Trial Information

Phase II Trial- Weekly Taxotere and Topotecan for Recurrent Ovarian, Primary Peritoneal, Endometrial and Uterine Cancers

Endometrial carcinoma is the most common gynecologic cancer, accounting for 6,500 deaths in
2002 in the United States. There has been a 128% increase in endometrial cancer deaths over
the past decade mainly due to recurrences. Although primary surgery with or without
adjuvant therapy can cure most patients, effective therapy for those patients with advanced
or recurrent disease is needed. Due to the advanced age of this patient population and
associated medical comorbidities, these patients are not always ideal candidates for
experimental therapies exploring dose intensity or toxic agents. Treatment options for
advanced or recurrent disease are limited. Cytotoxic therapy has made little impact on
survival.

Recent data has demonstrated efficacy of Topotecan in advanced or recurrent endometrial
cancer. A Phase II trial performed primarily by the New York Gynecologic Oncology Group
through ECOG found Topotecan to be an active first line treatment for metastatic or
recurrent endometrial cancer. The overall response rate was 20% with 3/40 patients complete
responders. A Phase II trial by the Gynecologic Oncology Group (GOG) of 29 patients with
advanced or recurrent endometrial cancer reported a 10% overall response rate to 5-day
intravenous Topotecan. However, 55% of patients had stable disease. Reported side effects
were mainly hematologic, specifically, neutropenia and thrombocytopenia. Finkler and
Holloway reported a phase I/II trial using weekly Topotecan in recurrent endometrial cancer.
23% of patients had partial response to therapy, with a decrease in grade 4 neutropenia and
thrombocytopenia compared to the 5-day infusion. In a pilot study examining the role of
5-day Topotecan in uterine papillary serous carcinoma (UPSC), Chambers et al. report 11 of
12 patients who received Topotecan as front-line therapy to be disease-free at 13 months
median follow-up. Anemia and neutropenia were managed effectively with hematopoietic
stimulating factors.

Taxanes have also been reported to be effective in the treatment of advanced and recurrent
endometrial cancer. Endometrial cancer cell lines have demonstrated sensitivity to
paclitaxel. Response rates of 35%-37% have been reported in two separate phase II trials.
Günthert et al., reported a complete response to Taxotere in a patient with recurrent
endometrial cancer.

Taxotere is an agent well documented in the management of advanced ovarian cancer, with a
response rate of approximately 30% in platinum-refractory patients. Taxotere has also
demonstrated clinical response in patients classified as paclitaxel-refractory, confirming
an incomplete cross-resistance between these two agents. Based on these data, there is
reason to believe that the combination of Topotecan and Taxotere in the second-line setting
may prove promising in patients initially treated with paclitaxel and platinum-based
therapy.

Topotecan and Taxotere have known activity in ovarian cancer patients. Recent weekly dosing
schedules suggest similar activity in ovarian cancer patients with less toxicity. Ovarian
cancer patients who have significant Taxane-related side effects, including neuropathy, do
well with weekly Taxotere. Both Topotecan and Taxotere have documented efficacy in
recurrent endometrial cancer, but no study, to date, has utilized them in combination for
the treatment of endometrial cancer. In addition to utilizing this regimen in a phase II
setting for recurrent ovarian cancer, we propose a phase II trial utilizing this
combination for the treatment of recurrent endometrial cancer. The justification for
including all of these tumor types in the same protocol is the known similar response rates
of these Gynecologic tumors to all chemotherapies. The endpoints and power are designed for
all of the histologic types, but subset analysis will be used for each tumor type after
completion of the trial.

Because of the broad spectrum of antitumor activity of both Topotecan and Taxotere, several
phase I/II trials have been conducted with this combination regimen. Lu and colleagues at
MD Anderson administered docetaxel (Taxotere) intravenously on Day 1 followed by bolus daily
intravenous Topotecan on days 1-3 with subcutaneous Neupogen (Filgrastim) support on days
4-13. Dose limiting toxicity for the regimen was febrile neutropenia, and the recommended
dose for phase II trials was docetaxel 75 mg/m2 IV on day 1 and topotecan 1.4 mg/m2 IV on
days 1-3 with Neupogen (filgrastim) 5 mcg/kg/d SC on days 4-13. Three of the 11 patients
enrolled experienced a response with the combination (1 CR and 1 PR in nasopharynx cancer
and 1 PR in SCLC). Aijaz and colleagues at New York Medical Center conducted a similar
pilot study in patients with recurrent ovarian and primary peritoneal cancer. In this
trial, all of the patients received docetaxel 80 mg/m2 IV on day 1 and topotecan 1.0 mg/m2
IV on days 1-5. The patients also received Neupogen (filgrastim) 10-mcg/kg beginning on day
6 and continuing until the neutrophil count recovered to ≥ 10,000/mL. The regimen was
relatively well tolerated, with neutropenia being the most frequently reported side effect.
Preliminary antitumor activity was impressive, with 1 complete response, 4 partial
responses, and 4 stable diseases reported among the twelve patients enrolled in the pilot
study. A final phase I study combining topotecan and docetaxel was also conducted at The
University of Wisconsin by Stella and colleagues. In this trial docetaxel was administered
IV on day 1 followed by daily IV bolus Topotecan on days 1-5. In contrast to the previous
studies, prophylactic growth factor support was not administered following chemotherapy
administration. Because of significant myelosuppression at the initial dose level, the
protocol was amended and the starting dose of Topotecan was reduced. As expected, the
dose-limiting toxicity was myelosuppression consisting of both neutropenia and
thrombocytopenia. The maximum tolerated dose for the combination regimen was docetaxel 60
mg/m2 IV on day 1 followed by Topotecan 0.75 mg/m2/d on days 1-5.

Recently, the combination of Topotecan and Taxotere has been used in a Phase I setting in
platinum sensitive patients with recurrent ovarian and primary peritoneal cancers. Eleven
patients have been treated to date with weekly docetaxel 30 mg/m2/wk plus topotecan 3.5
mg/m2/wk. Two patients were non-evaluable, one due to rapidly progressive disease and one
due to noncompliance. Of the nine evaluable patients, five patients experienced
dose-limiting toxicities as follows,

1. cycle 1 day 15 (C1D15) held due to platelets 33K in a heavily pretreated patient,
including previous oxaliplatin,

2. C1D15 dose decreased due to grade 3 diarrhea,

3. C1D8 held due to grade 3-4 nausea and vomiting (may have been disease related),

4. C1D15 held due to platelets 49 K (74 yo, heavily pretreated including previous XRT),

5. C1D15 held due to platelets 43K and declining creatinine clearance of 43 ml/min (3
prior regimens, including XRT, PS 2 and history of thrombocytopenia).

One additional patient is planned to complete this dose level, to provide 10 evaluable
patients. Of the 36 patients receiving 76 cycles of therapy, myelosuppression was brief and
reversible with no febrile neutropenia. Per verbal communication from Dr. Burris, the
recommended phase II dose will be docetaxel 30 mg/m2/wk plus topotecan 3.5 mg/m2/wk on days
1, 8 and 15 every 28 days for minimally pretreated patients.

In addition to possible synergy with this combination of drugs in other tumor types, the
weekly dosing may have a better safety profile. The dose-limiting toxicity for Topotecan
when administered on a daily x 5-administration schedule is myelosuppression. However, when
the drug is administered on a weekly administration schedule, the myelosuppression is
ameliorated and is no longer dose limiting. Additionally, weekly docetaxel administration
is gaining in popularity in the clinical arena due to the improved toxicity profile of the
drug. The possibility of synergy with the improved safety profile secondary to weekly
dosing makes this combined dosing regimen a rational possibility for this patient
population.