Know Cancer

forgot password

Phase I Study of Intravenous Triapine® (IND #68338) in Combination With Pelvic Radiation Therapy With or Without Weekly Intravenous Cisplatin Chemotherapy for Locally Advanced Cervical, Vaginal, or Pelvic Gynecologic Malignancies.

Phase 1
18 Years
Not Enrolling
Recurrent Cervical Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Vaginal Cancer, Recurrent Vulvar Cancer, Stage III Vaginal Cancer, Stage IIIA Cervical Cancer, Stage IIIA Ovarian Epithelial Cancer, Stage IIIA Vulvar Cancer, Stage IIIB Cervical Cancer, Stage IIIB Ovarian Epithelial Cancer, Stage IIIB Vulvar Cancer, Stage IIIC Ovarian Epithelial Cancer, Stage IIIC Vulvar Cancer, Stage IV Ovarian Epithelial Cancer, Stage IVA Cervical Cancer, Stage IVA Vaginal Cancer, Stage IVB Cervical Cancer, Stage IVB Vaginal Cancer

Thank you

Trial Information

Phase I Study of Intravenous Triapine® (IND #68338) in Combination With Pelvic Radiation Therapy With or Without Weekly Intravenous Cisplatin Chemotherapy for Locally Advanced Cervical, Vaginal, or Pelvic Gynecologic Malignancies.


I. To determine the maximum tolerated dose (MTD) of Triapine® when given in combination with
pelvic radiotherapy with or without weekly intravenous cisplatin chemotherapy.

II. To determine the dose limiting toxicity (DLT) of Triapine® when given in combination
with pelvic radiotherapy with or without weekly intravenous cisplatin chemotherapy.

III. To determine the safety and sequelae of intravenous Triapine® when given in combination
with pelvic radiotherapy with or without weekly intravenous cisplatin chemotherapy.


I. Evaluation of intravenous Triapine®'s targeted inhibition of ribonucleotide reductase
through tumor tissue biopsy at pretreatment evaluation and during external beam radiotherapy
(Day 10).

II. Serial monitoring of methemoglobin levels during therapy given Triapine®'s iron
chelating properties.

OUTLINE: This is a multicenter, dose-escalation study of 3-AP. Patients are assigned to 1 of
2 treatment groups based on eligibility* to receive cisplatin (yes vs no).

NOTE: *Patients who refuse or are not candidates for cisplatin chemotherapy due to prior
platinum adverse sensitivity, active neuropathy, or comobid illness, as determined by the
treating physician, are eligible to receive 3-AP alone with pelvic radiotherapy.

Group 1: Patients undergo external-beam pelvic radiotherapy once daily on days 1-5, 8-12,
15-19, 22-26, and 29-33. Patients also receive 3-AP IV over 2 hours on days 1, 3, 5, 8, 10,
12, 15, 17, 19, 22, 24, 26, 29, 31, and 33 and cisplatin IV over 1½ hours on day 2, 9, 16,
23, and 30.

Group 2: Patients undergo external-beam pelvic radiotherapy and receive 3-AP as in group 1.

In both groups, patients undergo intracavitary or interstitial brachytherapy at least once
weekly for 3-5 weeks during or after external-beam radiotherapy as per standard of care.

Cohorts of 3-6 patients in group 1 and 1-3 patients in group 2 receive escalating doses of
3-AP until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose
preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At
least 6 patients are treated at the MTD.

Patients undergo blood draws on days 1 and 10 before treatment with 3-AP and at 2, 4, 6, and
24 hours after starting treatment to assess methemoglobin levels and 3-AP plasma levels.
Patients also undergo punch biopsy on days 1 and 10 to determine R2 protein levels by
Western blot analysis, ribonucleotide reductase R2 protein levels by flow cytometry, and
cytidine deoxyphosphate reductase assay.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 24 patients will be accrued for this study.

Inclusion Criteria:

- Patients with pathologically-proven primary or recurrent locally advanced cervical,
vaginal, or vulvar cancers not amenable to curative surgical resection alone are

- Patients with pathologically-proven recurrent or persistent epithelial ovarian or
endometrial cancer a) not amenable to curative surgical resection alone, b) are
planned for pelvic radiotherapy, and c) are amenable to tumor biopsy through the
vaginal canal are eligible

- Patients with other active invasive malignancies are excluded; patients with prior
malignancies in remission for at least six months and not being currently treated are
eligible; patients are excluded if their previous cancer treatment as determined by
their treating physicians contraindicates this protocol therapy or if they have
received prior low abdominal or pelvic radiotherapy that would contribute radiation
dose that would exceed tolerance of normal tissues (as determined by the principal
investigator or co-investigators); for patients relapsing at least four weeks after
initial surgery or chemotherapy, they must have fully recovered from side effects of
prior treatment, have measurable disease in the pelvis; measurable lesions are
defined as those that can be accurately measured in at least one dimension (longest
diameter to be recorded) as >= 20 mm with conventional techniques (CT, MRI, x-ray or
as >= 10 mm with spiral CT scan; patients with metastatic disease to extra-pelvic
sites are eligible if pelvic radiotherapy is planned as primary management of the
site of pelvic disease. There is no numerical limit on prior chemotherapy regimens
previously received

- ECOG performance status 0-2; (Karnofsky >= 50%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/uL

- Absolute neutrophil count >= 1,500/uL

- Platelets >= 100,000/uL

- Hemoglobin >= 10 g/dL

- Total bilirubin =< 2.0 mg/dL

- AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal

- PT/aPTT =< 1.5 X institutional upper limit of normal

- Patients should have a serum creatinine =< 1.5mg/dL to receive weekly intravenous
cisplatin chemotherapy; patients whose serum creatinine is between 1.5 and 1.9 mg/dL
are eligible for cisplatin chemotherapy if the estimated creatinine clearance is >=
30 ml/min; for the purpose of estimating the creatinine clearance, the formula of
Jelliffe should be used: CCr = 0.9{98-[0.8(age-20)]}/Scr where CCr is the estimated
creatinine clearance, age is patient's age in years (from 20-80), and Scr is the
serum creatinine in mg/dL; patients eligible for cisplatin chemotherapy will also
receive intravenous Triapine®; patients who have refused or are not candidates for
cisplatin chemotherapy as defined above, have prior platinum adverse sensitivity,
have active neuropathy, or have intercurrent co-morbid illness as determined by
treating physicians will receive intravenous Triapine® alone with pelvic radiation;
to receive Triapine® alone with pelvic radiotherapy, patients must have a serum
creatinine =< 2.0mg/dL

- The effects of Triapine® on the developing human fetus are unknown; for this reason
and because heterocyclic carboxaldehyde thiosemicarbazones as well as other
therapeutic agents used in this trial 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

- Eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity or pharmacokinetics of Triapine® will be
determined following review of their case by the Principal Investigator

- Ability to undergo and the willingness to sign a written informed consent for
placement of a PICC line or a central venous catheter

- Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier
are excluded

- Patients may not be 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 Triapine® or other agents used in study

- Patients unable to receive intravenous chemotherapies as a consequence of poor
vascular access (for example, patient receiving hemodialysis) are ineligible

- 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; proteinuria or clinically significant renal function impairment (baseline
serum creatinine > 2mg/dL), or psychiatric illness/social situations that would limit
compliance with study requirements are excluded

- Patients with known glucose-6-phosphate dehydrogenase deficiency (G6PD) are excluded

- Pregnant women are excluded from this study because Triapine® is a heterocyclic
carboxaldehyde thiosemicarbazone with the potential for teratogenic or abortifacient
effects; screening b-hcg levels and diagnostic tests will be used to determine
eligibility; 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

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with Triapine®; 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Toxicity of radiotherapy and Triapine® combination therapy as documented by dose-limiting toxicities (DLTs) using Common Terminology Criteria for Adverse Events (CTCAE) criteria, version 3.0

Outcome Time Frame:

Up to 12 weeks

Safety Issue:


Principal Investigator

Charles Kunos

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Western Reserve University


United States: Food and Drug Administration

Study ID:




Start Date:

March 2006

Completion Date:

Related Keywords:

  • Recurrent Cervical Cancer
  • Recurrent Ovarian Epithelial Cancer
  • Recurrent Vaginal Cancer
  • Recurrent Vulvar Cancer
  • Stage III Vaginal Cancer
  • Stage IIIA Cervical Cancer
  • Stage IIIA Ovarian Epithelial Cancer
  • Stage IIIA Vulvar Cancer
  • Stage IIIB Cervical Cancer
  • Stage IIIB Ovarian Epithelial Cancer
  • Stage IIIB Vulvar Cancer
  • Stage IIIC Ovarian Epithelial Cancer
  • Stage IIIC Vulvar Cancer
  • Stage IV Ovarian Epithelial Cancer
  • Stage IVA Cervical Cancer
  • Stage IVA Vaginal Cancer
  • Stage IVB Cervical Cancer
  • Stage IVB Vaginal Cancer
  • Uterine Cervical Neoplasms
  • Vaginal Neoplasms
  • Vulvar Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Ovarian Neoplasms



Case Western Reserve University Cleveland, Ohio  44106