Clinical trial NCT00003567: Gene Therapy and Chemotherapy in Treating Patients With Advanced Solid Tumors or Non-Hodgkin's Lymphoma
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Lymphoma
Unspecified Adult Solid Tumor, Protocol Specific
Keywords: 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
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility 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

Primary outcomes:
measure: Gene transfer expression
timeFrame: measured at days 28, 56, 84, and 112, and then every 3 months for 1 year
Secondary outcomes:
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
state: Ohio
Study officials:
affiliation: Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center
name: Stanton L. Gerson, MD
role: STUDY_CHAIR
References: