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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Advanced Vaginal Adenocarcinoma, Advanced Vaginal Adenosquamous Carcinoma, Advanced Vaginal Squamous Cell Carcinoma, Cervical Adenocarcinoma, Cervical Adenosquamous Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB2 Cervical Cancer AJCC v6 and v7, Stage II Cervical Cancer AJCC v7, Stage II Vaginal Cancer AJCC v6 and v7, Stage IIA Cervical Cancer AJCC v7, Stage IIB Cervical Cancer AJCC v6 and v7, Stage III Vaginal Cancer AJCC v6 and v7, Stage IIIB Cervical Cancer AJCC v6 and v7, Stage IV Vaginal Cancer AJCC v6 and v7, Stage IVA Cervical Cancer AJCC v6 and v7, Stage IVA Vaginal Cancer AJCC v6 and v7, Unresectable Vaginal Carcinoma, Vaginal Adenocarcinoma, Vaginal Adenosquamous Carcinoma, Vaginal Carcinoma, Vaginal Squamous Cell Carcinoma, Not Otherwise Specified

Intervention / Treatment
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* Radiation: Brachytherapy
* Drug: Cisplatin
* Radiation: External Beam Radiation Therapy
* Radiation: Intensity-Modulated Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Radiation: Radiation Therapy
* Drug: Triapine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (cisplatin, IMRT or RT, brachytherapy)<br>Patients receive cisplatin 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 EBRT (either conventional RT or IMRT) QD 5 days a week for 25 fractions followed by LDR or HDR brachytherapy according to institution's standards. Treatment continues in the absence of disease progression or unacceptable toxicity. | Radiation: Brachytherapy<br>* Undergo brachytherapy<br>* Other names: Radiation, Internal;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Radiation Therapy<br>* Undergo conventional RT<br>* Other names: Therapy, Radiation;|
| Experimental: Arm II (cisplatin, IMRT or RT, brachytherapy, triapine)<br>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. | Radiation: Brachytherapy<br>* Undergo brachytherapy<br>* Other names: Radiation, Internal;Drug: Cisplatin<br>* Given IV<br>* Other names: Platosin;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Radiation, Intensity-Modulated Radiotherapy;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Radiation: Radiation Therapy<br>* Undergo conventional RT<br>* Other names: Therapy, Radiation;Drug: Triapine<br>* Given IV<br>* Other names: PAN-811;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Product-limit estimates according to the method of Kaplan and Meier and the one sided log-rank test (alpha = 0.1) will be used to compare survival endpoint (OS) between treatment arms. In addition, adjusted hazard ratios and respective 95% confidence intervals will be calculated using the Cox proportional hazards regression model. | Time (in months) since registration (and randomization) onto the study to the date death or last contact, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Product-limit estimates according to the method of Kaplan and Meier and the one sided log-rank test (alpha = 0.1) will be used to compare survival endpoint (PFS) between treatment arms. In addition, adjusted hazard ratios and respective 95% confidence intervals will be calculated using the Cox proportional hazards regression model. | Time (in months) since registration (and randomization) onto the study to the date of first documented recurrence/progression, death or last follow-up visit (contact), assessed up to 5 years | 
| Metabolic complete response (mCR) | Will be assessed by fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET)/computed tomography (CT). Frequency of mCR will be tabulated and the probability of attaining a mCR will be estimated. Differences in mCR rate between treatment arms will be assessed using either the Chi-square or Fisher's exact test. The relationship between patients' mCR status at T1 (yes or no) and PFS (and/or OS) will be assessed using regression models to facilitate evaluation of mCR as secondary short term endpoint for patient outcome. | Up to 3 months after completion of treatment | 
| Incidence of acute adverse events | Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The frequency and severity of adverse events will be assessed. Maximum grade of adverse effect will be tabulated for each adverse event and significance of observed differences between treatments arms within each adverse event category will be assessed using Chi-square or Fishers' exact test. | Up to 30 days after completion of study treatment | 
| Treatment compliance (amount of radiation, cisplatin and triapine administered, incidence and duration of treatment delays, reason for delays, and reason why off study therapy) | Treatment compliance will be evaluated and reported. | Up to 5 years | 
| Incidence of hematologic and gastrointestinal (GI) adverse events | Will be assessed by CTCAE version 4. The frequency and severity of adverse events will be assessed. Maximum grade of adverse effect will be tabulated for each adverse event and significance of observed differences between treatments arms within each adverse event category will be assessed using Chi-square or Fishers' exact test. | Up to 30 days after completion of study treatment | 
| Incidence of chronic or late adverse events | Will be assessed by CTACE version 4. The frequency and severity of adverse events will be assessed. Maximum grade of adverse effect will be tabulated for each adverse event and significance of observed differences between treatments arms within each adverse event category will be assessed using Chi-square or Fishers' exact test. | Up to 5 years |