DAC and CT: Lower Dose Decitabine (DAC)-Primed TC (Carboplatin-Paclitaxel) Regimen in Ovary Cancer

Sponsor

Chinese PLA General Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT02159820

Collaborator

(none)

500

Enrollment

Location

Arms

120

Duration (Months)

4.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Ovarian cancer is the most lethal gynecological cancer and the 5th leading cause of cancer death in women. Most patients are typically diagnosed with advanced-stage disease. Platinum-paclitaxel regimen has been widely adopted as a standard first-line treatment for advanced ovarian cancer. Multiple collaborative randomised phase III trials evaluating the addition of a third chemotherapy agent, maintenance therapy or alternative taxanes failed to demonstrate significant improvements over a standard carboplatin/taxane doublet.

Decitabine (DAC), one major DNA demethylating agent, has been approved for treatment of preleukemic hematological disease myelodysplastic syndrome (MDS) by the Food and Drug Administration. Past trials of these with high doses, i.e., the use of maximal tolerated dose, for patients with solid tumors showed a low therapeutic index, due to extreme toxicities that have probably confounded the ability to document the true clinical response.

Low dose DNA demethylation agent decitabine (DAC) can resensitize the therapeutic indexes of resistent ovary cancer cells in vivo and in vitro.

The investigators hypothesized that DAC-triggered epigenetic reprogramming of tumor cells and possible immune cells could induce pronounced long-dated clinical effect by chemosensitization- and immunopotentiation-driven maximal eradicating roles on the minimal/residual lesions in primary patients with poor prognosis.

Condition or Disease	Intervention/Treatment	Phase
Primary Malignant Neoplasm of Ovary FIGO Stages II to IV	Drug: Decitabine (DTC Arm) Drug: Paclitaxel and Carboplatin (TC Arm)	Phase 2/Phase 3

Detailed Description

Given the poor prognosis and the currently existed therapeutic strategies, The investigators will perform a prospective, randomized, phase II to III, intergroup trial to compare carboplatin plus paclitaxel (TC) with the DAC-primed TC (DTC) regimen in previously untreated patients with stage II to IV ovarian cancer.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Addition of Decitabine to Carboplatin-Paclitaxel in First-Line Treatment of Advanced Ovarian Cancer: A Phase 2-3, Open-label, Randomised Controlled Trial

Study Start Date :

Jun 1, 2014

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: DTC Arm Patients are randomly assigned to receive lower-dose decitabine treatment followed by TC regimen (ie, DTC arm).	Drug: Decitabine (DTC Arm) Patients in DTC arm will receive lower-dose decitabine (7 mg/m2) administered intravenously within 1 hour for a consecutive 5 days, followed by TC regimen on day 6.
Active Comparator: TC regimen Patients were randomly assigned to receive carboplatin plus paclitaxel (ie, TC arm).	Drug: Paclitaxel and Carboplatin (TC Arm) The TC arm consisted of paclitaxel 150 mg/m2 administered intravenously (IV) over 3 hours followed by carboplatin (area under the curve [AUC] 5) administered by IV over 30 to 60 minutes both on day 1 of a 3-week schedule. Dose reductions were allowed depending on hematologic or nonhematologic toxicity, as follows: carboplatin AUC4; paclitaxel 135 mg/m2. Patients who achieved partial remission after six cycles could receive additional cycles on their physicians' discretion.

Arm

Intervention/Treatment

Active Comparator: DTC Arm

Patients are randomly assigned to receive lower-dose decitabine treatment followed by TC regimen (ie, DTC arm).

Drug: Decitabine (DTC Arm)

Patients in DTC arm will receive lower-dose decitabine (7 mg/m2) administered intravenously within 1 hour for a consecutive 5 days, followed by TC regimen on day 6.

Active Comparator: TC regimen

Patients were randomly assigned to receive carboplatin plus paclitaxel (ie, TC arm).

Drug: Paclitaxel and Carboplatin (TC Arm)

The TC arm consisted of paclitaxel 150 mg/m2 administered intravenously (IV) over 3 hours followed by carboplatin (area under the curve [AUC] 5) administered by IV over 30 to 60 minutes both on day 1 of a 3-week schedule. Dose reductions were allowed depending on hematologic or nonhematologic toxicity, as follows: carboplatin AUC4; paclitaxel 135 mg/m2. Patients who achieved partial remission after six cycles could receive additional cycles on their physicians' discretion.

Outcome Measures

Primary Outcome Measures

Progression-free survival in DTC treated advanced ovary cancer [up to 20 months]
The primary endpoint of this trial was progression-free survival (PFS), defined as the time from the date of randomisation to the date of the first occurrence of any of the following events: appearance of any new lesions that could be measured or assessed clinically; or CA125 criteria of disease progression. For patients with measurable disease, clinical or radiographical tumour measurements had priority over CA125 levels, and progression during treatment could not be declared on the basis of CA125 alone.
Overall survival rate in DTC treated advanced ovary cancer [30 months]
Overall survival (OS), defined as the time from random assignment to death as a result of any cause, response rate, and adverse events.response to treatment, toxicity, and quality of life. Toxicities were evaluated per course and per patient (worst score over all courses).
Overall response rate in DTC treated advanced ovary cancer [1 year]
Tumor measurements were made before each cycle by physical examination, before every third cycle by imaging methods in patients with measurable or evaluable disease, and after the last cycle. The same tumor assessment methods that were employed for baseline measurement were used for each repeat evaluation. Tumor response was graded according to Response Evaluation Criteria in Solid Tumors (RECIST).
Toxicity in DTC treated advanced ovary cancer [8 months]
Adverse events and toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (NIC-CTC). Toxicities were recorded continuously; blood chemistry parameters were measured before each treatment cycle and weekly thereafter.Quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-OV28 questionnaires.

Secondary Outcome Measures

Pharmacokinetics of lower-dose decitabine [up to 8 weeks]
Blood samples were obtained prior to treatment and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after the first and fifth dose of decitabine. Plasma samples were stored and processed and further analyzed utilizing liquid chromatography/tandem mass spectrometry. Peak plasma concentration (Cmax) or area under the plasma concentration versus time curve (AUC) will be obtained from more than 10 patients treated at a decitabine dose level of 7mg/m2/d.

Other Outcome Measures

Pharmacodynamics of lower-dose decitabine [up to 8 weeks]
To assess the pharmacodynamics of decitabine and to establish its relationship to clinical PFS, before and after decitabine treatment, peripheral blood mononuclear cells and/or tumor samples will be harvested for measurement of the expression and methylation profile including genes such as MLH1, RASSF1A, HOXA10, and HOXA11 by quantitative polymerase chain reaction (qPCR) and methylation-sensitive PCR analyses.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stages II to IV fallopian tube cancer, or primary peritoneal cancer. If only the results of cytological examinations were available, patients needed to have the following criteria: a cytological diagnosis of adenocarcinoma; an abdominal mass more than 2 cm in diameter on abdominal images; and a CA125 to carcinoembryonic antigen (CEA) ratio10 of more than 25, or no evidence of gastrointestinal cancer if CA125/CEA ratio was less than or equal to 25. Previous chemotherapy was not allowed.
All patients had to be at least 18 years of age, to have an Eastern Cooperative
Oncology Group (ECOG) performance status of 0-3, and were required to have adequate hematologic, renal, and hepatic function.

Exclusion Criteria:

Patients were excluded if they had an ovarian tumour with a low malignant potential, or synchronous or metachronous (within 5 years) malignant disease other than carcinoma in situ.