A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination with Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer
The purpose of this study is to compare any good or bad effects of adding triapine to the usual cisplatin chemotherapy and radiation therapy, compared to using cisplatin chemotherapy and radiation therapy alone. Triapine is an experimental drug being tested in the treatment of cervical cancer to improve the effects of standard radiotherapy with concurrent chemotherapy.
1.1 Primary Objective:
To evaluate the efficacy of the experimental regimen of triapine (3AP), cisplatin, and radiation to increase progression-free survival relative to the standard / control regimen of cisplatin and radiation in women with uterine cervix and vaginal cancer.
1.2 Secondary Objectives:
1.2.1 To determine the post-therapy 3-month 18F-FDG PET/CT metabolic complete response rate in the uterine cervix and vaginal by treatment arm.
1.2.2 To determine overall survival after triapine-cisplatin radio-chemotherapy and cisplatin radio-chemotherapy.
1.2.3 To test the hypothesis that image guided intensity modulated radiation therapy (IG-IMRT) reduces hematologic (as assessed by clinical laboratory and positron emission tomography tests) and gastrointestinal (GI) toxicity compared to conventional pelvic radiotherapy.
1.2.4 To test the hypothesis that IG-IMRT increases quality of life, with equal or superior progression-free survival and overall survival, compared to conventional pelvic radiotherapy.
1.2.5 To summarize and compare differences in acute adverse events (CTCAE, v4.0) by treatment arm and radiation modality.
1.2.6 To summarize and compare differences in chronic or late (>/= 30-days from off study treatment date) adverse events (CTCAE, v4.0) by treatment arm and by radiation modality.
1.3 Tertiary Objectives:
1.3.1 To determine peripheral blood methemoglobin proportion before and after triapine infusion (optional for Arm 2 patients).
1.3.2 To determine whether knowledge-based planning (KBP) can improve IG-IMRT plans compared to plans that would have been delivered without KBP, estimate the resulting toxicity reduction using NTCP models, and determine whether KBP should be a requirement for future IG-IMRT protocols.
Potential participant has a new, unrated histologic diagnosis of stage IB2 (> 5 cm), II, IIIB or IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix or stage II-IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the vagina not amenable to curative surgical resection alone ; the presence or absence of para‐aortic lymph node metastasis will be based on pre-therapy 18F‐FDG PET/CT; if the baseline 18F‐FDG PET/CT identifies hypermetabolic para‐aortic disease, such patients will NOT be eligible; the patient must be able to tolerate imaging requirements of an 18F‐FDG PET/CT scan
Must provide study specific informed consent prior to study entry
Must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2 or equivalent
Adequate organ and marrow function as outlined in study documentation
Does not have uncontrolled diabetes mellitus (i.e., fasting blood glucose > 200 mg/dL)
Has a life expectancy of greater than 20 weeks
Does not have known brain metastases (testing optional)
Does not have known human immunodeficiency virus syndrome (HIV, testing optional); known HIV-positive patients receiving combination antiretroviral therapy are ineligible
Does not have a known allergy to compounds of similar or biologic composition as triapine
Does not have known glucose‐6‐phosphate dehydrogenase (G6PD) deficiency as the condition interferes with triapine antidote metabolism (G6PD testing optional)
Is not actively breastfeeding (or has agreed to discontinue breastfeeding before the initiation of protocol therapy)
Potential participant has another concurrent active invasive malignancy
Has had a prior invasive malignancy diagnosed within the last three years (except  non-melanoma skin cancer or  prior in situ carcinoma of the cervix); patients are excluded if they have received prior pelvic radiotherapy for any reason that would contribute radiation dose that would exceed tolerance of normal tissues at the discretion of the treating physician
Has uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within six months of protocol initiation, cardiac arrhythmia within six months of protocol initiation; known inadequately controlled hypertension; clinically significant pulmonary disease including dyspnea at rest, or patients requiring supplemental oxygen, or poor pulmonary reserve; proteinuria or clinically significant renal function impairment (baseline serum creatinine > 2 mg/dL); or psychiatric illness/social situations that would limit compliance with study requirements
Is receiving another investigational agent for the treatment of cancer
Is currently pregnant; participants must agree to use two forms of birth control if they are of child-bearing potential
Have had a hysterectomy or are planning to have an adjuvant hysterectomy following radiation as part of their cervical cancer treatment are ineligible
Scheduled to be treated with adjuvant consolidation chemotherapy at the conclusion of their standard chemoradiation
A self-reported or known diagnosis of G6PD deficiency
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