| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| epithelial ovarian cancer, fallopian tube cancer or peritoneal cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10016180 |
| E.1.2 | Term | Fallopian tube cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary objective:
Part 2 ( Phase 2):
o compare Progression-Free Survival (PFS) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives Part 2 (Phase 2):
o To provide preliminary evidence of efficacy enabling the choice of a treatment for a future phase III trial
o PFS in each group according to trial stratification factors
o Objective response rate according to RECIST (ORR)
o Overall response according to GCIG criteria (CA125 response; best overall response in patients without initial measurable disease and who are evaluable by CA125; best overall response with measurable disease and who are also evaluable by CA125)
o Disease control rate (DCR) (CR+PR+SD)
o Patient Reported Outcomes (PROs)
o Safety and tolerability
o Overall survival (OS) in each group according to trial stratification factors (exploratory objective)
o PFS in each group according to trial stratification factors
o PFS2 (Progression Free Survival 2)
o TFST (Time to First Subsequent Therapy)
o TSST (Time to Second Subsequent Therapy)
o OS in each group according to trial stratification factors (exploratory end point)
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
AVANOVA Phase I:
Niraparib and niraparib-bevacizumab combination against bevacizumab alone in Women with Homologous Recombination Deficient (HRD) platinum-sensitive epithelial ovarian, fallopian tube, or peritoneal cancer.
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.
Primary objective:
Part 1( Phase 1):
o safety and tolerability of bevacizumab-niraparib combination
Secondary objectives:
Part 1 ( Phase 1):
o determine the Recommended Phase 2 Dose (RP2D) of bevacizumab-niraparib combination
o determine the pharmacokinetics (PK) and pharmacodynamics (PDn) of bevacizumab-niraparib combination
o describe anti-tumor response in these patients
And
TRANSLATIONAL RESEARCH SUB-STUDY:
The specific translational research objectives are:
1. To evaluate the prognostic and predictive values of tumor biomarkers from tissue collected at the initial or later biopsies, and from blood samples for the clinical outcome to bevacizumab, niraparib or combination of both.
2. To perform pharmacokinetics of niraparib-bevacizumab combination.
3. To evaluate the prognostic and predictive values of tumor biomarkers from tissue for certain parameters measured prior to/at study entry, such as a) relation to HRD, RAD51, gBRCA status, and other mutations/amplifications.
4. Multi-gene panels (sequencing) will be performed to detect any predictive markers of response and toxicity in each cohort. A trial addressing this question will be important to help clinicians better utilize genetic testing results and allow them to capture a larger percentage of patients likely to benefit from these drugs.
5. To evaluate protein expression using immunohistochemical (IHC), and to analyze the obtained results with the purpose to develop an optimal classifier for selecting patients into sub-group for individual treatment strategies.
6. To evaluate prognostic or predictive markers, such as, germline or somatic mutations (BRCA1/2, EMSY, PTEN, ATM, ATR, Rad51, CHK1/2, Fanconi anaemia genes) with the purpose of a optimal characterization of patients with the purpose of future individual treatment strategies.
7. The Translational Research Steering Committee keeps the freedom to change the TR if new developments indicate more useful research can be done on these samples. |
|
| E.3 | Principal inclusion criteria |
Study population
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.
o 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.
o If tumor tissue is not sufficient to perform HRD test: these patients shall be randomized in HRD negative stratum as HRD unkown.
4. Prior line of therapy: Patients must have received platinum-containing therapy for primary disease.
o 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%.
o Up to one non-platinum-based line of therapy in recurrent setting.
o Patients who are treated with bevacizumab just prior to entering in the trial must not have progressed under or within 3 months after bevacizumab.
o 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.
Other inclusion criteria:
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
o Absolute neutrophil count (ANC) ≥1,5 x 109/L
o Platelets >100 x 109/L
o Hemoglobin ≥ 9g/dl
o Serum creatinine ≤1.5x upper limit of normal (ULN) or calculated creatinine clearance ≥50mL/min using Cockcroft-Gault formula
o Total bilirubin ≤1.5x ULN
o 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 |
|
| E.4 | Principal exclusion criteria |
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:
o Uncontrolled pulmonary embolism (PE)
o Deep venous thrombosis (DVT)
0 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-Free Survival (PFS) of patients treated with:
Niraparib-bevacizumab combination against niraparib alone
PFS is defined as the duration of time from date of randomization/enrolment to date of progression or death, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessment of Endpoints at Day 1 of each cycle (- 3 +1 days) and
Every 9 weeks (±7 days) During whole study period
The analysis can be performed when at least 74 events have occurred in the pair of arms subject for analysis. |
|
| E.5.2 | Secondary end point(s) |
o Objective Response Rate (ORR)
o Overall response according to GCIG criteria (CA125 response; best overall response in patients without initial measurable disease and who are evaluable by CA125; best overall response with measurable disease and who are also evaluable by CA125)
o Disease control rate (DCR) (CR+PR+SD)
o Patient Reported Outcomes (PROs)
o Safety and tolerability
Exploratory end-points (descriptive only)
o PFS in each group according to trial stratification factors
o PFS2 (Progression Free Survival 2)
o TFST (Time to First Subsequent Therapy)
o TSST (Time to Second Subsequent Therapy)
o Overall survival in each group according to trial stratification factors (exploratory end point)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessment of Endpoints at Day 1 of each cycle (- 3 +1 days) and
Every 9 weeks (±7 days) During whole study period
The analysis can be performed when at least 74 events have occurred in the pair of arms subject for analysis. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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