3-AP and Gemcitabine in Treating Patients With Advanced Solid Tumors or Lymphoma

September 27, 2013 updated by: National Cancer Institute (NCI)

A Phase I Study of a Prolonged Infusion of Triapine in Combination With a Fixed Dose Rate of Gemcitabine in Patients With Advanced Solid Tumors and Lymphomas

This phase I trial is studying the best dose of 3-AP and the side effects of giving 3-AP together with gemcitabine in treating patients with advanced solid tumors or lymphoma. Drugs used in chemotherapy, such as 3-AP and gemcitabine (GEM), work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 3-AP may help gemcitabine kill more cancer cells by making the cells more sensitive to the drug. 3-AP may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximal tolerable dose (MTD) of 3-AP administered as a 24 hour infusion in combination with and fixed-dose gemcitabine hydrochloride (GEM) in patients with advanced solid tumors or lymphomas.

SECONDARY OBJECTIVES:

I. To define the qualitative and quantitative toxicities of the 3-AP/GEM combination in regard to organ specificity, time course, predictability, and reversibility.

II. To document the therapeutic response of this combination in those patients when possible.

III. To measure deoxycytidine triphosphate (dCTP) levels in peripheral blood mononuclear cells (PBMCs) before and after treatment at specified times and try to correlate findings to activity and toxicity of 3-AP.

IV. To perform limited pharmacokinetic analysis.

OUTLINE: This is a dose-escalation study of 3-AP (Triapine®).Patients receive 3-AP (Triapine®) IV over 24 hours followed by gemcitabine hydrochloride IV over 100-125 minutes on days 1 and 8. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving complete response (CR) receive 1 additional course of therapy beyond documented CR.Cohorts of 3-6 patients receive escalating doses of 3-AP (Triapine®) 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.After completion of study treatment, patients are followed periodically for 2 years.

Study Type

Interventional

Enrollment (Actual)

30

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Histologically or cytologically confirmed advanced solid tumors or lymphoma

    • Disease considered incurable using standard treatment
  • ECOG performance status ≤ 2
  • Life expectancy > 12 weeks
  • WBC ≥ 3,000/mm^3
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Total bilirubin normal
  • AST/ALT ≤ 2.5 times upper limit of normal
  • Creatinine normal OR creatinine clearance ≥ 60 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception prior to and during study treatment
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to 3-AP (Triapine®) and/or gemcitabine hydrochloride
  • No known glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements
  • No pulmonary disease (e.g., dyspnea at rest, supplemental oxygen requirement, or baseline oxygen saturation < 92%)

  • Prior gemcitabine hydrochloride allowed if given as a standard 30-minute infusion

    • At least 4 weeks since prior gemcitabine hydrochloride
  • Patient may have received < 2 lines of chemotherapy in the metastatic setting
  • No prior 3-AP (Triapine®) or fixed-dose gemcitabine hydrochloride
  • At least 6 weeks since prior nitrosoureas or mitomycin C
  • More than 3 weeks since prior radiotherapy
  • No other concurrent investigational agents
  • No concurrent combination antiretroviral therapy in HIV-positive patients
  • No other concurrent anticancer agents or therapies

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (gemcitabine hydrochloride, triapine)
Patients receive 3-AP (Triapineî) IV over 24 hours followed by gemcitabine hydrochloride IV over 100-125 minutes on days 1 and 8. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.
Drug: gemcitabine hydrochloride
Other Names:
  • Gemzar
  • gemcitabine
  • dFdC
  • difluorodeoxycytidine hydrochloride
Drug: triapine
Other Names:
  • 3-AP
  • OCX-191

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
MTD as assessed by the number of patients with dose-limiting toxicity (DLT)
Time Frame: Observed clinically for 4 hours after each 3-AP infusion during the first cycle of treatment
MTD is the maximum dose level with fewer than 2 of 3/6 patients experiencing DLT. The study uses standard method phase I design of dose escalation. DLT will be defined as greater or equal to Grade 3 non-hematologic or greater or equal to Grade 4 hematologic adverse event EXCEPT: greater or equal to Grade 3 nausea and greater or equal to Grade 3 vomiting that improves with antiemetic therapy; greater or equal to Grade 3 diarrhea that improves with Lomotil; and greater or equal to Grade 4 Neutropenia that recovers to less or equal to Grade 3 within 7 days of first identification.
Observed clinically for 4 hours after each 3-AP infusion during the first cycle of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Toxicity as assessed using the NCI Common Toxicity Criteria, Version 3.0
Time Frame: Observed clinically for 4 hours after each 3-AP infusion during the first cycle of treatment and monitored until disease progression or for a maximum of 24 months following termination of treatment
Toxicities include neutropenia grade 4 (<500/mm3), neutropenic fever (grade 4 neutropenia and greater than or equal to grade 2 fever), thrombocytopenia Grade 3-4 (<50000/mm3), and non-hematologic toxicities grades 3-4. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for adverse event reporting.
Observed clinically for 4 hours after each 3-AP infusion during the first cycle of treatment and monitored until disease progression or for a maximum of 24 months following termination of treatment
Therapeutic response
Time Frame: Tumor and radiologic measurements every 8 weeks from start of treatment. In addition to a baseline scan, confirmatory scans will also be obtained 8 weeks following initial documentation of an objective response.
Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee. Complete Response (CR) is the disappearance of all target lesions. Partial Response (PR) requires at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. The results will be purely descriptive.
Tumor and radiologic measurements every 8 weeks from start of treatment. In addition to a baseline scan, confirmatory scans will also be obtained 8 weeks following initial documentation of an objective response.
Duration of overall response
Time Frame: Baseline until disease progression or for a maximum of 24 months following termination of treatment.
The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Baseline until disease progression or for a maximum of 24 months following termination of treatment.
Duration of stable disease
Time Frame: Baseline until disease progression or for a maximum of 24 months following termination of treatment.
Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
Baseline until disease progression or for a maximum of 24 months following termination of treatment.
Levels of dCTP in PBMCs correlated to activity and toxicity of 3-AP
Time Frame: PMBCs isolated immediately before and after 3-AP infusion (day 1), but before GEM is started on (day 2) on both course 1 and course 2 of treatment
If dCTP levels are diminished by 3-AP, there is a real possibility of ribonucleotide reductase (RR) inhibition in tumor cells with a higher growth fraction (known to have elevated RR levels). It will also be possible to correlate the steady state levels of 3-AP with the concentration of dCTP in circulating cells. The RT-PCR of PBMCs before and after infusion would be helpful to reassure that the change of dCTP pool is correlated with 3-AP inhibiting RR.
PMBCs isolated immediately before and after 3-AP infusion (day 1), but before GEM is started on (day 2) on both course 1 and course 2 of treatment
Pharmacokinetics as assessed by steady state concentration (Css) of 3-AP in serum
Time Frame: On the first day of infusion (course 1 only) during the last 4 hours of 3-AP infusion
On the first day of infusion (course 1 only) during the last 4 hours of 3-AP infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Tanios Bekaii-Saab, Ohio State University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2006

Primary Completion (Actual)

October 1, 2012

Study Registration Dates

First Submitted

February 16, 2006

First Submitted That Met QC Criteria

February 16, 2006

First Posted (Estimate)

February 17, 2006

Study Record Updates

Last Update Posted (Estimate)

September 30, 2013

Last Update Submitted That Met QC Criteria

September 27, 2013

Last Verified

September 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00119 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • U01CA076576 (U.S. NIH Grant/Contract)
  • 7043 (CTEP)
  • NCI-7043
  • OSU-2005C0031
  • CDR0000455043
  • OSU 05016 (Other Identifier: Ohio State University Medical Center)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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