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Triapine With Chemotherapy and Radiation Therapy in Treating Patients With IB2-IVA Cervical or Vaginal Cancer

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ClinicalTrials.gov Identifier: NCT02595879
Recruitment Status : Recruiting
First Posted : November 4, 2015
Last Update Posted : May 25, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 3, 2015
First Posted Date  ICMJE November 4, 2015
Last Update Posted Date May 25, 2021
Actual Study Start Date  ICMJE May 27, 2016
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 15, 2019)
  • Incidence of dose-limiting toxicity (DLT) to determine maximum tolerated dose [ Time Frame: 5 weeks ]
    MTD is defined as the dose level where < 2/6 DLTs are observed. DLT will be evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (version 5.0 beginning April 1, 2018).
  • Oral bioavailability of the oral form of the triapine [ Time Frame: Days 1 and 11 ]
    The oral bioavailability of the oral form of the triapine will be estimated with corresponding 95% CI.
Original Primary Outcome Measures  ICMJE
 (submitted: November 3, 2015)
Incidence of dose-limiting toxicity (DLT) to determine MTD, defined as the dose level where < 2/6 DLTs are observed, evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 5 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2019)
  • Incidence of toxicity [ Time Frame: Up to 3 months post-treatment ]
    Toxicity will be evaluated using the NCI CTCAE version 4.0 (version 5.0 beginning April 1, 2018). The rate of DLT at maximum tolerated dose will be calculated and the exact 95% confidence intervals (CI) will be provided. The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade. All DLTs and other serious (>= grade 3) events will be described on a patient-by-patient basis; descriptions will include dose level and any relevant baseline data. Statistics on the number of cycles received by patients and any dose reductions will also be tabulated.
  • Fludeoxyglucose F 18 (18F-FDG)-Positron emission tomography (PET) computed tomography (CT) metabolic complete response (mCR) rate [ Time Frame: 3 months post-treatment ]
    The mCR rate at recommended phase 2 dose will be calculated with corresponding 95% confidence interval.
  • Clinical overall response [ Time Frame: Up to 3 months post-treatment ]
    The overall response rate at recommended phase II dose (RP2D) will be calculated with corresponding 95% exact CI.
  • Overall survival [ Time Frame: Up to 3 months post-treatment ]
    Will be analyzed using the Kaplan-Meier's method. Median survival time will be reported with corresponding 95% CIs.
  • Progression free survival [ Time Frame: Up to 3 months post-treatment ]
    Will be analyzed using the Kaplan-Meier's method. Median survival time will be reported with corresponding 95% CIs.
  • Pharmacokinetics (PK) parameters [ Time Frame: Baseline (prior to infusion); 30, 60, 90, 110, 2 hours 30 minutes, and 3 hours after the start of the infusion ]
    Standard PK parameters will be determined and will include maximum concentration, time to maximum concentration, drug clearance, steady state concentration, and half-life. These parameters will be descriptively reported. The association of methemoglobin proportion (%) and PK parameters will be evaluated by Spearman correlation coefficients.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 3, 2015)
  • 18F-FDG-PET CT metabolic complete response (mCR) rate [ Time Frame: 3 months post-treatment ]
    The mCR rate at RP2d will be calculated with corresponding 95% confidence interval.
  • Basal expression of ribonucleotide reductase (RR) subunits (RRM1, RRM2, RRM2b) by immunohistochemistry [ Time Frame: Baseline ]
    The expression level of the RR will be compared between the metabolic responders and non-responders using Wilcoxon rank-sum test.
  • Change in gamma-H2AX levels measured by semi-quantitative multiplexed immunoblot assay [ Time Frame: Baseline to up to day 9 ]
    Trajectory plots will be used to study the trend of the level of H2AX over time. Wilcoxon signed-rank test will be used to compare the expression level at a specific time point and at baseline. When sample size permits, using a linear mixed effect model to assess the treatment effect over time will be considered.
  • Change in phosphorylated (p)-ATM levels measured by semi-quantitative multiplexed immunoblot assay [ Time Frame: Baseline to up to day 9 ]
    Trajectory plots will be used to study the trend of the level of p-ATM over time. Wilcoxon signed-rank test will be used to compare the expression level at a specific time point and at baseline. When sample size permits, using a linear mixed effect model to assess the treatment effect over time will be considered.
  • Incidence of toxicity, evaluated using the NCI CTCAE version 4.0 [ Time Frame: Up to 3 months post-treatment ]
    The rate of DLT at MTD will be calculated and the exact 95% confidence intervals (CI) will be provided. The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade. All DLTs and other serious (>= grade 3) events will be described on a patient-by-patient basis; descriptions will include dose level and any relevant baseline data. Statistics on the number of cycles received by patients and any dose reductions will also be tabulated.
  • Oral bioavailability of the oral form of the triapine [ Time Frame: Days 1 and 11 ]
    The oral bioavailability of the oral form of the triapine will be estimated with corresponding 95% CI.
  • PK parameters [ Time Frame: Baseline (prior to infusion); 30, 60, 90, 110, 2 hours 30 minutes, and 3 hours after the start of the infusion ]
    Standard PK parameters will be determined and will include maximum concentration, time to maximum concentration, drug clearance, steady state concentration, and half-life. These parameters will be descriptively reported.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Triapine With Chemotherapy and Radiation Therapy in Treating Patients With IB2-IVA Cervical or Vaginal Cancer
Official Title  ICMJE Phase I Dose-Escalation Bioavailability Study of Oral Triapine in Combination With Concurrent Chemoradiation for Locally Advanced Cervical Cancer (LACC) and Vaginal Cancer
Brief Summary This phase I trial studies the side effects and best dose of triapine when given with radiation therapy and cisplatin in treating patients with stage IB2-IVA cervical or vaginal cancer. Triapine may stop the growth of cancer cells by blocking an enzyme needed for cell growth. Cisplatin is a drug used in chemotherapy that kills cancer cells by damaging their deoxyribonucleic acid (DNA) and stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Adding triapine to standard treatment with cisplatin and radiation therapy may kill more cancer cells.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerable dose (MTD) and recommended phase II dose (RP2D) of oral triapine when used in combination with cisplatin plus radiation therapy.

II. To determine the oral bioavailability of triapine. III. To describe the pharmacokinetics (PK) of oral and intravenous triapine.

SECONDARY OBJECTIVES:

I. To determine whether the metabolic complete response (mCR) rate of oral triapine in combination with cisplatin chemoradiation using fludeoxyglucose F 18 (18F-FDG)-positron emission tomography (PET) computed tomography (CT) at post-therapy (3-month) is at least 70%.

II. To determine clinical overall response rate, progression-free survival, and overall survival.

III. To determine the correlation of methemoglobin proportion (%) and triapine pharmacokinetic exposure.

EXPLORATORY OBJECTIVE:

I. To determine whether active human immunodeficiency virus (HIV) antiretroviral therapy impacts the antitumor activity of triapine.

OUTLINE: This is a dose escalation study of triapine.

Patients undergo pelvic external beam radiation therapy (EBRT) or intensity modulated radiation therapy (IMRT) 5 days per week for 5 weeks (25 fractions) with a 3-day boost in week 6, and 1 or 2 applications of low dose rate (LDR) brachytherapy in week 6 or 5 fractions of high dose rate (HDR) brachytherapy at week 4 or 5. Patients also receive triapine intravenously (IV) over 120 minutes on day 1 and orally (PO) on days 2-5, 8-12, 15-19, 22-26, and 29-33 within 90 minutes after pelvic irradiation, and cisplatin IV over 60-120 minutes once weekly for 5 weeks (days 2, 9, 16, 23, and 30). Treatment continues in the absence of disease progression or unacceptable toxicity. Patients may receive a 6th cycle of cisplatin IV during the parametrial boost or any make-up radiation treatment in a sixth week of external beam radiotherapy.

After completion of study treatment, patients are followed up for 3 months.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group 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 IIA1 Cervical Cancer AJCC v7
  • Stage IIA2 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
  • Radiation: Brachytherapy
    Undergo LDR brachytherapy
    Other Names:
    • Brachytherapy, NOS
    • Internal Radiation
    • Internal Radiation Brachytherapy
    • Internal Radiation Therapy
    • Radiation Brachytherapy
    • Radiation, Internal
  • 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 pelvic EBRT
    Other Names:
    • Definitive Radiation Therapy
    • EBRT
    • External Beam Radiation
    • External Beam Radiotherapy
    • External Beam RT
    • external radiation
    • External Radiation Therapy
    • external-beam radiation
    • Radiation, External Beam
  • Radiation: High-Dose Rate Brachytherapy
    Undergo HDR brachytherapy
    Other Name: Brachytherapy, High Dose
  • Radiation: Intensity-Modulated Radiation Therapy
    Undergo IMRT
    Other Names:
    • IMRT
    • Intensity Modulated RT
    • Intensity-Modulated Radiotherapy
    • Radiation, Intensity-Modulated Radiotherapy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Drug: Triapine
    Given IV and PO
    Other Names:
    • 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
    • 3-AP
    • 3-Apct
    • OCX-0191
    • OCX-191
    • OCX191
    • PAN-811
Study Arms  ICMJE Experimental: Treatment (triapine, chemoradiation)
Patients undergo pelvic EBRT or IMRT 5 days per week for 5 weeks (25 fractions) with a 3-day boost in week 6, and 1 or 2 applications of LDR brachytherapy in week 6 or 5 fractions of HDR brachytherapy at week 4 or 5. Patients also receive triapine IV over 120 minutes on day 1 and PO on days 2-5, 8-12, 15-19, 22-26, and 29-33 within 90 minutes after pelvic irradiation, and cisplatin IV over 60-120 minutes once weekly for 5 weeks (days 2, 9, 16, 23, and 30). Treatment continues in the absence of disease progression or unacceptable toxicity. Patients may receive a 6th cycle of cisplatin IV during the parametrial boost or any make-up radiation treatment in a sixth week of external beam radiotherapy.
Interventions:
  • Radiation: Brachytherapy
  • Drug: Cisplatin
  • Radiation: External Beam Radiation Therapy
  • Radiation: High-Dose Rate Brachytherapy
  • Radiation: Intensity-Modulated Radiation Therapy
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Drug: Triapine
Publications * Not Provided

*   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: December 24, 2020)
76
Original Estimated Enrollment  ICMJE
 (submitted: November 3, 2015)
48
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient has a new, untreated histologic diagnosis of stage IB2 (> 5 cm), II, IIIB,IIIC 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; the patient must be able to tolerate imaging requirements of an 18F-FDG PET/CT scan
  • Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
  • Life expectancy greater than 6 months
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Hemoglobin (Hgb) >= 10.0 g/dL (blood transfusions to reach this amount are allowed)
  • Serum creatinine =< 1.5 mg/dL to receive weekly cisplatin

    • If serum creatinine is between 1.5 and 1.9 mg/dL, patients 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)
  • Total serum bilirubin =< 1.5 x upper limit of normal (ULN) (in patients with known Gilbert syndrome, a total bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  • Able to take oral medication
  • Not pregnant and not breastfeeding; the effects of triapine on the developing human fetus are unknown; for this reason as well as because heterocyclic carboxaldehydethiosemicarbazones and radiation are known to be teratogenic, women of child-bearing potential and men must agree to use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; patient must have documented negative urine pregnancy test must be resulted within 7 days before initiating protocol therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with triapine, breastfeeding should be discontinued if the mother is treated with triapine; these potential risks may also apply to other agents used in this study
  • For human immunodeficiency virus (HIV) and hepatitis B/C (HEPB/C):

    • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for the dose escalation portion of this trial; for those patients who are enrolled in the HIV positive (+) expansion cohort, they must be HIV infected and be on retroviral therapy with an undetectable viral load within 6 months of enrollment
    • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
    • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured; for patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Able to understand and willingness to sign a written informed consent document

Exclusion Criteria:

  • 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
  • Patients receiving any other investigational agents
  • Patients with known glucose-6-phosphate dehydrogenase deficiency (G6PD) are excluded due to an inability to administer the antidote for methemoglobinemia, methylene blue; pre-registration testing for G6PD is at the investigator's discretion and is not required for study enrollment
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to triapine or cisplatin
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; known inadequately controlled hypertension; significant pulmonary disease including dyspnea at rest, patients requiring supplemental oxygen, or poor pulmonary reserve; or psychiatric illness/social situations that would limit compliance with study requirements
  • Patients with uncontrolled diabetes mellitus (fasting blood glucose controlled by medication, =< 200 mg/dL allowed)
  • 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
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 United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02595879
Other Study ID Numbers  ICMJE NCI-2015-01907
NCI-2015-01907 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
UPCI 15-157
15-157
9892 ( Other Identifier: University of Pittsburgh Cancer Institute LAO )
9892 ( Other Identifier: CTEP )
UM1CA186690 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
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: Sarah E Taylor University of Pittsburgh Cancer Institute LAO
PRS Account National Cancer Institute (NCI)
Verification Date May 2021

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