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.
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. Patients undergo the collection of blood samples on study and undergo magnetic resonance imaging (MRI) and FDG-PET/CT during follow-up.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Undergo collection of blood samples
Undergo LDR brachytherapy
Given IV
Undergo FDG-PET/CT
Undergo pelvic EBRT
Undergo FDG-PET/CT
Undergo HDR brachytherapy
Undergo IMRT
Undergo MRI
Correlative studies
Undergo FDG-PET/CT
Given IV and PO
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Keck Medical Center of USC Pasadena
Pasadena, California, United States
University of Kansas Clinical Research Center
Fairway, Kansas, United States
University of Kansas Cancer Center
Kansas City, Kansas, United States
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
...and 7 more locations
Maximum Tolerated Dose (MTD)
The MTD was determined following a standard 3+3 design is as follows: Escalation at 0/3 DLTs, dose-reduction if \>1/3 DLT, and expansion to 6 if 1/3 DLTs. DLT is defined as the severe toxicity event that leads to the termination of the treatment as defined in section 5.5. The highest dose level where \<2/6 DLTs are observed will be declared MTD
Time frame: Up to 5 weeks
Number of Patients Who Experienced a DLT
Number of patients that experienced a DLT, evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. DLTs are defined as the following adverse events if considered at least "possibly related" to a component of the study therapy and which occur from the start of treatment until completion of EBRT, prior to initiation of brachytherapy (i.e. the first 5 weeks if no treatments are missed): Any nausea, vomiting, diarrhea and elevation of serum creatinine level Grade 3 toxicity not resolved with maximal intervention to Grade 0-2 over 7 days (except alopecia and fatigue); Any nausea, vomiting, diarrhea and elevation of serum creatinine level Grade 4 toxicity; Any other non-hematologic toxicity ≥Grade 3; Any hematologic toxicity of ≥ Grade 4; Grade ≥3 dyspnea; Inability to deliver at least 20 of the scheduled 25 administrations of triapine at the planned dose, allowing for 2 weeks to make up missed radiation days. Inability to deliver
Time frame: Up to 5 weeks
Bioavailability of Triapine
The oral bioavailability of the oral form of the triapine will be measured as a numeric value using mass spectrophotometry.
Time frame: Up to 2 weeks
Cmax
Maximum concentration
Time frame: Up to 24 hours after dosing
Tmax
Time to maximum concentration,
Time frame: Up to 24 hours after dosing
AUC
Area Under the Concentration-Time Curve (AUC 0-last)
Time frame: Up to 24 hours after dosing
Elimination Half-life (t 1/2)
Time frame: Up to 24 hours after dosing
Fludeoxyglucose F18-Positron Emission Tomography Computed Tomography Metabolic Complete Response (mCR) Rate
The mCR rate at recommended phase 2 dose, defined as a metabolic complete response on PET/CT will be defined as greater than -66% reduction in tumor FDG uptake at sites of abnormal tumor FDG uptake noted on pre-treatment FDG-PET study (considering normal cardiac or liver blood pool).
Time frame: At 3 months post-treatment
Clinical Overall Response Rate
Clinical response at the recommended phase 2 dose per RECIST v1.1 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Time frame: 3 months post-treatment
Progression Free Survival (PFS)
Median number of months that patients survive without disease progression from end of treatment. Per RECIST v1.1, Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: Up to 4 years and 2 months from start of treatment
Overall Survival (OS)
Median number of months that patients remain alive after end of treatment.
Time frame: Up to 4 years and 2 months from start of treatment
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