Radiation Therapy and Cisplatin With or Without Triapine in Treating Patients With Newly Diagnosed Stage IB2, II, or IIIB-IVA Cervical Cancer or Stage II-IVA Vaginal Cancer

PRIMARY OBJECTIVES:

I. 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.

SECONDARY OBJECTIVES:

I. To determine the post-therapy 3-month fludeoxyglucose F-18 (18F-FDG) positron emission
tomography (PET)/computed tomography (CT) metabolic complete rate of response rate in the
cervix and vaginal by treatment arm.

II. To determine overall survival after triapine-cisplatin radio-chemotherapy and cisplatin
radio-chemotherapy.

III. To evaluate incidence and severity of hematologic and gastrointestinal (GI) adverse
events by radiation modality; image guided intensity modulated radiation therapy (IG-IMRT)
versus conventional pelvic radiotherapy.

IV. To summarize and compare differences in acute adverse events (Common Terminology Criteria
for Adverse Events [CTCAE], version [v]4.0) by treatment arm and radiation modality.

V. 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.

TERTIARY OBJECTIVES:

I. To determine peripheral blood methemoglobin proportion before and after triapine infusion
(optional for Arm 2 patients).

II. To explore 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 normal tissue complication probability (NTCP) models, and determine whether KBP should
be a requirement for future IG-IMRT protocols.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cisplatin intravenously (IV) over 90 minutes on days 2, 9, 16, 23,
30, (and day 36 or 37 at the treating physician's discretion). Patients then undergo external
beam radiation therapy (EBRT) (either conventional radiation therapy [RT] or intensity
modulated radiation therapy [IMRT]) once daily (QD) 5 days a week for 25 fractions followed
by low dose rate (LDR) or high dose rate (HDR) brachytherapy according to institution's
standards. Treatment continues in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients receive cisplatin and undergo EBRT followed by brachytherapy as in Arm I.
Patients also receive triapine IV over 2 hours on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22,
24, 26, 29, 31, and 33. Treatment continues in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 and 3 months, every 3
months for 2 years, and then every 6 months for 3 years.

The patient data from NCI #9434 will be merged with NRG-GY006 per the Protocol Analysis Plan.

Inclusion Criteria:

- Patient 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

- Patient must provide study specific informed consent prior to study entry

- Patient must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2
or equivalent

- Absolute neutrophil count > 1,500/uL

- Platelets > 100,000/uL

- Hemoglobin > 10 g/dL

- Total bilirubin < 2.0 mg/dL

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal

- Prothrombin time (PT)/activated partial thromboplastin time (aPTT) < 1.5 X
institutional upper limit of normal

- Creatinine =< 1.5 mg/dL to receive weekly cisplatin

- Patients whose serum creatinine is between 1.5 and 1.9 mg/dL are eligible for
cisplatin if the estimated creatinine clearance (CCr) is >= 30 ml/min; for the
purpose of estimating the CCr, the formula of Cockcroft and Gault for females
should be used

- Patient does not have uncontrolled diabetes mellitus (i.e., fasting blood glucose >
200 mg/dL)

- Patient has a life expectancy of greater than 20 weeks

- Patient does not have known brain metastases (testing optional)

- Patient does not have known human immunodeficiency virus syndrome (HIV, testing
optional); known HIV-positive patients receiving combination antiretroviral therapy
are ineligible

- Patient does not have a known allergy to compounds of similar or biologic composition
as triapine

- Patient does not have known glucose‐6‐phosphate dehydrogenase (G6PD) deficiency (G6PD
testing optional)

- Patient is not actively breastfeeding (or has agreed to discontinue breastfeeding
before the initiation of protocol therapy)

Exclusion Criteria:

- Patient has another concurrent active invasive malignancy

- Patient has had a prior invasive malignancy diagnosed within the last three years
(except [1] non-melanoma skin cancer or [2] 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

- Patient 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

- Patient is receiving another investigational agent for the treatment of cancer

- Patient is currently pregnant; patient must agree to use two forms of birth control if
they are of child-bearing potential

- Patients who have had a hysterectomy or are planning to have an adjuvant hysterectomy
following radiation as part of their cervical cancer treatment are ineligible

- Patients scheduled to be treated with adjuvant consolidation chemotherapy at the
conclusion of their standard chemoradiation

- Patients with self-reported or known diagnosis of G6PD deficiency