Cisplatin and Radiation Therapy With or Without Tirapazamine in Treating Patients With Cervical Cancer

Phase 3

Terminated

Conditions: Cervical Adenocarcinoma
Cervical Adenosquamous Cell Carcinoma
Cervical Squamous Cell Carcinoma
Stage IB Cervical Cancer
Stage IIA Cervical Cancer
Stage IIB Cervical Cancer
Stage III Cervical Cancer
Stage IVA Cervical Cancer

Interventions: Drug: cisplatin
Drug: tirapazamine

Registration Number: NCT00262821

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This randomized phase III trial is studying cisplatin, radiation therapy, and tirapazamine to see how well they work compared to cisplatin and radiation therapy in treating patients with cervical cancer. Drugs used in chemotherapy, such as cisplatin and tirapazamine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Internal radiation uses radioactive material placed directly into or near a tumor to kill tumor cells. Cisplatin and tirapazamine may make tumor cells more sensitive to radiation therapy. It is not yet known whether giving cisplatin together with radiation therapy is more effective with or without tirapazamine in treating cervical cancer.

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: Female

Target Recruitment: 402

Inclusion Criteria

Histologically confirmed invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous cell carcinoma of the uterine cervix
- Stage IB2, IIA, IIB, IIIB, or IVA disease
  - Stage IIA tumors must be > 4 cm
- Primary, untreated disease
Negative, non-suspicious para-aortic nodes by lymphangiogram, CT scan, MRI, or lymphadenectomy
Must have been adequately clinically staged
Suitable for treatment with radical intent using concurrent chemotherapy and pelvic radiotherapy
No disease involvement of the lower third of the vagina regardless of stage (all stage IIIA, IIIB and IVA with lower one-third involvement)
No carcinoma of the cervical stump
Performance status - GOG 0-3
Absolute neutrophil count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
SGOT ≤ 3 times ULN
Alkaline phosphatase ≤ 3 times ULN
Creatinine ≤ ULN or calculated creatinine clearance ≥ 60mL/min
No New York Heart Association class III-IV heart failure
No history of myocardial infarction
No unstable angina
No uncontrolled hypertension
No pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No septicemia or severe infection
No other invasive malignancy within the past 5 years except nonmelanoma skin cancer
No prior hysterectomy or planned hysterectomy as part of initial cervix cancer therapy
No prior coronary artery bypass surgery
No prior cancer therapy that would preclude study treatment
No concurrent angina medication
No concurrent intensity-modulated radiotherapy

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (cisplatin, tirapazamine)	cisplatin	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.
Arm I (cisplatin)	cisplatin	Patients receive cisplatin IV on days 1, 8, 15, 22, 29, and 36 (weeks 1-6).
Arm II (cisplatin, tirapazamine)	tirapazamine	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.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival - Percentage of Patients Alive and Progression Free	From study entry until first disease progression, death or date of last contact, up to 6 years	Patients' progression status based on clinical, radiological or pathological (histological) evidence of disease after study therapy. Progression includes any death without evidence of disease progression. Progression-free Survival (PFS) is defined as time in month from study enrollment to disease progression, death or date of last contact.

Secondary Outcome Measures

Name	Time	Method
Adverse Events (Grade 3 or Higher) During Treatment Period	All Adverse Events (AEs) occuring during treatment and up to 30 days after stopping the study treatment are reported	Number of participants with a maximum grade of 3 or higher during treatment period. Adverse events are graded and categorized using CTCAE v3.0.
Overall Survival	From study entry to death or last contact, up to 6 years	The observed length of life from entry into the study to death or date of last contact.

Trial Locations

Locations (281): University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Mobile Infirmary Medical Center
🇺🇸
Mobile, Alabama, United States
Providence Alaska Medical Center
🇺🇸
Anchorage, Alaska, United States
Banner Good Samaritan Medical Center
🇺🇸
Phoenix, Arizona, United States
Western Regional CCOP
🇺🇸
Phoenix, Arizona, United States
Highlands Oncology Group PA - Fayetteville
🇺🇸
Fayetteville, Arkansas, United States
Washington Regional Medical Center - Fayetteville
🇺🇸
Fayetteville, Arkansas, United States
University of Arkansas for Medical Sciences
🇺🇸
Little Rock, Arkansas, United States
East Bay Radiation Oncology Center
🇺🇸
Castro Valley, California, United States
City of Hope Medical Center
🇺🇸
Duarte, California, United States
Scroll for more (271 remaining)
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States