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

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Brief Title

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

Official Title

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.

Brief Summary

      Drugs used in chemotherapy, such as 3-AP and cisplatin, work in different ways to stop the
      growth of tumor cells, either by killing the cells or by stopping them from dividing. 3-AP
      may also stop the growth of tumor cells by blocking some of the enzymes needed for cell
      growth. Radiation therapy uses high-energy x-rays to kill tumor cells. 3-AP and cisplatin may
      make tumor cells more sensitive to radiation therapy. Giving 3-AP and external-beam radiation
      therapy together with cisplatin may kill more tumor cells. This phase I trial is studying the
      side effects and best dose of 3-AP when given together with external-beam radiation therapy
      with or without cisplatin in treating patients with gynecologic cancer
    

Detailed Description

      PRIMARY OBJECTIVES:

      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.

      SECONDARY OBJECTIVES:

      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.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 RR R2 enzyme quantity

Condition

Recurrent Cervical Cancer

Intervention

triapine

Study Arms / Comparison Groups

 Treatment (triapine)
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

24

Start Date

March 2006


Primary Completion Date

October 2008

Eligibility Criteria

        Inclusion Criteria:

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

          -  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
             immediately

          -  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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Charles Kunos, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00335998

Organization ID

NCI-2012-03126

Secondary IDs

CASE 1805

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Charles Kunos, Principal Investigator, Case Western Reserve University


Verification Date

January 2013