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VNP40101M and Temozolomide in Treating Patients With Progressive or Relapsed Malignant Glioma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00516282
Recruitment Status : Terminated (The pharmaceutical collaborator filed for bankruptcy and as a result, the study was unable to move into the phase II portion.)
First Posted : August 15, 2007
Last Update Posted : August 26, 2011
Sponsor:
Collaborator:
Vion Pharmaceuticals
Information provided by (Responsible Party):
Northwestern University

Tracking Information
First Submitted Date  ICMJE August 14, 2007
First Posted Date  ICMJE August 15, 2007
Last Update Posted Date August 26, 2011
Study Start Date  ICMJE August 2007
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 21, 2010)
  • MTD of CLORETAZINE [ Time Frame: At the end of phase one ]
    To determine the MTD of CLORETAZINE when administered with Temodar® in patients with malignant gliomas in first or second relapse
  • Progression-free survival rate [ Time Frame: End of Phase II ]
    To determine the 6 and 12 month progression-free survival rate.
Original Primary Outcome Measures  ICMJE
 (submitted: August 14, 2007)
  • Maximum tolerated dose of VNP40101M (Phase I)
  • Toxicity (Phase I and II)
  • AGT expression in peripheral blood (Phase I and II)
  • Correlation of MGMT methylation status and other methylation patterns with outcome
  • Progression-free survival at 6 months (Phase II)
  • Overall survival (Phase II)
  • Complete and partial response rates (Phase II)
  • Cerebrospinal fluid penetration (Phase II)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2010)
  • Toxicities of CLORETAZINE when administered with Temodar®. [ Time Frame: Adverse events are monitored at screening/baseline;day one; termination visit; followup until death. ]
    To record the toxicities of CLORETAZINE when administered with Temodar®. (Toxicity is assessed continuously through routine medical monitoring of the patient throughout each cycle and all adverse events are recorded cumulatively on the case report forms).
  • MGMT Methylation Status [ Time Frame: Baseline and day seven of every cycle ]
    To determine MGMT methylation status as well as other methylation patterns in blood correlate with outcome.
  • Determine overall survival [ Time Frame: All patients will be followed until death ]
    To determine overall survival.
  • Response rate to CLORETAZINE after Temodar® in patients with malignant gliomas in first or second relapse [ Time Frame: Day one of every cycle ]
    To determine the response rate to CLORETAZINE after Temodar® in patients with malignant gliomas in first or second relapse.
  • Record the toxicities of CLORETAZINE when administered after Temodar [ Time Frame: Continuously after the first dose;within thirty days of each administration of investigational agent ]
    To record the toxicities of CLORETAZINE when administered after Temodar®
  • Measure the level of AGT expression [ Time Frame: Day seven of every cycle ]
    To measure the level of AGT expression in peripheral blood monocytes before treatment with Temodar® and just prior to the administration of CLORETAZINE.
  • CSF penetration of CLORETAZINE [ Time Frame: Day seven of cycle one of Phase 2 only ]
    To determine CSF penetration of CLORETAZINE once the MTD is reached from phase I and correlate with serum/plasma PK
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE VNP40101M and Temozolomide in Treating Patients With Progressive or Relapsed Malignant Glioma
Official Title  ICMJE A Phase I/II Trial of Cloretazine® (VNP40101M) and Temodar® (Temozolomide) for Patients With Malignant Glioma in First Relapse or Progression
Brief Summary

RATIONALE: Drugs used in chemotherapy, such as temozolomide and VNP40101M, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Temozolomide may also stop the growth of tumor cells by blocking blood flow to the tumor.

PURPOSE: This phase I/II trial is studying the side effects and best dose of VNP40101M when given together with temozolomide and to see how well it works in treating patients with progressive or relapsed malignant glioma.

Detailed Description

OBJECTIVES:

  • To determine the maximum tolerated dose (MTD) of VNP40101M when administered with temozolomide in patients with progressive or relapsed (first relapse) malignant glioma. (Phase I)
  • To record the toxicities of VNP40101M when administered with temozolomide. (Phase I and II)
  • To measure the level of AGT expression in peripheral blood monocytes before treatment with temozolomide and just prior to the administration of VNP40101M. (Phase I and II)
  • To determine MGMT methylation status as well as other methylation patterns in blood and tissue from patients treated with this regimen and correlate with outcome. (Phase I and II)
  • To determine the 6- and 12-month progression-free survival rates of patients treated with this regimen. (Phase II)
  • To determine overall survival of patients treated with this regimen. (Phase II)
  • To determine the complete and partial response rates in patients treated with this regimen. (Phase II)
  • To determine CSF penetration of VNP40101M once the MTD is reached from phase I and correlate with serum/plasma pharmacokinetics. (Phase II)

OUTLINE:

  • Phase I: Patients receive oral temozolomide on days 1-7 and VNP40101M IV over 15-30 minutes 2 hours after the last dose of temozolomide on day 7. Treatment repeats every 7 weeks in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of VNP40101M 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.

  • Phase II: Patients receive oral temozolomide and VNP40101M as in phase I. VNP40101M is given at the MTD determined in phase I.

In both phases, patients complete the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire on day 1 of each course.

Blood is collected for in vitro isolation of mononuclear cells for analysis of O^6 alkylguanine DNA alkyltransferase on days 1 and 7 of course 1. Blood, plasma, CSF, and formalin-fixed paraffin-embedded tissue blocks are collected for gene methylation studies, including MGMT, at baseline and on day 1 of each course.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Brain and Central Nervous System Tumors
Intervention  ICMJE
  • Drug: CLORETAZINE
    CLORETAZINE will be administered intravenously on day 7. The starting dose of CLORETAZINE will be 100 mg/m2 given within 3 hours after the last dose of Temodar on day 7. CLORETAZINE will be given as an IV infusion over 15-30 minutes via a freely flowing peripheral or central intravenous line. CLORETAZINE will be escalated by 50 mg/m2 for the second cohort then by 25 mg/m2 increments in the following cohorts of 3-6 patients using a standard phase I trial design until a MTD is determined. If dose level 2 has two DLTs then patients will be accrued to a new dose level of 125 mg/m2. Prior to receiving Cloretazine, blood will be drawn for gene methylation studies.
    Other Name: VNP40101M
  • Drug: temozolomide
    Temozolomide will be given orally at a dose of 75mg/m2 daily on day 1 through 7. There will be no dose modification for this agent. Prior to receiving Temozolomide, blood will be drawn for gene methylation studies.
    Other Name: Temodar
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 21, 2010)
14
Original Enrollment  ICMJE
 (submitted: August 14, 2007)
29
Actual Study Completion Date  ICMJE October 2009
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

Inclusion criteria:

  • Histologically proven malignant glioma including any of the following:

    • Glioblastoma multiforme
    • Gliosarcoma
    • Anaplastic astrocytoma
    • Anaplastic oligodendroglioma
    • Anaplastic mixed oligoastrocytoma
    • Malignant astrocytoma not otherwise specified
  • Unequivocal evidence of tumor recurrence or progression by MRI or CT scan with contrast
  • No more than one relapse
  • Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

    • More than 2 weeks from surgery and have recovered from the effects of surgery
    • Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study if a treatment failure can be evaluated
    • Enhanced CT scan/ MRI should be done no later than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively

      • If the 96-hour scan is more than 2 weeks from registration, the scan needs to be repeated
      • A baseline scan should be performed within 14 days prior to registration and on a steroid dosage that has been stable for 5 or more days otherwise a new baseline MRI/CT is required
      • The same type of scan (i.e., MRI or CT scan) must be used throughout the period of protocol treatment for tumor measurement
  • Must have failed prior external-beam radiotherapy
  • Must have failed one prior systemic treatment with chemotherapy or biologic agents

PATIENT CHARACTERISTICS:

Inclusion criteria:

  • Karnofsky performance status 60-100%
  • Life expectancy > 12 weeks
  • WBC > 3,000/mm³
  • ANC > 1,500/mm³
  • Platelet count > 100,000/mm³
  • Hemoglobin > 10 mg/dL
  • AST and ALT < 4 times upper limit of normal (ULN)
  • Bilirubin < 2 times ULN
  • Creatinine < 1.5 times ULN
  • Fertile patients must use acceptable contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device)
  • Negative pregnancy test
  • Not pregnant or nursing

Exclusion criteria:

  • Active uncontrolled bleeding
  • Active infection of any kind
  • Unwilling or unable to follow protocol requirements or to give informed consent
  • Active heart disease including any of the following:

    • Myocardial infarction within the past 3 months
    • Uncontrolled arrhythmias
    • Uncontrolled coronary artery disease
    • Uncontrolled congestive heart failure
  • Known HIV-positive patients (HIV testing is not required)
  • History of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix) unless in complete remission and off all therapy for that disease for a minimum of 3 years

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

  • See Disease Characteristics
  • Recovered from prior therapy
  • At least 2 weeks since prior vincristine
  • More than 4 weeks since prior cytotoxic therapy (6 weeks for nitrosoureas)
  • More than 4 weeks since prior radiotherapy
  • More than 4 weeks since prior experimental biologic agents (e.g., EGFR inhibitors, etc)
  • More than 3 weeks since prior procarbazine administration
  • More than 2 weeks since prior non-cytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin)

    • Radiosensitizer does not count
  • At least 2 weeks since prior and no concurrent enzyme inducing anticonvulsants

    • If patient is on an enzyme inducing anticonvulsant, they may be converted to a non-enzyme inducing anticonvulsant

Exclusion criteria:

  • Any other concurrent standard or investigational treatment for cancer, or any other investigational agent for any indication
  • Concurrent disulfiram
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00516282
Other Study ID Numbers  ICMJE NU 07C1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE Vion Pharmaceuticals
Investigators  ICMJE
Principal Investigator: Jeffrey Raizer, MD Northwestern University
PRS Account Northwestern University
Verification Date August 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP