Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Gene Therapy and Chemotherapy in Treating Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	18 to 70	NCI	CASE-CWRU-2Y97 NCI-T97-0060, NCT00003567, T97-0060, CASE-2Y97

Objectives

1. 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.
2. Determine the toxicity associated with reinfusion of ex vivo-transduced hematopoietic stem cells into these patients, including the detection of replication competent retrovirus.
3. 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.
4. Evaluate the feasibility of in vivo enrichment of the transduced hematopoietic progenitors in patients treated with BG and temzolomide.
5. Evaluate the toxicity of this regimen in these patients.
6. Determine the antitumor effect of this regimen in these patients.

Entry 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

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

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/mm³
• Platelet count at least 100,000/mm³
• 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

Expected Enrollment

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

Outcomes

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

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.

Trial Contact Information

Trial Lead Organizations

Case Comprehensive Cancer Center

Stanton Gerson, MD, Protocol chair		Ph: 216-844-8562

Registry Information
Official Title		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
Trial Start Date		1999-05-14
Trial Completion Date		2007-01-11
Registered in ClinicalTrials.gov		NCT00003567
Date Submitted to PDQ		1998-09-02
Information Last Verified		2007-03-01
NCI Grant/Contract Number		CA43703, CA76192

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