Tirapazamine, Cisplatin, and Radiation Therapy in Treating Patients With Stage IB, Stage II, Stage III, or Stage IVA Cervical Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as tirapazamine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Tirapazamine may help cisplatin kill more tumor cells by making tumor cells more sensitive to the drug. Radiation therapy uses high-energy x-rays to kill tumor cells. Tirapazamine may also make tumor cells more sensitive to radiation therapy. Giving radiation therapy in different ways together with combination chemotherapy may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of tirapazamine when given together with cisplatin and radiation therapy in treating patients with stage IB, stage II, stage III, or stage IVA cervical cancer.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose and the recommended phase II and III dose of tirapazamine when combined with cisplatin and radiotherapy in patients with Stage IB-IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the cervix. Determine the safety and tolerability of this regimen in these patients. Secondary Determine failure-free survival of patients treated with this regimen. Determine overall survival of patients treated with this regimen. Determine time to locoregional failure in patients treated with this regimen. Determine patterns of failure for the site of first failure in patients treated with this regimen. Determine the 12-week post-treatment complete response rate in patients treated with this regimen. OUTLINE: This is a multicenter, dose-escalation study of tirapazamine. Patients receive tirapazamine IV over 2 hours on day 1 of weeks 1-5 and on days 3 and 5 of weeks 1 and 2 (cohort 2 only), OR days 3 and 5 of weeks 1-4 (cohort 3 only). Patients also receive cisplatin IV over 1 hour on day 1 of weeks 1-6. Patients concurrently undergo external beam radiotherapy once daily on days 1-5 for 5-5.5 weeks. After completion of chemoradiotherapy, patients undergo low-dose brachytherapy (up to 2 implants within an 8-week period) OR high-dose brachytherapy twice weekly for 5 treatments. Treatment continues in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of tirapazamine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 10 patients are treated at the MTD. Patients are followed at 2, 4, and 8 weeks, at 3 and 6 months, every 3 months for 2 years, and then every 6 months for 2 years. PROJECTED ACCRUAL: A total of 3-22 patients will be accrued for this study.

Official Title
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A Phase I Study Of Tirapazamine In Combination With Radiation And Weekly Cisplatin In Patients With Locally Advanced Cervical Cancer

Conditions
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Cervical Cancer

Intervention / Treatment
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* Drug: cisplatin
* Drug: tirapazamine
* Radiation: brachytherapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the cervix Stage IB, IIA, IIB, III, or IVA disease No evidence of involvement of para-aortic nodes by CT scan, MRI, fluorodeoxyglucose positron emission tomography, or lymphadenectomy Involvement of common iliac nodes allowed No evidence of distant metastases PATIENT CHARACTERISTICS: Age Any age Performance status ECOG 0-2 Life expectancy More than 6 months Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic Bilirubin < 1.25 times upper limit of normal (ULN) AST and ALT ≤ 3 times ULN Renal Calculated creatinine clearance ≥ 60 mL/min OR Glomerular filtration rate ≥ 60 mL/min Cardiovascular No significant cardiac disease that would preclude IV fluid load required for administration of cisplatin No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Other No symptomatic peripheral neuropathy ≥ grade 2 No clinically significant sensori-neural hearing impairment interfering with activities of daily living or requiring a hearing aid Audiometric changes alone of any severity allowed No history of allergic reaction attributed to compounds of similar chemical or biological composition to tirapazamine or cisplatin No other invasive malignancy within the past 5 years except nonmelanoma skin cancer No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No other concurrent uncontrolled illness Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent epoetin alfa No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF) No concurrent pegfilgrastim Chemotherapy No prior chemotherapy for another malignancy Endocrine therapy Not specified Radiotherapy No prior pelvic or abdominal radiotherapy for another malignancy No prior radiotherapy to ≥ 15% of bone marrow-bearing areas No concurrent intensity-modulated radiotherapy No concurrent interstitial brachytherapy Surgery Not specified Other No prior treatment for invasive cervical cancer No other concurrent therapeutic investigational agents No other concurrent anticancer therapy No concurrent systemic retinoids No concurrent amifostine No concurrent combination antiretroviral therapy for HIV-positive patients
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cisplatin|nan|
|Drug: tirapazamine|nan|
|Radiation: brachytherapy|nan|
|Radiation: radiation therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of tirapazamine |  |  | 
| Safety and tolerability |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-free survival |  |  | 
| Overall survival |  |  | 
| Patterns of failure for the site of first failure (local-regional, distant, or both) |  |  | 
| Complete response rate at 12 weeks following study completion |  |  | 
| Hypoxia by 18F-azomycinarabinoside (FAZA) PET scan at baseline and 12 wks following completion of radiotherapy correlated w/ obj. tumor response by PET- fludeoxyglucose F 18 (FDG) and local-regional failure |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IB cervical cancer, stage IIA cervical cancer, stage IIB cervical cancer, stage III cervical cancer, stage IVA cervical cancer, cervical adenocarcinoma, cervical adenosquamous cell carcinoma, cervical squamous cell carcinoma