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O6-Benzylguanine (BG) and Temozolomide (TMZ) Therapy of Glioblastoma Multiforme (GBM) With Infusion of Autologous P140KMGMT+ Hematopoietic Progenitors to Protect Hematopoiesis


Phase 1
18 Years
70 Years
Open (Enrolling)
Both
Brain and Central Nervous System Tumors

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Trial Information

O6-Benzylguanine (BG) and Temozolomide (TMZ) Therapy of Glioblastoma Multiforme (GBM) With Infusion of Autologous P140KMGMT+ Hematopoietic Progenitors to Protect Hematopoiesis


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Feasibility of infusing autologous P140K MGMT-transduced hematopoietic progenitors into patients with GBM

Outcome Description:

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.

Outcome Time Frame:

up to 5 years

Safety Issue:

No

Principal Investigator

Andrew E. Sloan, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

CASE6307

NCT ID:

NCT01269424

Start Date:

December 2010

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • adult giant cell glioblastoma
  • adult glioblastoma
  • adult gliosarcoma
  • Glioblastoma
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms

Name

Location

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065