Background: Epithelial Ovarian Cancer is the most lethal amongst the gynecologic malignancies and is the fifth leading cause of cancer death in women in the United States.1 Despite initial high response rates, 50% to 75% of women who present with advanced disease suffer relapse and require re treatment2.The optimal treatment for platinum resistant ovarian cancer remains hotly debated. Combination chemotherapy is not favored due to its increased toxicity and lack of convincing benefit when compared to single agent chemotherapy.3,4 Recently, the addition of bevacizumab to single agent chemotherapy in the AURELIA study improved progression free survival (PFS) from 3.4 months to 6.7 months. Response rates were also improved from 11.8% versus 27.3% (p= 0 .001).9 Aim: To determine the maximal tolerated dose (MTD) of weekly paclitaxel in combination with LDWART. The recommended phase II dose (RP2D) will be based on the MTD in this Phase I study. Method: This study is designed as a prospective, single arm phase I study with 3+3 with dose de-escalation and cohort expansion. All patients will receive weekly paclitaxel at a pre specified dose of 80 mg/m2, 70 mg/m2, 60mg/m2 or 50 mg/m2 via intravenous infusion according to institution specific standard practices. Cycles of chemotherapy will be administered weekly without interruption on Days 1,8,15,22,29,36 for a total of 6 weekly cycles in combination with LDWART(Fig.1). LDWART will be given at 60 cGy fractions, twice daily for two days, with a minimum of 4 hours inter fraction interval, starting on day 1 of each cycle of weekly paclitaxel for 6 weeks.(Fig.1). Importance of proposed research: The combination of a LDWART with weekly paclitaxel may improve the efficacy of the current standard weekly paclitaxel in platinum resistant ovarian cancer patients. Potential benefits and risks: The combination may improve treatment response. Adding LDWART may increase treatment risks, but these will be monitored closely.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
All patients will receive weekly paclitaxel at a pre specified dose of 80 mg/m2, 70 mg/m2, 60mg/m2 or 50 mg/m2 via intravenous infusion according to institution specific standard practices. Cycles of chemotherapy will be administered weekly without interruption on Days 1,8,15,22,29,36 for a total of 6 weekly cycles in combination with LDWART. Post treatment assessments will be conducted starting Day 43. Patients will then continue chemotherapy off trial protocol with weekly paclitaxel without concurrent LDWART starting Day 50 till disease progression, intolerable toxicity, patient refusal or deemed inappropriate to continue treatment by treating physician.
LDWART will be given at 60 cGy fractions, twice daily for two days, with a minimum of 4 hours inter fraction interval, starting on day 1 of each cycle of weekly paclitaxel for 6 weeks. LDWART will not be administered if doses of weekly paclitaxel are withheld for any reason since it functions as a "chemosensitizer". LDWART will be administered together weekly paclitaxel immediately at point of recovery from toxicity and patient is deemed to be able to continue with treatment by investigator.
National University Hospital
Singapore, Singapore, Singapore
RECRUITINGMaximal tolerated dose (MTD) of weekly paclitaxel in combination with LDWART
The maximum tolerated dose (MTD) of weekly paclitaxel and LDWART is defined as the lowest dose cohort of weekly paclitaxel and LDWART where ≥ 2 out of initial 3 or ≥ 2 out of total 6 patients in any cohort develops a DLT
Time frame: Up to 6 weeks from initiation of treatment
Objective response rate (ORR)
Objective Response Rate will be assessed with RECIST v1.1 and GCIG CA-125 response criteria.
Time frame: From the time of their first treatment with weekly paclitaxel and LDWART till 30 days from end of last treatment
Progression Free Survival (PFS)
Progression Free Survival will be calculated from the date of initiation of therapy to the first day when the RECIST (version 1.1) criteria for progressive disease (PD) are met.
Time frame: From the time of their first treatment with weekly paclitaxel and LDWART till 1 year from end of last treatmen
Dose limiting toxicity (DLT)
Dose-limiting toxicities (DLT) occurring in the first 3 weeks of treatment in the phase I dose-escalation stage will be used in dose de-escalation decisions. Safety and toxicity will be assessed in all patients using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 to determine the MTD and RP2D.
Time frame: From the time of their first treatment with weekly paclitaxel and LDWART till 30 days from end of last treatment
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