A Randomized, Open-Label Study Comparing the Combination of YONDELIS and DOXIL/CAELYX With DOXIL/CAELYX Monotherapy for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
The goal of this clinical research study is to learn if adding trabectedin to DOXIL (liposomal doxorubicin) is more effective than liposomal doxorubicin alone in treating advanced-relapsed epithelial ovarian, primary peritoneal, or Fallopian tube cancer. The safety of these treatments will also be studied.
Disease Group: Ovary
Treatment Agent: Doxorubicin,Trabectedin
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: Janssen Research & Development, LLC
Primary Objective To compare the overall survival (OS) after treatment with trabectedin+DOXIL combination therapy to that observed after treatment with DOXIL monotherapy for subjects with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who have received 2 previous lines of platinum-based chemotherapy. Secondary Objectives To evaluate progression free survival (PFS). To evaluate the objective response rate (ORR). To characterize the plasma pharmacokinetics of trabectedin using a sparse sampling scheme in the trabectedin+DOXIL treatment group. To evaluate the safety of the trabectedin+DOXIL combination therapy and DOXIL monotherapy. Exploratory Objectives To conduct pharmacogenomic evaluations of OS, PFS and other endpoints in subjects with and without mutations in BRCA1 or BRCA2. To evaluate patient-reported outcomes (PROs).
IRB Review and Approval Date: 12/03/2015
Recruitment Status: Open
Projected Accrual: 670
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)
6) Have progression of disease based on imaging after the second-line platinum-based regimen. **Subjects treated with a DOXIL- 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's medical monitor prior to randomization.
8) Have evidence of measurable disease at screening as evaluated by RECIST (Version 1.1) criteria.
9) Be able to receive IV dexamethasone or an equivalent IV corticosteriod.
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 satus with the results available prior to randomization.
11) Have the following: (a) hemeoglobin >/=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. (b) albumin >/= 25g/L. (c) absolute netrophil count (ANC) >/=1,500/ mu L. (d) Platelet count >/=100,000/mu L (without transfusion in the prior 7 days). (e) either a serum creatinine </= 1.5 mg/dL or a calculated glomerular filtration rate >/=60 mL/min/1.73 m^2 (Cockcroft-Gault). (f) 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's syndrome (if direct bilirubin is within normal range, subject may be eligible).
13) Have alkaline phosphatase (ALP) </=2.5 x ULN; if the ALP is >2.5x ULN, then an ALP liver fraction or 5' nucleotidase must be </=ULN (as reported in absolute units of measure).
14) Have AST and ALT </= 2.5 x ULN.
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 to Grade 1 according to the National Cancer Institute - Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 4.0 (except for those laboratory criteria listed in eligibility criterion # 11)
17) Have a ngative pregnancy test (urinary or serum B-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 hysterctomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent (acceptability of this method is at the discrection of the investigator who will ensure and document that the subject understands the defination 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 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 thourghout the study and for 6 months therafter.
19) Be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
20) Each subjec (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 (where local regulations permit). Refusal to give consent for the optional research sample dose not exclude a subject from participation.
1) Has a diagnosis of ovarian carcinoma with mucinous histology.
2) Had more than 2 pior lines of chemotherapy.
3) Had prior exposure to trabectedin or hypersensitivity to any excipients.
4) Had prior treatment with doxorubicin or other anthracycline at cumulative doses greater than 300 mg/m^2 (calculated using doxorubicin equivalent doses: 1 mg doxoruicin = 1 mg DOXIL = 1.8 mg epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin).
5) Is unwilling or unable to have a central venous catheter placed.
6) Is pregnant or breast-feeding.
7) Is less than 3 weeks from radiation therapy, experimental therapy, hormonal therapy, prior chemotherapy, or biological therapy.
8) Has a history of another neoplastic disease (except non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin or cervical carcinoma in situ adequately treated) unless in remission for >/= 5 years.
9) Has known allegries hypersensitivity, or intolerance to DOXIL, dexamethasone, or their excipients.
10) Has a known history of central nervous system metastasis.
11) Has known significant chronic liver diseas, such as cirrhosis or active hepatitis (potential subjects who test positive for hepatitis B surface antigen or hepatitis C antibodies are allowed provided they do not have active disease requiring antivaral therapy).
12) Had a myocardial infarct within 6 months before enrollment, New York Heart Assocation (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrollled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or acitve conduction system abnormalities.
13) Has any of the following medical conditions: Uncontrolled diabetes. Psychiatric disorder (including dementia) that prevents compliance with protocol. Uncontrolled seizures. Newly diagnosed deep vein trombosis. Active systemic infection that is likely to interfere with study procedure or results.
14) Has any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements.
15) Is an employee of the investigator or study site, with direct involvment in the proposed study or other studies under the direction of that investigator or study site, as well as family members of the employees or the investigator.
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