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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

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ClinicalTrials.gov Identifier: NCT02466971
Recruitment Status : Recruiting
First Posted : June 9, 2015
Last Update Posted : April 23, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE June 5, 2015
First Posted Date  ICMJE June 9, 2015
Last Update Posted Date April 23, 2019
Actual Study Start Date  ICMJE January 15, 2016
Estimated Primary Completion Date July 23, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2019)
Progression-free survival (PFS) [ Time Frame: 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 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 5, 2015)
Progression-free survival (PFS) [ Time Frame: Time (in months) since registration to date first documented recurrence, death or last follow-up visit (contact), assessed up to 5 years ]
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.
Change History Complete list of historical versions of study NCT02466971 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2019)
  • Overall survival (OS) [ Time Frame: Time (in months) since registration (and randomization) onto the study to the date death or last contact, assessed up to 5 years ]
    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.
  • Metabolic complete response (mCR) [ Time Frame: Up to 3 months after completion of treatment ]
    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.
  • Incidence of acute adverse events [ Time Frame: Up to 30 days after completion of study treatment ]
    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.
  • Treatment compliance (amount of radiation, cisplatin and triapine administered, incidence and duration of treatment delays, reason for delays, and reason why off study therapy) [ Time Frame: Up to 5 years ]
    Treatment compliance will be evaluated and reported.
  • Incidence of hematologic and gastrointestinal (GI) adverse events [ Time Frame: Up to 30 days after completion of study treatment ]
    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.
  • Incidence of chronic or late adverse events [ Time Frame: Up to 5 years ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 5, 2015)
  • Changes in the proportion of peripheral blood methemoglobin [ Time Frame: Baseline to 24 hours after triapine infusion ]
    Difference in peak or in trend of blood methemoglobin levels before and after triapine infusion will be assessed using two tailed paired T-test at alpha = 0.05 significance level. Depending on the observed within subjects correlation, repeated measures analysis of variance may be utilized instead.
  • Incidence of adverse events as assessed by CTCAE version 4.0 [ Time Frame: Up to 30 days after completion of study treatment ]
    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.
  • Metabolic complete response (mCR) assessed by 18F-FDG PET/CT [ Time Frame: Up to 3 months after completion of treatment ]
    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.
  • Overall survival (OS) [ Time Frame: Time (in months) since registration to date death or last contact, assessed up to 5 years ]
    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.
  • Site of recurrence [ Time Frame: Up to 5 years ]
    Recurrence is defined as clinical, radiological or histological evidence of recurrence of disease post study treatment. Site(s) of first recurrence will be classified as: pelvic region only, distant region only, both pelvic and distant or no recurrence, and tabulated by treatment group. The test of the hypothesis that the probability of local failure is independent of randomized treatment will be assessed with exact logistic regression adjusting for known prognostic factors.
  • Treatment compliance (amount of radiation, cisplatin and triapine administered, incidence and duration of treatment delays, reason for delays, and reason why off study therapy) [ Time Frame: Up to 5 years ]
    Treatment compliance will be evaluated and reported.
Current Other Pre-specified Outcome Measures
 (submitted: January 22, 2018)
  • Changes in the proportion of peripheral blood methemoglobin [ Time Frame: Baseline to 24 hours after triapine infusion ]
    Difference in peak or in trend of blood methemoglobin levels before and after triapine infusion will be assessed using two tailed paired T-test at alpha = 0.05 significance level. Depending on the observed within subjects correlation, repeated measures analysis of variance may be utilized instead.
  • Type of intensity modulated radiation therapy (IG-IMRT) [ Time Frame: Up to 5 years ]
    Will 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
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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
Official Title  ICMJE 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
Brief Summary 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

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 or 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 response rate in the uterine cervix and vaginal by treatment arm.

II. To determine overall survival after 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.

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.

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.

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 compare acute toxicity and chemotherapy delivery for atlas-based IG-IMRT vs. PET/CT-based IG-IMRT vs. conventional radiation therapy (RT), and assess the impact of treatment on changes in hematopoietic compensatory response.

VII. 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Carcinoma
  • Cervical Squamous Cell Carcinoma, Not Otherwise Specified
  • 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 IVA Cervical Cancer AJCC v6 and v7
  • Stage IVA Vaginal Cancer AJCC v6 and v7
  • Vaginal Adenocarcinoma
  • Vaginal Adenosquamous Carcinoma
  • Vaginal Squamous Cell Carcinoma, Not Otherwise Specified
Intervention  ICMJE
  • Drug: Cisplatin
    Given IV
    Other Names:
    • Abiplatin
    • Blastolem
    • Briplatin
    • CDDP
    • Cis-diammine-dichloroplatinum
    • Cis-diamminedichloridoplatinum
    • Cis-diamminedichloro Platinum (II)
    • Cis-diamminedichloroplatinum
    • Cis-dichloroammine Platinum (II)
    • Cis-platinous Diamine Dichloride
    • Cis-platinum
    • Cis-platinum II
    • Cis-platinum II Diamine Dichloride
    • Cismaplat
    • Cisplatina
    • Cisplatinum
    • Cisplatyl
    • Citoplatino
    • Citosin
    • Cysplatyna
    • DDP
    • Lederplatin
    • Metaplatin
    • Neoplatin
    • Peyrone's Chloride
    • Peyrone's Salt
    • Placis
    • Plastistil
    • Platamine
    • Platiblastin
    • Platiblastin-S
    • Platinex
    • Platinol
    • Platinol- AQ
    • Platinol-AQ
    • Platinol-AQ VHA Plus
    • Platinoxan
    • Platinum
    • Platinum Diamminodichloride
    • Platiran
    • Platistin
    • Platosin
  • Radiation: External Beam Radiation Therapy
    Undergo EBRT
    Other Names:
    • Definitive Radiation Therapy
    • EBRT
    • External Beam Radiotherapy
    • External Beam RT
    • external radiation
    • External Radiation Therapy
    • external-beam radiation
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
  • Radiation: Internal Radiation Therapy
    Undergo brachytherapy
    Other Names:
    • BRACHYTHERAPY
    • internal radiation
    • Internal Radiation Brachytherapy
    • Radiation Brachytherapy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Radiation: Radiation Therapy
    Undergo conventional RT
    Other Names:
    • Cancer Radiotherapy
    • Irradiate
    • Irradiated
    • irradiation
    • Radiation
    • Radiotherapeutics
    • RADIOTHERAPY
    • RT
    • Therapy, Radiation
  • Drug: Triapine
    Given IV
    Other Names:
    • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
    • 3-AP
    • 3-Apct
    • OCX-191
Study Arms  ICMJE
  • Active Comparator: Arm I (cisplatin, IMRT or RT, brachytherapy)
    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.
    Interventions:
    • Drug: Cisplatin
    • Radiation: External Beam Radiation Therapy
    • Radiation: Intensity-Modulated Radiation Therapy
    • Radiation: Internal Radiation Therapy
    • Other: Laboratory Biomarker Analysis
    • Radiation: Radiation Therapy
  • Experimental: Arm II (cisplatin, IMRT or RT, brachytherapy, triapine)
    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.
    Interventions:
    • Drug: Cisplatin
    • Radiation: Intensity-Modulated Radiation Therapy
    • Radiation: Internal Radiation Therapy
    • Other: Laboratory Biomarker Analysis
    • Radiation: Radiation Therapy
    • Drug: Triapine
Publications * Kunos CA, Ivy SP. Triapine Radiochemotherapy in Advanced Stage Cervical Cancer. Front Oncol. 2018 May 7;8:149. doi: 10.3389/fonc.2018.00149. eCollection 2018.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 8, 2019)
348
Original Estimated Enrollment  ICMJE
 (submitted: June 5, 2015)
178
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date July 23, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02466971
Other Study ID Numbers  ICMJE NCI-2015-00835
NCI-2015-00835 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GY006
NRG-GY006 ( Other Identifier: NRG Oncology )
NRG-GY006 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Charles A Leath NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP