| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Patients with Platinum-Resistant Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer | |
| E.1.1.1 | Medical condition in easily understood language | | Ovarian, Fallopian Tube, or Primary 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 | 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 | 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 | 20.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10080244 | | E.1.2 | Term | Peritoneal cancer index | | E.1.2 | System Organ Class | 10022891 - Investigations | |
| 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 evaluate the antitumor activity of nemvaleukin alfa (‘nemvaleukin’, ALKS 4230) in combination with pembrolizumab as compared with chemotherapy in patients with platinum resistant ovarian cancer | |
| E.2.2 | Secondary objectives of the trial | • To evaluate the antitumor activity of nemvaleukin in combination with pembrolizumab as compared with chemotherapy
• To evaluate the safety of nemvaleukin in combination with pembrolizumab as compared with chemotherapy | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. Patient is female and ≥18 years of age.
2. Patient or patient's legal representative (as applicable per regional requirements) has provided written informed consent.
3. Patient is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the study.
4. Patient has histologically confirmed diagnosis of EOC, fallopian tube cancer, or primary peritoneal cancer and histology subtype, high-grade serous,
endometrioid of any grade, clear cell
5. Patient has platinum-resistant/refractory disease: resistant is defined as disease progression within 180 days following the last administered dose of platinum therapy beyond first-line setting (ie, initial platinum therapy); and refractory is defined as disease progression or lack of response followed by disease progression while receiving the most recent platinum-based therapy (beyond initial therapy) or lack of
or lack of response or disease progression while receiving the most recent platinum-based therapy (refractory). Patient must have progressed radiographically or by GCIG-defined CA-125 criteria on or after their most recent line of anticancer therapy beyond first-line setting.
a. Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression or the date progression was assessed by GCIG-defined CA-125 criteria, whichever comes first.
b. Note: Patients who have primary platinum-refractory or platinumresistant disease (disease progression <3 months after completion of first-line platinum based therapy) are excluded.
6. Patient must have received at least 1 prior line of platinum-based therapy (as noted below), and no more than 5 prior lines of systemic anticancer therapy in the platinum-resistant disease (4 additional lines after the patient developed platinum-resistant/refractory disease). Patient must have received at least 1 line of therapy containing bevacizumab. The following guidelines apply:
a. Patients who are primary platinum-resistant (developed resistance after initial platinum-based therapy) must have received at least 4 cycles of platinum, must have had a response (complete response [CR] or partial response [PR]) and then progressed ≥3 to ≤6 months after the date of the last dose of platinum
b. Prior PARP inhibitor is allowed if included within these limits of prior therapy. Prior PARP inhibitor is required for patients with a breast cancer gene (BRCA) mutation.
c. Adjuvant ± neoadjuvant is considered 1 line of therapy.
d. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (i.e., not counted independently).
e. Therapy that changed due to toxicity in the absence of progression will be considered part of the same line (ie, not counted independently).
f. Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance therapy.
7. Patient has at least one measurable lesion that qualifies as a target lesion based on RECIST v1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are not considered measurable unless there has been demonstrated progression in the lesion.
8. Patient is willing to provide a tumor tissue sample either collected from a prior biopsy or cytoreductive/debulking surgery occurring at any time since diagnosis or from a fresh biopsy (newly obtained tumor tissue) at Screening. A tumor tissue sample collected at Screening (fresh biopsy) is preferred. Collection of tumor tissue samples from both prior biopsy or cytoreductive/debulking surgery and fresh biopsy are recommended (when possible) to understand changes in the tumor microenvironment during treatment. Central testing of PD-L1 status will be required prior to randomization.
9. Patient has recovered from the effects of any previous chemotherapy, immunotherapy, other prior systemic anticancer therapy, radiotherapy, and/or surgery (i.e., residual toxicity no worse than Grade 1 [Grade 2 treatment-associated peripheral neuropathy and/or any grade of alopecia are acceptable assuming all other inclusion criteria are met]).
10. Patient who has received prior systemic anti-neoplastic agent(s) must wait at least 5 half-lives or 4 weeks (whichever is shorter) following prior therapy before enrollment into the study or 4 weeks if the half-life of a given investigational agent is not known.
11. Patient has an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 and an estimated life expectancy of at least 3 months.
Other protocol-defined criteria apply.
| |
| E.4 | Principal exclusion criteria | 1. Patient has primary platinum-refractory disease or primary platinum resistance: primary platinum-refractory disease is defined as disease progression during initial platinum based therapy; and primary platinum resistance is defined as disease progression in 3 months or less after completion of initial platinum-based therapy (resistant).
2. Patient has histologically confirmed diagnosis of EOC with mucinous or carcinosarcoma subtype.
3. Patient has nonepithelial tumor (eg, germline or stromal cell tumor) or ovarian tumor with low malignant potential (i.e., borderline or lowgrade serous tumor).
4. Patient requires recurrent (≥1 per month) fluid drainage (eg, paracentesis, thoracentesis, pericardiocentesis) or patient requires fluid drainage of ≥500 ml within 4 weeks of the expected date of the first dose of study drug.
5. Patient has received prior IL-2-based or IL-15-based cytokine therapy; patient has had exposure, including intralesional, to IL-12 or analogs thereof.
6. Patient has prior exposure to any antiPD1/PDL1 therapy.
7. Patient requires or has taken systemic corticosteroids (>10 mg of prednisone daily, or equivalent)within 14 days prior to the first dose of study drug(s); however, replacement doses, topical, ophthalmologic, and inhalational steroids are permitted.
8. Patient has taken nonsteroid systemic immunomodulatory agents (eg, etanercept, adalimumab, etc.) within 28 days prior to the first dose of study drug(s), or anticipates any use of these therapies during the study period.
9. Patient has undergone any major surgical procedure within 3 weeks prior to Screening. Patients who have not recovered from any previous surgery that occurred more than 3 weeks prior to Screening are also excluded.
10. Patient has undergone prior solid organ and/or non-autologous hematopoietic stem cell or bone marrow transplant.
11. Patient has received a live or live-attenuated vaccine(s) within 30 days prior to the first dose of study drug(s). Note: Coronavirus Disease 2019 (COVID-19) vaccine is allowed; see guidance on COVID-19 vaccines in Section 7.3.2).
12. Patient has had any active infection and/or a fever ≥38.5°C (≥ 101°F) within 3 days prior to the first dose of study drug(s) requiring systemic therapy. Antibiotics given for periprocedural prophylaxis or given presumptively for a limited time (eg, until infection was ruled out), as well as topical or intraocular antibiotics, shall not be exclusionary.
13. Patient has active autoimmune disease(s) requiring systemic treatment within the past 2 years or a documented history of clinically severe autoimmune disease that has required chronic or frequent systemic steroids. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is allowed.
14. Patient has underlying chronic lung disease, chronic obstructive pulmonary disease, metastatic lung disease, pleural effusions, or other lung disorders (eg, pulmonary embolism) with a baseline room air oxygen saturation of <92% at screening and/or dyspnea (≥Grade 3) which requires oxygen therapy.
15. Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
16. Patient has any other concurrent uncontrolled illness or laboratory findings that may interfere with the planned treatment, affect patient compliance, such as recent serious trauma, or mental illness or substance use, which may interfere with the ability of the patient to cooperate and participate in the study.
17. Patient is at high risk of treatment-related complications as described in the protocol.
18. Patient has had an active second malignancy within the previous 2 years.
19. Patient is currently pregnant, breastfeeding, or is planning to become pregnant or to begin breastfeeding during the study period or within 120 days after last study drug administration.
20. Patient has active or symptomatic central nervous system (CNS) metastases as described in the protocol.
21. Patient has known or suspected hypersensitivity to pembrolizumab, nemvaleukin, PLD, paclitaxel, topotecan, gemcitabine, or to any of their
excipients.
22. Patient has active uncontrolled coagulopathy.
23. Patient has QT interval corrected by the Fridericia Correction Formula values of >470 msec; patient who is known to have congenital prolonged QT syndromes; or patient who is on medications known to cause prolonged QT interval on ECG.
24. Patient is known to be positive for human immunodeficiency virus (HIV).
25. Patients with known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) are excluded.
Other protocol-defined criteria apply
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| E.5 End points |
| E.5.1 | Primary end point(s) | | Progression-free survival (PFS) as assessed by Investigator, based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Progression-free survival is defined as the time from randomization to the first documentation of objective tumor progression (by RECIST v1.1) or death due to any cause. | |
| E.5.2 | Secondary end point(s) | • Objective response rate (ORR) as assessed by Investigator, based on RECIST v1.1;
• Overall Survival (OS)
• Disease control rate (DCR), duration of response (DOR), and time to response (TTR) as assessed by Investigator, based on RECIST v1.1
• Cancer antigen (CA)-125 response as defined by the Gynecologic Cancer InterGroup (GCIG)
• Safety as assessed by treatment-emergent AEs (TEAEs), clinical laboratory parameters, vital signs, and electrocardiograms (ECGs) | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | - Response assessments will include computed tomography (CT) scans and/or magnetic resonance imaging (MRI) every 6 weeks (Year 1) and every 12 weeks (Year 2+).
- Overall survival (OS) is defined as the time from randomization to death due to any cause. For patients without documentation of death, patients will be censored at the date that the patient was last known to be alive or the date of study cutoff, whichever comes earlier.
- DCR is defined as the proportion of patients with objective evidence of CR, PR, or SD. For SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks.
- DOR is defined as the time from the first documentation of CR or PR to the first documentation of objective tumor progression or death due to any cause. | |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description | | Immunogenicity, Health-related quality of life (HRQoL) and Biomarkers assessments | |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 | | Singapore | | Taiwan | | Australia | | Canada | | Israel | | Korea, Republic of | | United Kingdom | | United States | | Austria | | Belgium | | Czechia | | Denmark | | France | | Germany | | Italy | | Lithuania | | Norway | | Poland | | Spain | |
| 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 | | The end of the study is defined as the date of the last patient’s last visit (or, if applicable, the last phone call with the Investigator during the Follow-up Period) as indicated in the SOA. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
