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Niraparib Versus Niraparib-bevacizumab Combination in Women With Platinum-sensitive Epithelial Ovarian Cancer (AVANOVA)

This study is currently recruiting participants.
Verified March 2017 by Nordic Society for Gynaecologic Oncology
Sponsor:
ClinicalTrials.gov Identifier:
NCT02354131
First Posted: February 3, 2015
Last Update Posted: April 4, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborators:
ENGOT
GCIG
University of Utah
Massachusetts General Hospital
Myriad Genetics, Inc.
Information provided by (Responsible Party):
Nordic Society for Gynaecologic Oncology
  Purpose

Part 1 (Phase 1): safety and tolerability of bevacizumab-Niraparib combination Part 2 (Randomized Phase 2): to compare Progression-Free Survival (PFS)

PARP inhibitors are active as monotherapy to treat patients with recurrent ovarian cancer; the strongest activity being observed in the platinum sensitive, gBRCAmut subgroup as well as in gBRCAwt, HRD population but also in HRD negative disease.

In the same population there is level one evidence that bevacizumab is beneficial. And a phase two randomized study has indicated that combination of a PARP inhibitor with anti-angiogenic drug is superior to PARP inhibitor alone.

The question is:

Is niraparib combined with bevacizumab superior to niraparib? The comparison of tolerability and efficacy of niraparib-bevacizumab combination against niraparib.


Condition Intervention Phase
Ovarian Cancer Drug: Niraparib Drug: Bevacizumab Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Part 1: AVANOVA1 - A Phase I Study to Evaluate the Safety and Tolerability of Bevacizumab-niraparib Combination Therapy and Determine the Recommended Phase 2 Dose (RP2D) in Women With Platinum-sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer Part 2: AVANOVA2 - A Two-arm, Open-label, Phase II Randomized Study to Evaluate the Efficacy of Niraparib Versus Niraparib-bevacizumab Combination in Women With Platinum-sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer.

Resource links provided by NLM:


Further study details as provided by Nordic Society for Gynaecologic Oncology:

Primary Outcome Measures:
  • Progression free survival [ Time Frame: 30 months ]
    This is pick the winer trial. The best arm will be used for phase 3 trial against standard of care.


Secondary Outcome Measures:
  • Disease Control Rate [ Time Frame: 30 months ]

Estimated Enrollment: 108
Actual Study Start Date: February 2015
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Niraparib monotherapy
Niraparib mono therapy until progression
Drug: Niraparib
Niraparib versus Bevacizumab-Niraparib combo
Experimental: Niraparib-bevacizumab combination
Niraparib-bevacizumab combination therapy until progression
Drug: Niraparib
Niraparib versus Bevacizumab-Niraparib combo
Drug: Bevacizumab

Detailed Description:

Part 1: This is a single-centre, phase 1a, open-label, dose-escalation study to evaluate the safety and tolerability of bevacizumab-niraparib combination and determine the RP2D in patients with platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The standard 3+3 design will be used. Part 2: (n=94) This multicenter, prospective, open-label, randomized phase 2 study is evaluating the efficacy of niraparib against niraparib-bevacizumab combination in Women with platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Stratification: Patients are stratified according to:

  1. HRD status (positive/negative)
  2. Treatment-Free interval to prior therapy (6-12 months > 12 months) Randomization: 1:1 randomization

Study arms: Patients are randomized to one of the two treatment arms:

Arm 1: Niraparib monotherapy until progression. Arm 2: Niraparib-bevacizumab combination therapy until progression.

  Eligibility

Information from the National Library of Medicine

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

Inclusion Criteria:

A patient will be eligible for inclusion only if all of the following criteria are fulfilled:

  1. Recurrent platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer (platinum sensitivity defined as no recurrence within 6 months of last receipt of platinum/chemotherapy).
  2. High-grade serious or high-grade endometrioid histology.
  3. Patient consents to perform HRD test.

    • Patients with known BRCA status: BRCA positive patients must submit the tissue for HRD test, though these patients need not to wait for HRD test results and can be randomized in HRD positive stratum.
    • If tumor tissue is not sufficient to perform HRD test: these patients shall be randomized in HRD negative stratum as HRD unknown.
  4. Prior line of therapy: Patients must have received platinum-containing therapy for primary disease.

    • No limits on number of platinum-based therapies. Population of patients who has previously received ≥ 3 lines of therapy for relapsed disease will be capped at 40%.
    • Up to one non-platinum-based line of therapy in recurrent setting.
    • Patients who are treated with bevacizumab just prior to entering in the trial must not have progressed under or within 3 months after bevacizumab.
    • Patients may have participated in a PARP inhibitor trial as first-line maintenance therapy and have not progressed within 3 months after PARP/placebo. Patients who received PARP inhibitor after relapse (definitive or maintenance therapy) are not eligible.
  5. Target group: Age 18+
  6. Histological confirmed ovarian, fallopian tube or peritoneal cancers
  7. Patients must give informed consent
  8. Patients may have undergone primary or interval debulking surgery
  9. Patients may have received bevacizumab though no other prior use of anti-angiogenic therapy
  10. Patients may have received a PARP inhibitor as first-line maintenance therapy.
  11. Patients must have disease that is measurable according to RECIST or assessable according to the GCIG criteria
  12. The patient agrees to complete PROs (QoL questionnaire) during study treatment AND at one additional time point 8 weeks following progression of disease
  13. ECOG performance status 0-2
  14. Adequate organ function

    • Absolute neutrophil count (ANC) ≥1,5 x 109/L
    • Platelets >100 x 109/L
    • Hemoglobin ≥ 9g/dl
    • Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥50mL/min using Cockcroft-Gault formula
    • Total bilirubin ≤1.5x ULN
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5x ULN unless liver metastases are present, in which case they must be ≤5x ULN.
  15. Able to take oral medications
  16. Life expectancy of at least 12 weeks
  17. Patients must fulfill all inclusions criteria and according to investigator fit to receive niraparib and/or bevacizumab.
  18. Women of childbearing potential must use adequate birth control for the duration of study participation

Exclusion Criteria:

A patient will not be eligible for inclusion if any of the following criteria are fulfilled:

  1. Ovarian sarcomas, small cell carcinoma with neuroendocrine differentiation, non-epithelial cancers and cancer types not mentioned in the inclusion criteria
  2. Concurrent cancer therapy
  3. Concurrent treatment with an investigational agent or participation in another clinical trial
  4. Major injuries or surgery within the past 21 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period
  5. Previous malignant disease: patients are not eligible for the study if diagnosis, detection or treatment of invasive cancer (other than ovarian cancer; with the exception of basal or squamous cell carcinoma of the skin that was definitively treated) was detected within 2 years prior to randomization
  6. Active infections or other serious underlying significant medical illness, abnormal laboratory finding or psychiatric illness/social situation that would, in the Investigator's judgment, makes the patient inappropriate for this study
  7. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
  8. History of bowel obstruction, including sub-occlusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction
  9. Known contraindications to PARP inhibitors or VEGF directed therapy
  10. Known uncontrolled hypersensitivity to the investigational drugs
  11. History of major thromboembolic event defined as:

    • Uncontrolled pulmonary embolism (PE)
    • Deep venous thrombosis (DVT)
    • Other related conditions, though patients with stable therapeutic anticoagulation for more than three months prior randomization are eligible for this study. This also apply to PE & DVT.
  12. History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 3 months
  13. History of clinically significant hemorrhage in the past 3 months
  14. Uncontrolled and/or symptomatic CNS metastasis or leptomeningeal carcinomatosis (Dexamethasone/prednisone therapy will be allowed if administered as stable dose for at least one month prior randomization)
  15. Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomization, congestive heart failure > NYHA III, severe peripheral vascular disease, QT prolongation >470 msec ,clinically significant pericardial effusion
  16. Pregnancy or breastfeeding. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards.
  17. Radiographic evidence of cavitation or necrotic tumors with invasion of adjacent major blood vessels
  18. Active or chronic hepatitis C and/or B infection
  19. Persistence of clinically relevant therapy related toxicity from previous chemotherapy
  20. Proteinuria as demonstrated by: (a) urine protein: creatinine (UPC) ratio >/= 1.0 at screening OR (b) urine dipstick for proteinuria >/=2+ (patients discovered to have >/=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hr urine collection and must demonstrate </=1g of protein in24 hours to be eligible
  21. Patients must not have any known history of MDS
  22. Patients must not have known persistent (> 4 weeks) ≥ Grade 2 hematological toxicity from prior cancer therapy
  23. Patients must not have known ≥ Grade 3 thrombocytopenia or anemia with the last chemotherapy regimen.
  Contacts and Locations
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): NCT02354131


Contacts
Contact: Mansoor R Mirza, MD +45 35453311 mansoor@rh.regionh.dk
Contact: Louisa Boufercha, MA +45 35453311 louisa.boufercha@regionh.dk

Locations
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States
Contact: Michael Birrer         
Denmark
Rigshospitalet Recruiting
Copenhagen, Sjaelland, Denmark, 2100
Sponsors and Collaborators
Nordic Society for Gynaecologic Oncology
ENGOT
GCIG
University of Utah
Massachusetts General Hospital
Myriad Genetics, Inc.
Investigators
Study Chair: Mansoor R Mirza, MD Nordic Society for Gynaecologic Oncology
  More Information

Responsible Party: Nordic Society for Gynaecologic Oncology
ClinicalTrials.gov Identifier: NCT02354131     History of Changes
Other Study ID Numbers: ENGOT-OV24-NSGO/AVANOVA
First Submitted: January 25, 2015
First Posted: February 3, 2015
Last Update Posted: April 4, 2017
Last Verified: March 2017

Keywords provided by Nordic Society for Gynaecologic Oncology:
Ovarian cancer
Niraparib
Bevacizumab
PARP
Phase 2 randomized

Additional relevant MeSH terms:
Ovarian Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Bevacizumab
Niraparib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action