Gene Therapy and Chemotherapy in Treating Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma
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| ClinicalTrials.gov Identifier: NCT00003567 |
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Recruitment Status :
Terminated
(slow accrual)
First Posted : January 27, 2003
Last Update Posted : June 11, 2010
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RATIONALE: Gene therapy may improve the body's ability to fight cancer or make the cancer more sensitive to chemotherapy. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: This phase I trial is studying the side effects and best dose of gene therapy together with chemotherapy in treating patients with advanced solid tumors or non-Hodgkin's lymphoma.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Brain and Central Nervous System Tumors Lymphoma Unspecified Adult Solid Tumor, Protocol Specific | Biological: filgrastim Biological: sargramostim Biological: therapeutic autologous lymphocytes Drug: O6-benzylguanine Drug: carmustine Drug: temozolomide Procedure: in vitro-treated peripheral blood stem cell transplantation | Phase 1 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 8 participants |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Study Start Date : | May 1999 |
| Actual Primary Completion Date : | January 2007 |
| Actual Study Completion Date : | February 2007 |
- Biological: filgrastim
Patients receive filgrastim (G-CSF) subcutaneously (SC) once daily on days 1-5 (or G-CSF twice daily alone for 4-5 days).
- Biological: sargramostim
Patients receive sargramostim (GM-CSF) subcutaneously (SC) once daily on days 1-5 (or G-CSF twice daily alone for 4-5 days).
- Biological: therapeutic autologous lymphocytes
- Drug: O6-benzylguanine
Patients receive O6-benzylguanine (BG) IV over 1 hour every 6 weeks for 5 courses. Four weeks after the completion of BG and carmustine, patients receive BG 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.
- Drug: carmustine
Patients receive carmustine IV over 1 hour every 6 weeks for 5 courses.Cohorts of 3-6 patients receive escalating numbers of CD34 stem cells targeted for retroviral infection and escalating doses of carmustine.
- Drug: temozolomide
Four weeks after the completion of BG and carmustine, patients receive 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.
- Procedure: in vitro-treated peripheral blood stem cell transplantation
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. Cohorts of 3-6 patients receive escalating numbers of CD34 stem cells targeted for retroviral infection and escalating doses of carmustine.
- Gene transfer expression [ Time Frame: measured at days 28, 56, 84, and 112, and then every 3 months for 1 year ]
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| Ages Eligible for Study: | 18 Years to 70 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
DISEASE CHARACTERISTICS:
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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
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00003567
| United States, Ohio | |
| Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center | |
| Cleveland, Ohio, United States, 44106-5065 | |
| Study Chair: | Stanton L. Gerson, MD | Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center |
| Responsible Party: | Stanton L. Gerson, MD, Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center |
| ClinicalTrials.gov Identifier: | NCT00003567 |
| Other Study ID Numbers: |
CWRU2Y97 R21CA076192 ( U.S. NIH Grant/Contract ) P30CA043703 ( U.S. NIH Grant/Contract ) CASE-CWRU-2Y97 ( Other Identifier: Case Comprehensive Cancer Center ) NCI-T97-0060 CASE-2Y97 ( Other Identifier: Case Comprehensive Cancer Center ) |
| First Posted: | January 27, 2003 Key Record Dates |
| Last Update Posted: | June 11, 2010 |
| Last Verified: | June 2010 |
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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 |
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Lymphoma Nervous System Neoplasms Central Nervous System Neoplasms Neoplasms Neoplasms by Histologic Type Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Neoplasms by Site Nervous System Diseases Temozolomide |
Carmustine O(6)-benzylguanine Lenograstim Sargramostim Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Adjuvants, Immunologic Immunologic Factors Physiological Effects of Drugs Enzyme Inhibitors |