Other	Association of PD-L1 expression and other immune biomarkers with clinical outcomes	Relationship between tumour immune-related or disease type-related biomarkers (including but not limited to mutational burden, PD-L1, tumor-infiltrating lymphocytes (TILs) and cluster of differentiation (CD)8) in tumour tissues or blood samples, and clinical outcomes	60 months
Other	Biomarkers predictive of the response to atezolizumab.	Relationship between exploratory biomarkers (circulating cell-free DNA) assessed from plasma before and during/after treatment, and clinical outcomes	60 months
Other	Biomarkers predictive of the response to atezolizumab.	Relationship between exploratory biomarkers (proteins) assessed from plasma before and during/after treatment, and clinical outcomes	60 months
Other	Biomarkers predictive of the response to atezolizumab.	Relationship between exploratory biomarkers (cytokines) assessed from plasma before and during/after treatment, and clinical outcomes	60 months
Other	Effect of antibiotic (ATB) use on the efficacy of atezolizumab.	Relationship between ATB use within 2 month before and 1 month after the first study administration with atezolizumab efficacy as measured by PFS.	60 months
Other	To evaluate the efficacy of atezolizumab vs placebo according to previous use of PARP inhibitors in front line.	Relationship between previous use of PARP inhibitors in front line and clinical outcomes.	60 months
Primary	Progression-free survival (PFS)	Period from study entry (day of randomization) until disease progression, death or date of last contact. Progression will be based on tumor assessment made by the investigators according to the RECIST v1.1 criteria.	30 months
Secondary	Overall survival (OS)	The observed length of life from entry into the study (day of randomization) to death due to any cause, or the date of last contact if patient alive.	60 months
Secondary	Time to first subsequent therapy or death (TFST)	Time from the date of randomization in the current study to the start date of the first subsequent anticancer therapy.	60 months
Secondary	Time to second subsequent therapy or death (TSST)	Time from the date of randomization in the current study to the start date of the second subsequent anticancer therapy	60 months
Secondary	Time to second progression or death (PFS2)	Time from treatment randomization to the earliest date of assessment of progression on the next anticancer therapy following study treatment or death by any cause.	60 months
Secondary	Incidence of Treatment Adverse Events	Frequency and severity of adverse events as assessed by CTCAE version 5.0 for the regimens administered on this study	60 months
Secondary	Patient-reported abdominal symptoms	Clinically-meaningful improvement in patient-reported abdominal pain or bloating, defined as a 10-point decrease from the baseline score on either of the two items of the EORTC quality of life questionnaire-ovarian cancer module (QLQ-OV28) abdominal/GI symptom scale (items 31 and 32)	60 months
Secondary	Patient-reported outcomes (PROs) of function and health related quality of life (HRQoL)	Clinical improvement, remaining stable, or deterioration in patient-reported function and HRQoL, defined as a 10-point increase, changes within 10 points, and a 10-point decrease, respectively, from the baseline score on each of the functional (physical, role, emotional, and social) and global health status/HRQoL scales of EORTC QLQ-C30	60 months
Secondary	Objective Response Rate (ORR)	Based on investigator assessment by RECIST v1.1 during the chemotherapy phase and during the maintenance phase	60 months
Secondary	Duration of response (DOR)	Based on investigator assessment by RECIST v1.1 during the chemotherapy phase and during the maintenance phase	60 months
Secondary	Progression-free survival (PFS) from the beginning of the maintenance phase in all patients, in patients in complete or partial response after completing chemotherapy and in patients with stable disease after completing chemotherapy	Period from start of maintenance treatment until disease progression, death or date of last contact assessed by the investigator according to RECIST v1.1 criteria, in all patients receiving maintenance treatment as well as in the subgroup of patients with complete response/partial response (CR/PR) of stable disease (SD) after completing chemotherapy	60 months
Secondary	Progression Free Survival (PFS) and BRCA status.	Relationship of PFS with BRCA mutational status	60 months
Secondary	Overall Survival (OS) and BRCA status.	Relationship of OS with BRCA mutational status	60 months
Secondary	Time to first subsequent therapy or death (TFST) and BRCA status.	Relationship of TFST with BRCA mutational status	60 months
Secondary	Objective Response Rate (ORR) and BRCA status.	Relationship of ORR with BRCA mutational status	60 months
Secondary	Duration of Response (DOR) and BRCA status.	Relationship of DOR with BRCA mutational status	60 months
Secondary	Progression Free Survival (PFS) and PD-L1 status	Relationship of PFS with PD-L1 expression status	60 months
Secondary	Overall Survival (OS) and PD-L1 status	Relationship of OS with PD-L1 expression status	60 months
Secondary	Time to first subsequent therapy or death (TFST) and PD-L1 status	Relationship of TFST with PD-L1 expression status	60 months
Secondary	Objective Response Rate (ORR) and PD-L1 status	Relationship of ORR with PD-L1 expression status	60 months
Secondary	Duration of Response (DOR) and PD-L1 status	Relationship of DOR with PD-L1 expression status	60 months
Secondary	Efficacy of atezolizumab compared to placebo in the PD-L1 negative and PD-L1 positive subgroups	To evaluate the immune response to atezolizumab	60 months