A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study

A phase I study with an expanded cohort to assess the feasibility of intravenous paclitaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with untreated ovarian, fallopian tube or primary peritoneal carcinoma: A Gynecologic Oncology Group study


Objective 
To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and IP paclitaxel in women with newly diagnosed Stages II–IV ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods 
Patients received escalating doses of paclitaxel IV and carboplatin IP on day 1 and paclitaxel IP 60mg/m² on day 8. A standard 3+3 design was used in the escalation phase. A two-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. Patient-reported neurotoxicity was assessed pre and post treatment.

Results 
Patients were treated with paclitaxel 175mg/m² IV and carboplatin IP from AUC 5–7 on day 1 and paclitaxel 60mg/m² IP on day 8. The MTD was estimated at carboplatin AUC 6 IP and 25 patients enrolled at this dose level. Within the first 4cycles, seven (35%) of twenty evaluable patients had dose-limiting toxicities (DLTs) including grade 4 thrombocytopenia (1), grade 3 neutropenic fever (3), >2week delay due to ANC recovery (1), grade 3 LFT (1), and grade 3 infection (1). De-escalation to paclitaxel 135mg/m² IV was given to improve the safety. After six evaluable patients completed 4 cycles without a DLT, bevacizumab was added and six evaluable patients completed 4cycles with one DLT (grade 3 hyponatremia).

Conclusions 
Paclitaxel at 175mg/m² IV, carboplatin AUC 6 IP day 1 and paclitaxel 60mg/m² IP day 8 yield 18–56% patients with DLTs. The tolerability of the regimen in combination with bevacizumab was indicated in a small cohort.

NCI Cancer Bulletin: Testing Dose-Dense Paclitaxel (Taxol) for Ovarian and Related Cancers - GOG-0262

"....Further bolstering evidence of dose-dense paclitaxel’s promise in ovarian cancer, the Japanese GOG conducted a phase III randomized clinical trial and showed that women receiving dose-dense therapy experienced statistically significantly longer progression-free survival and were more likely to be alive after 2 years....."

“Data from phase II studies show that dose-dense paclitaxel has activity in highly resistant ovarian cancer,” said Dr. Chan. “And the Japanese study has produced promising data, but there are differences in the prevailing ovarian cancer cell types, and possibly the genomic and toxicity profiles, of ovarian cancer in Asian compared with Western women. As such, these results need to be confirmed in other ethnicities before the dose-dense regimen can be considered the new standard of care.”

For More Information

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Phase I Oncology Studies: Evidence That in the Era of Targeted Therapies Patients on Lower Doses Do Not Fare Worse — Dr Maurie Markman et al

abstract:

"Purpose: To safely assess new drugs, cancer patients in initial cohorts of phase I oncology studies receive low drug doses. Doses are successively increased until the maximum tolerated dose (MTD) is determined. Because traditional chemotherapy is often more effective near the MTD, ethical concerns have been raised about administration of low drug doses to phase I patients. However, a substantial portion of oncology trials now investigate targeted agents, which may have different dose-response relationships than cytotoxic chemotherapies.......