BG & TMZ Therapy of Glioblastoma Multiforme

NCT ID: NCT01269424

Last Updated: 2023-03-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-22
• Study Completion Date: 2022-09-26

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. O6-benzylguanine may help temozolomide work better by making tumor cells more sensitive to the drug. Giving genetically modified peripheral blood stem cells during or after treatment may prevent side effects caused by chemotherapy.

PURPOSE: This clinical trial studies O6-benzylguanine and temozolomide in combination with genetically modified peripheral blood stem cells in treating patients with newly diagnosed glioblastoma multiforme.

Detailed Description

OBJECTIVES:

Primary

• To evaluate the feasibility of introducing and expressing P140K MGMT cDNA from a lentiviral-based provirus in autologous hematopoietic stem cells harvested from Glioblastoma multiforme (GBM) patients.
• To assess the safety associated with infusion of autologous hematopoietic stem cells transduced ex vivo with a lentiviral vector expressing P140K MGMT in patients with GBM.

Secondary

• To determine whether any patients who receive P140K MGMT-transduced CD34 cells tolerate O6-benzylguanine (BG) and dose-escalated temozolomide (TMZ) without myelosuppression.
• To evaluate the ability to detect P140K-transduced BG and TMZ-resistant hematopoietic cells from the bone marrow and peripheral blood in patients infused with P140K-transduced CD34 progenitors.
• To evaluate the feasibility of in vivo enrichment of P140K-expressing hematopoietic cells by repeated treatments of BG and TMZ at doses that appear therapeutic for GBM.
• To evaluate the efficacy of various types of chemotherapy with or without radiotherapy on conditioning the patient's bone marrow to host the transduced autologous hematopoetic stem cells.
• To evaluate tumor response, progression-free survival, and overall survival.

OUTLINE: Patients are assigned to 1 of 3 treatment cohorts.

• Cohort 1 (LV P140K MGMT gene transfer after concurrent chemoradiotherapy): Patients receive radiotherapy (60cGy in 30 2cGy daily doses) and TMZ 75mg/m2 /daily for 6 weeks, cell infusion at week 7 (T0) followed by BG 120 mg/m2 intravenous infusion over 1h and TMZ 50 mg/m2/day x 5 days, every 28 days (starting on T+28) for 6 cycles.
• Cohort 2 (LV P140K MGMT gene transfer prior to concurrent chemoradiotherapy): Patients receive BG 120mg/m2 intravenous infusion over 1h and TMZ 400 mg/m2 one dose given on day T-2 or T-3 days prior to cell infusion, followed within 72-96 hours by radiotherapy (60cGy in 30 2cGy daily doses) and concurrent BG + TMZ at 50 mg/m2/day x 5 days, every 28 days,starting on T+28 for a total of 7 cycles of BG + TMZ.
• Cohort 3 (intra-patient dose escalation of TMZ in patients with evidence of P140K-marked cells): Dose escalation of TMZ in patients with evidence of P140K marked cells in vivo given as described above for cohort 1 or cohort 2. After completion of radiotherapy, patients will receive BG + TMZ at 50 mg/m2/day x 5 days. Patients not experiencing any grade 3 toxicity will be increased to the next TMZ dose level of 65 mg/m2/day x 5. Subsequent dose escalation without grade 3 toxicity will be 80 mg/m2/day, 100 mg/m2/day, 120mg/m2/day and 140 mg/m2/day x 5. If at subsequent cycles a grade 3 or greater hematologic toxicity occurs, the dose level for the next cycle will be reduced one level.

Blood samples are collected periodically for replication-competent lentivirus detection and other laboratory biomarker studies.

After completion of study therapy, patients are followed up every 2 months.

Conditions

Glioblastoma Multiforme

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Cohort 1

LV gene transfer after concurrent chemo-radiotherapy

Group Type: ACTIVE_COMPARATOR

MGMTP140K-encoding retroviral vector

Intervention Type: BIOLOGICAL

O6-benzylguanine

Intervention Type: DRUG

temozolomide

Intervention Type: DRUG

laboratory biomarker analysis

Intervention Type: OTHER

autologous hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

in vitro-treated peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Cohort 2

LV gene transfer prior to concurrent chemo-radiotherapy

Group Type: ACTIVE_COMPARATOR

MGMTP140K-encoding retroviral vector

Intervention Type: BIOLOGICAL

O6-benzylguanine

Intervention Type: DRUG

temozolomide

Intervention Type: DRUG

laboratory biomarker analysis

Intervention Type: OTHER

autologous hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

in vitro-treated peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Cohort 3

Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells

Group Type: ACTIVE_COMPARATOR

MGMTP140K-encoding retroviral vector

Intervention Type: BIOLOGICAL

O6-benzylguanine

Intervention Type: DRUG

temozolomide

Intervention Type: DRUG

laboratory biomarker analysis

Intervention Type: OTHER

autologous hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

in vitro-treated peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Interventions

MGMTP140K-encoding retroviral vector

Intervention Type: BIOLOGICAL

O6-benzylguanine

Intervention Type: DRUG

temozolomide

Intervention Type: DRUG

laboratory biomarker analysis

Intervention Type: OTHER

autologous hematopoietic stem cell transplantation

Intervention Type: PROCEDURE

in vitro-treated peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

radiation therapy

Intervention Type: RADIATION

Eligibility Criteria

Inclusion Criteria

• Patients with histologically confirmed, newly diagnosed, supratentorial GBM who have undergone gross total tumor resections or near gross total resection (resection of >90% of enhancing tumor demonstrated by MRI) are eligible up to their third post-operative week. Patients with infratentorial disease, multifocal or leptomeningeal disease will be excluded. In general, patients will not have > 1 cm residual measurable or evaluable disease after surgical tumor resection.
• ECOG performance status 0-2 or Karnofsky ≥ 70.
• Patients must have received no myelosuppressive chemotherapy prior to the diagnosis of GBM.
• Life expectancy of at least 12 weeks.
• Adequate hematologic (ANC ≥ 1,000/mm3, platelets ≥ 100,000/mm3, Hgb ≥ 9.5) , hepatic (Bilirubin ≤ 2.0 mg/dl, AST and ALT less than or equal to 3 times upper limit of normal, prothrombin time <1.2 times normal), and renal (Serum creatinine ≤ 2.0 mg/dl or Creatinine Clearance ≥ 60mL/min/1.73 m2 for subjects with serum creatinine levels above institutional normal) . These tests will be repeated within 2 weeks of treatment with BG and TMZ, and must meet the same criteria.
• EKG without evidence of acute cardiac disease.
• Left ventricular ejection fraction (LVEF) ≥ 40
• Post-operative steroids are tapered to ≤ 24 mg decadron/d
• Patients of child-bearing potential must be using single barrier contraception
• Willingness and ability to provide informed consent.
• Patient must have all sutures removed prior to registration
• Patient must be considered to be clinically stable.

Exclusion Criteria

• Medical condition associated with immunosuppression, active infection or medical illness which may jeopardize patient safety.
• HIV seropositivity. This exclusion is included for two reasons. First, there is evidence of decreased marrow reserve in HIV+ patients and antiviral treatment is associated with myelosuppression. Thus, drug treatment designed to be myelosuppressive may be more toxic in this patient population. Second, extensive laboratory culturing of the bone marrow and peripheral blood progenitor cells is required. No preclinical samples which are HIV+ have been evaluated with the gene transfer modality proposed and thus the feasibility and safety of gene transfer and selection in HIV+ samples cannot yet be advocated. Such studies are planned so as to not preclude HIV+ patients in later studies.
• Pregnant or lactating women. There is data to indicate that TMZ is teratogenic and carcinogenic. Thus, its use in pregnant women would confer unnecessary risk to the fetus.
• Patients with symptomatic pulmonary disease and other severe co-morbid conditions
• Patients with cardiac insufficiency and an LVEF of < 40%. History of acute coronary event disease or arrhythmia within 6 months prior to enrollment
• Prior chemotherapy (including gliadel wafers) or hematopoietic cell transplantation.
• Inability to undergo repeated MRI evaluation.
• Prior diagnosis of malignant disease within a three year period with the exception of surgically cured basal cell carcinoma or carcinoma in situ of the cervix
• Mental incapacity or psychiatric illness preventing informed consent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Stanton Gerson MD

OTHER

Sponsor Role: lead

Responsible Party

Stanton Gerson MD

Director, Case Comprehensive Cancer Center

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Andrew Sloan, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Locations

University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Cleveland, Ohio, United States

Countries

United States

Other Identifiers

8274

Identifier Type: OTHER

Identifier Source: secondary_id

U01CA062502

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CASE6307

Identifier Type: -

Identifier Source: org_study_id