O6-Benzylguanine (BG) and Temozolomide (TMZ) Therapy of Glioblastoma Multiforme (GBM) With Infusion of Autologous P140KMGMT+ Hematopoietic Progenitors to Protect Hematopoiesis
- To evaluate the feasibility of introducing and expressing P140K MGMT cDNA from a
lentiviral-based provirus in autologous hematopoietic stem cells harvested from GBM
- 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.
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Feasibility of infusing autologous P140K MGMT-transduced hematopoietic progenitors into patients with GBM
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.
up to 5 years
Andrew E. Sloan, MD
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
United States: Food and Drug Administration
|Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center||Cleveland, Ohio 44106-5065|