| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 given alone or in combination with Pegylated
liposomal doxorubicin (PLD) is superior to (PLD) alone in prolonging Overall
Survival (OS) in patients with platinum -resistant/platinum-refractory ovarian cancer,
● To demonstrate that avelumab given alone or in combination with PLD is superior to PLD alone in prolonging PFS in patients with platinum-resistant/platinum-refractory ovarian cancer.
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| E.2.2 | Secondary objectives of the trial |
• To evaluate anti-tumor activity of avelumab given alone or in combination with PLD versus PLD alone in ovarian cancer patients.
• To evaluate the overall safety profile of avelumab alone or in combination with PLD versus PLD alone in ovarian cancer patients.
• To characterize the PK of doxorubicin (PLD samples) and avelumab when administered in combination, and to assess the effect of avelumab on the PK of doxorubicin (PLD samples) and the effect of PLD on PK of avelumab.
• To assess the immunogenicity of avelumab.
• To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab alone or PLD in combination with avelumab in pre-treatment tumor tissue, that may aid in the identification of patient subpopulations most likely to benefit from treatment.
• To compare the effect of avelumab alone or in combination with PLD versus PLD alone on patient-reported outcomes (PRO) in patients with ovarian cancer. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, including malignant mixed Müllerian tumors with highgrade serous component.
2. Platinum-resistant/refractory disease, defined as disease progression within 180 days following the last administered dose of platinum therapy (resistant), or lack of response or disease progression while receiving the most recent platinum-based therapy (refractory), respectively.
3. Received up to 3 lines of systemic anticancer therapy for platinum-sensitive disease, most recently platinum-containing, and no prior systemic therapy for platinum-resistant disease.
4. Measurable disease by investigator assessment with at least 1 unidimensional measurable lesion by RECIST v.1.1 that has not previously been irradiated.
5. At least 18 years of age (≥20 years of age in Japan).
6. ECOG performance status (PS) 0 to 1.
7. Estimated life expectancy of at least 3 months.
8. Mandatory tumor biopsy must be performed prior to enrollment for all patients (unless there is a documented clinical contraindication). In addition, availability of archived FFPE tumor tissue should be confirmed. If a patient underwent tumor tissue collection within 3 months prior to enrollment with no intervening treatment, and the sample is provided, then a new de novo tumor biopsy is not required.
9. Adequate bone marrow function, including:
a. Absolute neutrophil count (ANC) ≥1.5 x 109/L;
b. Platelet count ≥100 x 109/L;
c. Hemoglobin ≥9 g/dL (may have been blood transfused).
10. Adequate liver function, including:
a. Total bilirubin level ≤1.5 × the upper limit of normal (ULN).
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN.
11. Adequate renal function as evidenced by:
a. Creatinine clearance ≥50 mL/min as calculated using the Cockcroft-Gault equation.
12. Serum/urine pregnancy test (for females of childbearing potential) negative at screening.
13. Female patients, of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and after the last dose of assigned treatment for the following lengths of time.
a. Patients who receive avelumab only: for at least 60 days after the last avelumab dose.
b. Patients who receive PLD (alone or in combination with avelumab): for at least 6 months after the last PLD dose.
14. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
15. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study. |
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| E.4 | Principal exclusion criteria |
1. Non-epithelial tumor, or ovarian tumors with low malignant potential (ie, borderline tumors).
2. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA 4) antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways).
3. Patients with PLD-resistant EOC, as evidenced by lack of response or progression within 6 months of the last dose of PLD.
4. 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 entry, have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to study entry and are neurologically stable.
5. Concurrent anticancer treatment within 28 days prior to study entry, eg, cytoreductive therapy, radiotherapy [with the exception of palliative radiotherapy], immunotherapy, or cytokine therapy (except for erythropoietin); major surgery within 28 days prior to study entry (excluding diagnostic biopsy); use of hormonal agents within 7 days prior to study entry; or use of any investigational drug within 28 days prior to study entry. Note: patients receiving bisphosphonate or denosumab are eligible provided treatment was initiated at least 14 days prior to study entry.
6. Diagnosis of any other malignancy within 5 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix.
7. Any one of the following currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation, bradycardia defined as <50 bpm), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF New York Heart Association Class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
8. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥3, atrial fibrillation of any grade, or QTcF interval >470 msec at screening (average of triplicate ECG).
9. Left ventricular ejection fraction (LVEF) <50% by MUGA or echocardiography.
10. Prior anthracycline-related cardiotoxicity or prior anthracycline exposure approaching the lifetime limit.
11. Prior organ transplantation including allogeneic stem-cell transplantation.
12. Known history of a positive test for human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness.
13. Active infection requiring systemic therapy.
14. 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 positive).
15. Administration of a live vaccine within 30 days prior to study entry.
16. Current or prior use of immunosuppressive medication within 7 days prior to randomization. The following are exceptions to this exclusion criterion:
a. Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent;
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
17. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
18. Known severe hypersensitivity reactions to monoclonal antibodies or liposomal preparations. Known hypersensitivity to any component of the Investigational Products.
19. Persisting Grade ≥2 toxicity related to prior therapy; however, Grade 2 sensory neuropathy or alopecia is acceptable.
20. Severe gastrointestinal conditions such as clinical or radiological evidence of bowel obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4 weeks prior to enrollment, or history of inflammatory bowel disease.
21. Other severe acute or chronic medical condition including pneumonitis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Please refer to the protocol for the rest of the exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Overall Survival (OS)
• Progression Free Survival as determined by Blinded Independent Central Review
according to RECIST version 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Efficacy: Objective response (OR), Duration of Response (DR), and Disease Control (DC) as determined by Blinded Independent Central Review (BICR) and Investigator [As assessed by RECIST version 1.1].
• PFS as determined by Investigator according to RECIST version 1.1.
• Safety: AEs (as graded by NCI CTCAE v.4.03); laboratory abnormalities (as graded by NCI CTCAE v.4.03); vital signs (blood pressure, pulse rate); electrocardiograms (ECGs), ECHO or MUGA scans.
• Pharmacokinetics: PK parameters, including Ctrough and Cmax for avelumab, Cmax, volume of distribution (Vd), clearance (CL), area under the concentration-time curve (AUC) for doxorubicin (PLD samples).
• Immunogenicity: Incidence of anti-drug antibodies (ADA) and neutralizing antibodies (Nab) against avelumab.
• Candidate predictive biomarkers in tumor tissue including, but not limited to, PD-L1 expression and tumor infiltrating CD8+ T lymphocytes as assessed by immunohistochemistry (IHC).
• Patient-Reported Outcomes: EORTC QLQ-C30, EORTC QLQ-OV28, and (EQ-5D-5L). |
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| 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 | 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) | 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| 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 |
| Canada |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Singapore |
| Taiwan |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Greece |
| Hungary |
| Ireland |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
| Czechia |
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| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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