Efficacy Study of Weekly Taxotere and Topotecan for Recurrent Gynecologic (GYN) Cancers
Information source: Montefiore Medical Center
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Ovarian Neoplasms; Uterine Neoplasms
Intervention: Topotecan and Taxotere (Drug)
Phase: Phase 2
Sponsored by: Montefiore Medical Center
Official(s) and/or principal investigator(s):
Mark H Einstein, M.D., M.S., Principal Investigator, Affiliation: Montefiore Medical Center and Albert Einstein College of Medicine
The primary aim of this study is:
- To determine the overall clinical response rate of weekly Topotecan and Taxotere in
women with recurrent ovarian, primary peritoneal, endometrial and uterine cancers.
The secondary aims of this study are:
- To evaluate the safety and tolerability of the combination therapy with weekly Topotecan
and Taxotere in patients with recurrent ovarian, primary peritoneal, endometrial or
- To determine the progression free survival and overall survival in women treated with
weekly Topotecan and Taxotere in patients with recurrent ovarian, primary peritoneal,
endometrial and uterine cancers who have been previously treated with chemotherapy
and/or radiation therapy.
Official title: Phase II Trial- Weekly Taxotere and Topotecan for Recurrent Ovarian, Primary Peritoneal, Endometrial and Uterine Cancers
Study design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Primary outcome: To determine the overall clinical response rate of weekly Topotecan and Taxotere in women with recurrent ovarian, primary peritoneal, endometrial and uterine cancers
To evaluate the safety and tolerability of weekly Topotecan and Taxotere in patients with recurrent ovarian, primary peritoneal, endometrial or uterine cancers
To determine the progression free survival and overall survival with weekly Topotecan and Taxotere in patients with recurrent ovarian, primary peritoneal, endometrial and uterine cancers who have been previously treated with chemotherapy
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
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
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
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.
Minimum age: 18 Years.
Maximum age: N/A.
- Histologically documented recurrent endometrial adenocarcinoma, papillary serous
(UPSC), or mixed mullerian tumor (MMT) for which a cure or substantial palliation is
unlikely using surgery and/or radiotherapy. Patients must have measurable disease or
disease felt to be reproducibly measurable on CT scan, chest x-ray and/or tumor marker
- Recurrent ovarian or primary peritoneal cancers as defined as either:
1. Measurable disease either by physical examination or by imaging or
2. Non-measurable evidence of disease such as any or all of the following standard
1. Peritoneal implants <2 cm
2. Abnormal densities on computerized tomography (CT) scan and/or loculated
3. Elevated CA-125 (>100 U/mL on 2 measurements at least 1 week apart) and
disease- related symptoms.
- Patients with the following histologic ovarian or uterine epithelial cell types are
- Serous adenocarcinoma
- Endometrioid adenocarcinoma
- Mucinous adenocarcinoma
- Undifferentiated carcinoma
- Clear cell adenocarcinoma
- Mixed epithelial carcinoma
- Transitional cell
- Malignant Brenner’s tumor
- Adenocarcinoma NOS
- Age ≥ 18 years.
- ECOG performance status of ≤ 2.
- Peripheral neuropathy must be ≤ grade 1
- Previously treated patients must have received no antineoplastic treatment for at
least 4 weeks. Patients will not have received more than two previous chemotherapy
- In patients previously irradiated, the recurrent disease should be outside of the
radiotherapy portal or have developed disease progression within the radiated field.
- No concurrent chemotherapy, radiotherapy, immunotherapy, or hormone therapy.
- Total bilirubin ≤ ULN
- AST and ALT and alkaline phosphatase must be within the range allowing for
- Patients must be alert, oriented, and have signed an informed consent in accordance
with institutional policies and be aware of the investigational nature of the study.
- Women of childbearing potential must be willing to consent to using effective
contraception while on treatment and for at least 3 months thereafter
- Patient has impairment of hepatic, renal or hematologic function as defined by the
following baseline laboratory values:
1. Serum creatinine clearance ≤ 50 ml/min
2. Platelets <100,000/mm3
3. Absolute neutrophil count (ANC) <1500/mm3
4. Hemoglobin <8. 0 g/dl (the patient may be transfused prior to study entry)
- History of chronic or active hepatitis
- Patient has severe or uncontrolled medical disease (eg. uncontrolled diabetes,
unstable angina, myocardial infarction within 6 months, congestive heart failure,
- Patients with dementia or altered mental status that would prohibit the giving and
understanding of informed consent at time of study entry.
- Patients with a history of severe hypersensitivity to Taxotere®, Topotecan®, or other
drugs formulated with polysorbate 80.
- Women who are pregnant or breast-feeding
Locations and Contacts
Montefiore Medical Center, Bronx, New York 10461, United States
Starting date: November 2004
Ending date: March 2007
Last updated: April 18, 2007