| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Platinum-resistant 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033130 |
| E.1.2 | Term | Ovarian cancer NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine a difference in progression-free-survival (PFS) between lurbinectedin (PM01183) and pegylated liposomal doxorubicin (PLD) or topotecan in platinum-resistant ovarian cancer patients according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
- Overall survival (OS).
- Antitumor activity.
- Safety profile.
- Patient-reported outcomes (PRO).
To characterize the plasma pharmacokinetics (PK) of PM01183 using a sparse sampling scheme in the PM01183 treatment arm (Arm A).
Subgroup analyses of the PM01183 arm versus PLD or topotecan.
To conduct an exploratory pharmacogenetic and pharmacogenomic (PGx) sub-study. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOKINETIC EVALUATIONS - will be collected in all patients enrolled in the PM01183 arm (Arm A). The samples will be obtained in two cycles (in Cycle 1 and in a second cycle between Cycle 2 and 4). The selection of the second cycle with sample collection for the measurement of PM01183 will be assigned once the patient is randomized into Arm A.
PHARMACOGENETIC EVALUATIONS - To explore factors that may help to explain individual variability in main pharmacokinetic (PK) parameters, the presence or absence of germline mutations or polymorphisms will be analyzed in leukocyte DNA extracted from a blood sample obtained before treatment start in the PM01183 arm (Arm A).
PHARMACOGENOMIC EVALUATIONS - The analysis of potential predictive factors to PM01183 treatment will be analyzed on prior available paraffin-embedded tumor tissue samples from consenting patients. |
|
| E.3 | Principal inclusion criteria |
1) Voluntary written informed consent (IC) of the patient obtained before any study-specific procedure.
2) Age ≥ 18 years.
3) Histologically or cytologically confirmed diagnosis of unresectable epithelial ovarian, fallopian tube or primary peritoneal cancer.
4) Platinum-resistant disease (PFI: 1-6 months after last platinum-containing chemotherapy).
5) Radiologically measurable and/or non-measurable progressive disease according to RECIST v 1.1.
6) No more than three prior systemic chemotherapy regimens. Note: in case that a patient had started a new systemic chemotherapy without disease progression to the prior chemotherapy line (e.g., treatment discontinuations due to toxicity; neoadjuvant followed by adjuvant chemotherapy regimens), these two chemotherapy regimens will considered as one.
7) ECOG PS ≤ 2.
8) Adequate hematological, renal, metabolic and hepatic function:
a) Hemoglobin ≥ 9 g/dl [patients may have received prior red blood cell (RBC) transfusion]; absolute neutrophil count (ANC) ≥ 2.0 x 109/l, and platelet count ≥ 100 x 109/l.
b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN).
c) Alkaline phosphatase (AP) < 5.0 x ULN.
d) Total bilirubin ≤ ULN or direct bilirubin ≤ ULN if total bilirubin is > ULN.
e) Albumin ≥ 3.0 g/dl.
f) Calculated creatinine clearance (CrCL) ≥ 30 ml/min (using Cockcroft and Gault's formula).
g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN.
9) At least three weeks since last prior therapy, and grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding grade ≤ 2 alopecia or peripheral neuropathy) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v. 4).
10) Women of childbearing potential must have pregnancy excluded by appropriate testing before study entry. A medically acceptable method of contraception must be maintained throughout the treatment period and for at least six months after treatment discontinuation. |
|
| E.4 | Principal exclusion criteria |
1) Concomitant diseases/conditions:
a) History of cardiac disease: myocardial infarction or symptomatic/uncontrolled angina within the year prior to enrollment; or congestive heart failure defined as abnormal left ventricular ejection fraction (LVEF) < 50% assessed by multiple-gated acquisition scan (MUGA) or equivalent by ultrasound (US); or symptomatic arrhythmia.
b) Patients with any immunodeficiency, including those known to be infected by human immunodeficiency virus (HIV).
c) Chronic active hepatitis or cirrhosis. For Hepatitis B, this includes positive tests for both Hepatitis B surface antigen and quantitative Hepatitis B polymerase chain reaction (PCR). For Hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR.
d) Active uncontrolled infection.
e) Bowel obstruction.
f) Requirement of permanent or frequent (i.e., once per week) external drainages within two weeks prior to randomization.
g) Limitation of the patient's ability to comply with the treatment or to follow-up the protocol.
h) Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
2) Platinum-refractory or platinum-sensitive disease (PFI <1 or > 6 months).
3) Prior treatment with PM01183, trabectedin, or with both PLD and topotecan.
Note: if 60% of recruitment is reached in one of the control treatment options (i.e., PLD or topotecan), patients could only be eligible if they did not previously receive the other control treatment option available (the Sponsor will inform the sites, if this occurs).
4) Known brain metastases or leptomeningeal disease involvement.
5) History of another neoplastic disease (except for curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or properly treated carcinoma in situ of the uterine cervix or breast) within three years prior to randomization.
6) Pregnant or breast feeding women. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS)
Overall survival (OS)
Landmark analyses:
PFS at 6 and 12 months by IRC/IA
OS at 12 and 24 months
Best antitumor response by IRC/IA
Duration of response (DR) by IRC/IA
Best response according to tumor marker evaluation (CA-125)
Treatment safety profile
Patient-reported outcomes (PRO):
Plasma pharmacokinetics (PK) of PM01183
Subgroup analyses: Subgroup analyses of the PM01183 arm versus PLD or topotecan
Pharmacogenetics
Pharmacogenomics |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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
| Yes |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 79 |
| 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 |
| Austria |
| Belgium |
| Bulgaria |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Romania |
| Serbia |
| Spain |
| 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
|
| 24 months after randomization of the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
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