Trial Information

A Phase III, Randomized Trial of Weekly Cisplatin and Radiation Versus Cisplatin and Tirapazamine (IND #46525) and Radiation in Stage IB2, IIA, IIIB and IVA Cervical Carcinoma Limited to the Pelvis

PRIMARY OBJECTIVE:

I. Compare the progression-free survival of patients with stage IB, IIA, IIB, IIIB, or IVA
carcinoma of the cervix treated with cisplatin and radiotherapy with vs without
tirapazamine.

SECONDARY OBJECTIVES:

I. Compare overall survival of patients treated with these regimens. II. Compare the
toxicity of these regimens in these patients.

TERTIARY OBJECTIVES:

I. Correlate study treatment with tumor expression of carbonic anhydrase IX (CA-IX) and
recurrence-free survival, overall survival, or metastasis in patients treated with these
regimens.

II. Correlate expression of CA-IX, hypoxia inducible factor-1α, CD-31, thrombospondin-1,
CD-105, or vascular endothelial growth factor (VEGF) in primary tumor tissue with
recurrence-free survival, overall survival, or metastasis in patients treated with these
regimens.

III. Correlate pre-treatment and/or post-treatment serum concentrations of angiogenic
markers including angiogenin or VEGF with recurrence-free survival, overall survival, or
metastasis in patients treated with these regimens.

IV. Correlate various combinations of biological markers of hypoxia and angiogenesis with
recurrence-free survival, overall survival, or metastasis in patients treated with these
regimens.

V. Correlate levels of individual biological markers of hypoxia or angiogenesis with
clinicopathological characteristics including tumor size, histologic subtype, FIGO stage,
depth of invasion, pelvic node status, site of recurrence, and hemoglobin level as well as
patient, age, race and performance status in patients treated with these regimens.

OUTLINE: This is a randomized, controlled, multicenter study. Patients are stratified
according to FIGO stage of disease (IB2 vs IIA vs IIB vs IIIB vs IVA), brachytherapy method
(low-dose rate vs high-dose rate), surgical staging of para-aortic nodes (yes vs no).
Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cisplatin IV over 30-60 minutes once weekly on days 1, 8, 15, 22,
29, and 36 (weeks 1-6). Patients also undergo external beam radiotherapy to the pelvis once
daily on days 1-5, 8-12, 15-19, 22-26, and 29-33 (weeks 1-5). Patients then receive either 1
or 2 applications of low-dose rate brachytherapy in weeks 6-8 OR 5 applications of high-dose
rate (HDR)* brachytherapy once weekly in weeks 4-8 and 3-5 days of parametrial boost
radiotherapy** beginning after the first brachytherapy implant. Treatment continues in the
absence of disease progression or unacceptable toxicity.

ARM II: Patients receive tirapazamine IV over 2 hours on days 1, 8, 10, 12, 15, 22, 24, 26,
and 29 and cisplatin IV over 1 hour on days 1, 15, and 29. Patients also undergo
radiotherapy and brachytherapy as in arm I. Treatment continues in the absence of disease
progression or unacceptable toxicity.

NOTE: *No external beam radiotherapy is administered on the day of HDR brachytherapy. If the
majority of external beam radiotherapy has been administered, HDR brachytherapy may be
administered in 2 applications per week (separated by at least 72 hours) in order to
complete all treatment within 8 weeks.

NOTE: ** Patients may receive a parametrial boost at the discretion of the treating
radiation oncologist.

After completion of study treatment, patients are followed for at least 5 years.