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 EC145 and pegylated liposomal doxorubicin (PLD) (i.e., EC145 + PLD) with that of participants with platinum-resistant ovarian cancer who
receive PLD and placebo. The co-primary analyses will be conducted in:
• EC20(++/+): All randomized EC20 positive participants, i.e., the Intent to Treat (ITT) population of participants with at least 1 EC20 positive tumor lesion.
• EC20(++): The subset of participants that have 100% of their tumor lesions positive by EC20 scan. |
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E.2.2 | Secondary objectives of the trial |
Compare overall survival (OS) between treatment arms in the ITT population. |
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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 lesion.
5. 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.
6. Participants must have platinum-resistant ovarian cancer. Note that primary or secondary platinum resistance is allowed. Participants with primary platinum-refractory disease are not allowed.
a. Primary platinum resistance is defined as disease that responded to primary platinum therapy and then progressed within 6 months of the last dose of primary platinum therapy.
b. Secondary platinum resistance is defined as disease that responded to primary platinum therapy and subsequently progressed during or within 6 months of completing secondary platinum therapy (ie, last platinum dose).
7. 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.
8. 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).
a. For participants with a history of CNS metastasis, baseline radiological imaging must include evaluation of the head.
9. Participants must have had prior debulking surgery (with the exception of participants who have primary peritoneal carcinoma not requiring debulking surgery).
10. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
11. Participants must have recovered (to baseline/stabilization) from prior cytotoxic therapy-associated acute toxicities. Participants who have recovered from non-cytotoxic therapy-associated toxicity or who have “controlled” non-cytotoxic therapy toxicity (eg, vascular endothelial growth factor [VEGF]-related hypertension) can be entered into the trial after a drug wash-out period of 4 half lives.
12. Participants must have adequate organ function including:
i. Bone marrow reserve:
a) Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L prior to treatment (1.5 x 10^9/L is equivalent to 1.5 x 10^3/µL and 1.5 x K/µL and 1.5 x 10^3/cumm and 1500/µL). Participants on maintenance doses of granulocyte colony stimulating factor (G CSF) are eligible.
b) Platelets ≥ 100 x 10^9/L (100 x 10^9/L is equivalent to 100 x 10^3/µL and 100 x K/µL and 100 x 10^3/cumm and 100000/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 EC145/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/1.73m^2 (50 mL/min/1.73m^2 is equivalent to 0.83 mL/s/m^2).
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.
13. Participants of childbearing potential must:
i. Have a negative serum pregnancy test within 1 week prior to exposure to EC20 and within 1 week prior to treatment with EC145/placebo and PLD. If the pre-EC20 pregnancy test occurs 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 3 months following the last dose of study drug.
14. 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, EC145, EC0225, farletuzumab).
5. Prior therapy with vinorelbine (Navelbine®) or vinca-containing compounds.
6. Prior abdominal or pelvic radiation therapy or radiation therapy to > 10% of the bone marrow at any time in the past; or prior radiation therapy within the past 3 years to the breast/sternum, dermal lesions, head, or neck.
7. Recent (ie, ≤ 6 weeks) history of abdominal surgery or peritonitis.
8. Serious comorbidities (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 comorbid conditions (eg, rheumatoid arthritis) will be excluded from the trial.
9. Pregnant or nursing.
10. Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma in situ).
11. Symptomatic central nervous system (CNS) metastasis.
12. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
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 EC145 and pegylated liposomal doxorubicin (PLD) (i.e., EC145 + PLD) with that of participants with platinum-resistant ovarian cancer who receive PLD and placebo. The co-primary analyses will be conducted in:
· EC20(++/+): All randomized EC20 positive participants, i.e., the Intent to Treat (ITT) population of participants with at least 1 EC20 positive tumor lesion.
· EC20(++): The subset of participants that have 100% of their tumor lesions positive by EC20 scan. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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 as summarized in Appendix 2 of this document. The date of disease progression is defined as the date of the radiologic assessment on which RECIST-defined progression is identified. |
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E.5.2 | Secondary end point(s) |
Compare overall survival (OS) between treatment arms in the ITT population. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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.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 | 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 | 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 | 10 |
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 |
Czech Republic |
France |
Hungary |
Israel |
Italy |
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
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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 | 1 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |