| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Platinum Resistant Advanced High-Grade Epithelial Ovarian, Primary Peritoneal, or Fallopian
Tube Cancers with High Folate Receptor-Alpha Expression |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of ovary and related organs |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061269 |
| E.1.2 | Term | Malignant peritoneal neoplasm |
| 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 | 10061328 |
| E.1.2 | Term | Ovarian epithelial 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the progression-free survival (PFS) of patients
randomized to mirvetuximab soravtansine vs. Investigator's
choice (IC) of chemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
• To compare the objective response rate (ORR) of patients randomized
to mirvetuximab soravtansine vs. IC Chemotherapy
• To compare overall survival (OS) of patients randomized to mirvetuximab soravtansine vs. IC Chemotherapy
• To compare the primary patient-reported outcome (PRO) using the
European Organization for Research and Treatment of Cancer (EORTC)
QLQ-OV28 (Abdominal/GI Symptom Scale) assessment from patients
randomized to mirvetuximab soravtansine vs. IC Chemotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female patients ≥ 18 years of age
2. Patients must have a confirmed diagnosis of high-grade serous EOC,
primary peritoneal cancer, or fallopian tube cancer
3. Patients must have platinum-resistant disease (defined as progression
within 6 months from completion of a minimum of four cycles of platinum-containing therapy)
Note: This should be calculated from the date of the last administered
dose of platinum therapy to the date of the radiographic imaging
showing progression.; Patients who are platinum-refractory during
front-line treatment are excluded (see exclusion criteria)
4. Patients must have progressed on or after their most recent line of
therapy
Note: Progression must be determined radiographically and/or by CA-125 GCIG progression criteria
5. Patients must be willing to provide an archival tumor tissue block or
slides, or undergo procedure to obtain a new biopsy using a low risk,
medically routine procedure for immunohistochemistry (IHC)
confirmation of FRα positivity
6. Patient's tumor must be positive for FRα expression as defined by the
Ventana FOLR1 (FOLR-2.1) CDx assay
7. Patients must have at least one lesion that meets the definition of
measurable disease by RECIST v1.1 (radiologically measured by the
Investigator)
8. Patients must have received at least 1 but no more than 3 prior
systemic lines of anticancer therapy, and for whom single-agent therapy
is appropriate as the next line of treatment:
a. Adjuvant ± neoadjuvant considered one line of therapy
b. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be
considered as part of the preceding line of therapy (ie, not counted
independently)
c. Therapy changed due to toxicity in the absence of progression will be
considered as part of the same line (ie, not counted independently)
d. Hormonal therapy will be counted as a separate line of therapy unless
it was given as maintenance.
9. Patient must have an Eastern Cooperative Oncology Group
Performance Status (ECOG PS) of 0 or 1
10. Time from prior therapy:
a. Systemic antineoplastic therapy (5 half-lives or 4 weeks, whichever is
shorter)
b. Focal radiation completed at least 2 weeks prior to first dose of study
drug
11. Patients must have stabilized or recovered (Grade 1 or baseline)
from all prior therapy-related toxicities
12. Major surgery must be completed at least 4 weeks prior to first dose
and have recovered or stabilized from the side effects of prior surgery
13. Patients must have adequate hematologic, liver and kidney functions
defined as:
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1,500/μL)
b. Platelet count ≥ 100 x 109/L (100,000/μL) without platelet
transfusion in the prior 10 days
c. Hemoglobin ≥ 9.0 g/dL
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN
f. Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of
Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN)
g. Serum albumin ≥ 2 g/dL
14. Patients or their legally authorized representative must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements
15. Women of childbearing potential (WCBP) must agree to use highly
effective contraceptive method(s) in while on
study drug and for at least 3 months after the last dose of mirvetuximab soravtansine or at least 6 months after the last dose of Pac, PLD, or Topo
16. WCBP must have a negative pregnancy test within 4 days prior to the
first dose of study drug |
|
| E.4 | Principal exclusion criteria |
1. Patients with endometrioid, clear cell, mucinous, or sarcomatous
histology, mixed tumors containing any of the above histologies, or lowgrade
or borderline ovarian tumor
2. Patients with primary platinum-refractory disease, defined as disease that did not respond to or has progressed within 3 months of the last dose of first
line platinum-containing chemotherapy
3. Patients with prior wide-field radiotherapy (RT) affecting at least 20% of the bone marrow
4. Patients with > Grade 1 peripheral neuropathy per Common
Terminology Criteria for Adverse Events (CTCAE)
5. Patients with active or chronic corneal disorders, history of corneal
transplantation, or active ocular conditions requiring ongoing
treatment/monitoring such as uncontrolled glaucoma, wet age-related
macular degeneration requiring intravitreal injections, active diabetic
retinopathy with macular edema, macular degeneration, presence of
papilledema, and /or monocular vision
6. Patients with serious concurrent illness or clinically relevant active
infection, including, but not limited to the following:
a. Active hepatitis B or C infection (whether or not on active antiviral
therapy)
b. HIV infection
c. Cytomegalovirus infection
d. Any other concurrent infectious disease requiring IV antibiotics within
2 weeks before starting study drug
7. Patients with history of multiple sclerosis or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome)
8. Patients with clinically significant cardiac disease including, but not
limited to, any one of the following:
a. Myocardial infarction ≤ 6 months prior to first dose
b. Unstable angina pectoris
c. Uncontrolled congestive heart failure (New York Heart Association >
class II)
d. Uncontrolled ≥ Grade 3 hypertension (per CTCAE)
e. Uncontrolled cardiac arrhythmias
9. Patients assigned to PLD stratum only:
• Left ventricular ejection fraction (LVEF) below the institutional limit of
normal as measured by echocardiography (ECHO) or multigated
acquisition (MUGA) scan
10. Patients with a history of hemorrhagic or ischemic stroke within six
months prior to randomization
11. Patients with a history of cirrhotic liver disease (Child-Pugh Class B
or C)
12. Patients with a previous clinical diagnosis of non-infectious
interstitial lung disease (ILD), including noninfectious pneumonitis
13. Patients with required use of folate-containing supplements (eg, folate deficiency)
14. Patients with prior hypersensitivity to monoclonal antibodies
15. Women who are pregnant or lactating
16. Patients with prior treatment with MIRV or other FRα-targeting agents
17. Patients with untreated or symptomatic central nervous system
(CNS) metastases
18. Patients with a history of other malignancy within 3 years prior to
randomization
Note: does not include tumors with a negligible risk for metastasis or
death (eg, adequately controlled basal-cell carcinoma or squamous-cell
carcinoma of the skin, or carcinoma in situ of the cervix or breast) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PFS, defined as the time from date of randomization until Investigator-assessed
progressive disease (PD) or death, whichever occurs first.
Results will be summarized by arm
− Kaplan-Meier method for survival function estimate
− Stratified Cox proportional hazard regression for hazard ratio (HR)
estimate
− Stratified log-rank test for hypothesis testing |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Radiologic Tumor Evaluation: Every 6 weeks (± 1 week) for the first 36 weeks and every 12 weeks (± 1 week) thereafter. |
|
| E.5.2 | Secondary end point(s) |
Objective response includes best response of complete response (CR)
or partial response (PR) as assessed by the Investigator
− Stratified Cochran-Mantel-Haenszel (CMH) test for treatment
comparison
− Clopper-Pearson method for 95% CI estimation
OS defined as the time from date of randomization until the date of
death. Patients alive at the time of analysis will be censored at the last
known date known to be alive
− Kaplan-Meier method for survival function estimate
− Stratified Cox proportional hazard regression for HR estimate
− Stratified log-rank test for hypothesis testing
Primary PRO assessment, defined as the number of patients achieving
at least 15 point absolute improvement at Week 8 or Week 9 in the
abdominal/GI scale of EORTC QLQ-OV28 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Radiologic Tumor Evaluation: Every 6 weeks (± 1 week) for the first 36 weeks and every 12 weeks (± 1 week) thereafter.
PRO assessment: screening, every 9 (± 1) weeks from cycle 1, Day 1 until disease progression (per investigator), end of treatment (EOT) and every 3 months (± 1 month) from EOT |
|
| 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 | No |
| 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 | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 102 |
| 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 |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Germany |
| Israel |
| Italy |
| Korea, Democratic People's Republic of |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Serbia |
| 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
|
| EOS will occur after the final analysis of OS, which will be conducted when at least 300 deaths have occurred. It is projected that the final analysis for OS will be approximately 1 year after the final analysis of PFS. After the final analysis of OS, the last survival follow-up visit for the last patient will be performed and the study will close. |
|
| 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 | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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