| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Recurrent, Platinum-Sensitive Ovarian Cancer | |
| E.1.1.1 | Medical condition in easily understood language | |
| 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 | 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | Demonstrate superiority in Progression-free Survival (PFS) as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 of upifitamab rilsodotin versus placebo as maintenance therapy | |
| E.2.2 | Secondary objectives of the trial | Key Secondary Objective:
• Compare Overall Survival (OS) of upifitamab rilsodotin versus placebo as maintenance therapy
Other Secondary Objectives:
• Compare PFS as assessed by Investigator using RECIST v1.1 of upifitamab rilsodotin versus placebo as maintenance therapy
• Compare the Objective Response Rate (ORR) as assessed by Investigator using RECIST v1.1 of upifitamab rilsodotin versus placebo as maintenance therapy
• Evaluate safety and tolerability in participants treated with upifitamab rilsodotin versus placebo as maintenance therapy | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1.Participants must be at least 18 years of age, and female.
2.Participant must have an ECOG performance status 0 or 1
3.Participant must have a histological diagnosis of high grade serous ovarian cancer, which includes fallopian tube and primary peritoneal cancer, that is metastatic or recurrent.
4.Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent.
5.Participant must have platinum-sensitive recurrent disease, defined as having achieved either a partial or complete response to 4 or more cycles in their penultimate platinum- containing regimen and their disease progressing more than 6 months after completion of the last dose of platinum containing therapy in the penultimate regimen.
6.Participant must have had 4 to 8 cycles of platinum-based chemotherapy in 2nd to 4th line setting in their most recent treatment regimen as defined below:
a. Platinum-based chemotherapy regimens allowed immediately preceding enrollment to the study: carboplatin or cisplatin ±: paclitaxel, docetaxel, pegylated liposomal doxorubicin or gemcitabine.
b. Participant must receive first study treatment infusion between 4 and 12 weeks after completing final dose of platinum in the most recent platinum-based regimen.
c. Definitions for prior lines of therapy:
-Adjuvant ± neoadjuvant considered one line of therapy as long as they are the same regimens (e.g., platinum/taxane for 4 cycles before surgery followed by platinum/taxane for 4 cycles after surgery)
-Maintenance therapy (e.g., bevacizumab, PARPi, endocrine therapy) will be considered as part of the preceding line of therapy (i.e., not counted independently)
- Therapy given for only 1 cycle and discontinued due to toxicity in the absence of progression will not be counted as a new line of therapy; therapy given for 2 or more cycles will be counted as a line of therapy. Substitutions of different platinum agents or taxanes will not be counted as new lines.
-Hormonal therapy (e.g., tamoxifen, letrozole) will be counted as a separate line of therapy unless given as maintenance.
7. Participant must have had as their best response to last line of treatment one of the following: No Evidence of Disease (NED); Complete Response (CR); Partial Response (PR); OR Stable Disease (SD)
8. Participants with NED, CR, or PR as their best response to most recent line of treatment and who have not received treatment with a prior PARP inhibitor must have definitive BRCA1 and BRCA2 testing results that demonstrate no evidence of a deleterious BRCA1 or BRCA2 mutation. Somatic BRCA mutation testing is required for participants who are classified as not having a deleterious mutation by germline testing alone.
9. Participant must provide either a tumor tissue block or fresh cut slides for measurement of NaPi2b expression by a central laboratory. If sufficient archival tumor tissue is not available, then a tumor tissue block or slides must be obtained from a fresh biopsy and provided to the central laboratory. Confirmation of a NaPi2b-H/positive tumor by the central laboratory is required prior to randomization.
10. Participants with toxicity from prior therapy or surgical procedures must have recovered to Grade ≤1. Participants with alopecia, stable immune-related toxicity such as hypothyroidism on hormone replacement, adrenal insufficiency treated with ≤10 mg daily prednisone (or equivalent), or chronic Grade 2 peripheral sensory neuropathy after prior taxane therapy is an exception to this criterion and may qualify for this study.
11. Participants must have cardiac left ventricular ejection fraction (LVEF) ≥50% or ≥ the institution's lower limit of normal as measured by either Echo or MUGA scan
12. Participants must have adequate organ function within 14 days prior to enrollment
13. During the study, female study participants of child-bearing potential (WOCBP) must a contraceptive method that is highly effective during study treatment and for at least 6 months after the last dose of study treatment. | |
| E.4 | Principal exclusion criteria | 1. Participant has received prior treatment with mirvetuximab soravtansine or another ADC containing an auristatin or maytansinoid payload.
2. Participant has received bevacizumab in combination with last platinum-based regiment or plans to receive maintenance therapy outside the study intervention.
3. Participant has clinical signs or symptoms of gastrointestinal obstruction and/or requirement for parenteral hydration or nutrition.
4. Participant has ascites or pleural effusion managed with therapeutic paracentesis or thoracentesis within 28 days prior to signing the principal study consent form.
5. Participant has history of cirrhosis, hepatic fibrosis, esophageal or gastric varices, or other clinically significant liver disease. Testing beyond laboratory studies otherwise defined in the eligibility criteria, to diagnose potentially clinically significant liver disease based on risk factors such as hepatic steatosis or history of excessive alcohol intake, will be based on clinical judgement of the investigator.
6. Participants cannot receive drugs associated with hepatotoxicity concurrent with upifitamab rilsodotin administration except as outlined in Appendix 4.
7. Participant currently uses either constant or intermittent supplementary oxygen therapy.
8. Participant has history of or suspected pneumonitis or interstitial lung disease.
9. Participant has oxygen saturation on room air <93%.
10. Participant has had major surgery or systemic anti-cancer therapy within 28 days of starting study treatment.
11. Participant has a low-grade, clear cell, endometrioid, mucinous, carcinosarcoma, germ- cell, mixed histology, or stromal tumor.
12. Participant has untreated CNS metastases (including new and progressive brain metastases), history of leptomeningeal metastasis, or carcinomatous meningitis.
- Participants are eligible if CNS metastases are adequately treated and are neurologically stable for at least 2 weeks prior to enrollment.
- In addition, participants must be either off corticosteroids, or on a stable/decreasing dose of ≤ 10 mg daily prednisone (or equivalent). Anticonvulsants are allowed except for those drugs associated with liver toxicity.
13. Participant has untreated, known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). In addition, negative serology is required during screening (baseline) for HBV and HCV:
- HBV: Participants with serologic evidence of chronic HBV infection should have an HBV viral load below the limit of quantification to be eligible.
- HCV: Participants with a history of HCV infection should have completed curative antiviral treatment and HCV viral load below the limit of quantification.
- Screening for HIV is not required except if mandated by local regulations or indicated based on clinical assessment.
14. Participant has current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) or intercurrent illness that could interfere with per-protocol evaluations. Further, participants are excluded with the following characteristics:
- A marked baseline prolongation of QTcF interval CTCAE Grade >1: repeated demonstration of a QTcF interval >480 milliseconds (ms) using Fridericia's QT correction formula.
- A history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
15. Has a diagnosis of additional malignancy that required treatment within 2 years prior to screening, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix
16. Participant has clinically significant corneal disease.
17. Participant is unwilling to be transfused with blood components.
18. Participant is receiving concurrent anti-cancer therapy (e.g. chemotherapy, radiation therapy, biologic therapy, immunotherapy, hormonal therapy, investigational therapy).
19. Participant is unable or unlikely to comply with dosing schedule and study evaluations.
20. Participant is using strong CYP450 3A4 inhibitors or inducers that cannot be discontinued while receiving study treatment (see Appendix 5).
21. Participants who are WOCBP must not be pregnant or nursing. Pregnancy status must be confirmed with a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 72 hours before the first dose of study treatment. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Progression-free survival (PFS) assessed by Blinded Independent Central Review (BICR)
| |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | Every 6 weeks and then every 12 weeks until disease progression or start of a new therapy, assessed up to an average of 12 months | |
| E.5.2 | Secondary end point(s) | - Assessment of overall survival (OS)
- Investigator determined PFS
- Overall Safety
- Investigator determined Objective Response Rate (ORR)
| |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | - OS: Duration of treatment, continuing every 90 days following completion of treatment, up to an average of 4 years
- Investigator determined PFS: Every 6 weeks and then every 12 weeks until disease progression or start of a new therapy, assessed up to an average of 12 months.
- Overall safety: Up to 60 days past last dose
- Investigator determined ORR: Every 6 weeks and then every 12 weeks until disease progression or start of a new therapy, assessed up to an average of 12 months.
| |
| 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 | 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 | | Israel | | Korea, Republic of | | New Zealand | | United States | | Austria | | Finland | | France | | Sweden | | Netherlands | | Spain | | Germany | | Italy | | Belgium | | Denmark | | Norway | | United Kingdom | |
| 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 trial is defined as the last data collection point for the last participant on the trial, defined as the last follow-up for Survival captured for the last participant | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 21 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
