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

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.

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