| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously untreated advanced cancer of the ovaries |
|
| 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 | LLT |
| E.1.2 | Classification code | 10033130 |
| E.1.2 | Term | Ovarian cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging progression-free survival (PFS) in patients with advanced ovarian cancer with defects in DNA damage repair (DDR+). |
|
| E.2.2 | Secondary objectives of the trial |
- To demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging overall survival (OS) in patients with advanced ovarian cancer with defects in DNA damage repair (DDR+).
- To demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging PFS in patients with advanced ovarian cancer unselected for DDR status.
Refer to protocol for the full list of Secondary Objectives. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed Stage III-IV epithelial ovarian, fallopian tube, or primary peritoneal cancer (according to American Joint Committee on Cancer (AJCC)/UICC TNM and International Federation of Gynecology and Obstetrics (FIGO) Staging System 2014 edition), including carcinosarcoma with high-grade serous component.
2. Patients must be candidates for bevacizumab in combination with platinum based chemotherapy and previously untreated.
3. Must have completed a primary surgical debulking procedure, or be candidates for neoadjuvant chemotherapy with planned interval debulking surgery.
a. Patients who completed primary debulking must have had incompletely resected disease that is macroscopically/grossly visible and at least with lesions >1 mm and be randomized at a maximum of 8 weeks after surgery.
b. For patients who are candidates for neoadjuvant chemotherapy, the diagnoses must have been confirmed by:
- Core tissue (not fine-needle aspiration) biopsy is required for diagnosis. The tissue must be consistent with inclusion criteria #1 above.
- Stage IIIC–IV documented via imaging or surgery (without attempt at cytoreduction).
- Serum CA-125/CEA ratio >25. If the serum CA-125/CEA ratio is <25, then workup should be negative for the presence of a primary gastrointestinal or
breast malignancy (<6 weeks before start of neoadjuvant treatment).
- Randomization must occur within 8 weeks after diagnosis.
4. Availability of an archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or a minimum of 25 slides, together with an accompanying original Hemotoxylin and Eosin (H&E) slide. If archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample must be obtained in accordance with local institutional practice for tumor biopsies. Tumor tissue must contain 40% or greater tumor nuclei per central laboratory assessment.
- Sites may randomize/enroll patients who meet all other eligibility criteria while awaiting central confirmation of tissue acceptance, but must provide
additional tumor samples in the event that the central lab review shows insufficient sample quality.
5. Eastern Cooperative Group (ECOG) performance status 0-1.
6. Age ≥18 years (or ≥20 years in Japan).
7. Adequate bone marrow function including: absolute neutrophil count (ANC) ≥1,500/mm3 or 1.5 x 109/L; Platelets ≥100,000/mm3 or ≥100 x 109/L; hemoglobin ≥9.0 g/dL (may have been transfused).
8. Adequate hepatic function defined by a total bilirubin level ≤1.5 x upper limit of normal range (ULN), an ALT/AST level ≤2.5 x ULN.
9. Adequate renal function by estimated creatinine clearance ≥60 mL/min as calculated using the Cockcroft-Gault method or by 24 hour urine collection for creatinine clearance or according to local institutional standard method.
10. Adequate blood coagulation parameters: International normalized ratio (INR) ≤1.5 and aPTT <1.2 times the upper limit of normal.
11. Ability to swallow study drugs.
12. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
13. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
14. Patients of childbearing potential and at risk for pregnancy must agree to use 2 methods of contraception (at least one of which is considered to be highly effective with low user dependency) as outlined in this protocol for the duration of the study and for at least 30 days after the last dose of avelumab, 6 months after the last talazoparib dose, and for 6 months after the last dose of bevacizumab.
15. Patients of non-childbearing potential must meet at least 1 of the following criteria:
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure; or
- Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or
physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state.
All other patients (including patients with tubal ligations) will be considered to be of childbearing potential. |
|
| E.4 | Principal exclusion criteria |
1. Non-epithelial tumors or ovarian tumors with low malignant potential (ie, borderline tumors) or mucinous tumors.
2. Patients for whom intraperitoneal cytotoxic chemotherapy is planned.
3. Prior exposure to immunotherapy with interleukin (IL)-2, interferon alpha (IFN-α), or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, excluding therapeutic anticancer vaccines.
4. Prior treatment with a PARP inhibitor.
5. Prior treatment with any anti-vascular endothelial growth factor (VEGF) drug, including bevacizumab.
6. Major surgery (other than debulking or exploratory surgery for ovarian cancer) for any reason within 4 weeks prior to randomization and/or incomplete recovery from surgery.
7. Prior radiotherapy to any portion of the abdominal cavity or pelvis. Prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease.
8. Prior targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their ovarian, peritoneal primary or fallopian tube carcinoma.
9. Prior organ transplantation including allogenic stem cell transplantation.
10. Diagnosis of Myelodysplastic Syndrome (MDS).
11. Known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable.
12. Current or anticipated use of a strong P-glycoprotein (Pgp) inhibitor (eg, dronedarone, quinidine, ranolazine, itraconazole, ketoconazole), strong P-gp inducer (eg, rifampin, ritonavir, tipranavir), or strong inhibitor of breast cancer resistance protein (eg, elacridar [GF120918]).
13. Current use of immunosuppressive medication at the time of randomization, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (eg, intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
14. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroidism not requiring immunosuppressive treatment are eligible.
15. Clinically significant (ie, active) cardiovascular disease: cerebrovascular accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (greater than New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
16. Uncontrolled hypertension, defined as systolic >140 mm Hg or diastolic >90 mm Hg documented by 2 blood pressure readings taken at least 1 hour apart. Use of antihypertensive medications to control blood presuure (BP) is allowed.
17. Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
18. Active infection requiring systemic therapy.
19. Known history of testing positive for human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS).
20. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive).
21. Administration of a live vaccine within 30 days prior to study enrollment.
22. Known severe hypersensitivity reactions to investigational products or any component in their formulations or to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥3).
23. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however alopecia, sensory neuropathy Grade ≤2, or other Grade ≤2 AEs not constituting a safety risk based on investigator's judgment are acceptable.
24. Previous malignant disease other than the target malignancy to be investigated in this trial within the last 5 years with the exception of adequately treated basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, lobular carcinoma in situ (LCIS), or ductal carcinoma in situ (DCIS) and in situ carcinoma of the bladder.
Refer to protocol for the full list of exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival (PFS) as determined based on Blinded Independent Central Review (BICR) assessment per RECIST v1.1 in patients with newly diagnosed advanced ovarian cancer with defects in DNA damage repair (DDR+). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
OS in patients with tumors that are DDR+ and in patients unselected for DDR status.
- PFS based on BICR assessment per RECIST v1.1 in patients unselected for DDR status.
- PFS based on investigator assessment per RECIST v1.1 in patients with tumors that are DDR+ and in patients unselected for DDR status.
- PFS2 based on investigator assessment in patients with tumors that are DDR+ and in patients unselected for DDR status.
- PFS based on investigator assessment per Gynecological Cancer Intergroup (GCIG) criteria in patients with tumors that are DDR+ and in patients unselected for DDR status.
- AEs (as graded by NCI CTCAE v4.03); laboratory abnormalities (as graded by NCI CTCAE v4.03); vital signs (blood pressure, pulse rate);
electrocardiograms (ECGs).
- PK parameters, including Ctrough and Cmax for avelumab and Ctrough for talazoparib.
- Anti-drug antibodies (ADA) and neutralizing antibody (NAb) against avelumab.
- Disease related symptoms and treatment side effects as measured by the NCCN-FACT FOSI-18 and health-related quality of life (HRQOL) as measured by NCCN-FACT FOSI-18 and the EuroQol Group 5-Dimension 5-Level (EQ-5D-5L).
- PD-L1 expression, TMB, genomic scarring and the presence of defects in select genes, considered critical to effective DDR, in baseline tumor tissue.
- Assessment of defects in a panel of key oncogenes, including several considered critical to effective DDR and TMB in ctDNA at baseline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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 | 3 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 89 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Croatia |
| Czech Republic |
| Estonia |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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