BG & TMZ Therapy of Glioblastoma Multiforme
- Conditions
- Interventions
- Registration Number
- NCT01269424
- Lead Sponsor
- Stanton Gerson MD
- 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 treat...
- 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.
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Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 10
- 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
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 3 temozolomide Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells Cohort 3 radiation therapy Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells Cohort 1 autologous hematopoietic stem cell transplantation LV gene transfer after concurrent chemo-radiotherapy Cohort 1 radiation therapy LV gene transfer after concurrent chemo-radiotherapy Cohort 2 radiation therapy LV gene transfer prior to concurrent chemo-radiotherapy Cohort 3 O6-benzylguanine Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells Cohort 3 autologous hematopoietic stem cell transplantation Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells Cohort 1 laboratory biomarker analysis LV gene transfer after concurrent chemo-radiotherapy Cohort 2 MGMTP140K-encoding retroviral vector LV gene transfer prior to concurrent chemo-radiotherapy Cohort 2 autologous hematopoietic stem cell transplantation LV gene transfer prior to concurrent chemo-radiotherapy Cohort 1 in vitro-treated peripheral blood stem cell transplantation LV gene transfer after concurrent chemo-radiotherapy Cohort 1 temozolomide LV gene transfer after concurrent chemo-radiotherapy Cohort 2 laboratory biomarker analysis LV gene transfer prior to concurrent chemo-radiotherapy Cohort 1 MGMTP140K-encoding retroviral vector LV gene transfer after concurrent chemo-radiotherapy Cohort 1 O6-benzylguanine LV gene transfer after concurrent chemo-radiotherapy Cohort 3 in vitro-treated peripheral blood stem cell transplantation Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells Cohort 2 in vitro-treated peripheral blood stem cell transplantation LV gene transfer prior to concurrent chemo-radiotherapy Cohort 3 MGMTP140K-encoding retroviral vector Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells Cohort 3 laboratory biomarker analysis Intra patient dose escalation of TMZ in patients with evidence of P140K marked cells Cohort 2 O6-benzylguanine LV gene transfer prior to concurrent chemo-radiotherapy Cohort 2 temozolomide LV gene transfer prior to concurrent chemo-radiotherapy
- Primary Outcome Measures
Name Time Method Feasibility and safety of infusing autologous P140K MGMT-transduced hematopoietic progenitors into patients with GBM up to 5 years Patients will be assessed for clinical symptoms and side-effects - CTCAE v 4.0 - from time of treatment until protocol is stopped due to toxicity, progression, patient choice, or patient election to enroll on new therapeutic option.
- Secondary Outcome Measures
Name Time Method Successful transduction rate up to 4 years 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 up to 4 years To evaluate the in vivo enrichment of P140K expressing hematopoietic cells by repeated treatments of BG and TMZ
Progression-free up to 5 years 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
Overall Survival up to 5 years From the date of enrollment to death, last contact or last tumor assessment before further anti-tumor therapy, assessed up to 5 years. .
Number of patients with radiological progression up to 5 years 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.
Trial Locations
- Locations (1)
University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
🇺🇸Cleveland, Ohio, United States