Combination Chemotherapy and Autologous Peripheral Stem Cell Transplant in Treating Patients With Stage III, Stage IV, or Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cancer, or Fallopian Tube Cancer

Phase I Trial of Tandem Chemotherapy Cycles as Consolidation Therapy for High-Risk Epithelial Ovarian and Primary Peritoneal Cancer Utilizing Intraperitoneal Paclitaxel/IV Cyclophosphamide Followed by IV Topotecan/Intraperitoneal Cisplatin/IV Melphalan Using Hematopoietic Stem Cell Support

RATIONALE: Giving chemotherapy before a peripheral stem cell transplant stops the growth of tumor cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

PURPOSE: This phase I trial is studying the side effects and best dose of topotecan when given together with cyclophosphamide, paclitaxel, melphalan, and cisplatin, followed by an autologous peripheral stem cell transplant in treating patients with stage III, stage IV, or recurrent ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cavity Cancer
• Intervention / Treatment: Drug: cyclophosphamide; Genetic: gene expression analysis; Other: pharmacological study; Drug: cisplatin; Procedure: peripheral blood stem cell transplantation; Drug: paclitaxel; Biological: filgrastim; Drug: melphalan; Other: immunohistochemistry staining method; Drug: topotecan hydrochloride; Genetic: TdT-mediated dUTP nick end labeling assay

Detailed Description

OBJECTIVES:

• To establish the maximum tolerated dose (MTD) of continuous infusion intravenous topotecan hydrochloride when administered with intraperitoneal (IP) cisplatin and intravenous melphalan in patients with stage III, stage IV, or recurrent ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer.
• To describe the toxicities of each dose studied.
• To evaluate the pharmacokinetics of topotecan hydrochloride when administered at the maximum tolerated dose and cisplatin.
• To confirm the pharmacokinetic advantage of high-dose IP cisplatin and IP paclitaxel.
• To obtain tissue at the time of peritoneal catheter placement in order to evaluate the molecular determinants of apoptosis (including p53 status, p21 gene expression, bcl-2 gene expression, and bcl-2/bax ratio) and the extent of apoptosis by the TdT assay.
• To evaluate the molecular determinants of DNA damage and repair, including expression levels of ERCC1 and MDR1, and HER2/neu expression by immunohistochemistry.

OUTLINE: This is a dose-escalation study of topotecan hydrochloride.

Patients undergo surgical placement of an intraperitoneal (IP) catheter. Tumor biopsies are obtained during surgery for laboratory analysis of molecular determinants of apoptosis (including p53 status, p21 gene expression, bcl-2 gene expression, bcl-2/bax ratio) and molecular determinants of DNA damage and repair (including expression levels of ERCC1 and MDR1, and HER2/neu expression by immunohistochemistry). The extent of apoptosis is also assessed using the TdT assay.

• Course 1: Patients receive paclitaxel IP on day 1, cyclophosphamide IV on day 2, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 3 and continuing until apheresis is completed. Patients undergo apheresis until ≥ 2.5 X 10^6 CD34-positive cells/kg are collected. Two weeks later, patients proceed to course 2.
• Course 2: Patients receive cisplatin IP and melphalan IV on days -11 and -4 and topotecan hydrochloride by continuous infusion over 120 hours on days -10 to -6. Patients receive 25% of their peripheral blood stem cells (PBSCs) on day -3 and G-CSF IV beginning on day -3 and continuing until blood counts recover. Patients receive their remaining PBSCs on day 0.

Patients undergo daily blood sample collection during topotecan hydrochloride administration for pharmacokinetic studies. Patients treated at the maximum tolerated dose of topotecan hydrochloride undergo additional blood sample collections for pharmacokinetic studies.

After completion of study therapy, patients are followed every 3 months.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed ovarian epithelial carcinoma, primary peritoneal cavity carcinoma, or epithelial carcinoma of the fallopian tubes, meeting 1 of the following criteria:

  • Stage III or IV disease that was treated with initial therapy comprising a standard platinum-containing regimen

    • Must have < 2 cm of residual disease with no evidence of disease progression after initial chemotherapy AND have no disease progression immediately prior to stem cell collection
    • Patients initially presenting with stage IV disease who have achieved a clinical response (complete response [CR] or partial response [PR]) after initial therapy are eligible

  • Responding recurrent disease

    • Patients who have had recurrence with elevated CA 125 levels (> 100 U/mL) and who have achieved a reduction of CA 125 level by 50% for 4 weeks following the most recent course of reinduction chemotherapy are eligible
    • Patients who have achieved a CR or PR after salvage chemotherapy for relapsed disease are eligible
• Patients with measurable or evaluable disease must have achieved a PR after prior therapy
• No clinically significant pleural effusions

PATIENT CHARACTERISTICS:

• Karnofsky performance status 70-100%
• ANC > 1,000/μL
• Platelet count > 100,000/μL
• Serum bilirubin < 1.5 mg/dL
• SGOT and SGPT ≤ 2.5 times normal
• Creatinine clearance ≥ 60 mL/min
• No active cardiac disease that, in the opinion of the investigator, would preclude safe administration of chemotherapy
• Cardiac ejection fraction normal at rest by MUGA
• No history of potentially disabling psychiatric disorders
• Hepatitis B antigen, hepatitis C antibody, and HIV antibody negative
• No clinically significant peripheral neuropathy
• FEV_1 ≥ 2.0 L or ≥ 75% of the lower limit of normal

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy or radiotherapy
• No prior radiotherapy to the whole abdomen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Toxicity
Time to progression
Progression-free survival
Overall survival
Disease progression
Tumor response
Reason patient is removed from study

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Robert J. Morgan, MD, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: January 1, 2001
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: October 22, 2007
• First Submitted That Met QC Criteria: October 25, 2007
• First Posted (Estimate): October 30, 2007

Study Record Updates

• Last Update Posted (Estimate): October 7, 2014
• Last Update Submitted That Met QC Criteria: October 3, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: stage III ovarian epithelial cancer; stage IV ovarian epithelial cancer; recurrent ovarian epithelial cancer; fallopian tube cancer; peritoneal cavity cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Cyclophosphamide; Paclitaxel; Melphalan; Topotecan
• Other Study ID Numbers: 00067; P30CA033572 (U.S. NIH Grant/Contract); CCC-PHI-31; CHNMC-00067; CDR0000567474 (Registry Identifier: NCI PDQ)