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

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.

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