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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 : Suspended (Drug Supply Issues)
First Posted : November 4, 2015
Last Update Posted : February 6, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
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 Drug: Cisplatin Radiation: External Beam Radiation Therapy Radiation: High-Dose Rate Brachytherapy Radiation: Intensity-Modulated Radiation Therapy Radiation: Internal Radiation Therapy Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Triapine Phase 1

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 OBJECTIVES:

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 2 hours on days 1 and 11 and orally (PO) on days 2-5, 8-10, 12, 15-19, 22-26, and 29-33 within 90 minutes after pelvic irradiation, and cisplatin IV over 90-120 minutes once weekly for 5 weeks (days 2, 9, 16, 23, and 30). Treatment continues in the absence of disease progression or unacceptable toxicity.

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Dose-Escalation Bioavailability Study of Oral Triapine in Combination With Concurrent Chemoradiation for Locally Advanced Cervical Cancer (LACC) and Vaginal Cancer
Actual Study Start Date : May 27, 2016
Estimated Primary Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Vaginal Cancer

Arm Intervention/treatment
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 2 hours on days 1 and 11 and PO on days 2-5, 8-10, 12, 15-19, 22-26, and 29-33 within 90 minutes after pelvic irradiation, and cisplatin IV over 90-120 minutes once weekly for 5 weeks (days 2, 9, 16, 23, and 30). Treatment continues in the absence of disease progression or unacceptable toxicity.
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 Radiotherapy
  • External Beam RT
  • external radiation
  • External Radiation Therapy
  • external-beam radiation

Radiation: High-Dose Rate Brachytherapy
Undergo HDR brachytherapy

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy

Radiation: Internal Radiation Therapy
Undergo LDR brachytherapy
Other Names:
  • BRACHYTHERAPY
  • internal radiation
  • Internal Radiation Brachytherapy
  • Radiation Brachytherapy

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-191




Primary Outcome Measures :
  1. 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).

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient has a new, untreated 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
  • 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) >= 9.0 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 adequate 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
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial; 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 with hypermetabolic para-aortic disease identified on baseline 18-FDG-PET-CT
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02595879


Locations
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United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
United States, Virginia
University of Virginia Cancer Center
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Sarah E Taylor University of Pittsburgh Cancer Institute LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02595879     History of Changes
Other Study ID Numbers: 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 )
First Posted: November 4, 2015    Key Record Dates
Last Update Posted: February 6, 2019
Last Verified: January 2019

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Adenocarcinoma
Uterine Cervical Neoplasms
Vaginal Neoplasms
Carcinoma, Adenosquamous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Vaginal Diseases
Neoplasms, Complex and Mixed
Cisplatin
Antineoplastic Agents