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Randomized Phase II Study of Intravenous 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine® NSC #663249) Cisplatin-Radiochemotherapy Versus Intravenous Cisplatin-Radiochemotherapy in Women Diagnosed With Stage IB-IVA Cervical Cancer and Stage II-IVA Vaginal Cancer

Phase 2
18 Years
Not Enrolling
Cervical Adenocarcinoma, Cervical Adenosquamous Cell Carcinoma, Cervical Squamous Cell Carcinoma, Stage IB Cervical Cancer, Stage II Vaginal Cancer, Stage IIA Cervical Cancer, Stage IIB Cervical Cancer, Stage III Vaginal Cancer, Stage IIIA Cervical Cancer, Stage IIIB Cervical Cancer, Stage IVA Cervical Cancer, Stage IVA Vaginal Cancer, Vaginal Adenocarcinoma, Vaginal Squamous Cell Carcinoma

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Trial Information

Randomized Phase II Study of Intravenous 3-Aminopyridine-2-Carboxaldehyde Thiosemicarbazone (3-AP, Triapine® NSC #663249) Cisplatin-Radiochemotherapy Versus Intravenous Cisplatin-Radiochemotherapy in Women Diagnosed With Stage IB-IVA Cervical Cancer and Stage II-IVA Vaginal Cancer


I. To determine the posttherapy 3-month fludeoxyglucose F 18 (18F-FDG) positron emission
tomography (PET)/computed tomography (CT) complete metabolic response of
3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) (triapine) radiochemotherapy.


I. Determining acute < 30 day adverse events of 3-AP radiochemotherapy by Common Terminology
Criteria for Adverse Events (CTCAE), version 4.

II. Determining the late >= 30 day adverse events of 3-AP radiochemotherapy by CTCAE version

III. Determining post-therapy clinical response by Response Evaluation Criteria in Solid
Tumors (RECIST), version 1.1.

IV. Determining the progression-free interval of 3-AP radiochemotherapy. V. Determining
peripheral blood methemoglobin proportion before and after 3-AP infusion. (Optional)

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,
and 30 of radiation therapy. Patients undergo external beam radiation therapy (EBRT) five
days a week for 5 weeks with a boost in week 6 followed by 5 sessions of high dose rate
(HDR) brachytherapy once or twice weekly beginning in week 4 or up to 2 sessions of low dose
rate (LDR) brachytherapy within 3 weeks of completion of EBRT.

ARM II: Patients receive triapine IV over 90-120 minutes on days 1, 3, 5, 8, 10, 12, 15, 17,
19, 22, 24, 26, 29, 31, and 33 of radiation therapy. Patients also receive cisplatin IV and
undergo EBRT and brachytherapy as in Arm I.

In both arms, treatment continues for up to 6 weeks in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 1, 3, and 6 months.

Inclusion Criteria:

- Patients are eligible with untreated squamous, adenosquamous, or adenocarcinoma
cancers of stage IB2-IVA carcinoma of the uterine cervix or stage II-IVA vaginal
carcinoma not amenable to curative surgical resection; pathological verification of
diagnosis must be obtained and recorded; 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 for participation; the patient must be able to tolerate the requirements for
18F-FDG PET/CT scanning

- Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or

- Patients must have a life expectancy of greater than 20 weeks

- Absolute neutrophil count > 1,500/µL

- Platelets > 100,000/µL

- 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 intravenous cisplatin*; *patients whose
serum creatinine is between 1.5 and 1.9 mg/dL are eligible for cisplatin if the
estimated creatinine clearance is >= 30 ml/min; for the purpose of estimating the
creatinine clearance, the formula of Cockcroft and Gault for females should be used

- All patients must have measurable cervical cancer or vaginal cancer disease;
measurable disease is defined as at least one lesion that can be accurately measured
in at least one dimension (longest diameter to be recorded); each lesion must be >=
40 mm when measured preferably by clinical exam or alternatively by computed
tomography (CT), magnetic resonance imaging (MRI)

- Patient is not pregnant; the effects of 3-AP 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; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately; if in the investigator's opinion the patient is of child-bearing age, a
negative urine pregnancy test must be resulted within 7 days before initiating
protocol therapy; women should not breast feed during therapy (or has agreed to
discontinue breastfeeding before initiation of therapy)

- Patients must have an ability to understand and willingness to sign a written
informed consent document

Exclusion Criteria:

- Patients with other active invasive malignancies are excluded; patients with prior
malignancies are excluded (except non-melanoma skin cancer or prior in situ carcinoma
of the cervix; patients with other invasive malignancies who had [or have] cancer
present within the last five years); 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

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 3-AP (triapine) or other agents used in study

- 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, known inadequately controlled
hypertension, significant pulmonary disease including dyspnea at rest, 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 are excluded

- Patient does not have uncontrolled diabetes mellitus (fasting blood glucose > 200

- Patients with known glucose-6-phosphate dehydrogenase deficiency (G6PD) are excluded
due to an inability to administer the antidote for methemoglobinemia, methylene blue;
testing for G6PD is not required for study enrollment and optional

- Known human immunodeficiency virus (HIV)-positive patients receiving combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with 3-AP; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated;
HIV testing is not required for study enrollment and optional

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

18F-FDG PET/CT response by European Organization for Research and Treatment of Cancer (EORTC) criteria

Outcome Time Frame:

3 months

Safety Issue:


Principal Investigator

Charles Kunos

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

April 2013

Completion Date:

Related Keywords:

  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Cell Carcinoma
  • Cervical Squamous Cell Carcinoma
  • Stage IB Cervical Cancer
  • Stage II Vaginal Cancer
  • Stage IIA Cervical Cancer
  • Stage IIB Cervical Cancer
  • Stage III Vaginal Cancer
  • Stage IIIA Cervical Cancer
  • Stage IIIB Cervical Cancer
  • Stage IVA Cervical Cancer
  • Stage IVA Vaginal Cancer
  • Vaginal Adenocarcinoma
  • Vaginal Squamous Cell Carcinoma
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Uterine Cervical Neoplasms
  • Vaginal Neoplasms
  • Carcinoma, Adenosquamous



Case Western Reserve University Cleveland, Ohio  44106