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Cisplatin Induction Followed by Paclitaxel Consolidation for the Treatment of Stage III and IV Epithelial Ovarian Cancer and Primary Peritoneal Cancer With In Vitro Correlates of Response

Phase 2
18 Years
Not Enrolling
Epithelial Ovarian Cancer, Primary Peritoneal Cancer

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Trial Information

Cisplatin Induction Followed by Paclitaxel Consolidation for the Treatment of Stage III and IV Epithelial Ovarian Cancer and Primary Peritoneal Cancer With In Vitro Correlates of Response

Malignant neoplasms of the ovary are the cause of more deaths than any other gynecologic
cancer. Approximately 26,500 new cases are diagnosed each year in the United States, and
about 14,500 deaths occur annually as a result of this disease. Clinicians continue to be
frustrated by both the paucity of data concerning the etiologic factors in epithelial
ovarian cancer and by the failure to achieve a significant reduction in mortality over the
past several decades.

Since the introduction of cisplatin-based chemotherapy, no treatment has been shown to
improve survival in subjects with advanced ovarian cancer until the incorporation of
paclitaxel into primary therapy for this disease. In 1996, the Gynecologic Oncology Group
(GOG) published the results of a large prospective, randomized trial of cisplatin and
cyclophosphamide compared to cisplatin and paclitaxel. The cisplatin plus paclitaxel
regimen was noted to be superior based on: 1) an overall improved response rate; 2) an
increased clinical response rate (51% vs. 31%); 3) an increased rate of negative second look
laparotomies; 4) an increase in median progression free survival; and importantly 5) an
increased overall median survival (38 months vs. 24 months). The GOG results were recently
confirmed by the Canadian- European consortium randomized phase III trial (OV 10).

These large randomized trials established the combination of paclitaxel and cisplatin as the
standard, first line therapy for women with advanced ovarian cancer following cytoreductive
surgery. Although the majority of women with advanced ovarian cancer will demonstrate an
objective response to this combination; the response is generally of limited duration. The
five-year survival for advanced stage ovarian cancer is 20-40%. Consequently, there remains
a need for an improved chemotherapeutic approach in the management of ovarian cancer.

Topotecan is a semi-synthetic analog of camptothecin, a topoisomerase inhibitor. It has been
investigated in a number of phase II trials as salvage therapy for recurrent ovarian cancer.
Overall response rates have ranged from 6% to 27%. In a randomized comparative trial of
topotecan versus paclitaxel, overall response rates were 21% and 14% respectively. The
median survival for topotecan was 63 weeks as compared to 53 weeks for paclitaxel. Both
drugs demonstrated higher response rates in platinum-sensitive tumors than
platinum-resistant tumors. These data suggest that topotecan may be as active as
paclitaxel, and partially non-cross resistant with cisplatin.

Topotecan may be a better agent than paclitaxel for use in combination with cisplatin for
multiple reasons. First, Kern et al demonstrated that paclitaxel may antagonize the
activity of cisplatin. Second, topotecan has been demonstrated to be synergistic with both
cisplatin and paclitaxel in vitro. It has been demonstrated that topotecan can dramatically
potentiate the effects of platinum, perhaps by its ability to inhibit repair of platinum-DNA

Clinically, there has been extensive experience with topotecan and cisplatin. Recently,
several investigators have evaluated the combination of paclitaxel, cisplatin and topotecan.
As expected, myelosuppression was the dose-limiting factor. Herben et al recently reported
the results of a phase I trial using the combination of paclitaxel, cisplatin, and topotecan
as first line therapy in advanced stage ovarian cancer. Interestingly, the authors could not
achieve a dose of topotecan that would be considered "optimal" for the treatment of relapsed
disease in a single-agent fashion. The inability to utilize a therapeutic dose when
combined with either platinum or paclitaxel has been demonstrated in previous reports and
affirms the bone marrow suppressive effect. The clinical response rate from this trial was
reported as 86.7%.

Inclusion Criteria

Eligible Subjects:

1. Subjects with a histologic diagnosis of epithelial ovarian cancer or primary
peritoneal carcinoma, stage III or IV, as outlined above. All subjects must have
appropriate surgery for ovarian carcinoma with appropriate tissue for histologic
evaluation and evaluated by the EDR assay.

2. Eligible cell types include:

Serous adenocarcinoma Endometrioid adenocarcinoma Mucinous adenocarcinoma
Undifferentiated carcinoma Clear cell adenocarcinoma Mixed epithelial carcinoma
Transitional cell carcinoma Malignant Brenner's Tumor

3. Adequate bone marrow, renal, and hepatic function as defined by WBC3000cells/mcl,
platelets 100,000/mcl, serum creatinine 2mg/dcl, bilirubin 1.5times normal, and SGOT
3 times normal.

4. Subjects with GOG Performance Status of 0, 1, or 2.

5. Subjects must have a complete history and physical examination done by the
investigators of this study. Also, CBC with differential, electrolytes, serum
creatinine, liver function tests and CA 125 must be done 14 days prior to

6. Subjects must be informed of the investigational nature of this study and must
provide informed consent in accordance with institutional and federal guidelines.

7. All subjects must have histologic slides available for pathology review.

8. Subjects must be entered within six weeks of surgery.

Ineligible Subjects:

1. Subjects with epithelial ovarian carcinoma of low malignant potential.

2. Subjects who have received prior radiotherapy or chemotherapy.

3. Subjects with septicemia, severe infection, or acute hepatitis.

4. Subjects with severe gastrointestinal bleeding.

5. Subjects with a GOG Performance Status of 3 or 4.

6. Subjects with other invasive malignancies, with the exception of non-melanoma skin
cancer, who had or have any evidence of other cancer within the last 5 years or whose
previous cancer treatment contradicts this protocol therapy.

7. Subjects who are pregnant will be excluded.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Recurrence-Free Interval

Principal Investigator

John P Fruehauf, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Chao Family Comprehensive Cancer Center


United States: Institutional Review Board

Study ID:

UCI 99-25



Start Date:

September 2005

Completion Date:

April 2007

Related Keywords:

  • Epithelial Ovarian Cancer
  • Primary Peritoneal Cancer
  • Ovarian
  • Peritoneal
  • Ovarian Neoplasms
  • Peritoneal Neoplasms
  • Neoplasms, Glandular and Epithelial



Chao Family Comprehensive Cancer CenterOrange, California  92868