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Mutant MGMT Gene Transfer Into Human Hematopoietic Progenitors to Protect Hematopoiesis During O6-Benzylguanine (BG, NSC 637037) and Carmustine Followed by Temozolomide Therapy of Advanced Solid Tumors


Phase 1
18 Years
70 Years
Not Enrolling
Both
Brain and Central Nervous System Tumors, Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Mutant MGMT Gene Transfer Into Human Hematopoietic Progenitors to Protect Hematopoiesis During O6-Benzylguanine (BG, NSC 637037) and Carmustine Followed by Temozolomide Therapy of Advanced Solid Tumors


OBJECTIVES:

- Evaluate the feasibility of introducing and expressing mutant MGMT-G156A cDNA in
hematopoietic progenitors taken from patients with advanced solid tumors (including
gliomas) or non-Hodgkin's lymphoma using a safety modified retroviral vector MFG.

- Determine the toxicity associated with reinfusion of ex vivo-transduced hematopoietic
stem cells into these patients, including the detection of replication competent
retrovirus.

- Evaluate the feasibility of identifying mutant MGMT-G156A-transduced and
O6-benzylguanine (BG)- and temzolomide-resistant hematopoietic and stromal progenitors
from the bone marrow of these patients.

- Evaluate the feasibility of in vivo enrichment of the transduced hematopoietic
progenitors in patients treated with BG and temzolomide.

- Evaluate the toxicity of this regimen in these patients.

- Determine the antitumor effect of this regimen in these patients.

OUTLINE: This is a dose-escalation study of CD34 stem cells and carmustine.

After a negative bone marrow sampling, patients receive sargramostim (GM-CSF) and filgrastim
(G-CSF) subcutaneously (SC) once daily on days 1-5 (or G-CSF twice daily alone for 4-5
days). Peripheral blood progenitor cells are collected 24 hours after the last dose of
growth factor injection on day 5 and also on day 6, if necessary. The CD34 positive stem
cells are then infected by the retroviral mutant MGMT-G156A ex vivo.

Patients receive O6-benzylguanine (BG) IV over 1 hour followed by carmustine IV over 1 hour
every 6 weeks for 5 courses, assuming recovery of peripheral blood counts. Approximately 72
hours after the end of the first course of chemotherapy, patients receive reinfusion of
retrovirally-transduced hematopoietic stem cells over 5-10 minutes. Four weeks after the
completion of BG and carmustine, patients receive BG IV over 1 hour followed by temozolomide
IV over 1 hour every 4 weeks for up to 5 courses, in the absence of hematologic toxicity.
Patients with responding disease may continue to receive BG and temzolomide in the absence
of disease progression or unacceptable toxicity provided other phase II studies indicate the
safety of more than 5 courses.

Cohorts of 3-6 patients receive escalating numbers of CD34 stem cells targeted for
retroviral infection and escalating doses of carmustine.

Patients are followed monthly for 2 months, every 4 months for 8 months, and then every 6
months thereafter.

PROJECTED ACCRUAL: A total of 12-18 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- One of the following histologically confirmed diseases for which no curative
surgical, radiotherapy, or chemotherapy programs are available and standard therapy
offers, at best, a modest clinical benefit

- Solid tumors

- Gliomas

- Non-Hodgkin's lymphoma

- Primary and metastatic CNS malignancies are eligible

- Evaluable or measurable disease

- CD34 count at least 2.0 cells/μL

- No bone marrow involvement

- Histologically negative bone marrow biopsy

PATIENT CHARACTERISTICS:

Age:

- 18 to 70

Performance status:

- ECOG 0-2

Life expectancy:

- At least 12 weeks

Hematopoietic:

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Hemoglobin at least 8.5 g/dL

Hepatic:

- Bilirubin no greater than 1.5 mg/dL

- AST and ALT less than 2.5 times normal

- Prothrombin time less than 1.2 times normal

Renal:

- Creatinine no greater than 2.0 mg/dL

Cardiovascular:

- No acute cardiac disease by EKG

Pulmonary:

- No symptomatic pulmonary disease

Other:

- HIV negative

- No other severe comorbid conditions

- Not pregnant or nursing

- Fertile patients must use effective contraception during and for 2 months after study
completion

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- See Chemotherapy

- No prior hematopoietic stem cell transplantation

Chemotherapy:

- No prior high-dose chemotherapy

- Prior adjuvant chemotherapy allowed

Endocrine therapy:

- Not specified

Radiotherapy:

- No prior radiotherapy to 25% or more of bone marrow

Surgery:

- Not specified

Other:

- At least 4 weeks since prior myelosuppressive therapy

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Gene transfer expression

Outcome Time Frame:

measured at days 28, 56, 84, and 112, and then every 3 months for 1 year

Safety Issue:

No

Principal Investigator

Stanton L. Gerson, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

CWRU2Y97

NCT ID:

NCT00003567

Start Date:

May 1999

Completion Date:

February 2007

Related Keywords:

  • Brain and Central Nervous System Tumors
  • Lymphoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • recurrent adult brain tumor
  • adult brain stem glioma
  • stage IV grade 1 follicular lymphoma
  • stage IV grade 2 follicular lymphoma
  • stage IV grade 3 follicular lymphoma
  • stage IV adult diffuse small cleaved cell lymphoma
  • stage IV adult diffuse mixed cell lymphoma
  • stage IV adult diffuse large cell lymphoma
  • stage IV adult immunoblastic large cell lymphoma
  • stage IV adult lymphoblastic lymphoma
  • stage IV adult Burkitt lymphoma
  • recurrent grade 1 follicular lymphoma
  • recurrent grade 2 follicular lymphoma
  • recurrent grade 3 follicular lymphoma
  • recurrent adult diffuse small cleaved cell lymphoma
  • recurrent adult diffuse mixed cell lymphoma
  • recurrent adult diffuse large cell lymphoma
  • recurrent adult immunoblastic large cell lymphoma
  • recurrent adult lymphoblastic lymphoma
  • recurrent adult Burkitt lymphoma
  • adult mixed glioma
  • stage IV mantle cell lymphoma
  • recurrent mantle cell lymphoma
  • unspecified adult solid tumor, protocol specific
  • adult anaplastic astrocytoma
  • adult anaplastic oligodendroglioma
  • adult glioblastoma
  • adult pilocytic astrocytoma
  • adult subependymoma
  • adult anaplastic ependymoma
  • adult myxopapillary ependymoma
  • adult ependymoblastoma
  • recurrent marginal zone lymphoma
  • recurrent small lymphocytic lymphoma
  • stage IV small lymphocytic lymphoma
  • stage IV marginal zone lymphoma
  • extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
  • nodal marginal zone B-cell lymphoma
  • splenic marginal zone lymphoma
  • adult oligodendroglioma
  • adult giant cell glioblastoma
  • adult gliosarcoma
  • adult diffuse astrocytoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Nervous System Neoplasms
  • Lymphoma, Large-Cell, Immunoblastic
  • Central Nervous System Neoplasms
  • Neoplasms

Name

Location
Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center Cleveland, Ohio  44106-5065