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

Phase 1
18 Years
Not Enrolling
Brain and Central Nervous System Tumors

Thank you

Trial Information

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


- 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

- 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

- 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)


- 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.

Inclusion Criteria


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

- 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


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


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,

- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:


Outcome Description:

To determine the MTD of CLORETAZINE when administered with Temodar® in patients with malignant gliomas in first or second relapse

Outcome Time Frame:

At the end of phase one

Safety Issue:


Principal Investigator

Jeffrey Raizer, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Northwestern University


United States: Food and Drug Administration

Study ID:

NU 07C1



Start Date:

August 2007

Completion Date:

October 2009

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult glioblastoma
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • adult anaplastic astrocytoma
  • adult anaplastic oligodendroglioma
  • adult mixed glioma
  • Glioma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms



Hematology-Oncology Associates of IllinoisChicago, Illinois  60611-2998
Northwestern UniversityChicago, Illinois  60611