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

Sponsor

Northwestern University (Other)

Overall Status

Terminated

CT.gov ID

NCT00516282

Collaborator

Vion Pharmaceuticals (Industry)

Enrollment

Locations

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: CLORETAZINE Drug: temozolomide	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

14 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2007

Actual Primary Completion Date :

Oct 1, 2009

Actual Study Completion Date :

Oct 1, 2009

Outcome Measures

Primary Outcome Measures

MTD of CLORETAZINE [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 [End of Phase II]
To determine the 6 and 12 month progression-free survival rate.

Secondary Outcome Measures

Toxicities of CLORETAZINE when administered with Temodar®. [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 [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 [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 [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 [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 [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 [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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