O6-Benzylguanine and Temozolomide in Combination With Genetically Modified Peripheral Blood Stem Cells in Newly Diagnosed Glioblastoma Multiforme

This study is currently recruiting participants.
Verified February 2013 by Case Comprehensive Cancer Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Stanton Gerson MD, Case Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01269424
First received: December 31, 2010
Last updated: February 6, 2013
Last verified: February 2013

December 31, 2010
February 6, 2013
December 2010
August 2013   (final data collection date for primary outcome measure)
  • Feasibility of infusing autologous P140K MGMT-transduced hematopoietic progenitors into patients with GBM [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
    Patients will be assessed for clinical symptoms and side-effects from time of treatment until protocol is stopped due to toxicity, progression, patient choice, or patient election to enroll on new therapeutic option.
  • Safety (grade IV toxicity) [ Time Frame: up to 5 years ] [ Designated as safety issue: Yes ]
    CTCAE v 4.0 will be used as the criteria for evaluating infusion-related events.
  • Feasibility of infusing autologous P140K MGMT-transduced hematopoietic progenitors into patients with GBM [ Designated as safety issue: No ]
  • Safety (grade IV toxicity) [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01269424 on ClinicalTrials.gov Archive Site
  • Successful transduction rate [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    Quantitate P140K transduced hematopoietic cells from the bone marrow and peripheral blood in patients infused with P140K transduced CD34 progenitors
  • To evaluate the in vivo enrichment of P140K expressing hematopoietic cells by repeated treatments of BG and TMZ [ Time Frame: up to 4 years ] [ Designated as safety issue: No ]
    To evaluate the in vivo enrichment of P140K expressing hematopoietic cells by repeated treatments of BG and TMZ
  • Progression-free [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
    Progression-free survival defined as the time interval between the date of initial histological diagnosis and the date of disease progression or death, whichever comes first
  • Number of patients with radiological progression [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
    New tumor or increased tumor size on T1WI + Gd of > 25% as measured by the sum of two perpendicular diameters compared to the smallest measurements ever recorded for the same lesion by the same technique.
  • Overall Survival [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
    From the date of enrollment to death, last contact or last tumor assessment before further anti-tumor therapy, assessed up to 5 years.
  • Successful transduction rate [ Designated as safety issue: No ]
  • Rate of myelosuppression [ Designated as safety issue: No ]
  • Progression-free and overall survival [ Designated as safety issue: No ]
  • Tumor response rate [ Designated as safety issue: No ]
Not Provided
Not Provided
 
O6-Benzylguanine and Temozolomide in Combination With Genetically Modified Peripheral Blood Stem Cells in Newly Diagnosed Glioblastoma Multiforme
O6-Benzylguanine (BG) and Temozolomide (TMZ) Therapy of Glioblastoma Multiforme (GBM) With Infusion of Autologous P140KMGMT+ Hematopoietic Progenitors to Protect Hematopoiesis

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.

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 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 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 concurrent radiotherapy 5 days a week and oral temozolomide (TMZ) daily for 6 weeks. Patients then undergo cell reinfusion of autologous P140K MGMT-transduced hematopoietic cells over 5-10 minutes at week 7. Beginning 4 weeks later, patients receive O6-benzylguanine (BG) IV over 1 hour on days 1-28 and oral TMZ on days 1-5. Treatment with BG and TMZ repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • Cohort 2 (LV P140K MGMT gene transfer prior to concurrent chemoradiotherapy): Patients receive BG IV over 1 hour and a single dose of oral TMZ 2-3 days prior to reinfusion of autologous P140K MGMT-transduced hematopoietic cells over 5-10 minutes on day 0. Patients then undergo radiotherapy 5 days a week and receive concurrent BG daily and TMZ 5 days a week beginning on days 28 and 56. Beginning on day 56, treatment with BG and TMZ repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • Cohort 3 (intra-patient dose escalation of TMZ in patients with evidence of P140K-marked cells [using the preferred treatment schema determined from Cohorts 1 and 2 above]): After completion of radiotherapy, patients receive BG and TMZ and undergo cell infusion as in cohort 1 (cohort 3a) or 2 (cohort 3b). TMZ dose may be increased, as tolerated, during the 6 courses after radiotherapy.

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.

Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Brain and Central Nervous System Tumors
  • Biological: MGMTP140K-encoding retroviral vector
  • Drug: O6-benzylguanine
  • Drug: temozolomide
  • Other: laboratory biomarker analysis
  • Procedure: autologous hematopoietic stem cell transplantation
  • Procedure: in vitro-treated peripheral blood stem cell transplantation
  • Radiation: radiation therapy
  • Active Comparator: Cohort 1
    LV gene transfer after concurrent chemo-radiotherapy
    Interventions:
    • Biological: MGMTP140K-encoding retroviral vector
    • Drug: O6-benzylguanine
    • Drug: temozolomide
    • Other: laboratory biomarker analysis
    • Procedure: autologous hematopoietic stem cell transplantation
    • Procedure: in vitro-treated peripheral blood stem cell transplantation
    • Radiation: radiation therapy
  • Active Comparator: Cohort 2
    LV gene transfer prior to concurrent chemo-radiotherapy
    Interventions:
    • Biological: MGMTP140K-encoding retroviral vector
    • Drug: O6-benzylguanine
    • Drug: temozolomide
    • Other: laboratory biomarker analysis
    • Procedure: autologous hematopoietic stem cell transplantation
    • Procedure: in vitro-treated peripheral blood stem cell transplantation
    • Radiation: radiation therapy
  • Active Comparator: Cohort 3
    Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells
    Interventions:
    • Biological: MGMTP140K-encoding retroviral vector
    • Drug: O6-benzylguanine
    • Drug: temozolomide
    • Other: laboratory biomarker analysis
    • Procedure: autologous hematopoietic stem cell transplantation
    • Procedure: in vitro-treated peripheral blood stem cell transplantation
    • Radiation: radiation therapy
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
18
Not Provided
August 2013   (final data collection date for primary outcome measure)

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.
  • Patients aged 18-70. Patients >70 will be excluded due to difficulties in mobilization and collection of adequate numbers of peripheral progenitors.
  • ECOG performance status 0-2 or Karnofsky ≥ 60.
  • Patients must have received no myelosuppressive chemotherapy prior to the diagnosis of GBM.
  • Life expectancy of at least 12 weeks.
  • Adequate hematologic (ANC ≥ 1500/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.
  • 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.

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
  • 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
Both
18 Years to 70 Years
No
Not Provided
United States
 
NCT01269424
CASE6307, NCI-2011-02566, 8274
Yes
Stanton Gerson MD, Case Comprehensive Cancer Center
Stanton Gerson MD
National Cancer Institute (NCI)
Principal Investigator: Andrew E. Sloan, MD Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Case Comprehensive Cancer Center
February 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP