A Randomized, Open-Label Study Comparing the Combination of YONDELIS(RegisteredTM) and DOXIL(RegisteredTM)/CAELYX(RegisteredTM) With DOXIL(RegisteredTM)/CAELYX(RegisteredTM) Monotherapy for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
This is a randomized, open-label, active-controlled, multicenter study designed to assess the efficacy and
safety of trabectedin+DoXiL as a third-line chemotherapy in subjects with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum-based chemotherapy. approximately 670 subjects will be enrolled in this study, with 335 subjects per planned treatment group.
During the Screening Phase, potential subjects will be assessed for study eligibility after providing informed consent to participate in the study. Baseline radiographic disease assessments must be performed within 30 days before randomization.
at randomization, subjects will be stratified by 4 criteria: 1) the time from the last dose of first-line platinum therapy to disease progression (6 months to 12 months vs [Greater Than]12 months to 24 months vs [Greater Than]24 months), 2) eastern Cooperative oncology Group (eCoG) performance status grade (0 vs 1), 3) BRCa 1/2 status (mutation vs no mutation), and 4) prior pegylated liposomal doxorubicin therapy (no vs yes). Subjects will then be randomly assigned in a 1:1 ratio to the trabectedin+DoXiL combination therapy group (arm a) or to the DoXiL monotherapy group (arm B).
* overall survival (oS), is defined as the time between the date of randomization and the date
* Progression-free survival (PFS), is defined as the time between the date of randomization
and the date of disease progression or death;
* objective response rate (oRR), defined as the total number of subjects with either a CR or
* Population PK using a sparse sampling scheme
* Safety will be described according to the frequency of adverse events that occur in the
* Pharmacogenomic evaluation of BRCa1 and BRCa 2 mutation status (mutation vs no
* Patient reported outcomes using the QLQ-oV28 and eQ-5D questionnaires
Each potential subject must satisfy all of the following criteria to be enrolled in the study. Each
1. Be a woman 18 years of age or older.
2. Have histologically proven advanced-relapsed epithelial ovarian, primary peritoneal, or
fallopian tube cancer.
3. Have an ECOG performance status grade of 0 or 1.
4. Have received first-line treatment with a platinum-based regimen and had no evidence of
disease progression for >=6 months after the last dose.
5. Have received second-line treatment with a platinum-based regimen, with progression of
disease after attaining a CR or PR. Complete response or PR could have been determined by
imaging or by CA-125 as outlined by the Gynecologic Cancer Intergroup (GCIG) (Attachment 1).
6. Criterion modified per amendment
6.1. Have progression of disease based on imaging after the second-line platinum-based
o Subjects treated with a pegylated liposomal doxorubicin-containing regimen as a
second-line therapy are eligible if subsequent disease progression occurs >=9 months
from the first dose.
7. Have disease response and disease progression events as noted in criteria #5 and #6
reviewed by the sponsor[Single Quote]s medical monitor prior to randomization.
8. Have evidence of measurable disease at screening as evaluated by RECIST (Version 1.1)
criteria (Attachment 2).
9. Be able to receive IV dexamethasone or an equivalent IV corticosteroid.
10. Have a known BRCA 1/2 mutation status. For subjects who do not have a known BRCA 1/2
status at screening, a blood sample will be collected to determine the status with the results
available prior to randomization.
11. Have all of the following:
[?] hemoglobin >=9 g/dL (without transfusion in the prior 7 days). Subjects may be enrolled into
the study while receiving recombinant erythropoietin provided the recombinant
erythropoietin is administered at least 28 days before the first dose of study medication.
[?] albumin >=25 g/L
[?] absolute neutrophil count (ANC) >=1,500/[MICRO-SYMBOL]L
[?] platelet count >=100,000/[MICRO-SYMBOL]L (without transfusion in the prior 7 days)
[?] either a serum creatinine <=1.5 mg/dL or a calculated glomerular filtration rate >=60 mL/min/1.73 m2 (Cockcroft-Gault) (Attachment 6)
[?] CPK <=2.5 x upper limit of normal (ULN)
12. Have total bilirubin <=ULN. If total bilirubin is >ULN, measure direct and indirect bilirubin
to evaluate for Gilbert[Single Quote]s syndrome (if direct bilirubin is within normal range, subject may be
13. Have alkaline phosphatase (ALP) <=2.5xULN; if the ALP is >2.5xULN, then an ALP liver
fraction or 5' nucleotidase must be <=ULN (as reported in absolute units of measure).
14. Have AST and ALT <=2.5xULN.
15. Have LVEF by MUGA scan or 2D-ECHO within normal limits for the institution.
16. Have side effects (except alopecia) of prior treatment resolved to at least Grade 1 according
to the National Cancer Institute x Common Terminology Criteria of Adverse Events (NCICTCAE)
Version 4.0 (except for those laboratory criteria listed in eligibility criterion #11).
17. Have a negative pregnancy test (urinary or serum [BETA]-human chorionic gonadotropin [HCG])
at screening (applicable to women of child bearing potential).
18. Be postmenopausal (no spontaneous menses for at least 2 years), surgically sterile (have had
a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of
pregnancy), abstinent (acceptability of this method is at the discretion of the investigator
who will ensure and document that the subject understands the definition of "abstinence",
and who will periodically remind and counsel the subject on this topic), or if heterosexually
active, be practicing two effective methods of birth control (eg, prescription hormonal
contraceptive, intrauterine device, double-barrier method [eg, condoms, occlusive cap
(diaphragm or cervical/vault caps) with spermicidal foam, cream, gel, film, or suppository]),
before enrollment, and must agree to continue to use the same two methods of contraception
throughout the study and for 6 months thereafter.
19. Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
(Section 4.3, Prohibitions and Restrictions)
20. Each subject (or their legally acceptable representative) must sign an informed consent form
(ICF) indicating that she understands the purpose of and procedures required for the study
and is willing to participate in the study.
21. Each subject (or their legally acceptable representative) must sign a separate ICF if she
agrees to provide an optional blood sample for pharmacogenomics research (where local
regulations permit). Refusal to give consent for the optional research sample does not
exclude a subject from participation in the study