| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum Resistant Ovarian Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Ovarian cancer which has either progressed after primary treatment with platinum therapy or progressed on or after secondary treatment with platinum therapy. |
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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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033130 |
| E.1.2 | Term | Ovarian cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 |
Compare progression-free survival (PFS), based upon investigator assessment using RECIST v 1.1 in participants with platinum-resistant ovarian cancer who receive combination therapy with vintafolide and pegylated liposomal doxorubicin (PLD) (i.e., vintafolide + PLD) with that of participants with platinum-resistant ovarian cancer who
receive PLD and placebo. The primay analysis will be conducted in FR (100%) participants as determined by etarfolatide scan. |
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| E.2.2 | Secondary objectives of the trial |
Compare overall survival (OS), the single secondary endpoint of the phase 3 study, between treatment arms in the FR (100%) population.
Compare PFS and OS between treatment arms for other populations based on percentage of target lesions that are etarfolatide (FR) positive. A hierarchical stepdown analysis will be conducted in a nested fashion to determine if there is a lower FR threshold that maintains statistical significance. Additionally, analyses of individual and mutually exclusive subgroups defined by FR levels will be conducted. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Participants must sign an approved informed consent form (ICF).
2.Participants must be ≥ 18 years of age.
3.Participants must have pathology-confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
4.Participants must have at least a single (RECIST v1.1-defined) measurable target lesion evaluable on etarfolatide SPECT scan by the central nuclear medicine reader.
5.Participants must have at least one target lesion positive for folate receptor by etarfolatide scan.
6.Participants must have received prior platinum-based chemotherapy for management of primary disease but must not have received more than 2 prior systemic cytotoxic regimens.
7.Participants must have platinum-resistant ovarian cancer. Note that primary or secondary platinum resistance is allowed.
i. Primary platinum resistance defined as disease that progressed radiologically within 6 months of the last dose of primary platinum therapy.
ii. Secondary platinum resistance defined as disease that progressed radiologically during or within 6 months of completing secondary platinum therapy (i.e. last platinum dose)
8.Participants are allowed to have received, but are not required to have received, one additional non-cytotoxic anti-tumor agent (eg, biologic or cytostatic) for the management of ovarian cancer.
9.For the purpose of obtaining a RECIST v1.1 baseline scan, participants must have a radiological evaluation conducted no more than 28 days prior to beginning study therapy (EC145/Placebo and PLD). Note: For participants with a history of CNS metastasis, baseline radiological imaging must include evaluation of the head.
10.Participants must have had prior debulking surgery (with the exception of participants who have primary peritoneal carcinoma not requiring debulking surgery).
11.Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
12.Participants must have recovered (to baseline/stabilization) from prior therapy-associated acute toxicities.
13.Participants must have adequate organ function:
i.Bone marrow reserve:
a)Absolute neutrophil count (ANC) ≥ 1.5x109/L prior to treatment (1.5x109/L is equivalent to 1.5x103/µL and 1.5xK/µL and 1.5x103/cumm and 1500/µL). Participants on maintenance doses of granulocyte colony stimulating factor (G-CSF) are eligible.
b)Platelets ≥ 100x109/L (100x109/L is equivalent to 100x103/µL and 100xK/µL and 100x103/cumm and 100,000/µL)
c)Hemoglobin ≥ 9 g/dL (9 g/dL is equivalent to 90 g/L and 5.59 mmol/L)
d)Use of supportive care measures (eg, use of white blood cell [WBC] growth factors, antiemetics, epoetin) should follow the ASCO guidelines as listed at www.asco.org. Participants should receive full supportive care, including transfusion of blood as mandated by clinical need; however, transfusions administered for the sole purpose of meeting the study inclusion criteria between the time informed consent is signed and first dose of vintafolide/placebo/PLD is administered are not allowed.
ii.Hepatic: Total bilirubin level ≤ 1.5 x ULN and alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and alkaline phosphatase levels ≤ 2.5 x ULN.
iii.Renal: Serum creatinine level ≤ 1.5 x ULN or for participants with serum creatinine levels above 1.5 x ULN, creatinine clearance ≥ 50 mL/min/1.73m2 (50 mL/min/1.73m2 is equivalent to 0.83 mL/s/m2).
iv.Cardiac: Left ventricular ejection fraction (LVEF) equal to or greater than the institutional lower limit of normal. LVEF must be evaluated within 28 days prior to C1D1.
14.Participants of childbearing potential must:
i.Have a negative serum pregnancy test within 1 week prior to exposure to etarfolatide and within 1 week prior to treatment with vintafolide/placebo and PLD. If the pre-etarfolatide pregnancy test falls within one week prior to Cycle 1 Day 1, a repeat pregnancy test is not required.
ii.Practice an effective method of birth control (eg, oral, transdermal or injectable contraceptives, intrauterine device [IUD], double-barrier contraception, such as diaphragm and spermicidal jelly) for the duration of their participation in the trial through 6 months following the last dose of study drug.
15.Willingness to participate in the Quality of Life assessment
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| E.4 | Principal exclusion criteria |
1.Participants’ refractory to primary platinum therapy where “refractory” is defined as disease progression within 6 months of first dose of initial platinum-based therapy.
2.Diagnosis of “tumor of low-malignant potential”.
3.Prior exposure to PLD or anthracycline therapy.
4.Prior exposure to FR-targeted therapy (eg, vintafolide, EC0225, EC0489, farletuzumab).
5.Folic acid intake such as vitamins, or anti-folate therapy such as methotrexate within one week prior to etarfolatide scan.
6.Prior therapy with vinorelbine (Navelbine®) or vinca-containing compounds.
7.Prior abdominal or pelvic radiation therapy. Prior radiation therapy within the past 3 years to the breast/sternum, dermal lesions, head, or neck.
8.Recent (ie, < 6 weeks) history of abdominal surgery or peritonitis.
9.Serious co-morbidities (as determined by the investigator) such as, but not limited to, active congestive heart failure or recent myocardial infarction. Participants who require antifolate therapy for the management of co-morbid conditions (eg, rheumatoid arthritis) will be excluded from the trial.
10.Participants with bowel obstruction or subocclusion.
11.Pregnant or nursing.
12.Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ).
13.Symptomatic central nervous system (CNS) metastasis.
14.Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational (ie, used for non-approved indications(s) and in the context of a research investigation). Use of low-dose corticosteroid therapy (eg, for nausea prophylaxis) is acceptable; however, concomitant tamoxifen therapy is not. Supportive care measures are allowed.
15.Participants with active infections (e.g. hepatitis or HIV carriers) are excluded from the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint for this study is PFS, defined as the duration from randomization to the first occurrence of either PD or death. A participant may be declared to have PD on the basis of RECIST v1.1-defined criteria. The date of disease progression is defined as the date of the radiologic assessment on which RECIST-defined progression is identified. Futility and efficacy bounds for PFS and overall survival are provided in a separate statistical analysis plan in order to limit distribution of stopping guidance. Further guidance on early trial discontinuation will be provided in the DSMB charter. Formal efficacy analyses will be performed at four times based on the FR(100%) population:
1.After approximately 98 PFS events are available for analysis in the FR(100%) population, an analysis primarily focused on futility for PFS will be performed. No testing to stop for efficacy is planned.
2.When 250 FR(100%) patients have been enrolled, an analysis focused on futility for PFS and OS will be performed to enable a decision on whether or not to enroll an additional 100 FR(100%) patients. No testing to stop for efficacy is planned.
3.Assuming the trial continues, the final analysis of PFS will take place when either 350 FR(100%) patients have been enrolled or after 245 PFS events are available for analysis in FR(100%) patients, whichever comes later. The DSMB may consider stopping the trial if both overall survival and PFS are shown to be clinically and statistically significantly better in the Vintafolide + PLD group.
4.The final analysis of OS is planned when 280 deaths are available in the FR(100%) population.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS time for participants without radiological progression or death will be censored on the last date that the participant was known to be progression free, defined as the date of the last radiologic assessment not indicating progression; or if no tumor assessment was performed after the baseline visit, at the time of randomization plus 1 day. |
|
| E.5.2 | Secondary end point(s) |
| OS is defined as the duration from the date of randomization to the date of death from any cause. Participants who are alive or lost to follow-up at the time of the analysis will be censored at the last known date they were alive. If a participant has not died, then OS time will be censored at the last study visit, or the last contact date, or the date the participant was last known to be alive, whichever is more temporally distal. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| OS is the single secondary endpoint of the phase 3 study, and no alpha sharing will be involved with other analyses. The initial OS analysis will be conducted on the FR(100%) group. Additionally the same hierarchical and subgroup analyses as defined by FR levels and as described for PFS will be conducted. Survival rates will be estimated for each treatment group using Kaplan-Meier techniques; 12- and 18-month OS rates will be estimated and compared between arms. The magnitude of the treatment effect will be estimated based on adjusted hazard ratios using a Cox multivariate model. |
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| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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) | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Israel |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
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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
|
| The last site will not be closed with their Ethics Committee until the last patient has completed Long Term Follow Up (LTFU). |
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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 |
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