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

A Phase I/II Trial of Cloretazine® (VNP40101M) and Temodar® (Temozolomide) for Patients With Malignant Glioma in First Relapse or Progression

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.

Study Overview

• Status: Terminated
• Conditions: Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: CLORETAZINE; Drug: temozolomide

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: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611-2998
      • Hematology-Oncology Associates of Illinois
    • Chicago, Illinois, United States, 60611-3013
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD of CLORETAZINE	To determine the MTD of CLORETAZINE when administered with Temodar® in patients with malignant gliomas in first or second relapse	At the end of phase one
Progression-free survival rate	To determine the 6 and 12 month progression-free survival rate.	End of Phase II

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicities of CLORETAZINE when administered with Temodar®.	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).	Adverse events are monitored at screening/baseline;day one; termination visit; followup until death.
MGMT Methylation Status	To determine MGMT methylation status as well as other methylation patterns in blood correlate with outcome.	Baseline and day seven of every cycle
Determine overall survival	To determine overall survival.	All patients will be followed until death
Response rate to CLORETAZINE after Temodar® in patients with malignant gliomas in first or second relapse	To determine the response rate to CLORETAZINE after Temodar® in patients with malignant gliomas in first or second relapse.	Day one of every cycle
Record the toxicities of CLORETAZINE when administered after Temodar	To record the toxicities of CLORETAZINE when administered after Temodar®	Continuously after the first dose;within thirty days of each administration of investigational agent
Measure the level of AGT expression	To measure the level of AGT expression in peripheral blood monocytes before treatment with Temodar® and just prior to the administration of CLORETAZINE.	Day seven of every cycle
CSF penetration of CLORETAZINE	To determine CSF penetration of CLORETAZINE once the MTD is reached from phase I and correlate with serum/plasma PK	Day seven of cycle one of Phase 2 only

Collaborators and Investigators

• Sponsor: Northwestern University
• Collaborators: Vion Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): October 1, 2009

Study Registration Dates

• First Submitted: August 14, 2007
• First Submitted That Met QC Criteria: August 14, 2007
• First Posted (Estimate): August 15, 2007

Study Record Updates

• Last Update Posted (Estimate): August 26, 2011
• Last Update Submitted That Met QC Criteria: August 24, 2011
• Last Verified: August 1, 2011

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma; adult anaplastic astrocytoma; adult anaplastic oligodendroglioma; adult mixed glioma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: NU 07C1