PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation

Study Overview
=================
Brief Summary
-----------------
To obtain preliminary data in a randomized phase II study whether PPX/RT improves progression-free survival as compared to temozolomide/RT for patients with GBM without MGMT methylation.

Detailed Description
-----------------
To evaluate the toxicities of PPX/RT To evaluate neuro-cognitive functional assessments of patients with GBM receiving PPX/RT To obtain preliminary data in a randomized phase II study whether PPX/RT improves overall survival as compared to temozolomide /RT for patients with GBM without MGMT methylation to facilitate planning a phase III study.

Official Title
-----------------
PPX and Concurrent Radiation for Newly Diagnosed Glioblastoma Without MGMT Methylation: A Randomized Phase II Study

Conditions
-----------------
Glioblastoma Multiforme

Intervention / Treatment
-----------------
* Drug: PPX (CT2103)
* Drug: Temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven diagnosis of glioblastoma or gliosarcoma (WHO grade IV) GBM must have unmethylated MGMT as determined by central laboratory Diagnosis of GBM must be made by biopsy or surgical excision, either partial or complete; as long as there is sufficient tissue to determine MGMT status No prior chemotherapy or radiation for brain tumor Must be able to tolerate brain MRIs. *A diagnostic contrast-enhanced MRI must be performed postoperatively within 42 days prior to study registration. KPS >60. Age > 18 Life expectancy of at least 3 months. Absolute neutrophil count > 1500/mm3, Platelets > 100,000/mm, Creatinine < 2 x ULN ALT or AST < 3 x upper limit of normal (ULN) and total bilirubin < 1.5x ULN. Patients with a prior history of low grade glioma who did not receive prior radiation or chemotherapy with transformation to grade IV brain tumor are eligible. Women must be non-lactating, and surgically sterile, post-menopausal or have a negative serum pregnancy test and agree to use adequate birth control. Males must agree to use adequate birth control. Voluntary, signed informed consent. Exclusion Criteria: Acute infection or other medical condition that would impair study treatment No other active invasive malignancy unless disease free for at least 3 years. Prior temozolomide or PPX. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields. No diffuse leptomeningeal disease, or gliomatosis cerebri. Use of any other experimental chemotherapy drug within the 60 days prior to randomization and during the trial. (Use of a non-chemotherapy investigational agent must be approved by the Brown University Oncology Group)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: radiation plus PPX(CT2103<br>Radiation therapy, Monday through Friday, for 6 weeks for a total of 30 treatments + intravenous PPX every week x 6 weeks for a total of 6 treatments | Drug: PPX (CT2103)<br>* XRT: 60 Gy at 2 Gy/fraction x 30 fractions PPX: 50 mg/m2/week x 6 weeks during radiation Temozolomide maintenance: Beginning 4 weeks after completion of chemoradiation, temozolomide d1-5 of 28 day cycle for 12 cycle maximum.<br>|
| Active Comparator: radiation + Temozolomide<br>Radiation therapy, Monday through Friday, for 6 weeks for a total of 30 treatments + Daily oral temozolomide(TMZ) (7 days) x 6 wks for a total of 42 days | Drug: Temozolomide<br>* XRT: 60 Gy at 2 Gy/fraction x 30 fractions Temozolomide, 75 mg/m2/day, 7 days per week, from the first to the last day of radiotherapy Temozolomide maintenance: Beginning 4 weeks after completion of chemoradiation, temozolomide d1-5 of 28 day cycle for 12 cycle maximum<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival PPX/RT Versus TMZ/RT for Patients With GBM Without Methylation | MRI response evaluated by RANO criteria Complete Response (CR): Circumstance when the enhancing tumor is no longer seen by neuroimaging, with the patient off all steroids or on adrenal maintenance only; CR will be coded only if confirmed by a second CT/MR scan performed a minimum of 4 weeks after the initial scan coding a response. Partial Response (PR): Decrease of > 50% in the product of two diameters. Patients should be receiving stable or decreasing doses of steroids. PR will be coded only if confirmed by a second CT/MR scan performed a minimum of 4 weeks after the initial scan. Progression (P): A > 25% increase in tumor area (two diameters) provided that the patient has not had his/her dose of steroids decreased since the last evaluation period. This will not need a confirmatory scan. A concomitant decrease in steroid dose will rule out a progression designation during the first 2 months after completion of XRT. | Q 3 months on study then Q3 months in f/u for yr 1, q 4 months yr 2, q 6 months for approximately 4 ys. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Brain Tumors, Glioblastoma Multiforme, GBM