| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Persistent or Recurrent Rare Epithelial Ovarian Tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ovarian cancer is a type of cancer that begins in 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 | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10033129 |
| E.1.2 | Term | Ovarian neoplasms malignant (excl germ cell) |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10026669 |
| E.1.2 | Term | Malignant peritoneal neoplasm NOS |
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033159 |
| E.1.2 | Term | Ovarian epithelial cancer NOS |
| 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 | 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| ● To evaluate the efficacy of biomarker-driven treatments based on confirmed objective response rate (ORR) as determined by the investigator |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate the efficacy of biomarker-driven treatments based on duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) as determined by the investigator and by the Independent Review Committee
● To evaluate the efficacy of biomarker-driven treatments based on overall survival (OS)
● To evaluate the efficacy of biomarker-driven treatments based on confirmed ORR as determined by the Independent Review Committee
● To evaluate the safety of biomarker-driven treatments
● To characterize the pharmacokinetic (PK) profile of atezolizumab
● To evaluate the immune response to atezolizumab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
● Female, aged >=18 years
● Ability to comply with the study protocol
● Persistent or recurrent epithelial ovarian cancer (EOC) that meets the following criteria: a) Histologically confirmed non-high-grade serous, non-high-grade endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer (i.e., low-grade serous ovarian cancer, clear cell carcinoma, mucinous carcinoma, carcinosarcoma, undifferentiated carcinoma, seromucinous carcinoma, malignant Brenner tumors, Grades 1 or 2 endometrioid carcinoma, or small cell carcinoma of the ovary, hypercalcemic type) b) Disease that is not amenable to curative surgery
● Measurable disease (at least one target lesion) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
● Previous treatment with one to four lines of therapy, at least one of which was platinum-based. Hormonal therapy does not count as a line of therapy
● Platinum-resistant disease (disease progression within 6 months of last platinum therapy)
● At the time of prescreening, submission of a representative tumor specimen that is suitable for central molecular analysis (for mandatory next-generation sequencing (NGS) testing to determine treatment arm assignment). Baseline tumor tissue samples will be collected from all patients, preferably by means of a biopsy performed during prescreening. If a biopsy is not deemed feasible by the investigator, archival tumor tissue obtained within 5 years prior to prescreening may be submitted after confirmation from the Medical Monitor. A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study enrollment. The tumor tissue used in the report should be obtained within 5 years prior to prescreening
● At the time of prescreening, submission of stained pathology slides, along with the associated pathology report. At least one representative hematoxylin and eosin (H&E)-stained slide demonstrating the histologic cell types will be required. Additional stained slides should be submitted if needed to support the local pathology diagnosis, and additional tissue may be requested if slides do not support the local diagnosis.
● Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
● Adequate hematologic and end-organ function on the defined laboratory test results, obtained within 14 days prior to initiation of study treatment.
● For patients in the atezolizumab+bevacizumab (Atezo+Bev) arm not receiving therapeutic anticoagulation: INR <=1.5 and/or aPTT <=1.5* upper limit of normal (ULN) within 7 days prior to initiation of study treatment
● For patients in the Atezo+Bev arm receiving therapeutic anticoagulation: use of full-dose oral or parenteral anticoagulants is allowed, if INR and/or aPTT is within therapeutic limits within 7 days prior to initiation of study treatment and anticoagulant regimen has been stable for >=2 weeks prior to initiation of study treatment
● Negative human immunodeficiency viruses (HIV) test at screening, with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >=200/microliter, and have an undetectable viral load
● Negative hepatitis B surface antigen (HBsAg) test at screening
● Negative hepatitis C virus (HCV) antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening The HCV RNA test must be performed for patients who have a positive HCV antibody test
● Positive hepatitis B surface antibody (HBsAb) test at screening or negative HBsAb at screening accompanied by either of the following: a) Negative total hepatitis B core antibody (HBcAb) b) Positive total HBcAb test followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA test
● For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs (if applicable)
|
|
| E.4 | Principal exclusion criteria |
● Pregnant or breastfeeding, or intending to become pregnant or breastfeed during study
● Primary platinum-refractory disease, defined as progression during or within 4 weeks after the last dose of the first-line platinum treatment
● Histologic diagnosis of high-grade serous or high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer
● Current diagnosis of solely borderline epithelial ovarian tumor (formerly considered tumors of low malignant potential)
● Current diagnosis of non-epithelial ovarian tumors (e.g., germ cell tumors, sex cord-stromal tumors)
● Current diagnosis of synchronous primary endometrial cancer
● Prior history of primary endometrial cancer, with the following exception: a prior diagnosis of primary endometrial cancer is permitted if it meets all of the following conditions: Stage IA, no lymphovascular invasion, FIGO Grade 1 or 2, not a high-grade subtype (e.g., papillary serous or clear cell)
● History of malignancy within 5 years prior to screening, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ, or Stage I uterine cancer
● 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.
● Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >12 mg/dL, or corrected calcium > ULN)
● Symptomatic, untreated, or actively progressing CNS metastases. Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:
– Measurable disease, per RECIST v1.1, must be present outside the CNS.
– The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
– The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.
– The patient has no ongoing requirement for corticosteroids as therapy for CNS disease.
– If the patient is receiving anti-convulsant therapy, the dose is considered stable.
● History of leptomeningeal disease
● Uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment.
● Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
● Any disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
● Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact patient safety
● Active infection requiring systemic anti-microbial treatment (including antibiotics, anti-fungal agents, and anti-viral agents)
● Treatment with chemotherapy, radiotherapy, antibody therapy or other immunotherapy, gene therapy, vaccine therapy, or investigational therapy within 28 days prior to initiation of study treatment
● Treatment with hormonal therapy within 14 days prior to initiation of study treatment
● Toxicity from prior therapy that has not resolved to Grade 1 or better, with the exception of alopecia of any grade
● In addition to the general exclusion criteria above, in order to be enrolled in a treatment arm of the study, participants must not meet any of the arm-specific exclusion criteria
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Confirmed ORR as determined by the investigator according to RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 5 years |
|
| E.5.2 | Secondary end point(s) |
1. DOR as determined by the investigator and IRC according to RECIST v1.1
2. DCR as determined by the investigator and IRC according to RECIST v1.1
3. PFS as determined by the investigator and IRC according to RECIST v1.1
4. Overall survival
5. Confirmed ORR, as determined by the IRC according to RECIST v1.1
6. Incidence and severity of adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0)
7. Serum concentration of atezolizumab at specified timepoints
8. Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline
9. Incidence of ADAs to atezolizumab during the study
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-6. Up to approximately 5 years
7. Atezo+Bev Arm: At Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 and at treatment discontinuation visit
8. Baseline (Days -28 to -1)
9. Atezo+Bev Arm: At Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16 and at treatment discontinuation visit
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| platform, biomarker-driven |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| Korea, Republic of |
| Russian Federation |
| Turkey |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
| Switzerland |
| United Kingdom |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
Print
