Testing the Addition of a New Anti-Cancer Drug, Triapine, to the Usual Chemotherapy Treatment (Cisplatin) During Radiation Therapy for Advanced-stage Cervical and Vaginal Cancers
Testing the Addition of a New Anti-Cancer Drug, Triapine, to the Usual Chemotherapy Treatment (Cisplatin) During Radiation Therapy for Advanced-stage Cervical and Vaginal Cancers
This randomized phase III trial studies radiation therapy and cisplatin with triapine to see
 how well they work compared to the standard radiation therapy and cisplatin alone in treating
 patients with newly diagnosed stage IB2, II, or IIIB-IVA cervical cancer or stage II-IVA
 vaginal cancer. Radiation therapy uses high energy protons to kill tumor cells and shrink
 tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the
 growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
 stopping them from spreading. Triapine may stop the growth of tumor cells by blocking some of
 the enzymes needed for cell growth. It is not yet known whether radiation therapy and
 cisplatin are more effective with triapine in treating cervical or vaginal cancer.
PRIMARY OBJECTIVE:

 I. To evaluate the efficacy of the experimental regimen of triapine (3AP), cisplatin, and
 radiation to increase overall survival relative to the standard/control regimen of cisplatin
 and radiation in women with uterine cervix or vaginal cancer.

 SECONDARY OBJECTIVE:

 I. To determine the relative progression-free survival impact of triapine-cisplatin
 radio-chemotherapy and cisplatin radio-chemotherapy.

 TERTIARY OBJECTIVES:

 I. 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. (05/30/2017) II. To summarize and compare differences in
 acute adverse events (Common Terminology Criteria for Adverse Events [CTCAE], version [v]4.0)
 by treatment arm and by radiation modality. (05/30/2017) III. 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. (05/30/2017) IV. To determine
 peripheral blood methemoglobin proportion before and after triapine infusion (optional for
 Arm 2 patients).

 V. 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.

 VI. To determine the post-therapy 3-month fludeoxyglucose F-18 (18F-FDG) PET/CT metabolic
 complete response rate by treatment arm VII. To compare acute toxicity and chemotherapy
 delivery for atlas-based IG-IMRT vs. positron emission tomography (PET)/computed tomography
 (CT)-based IG-IMRT vs. conventional radiation therapy (RT), and assess the impact of
 treatment on changes in hematopoietic compensatory response.

 VIII. To develop and validate machine learning and radiomics techniques for dose
 accumulation, automated treatment planning, and prediction of treatment response.

 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 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 (> 4 cm), II, IIIB or IVA
 squamous, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix (FIGO 2009)
 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; NOTE: 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 because of the potential for pharmacokinetic interactions with triapine

 -  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 as the
 condition interferes with triapine antidote metabolism (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; 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 does not 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
 (05/30/2017)

 -  Patients scheduled to be treated with adjuvant consolidation chemotherapy or other
 anti-neoplastic therapy at the conclusion of their standard chemoradiation
 (05/30/2017)

 -  Patients with self-reported or known diagnosis of G6PD deficiency (05/30/2017)

 -  Patients with vaginal cancer may have previously undergone a hysterectomy for various
 indications; patients with vaginal cancer who underwent a hysterectomy for treatment
 of cervical cancer less than five years prior to their diagnosis of vaginal cancer are
 ineligible