Dose Escalation Trial of Re-irradiation in Good Prognosis Recurrent Glioblastoma

Study Overview
=================
Brief Summary
-----------------
Background: A glioblastoma is a tumor in the brain. It is treated with surgery, chemotherapy and radiation therapy. However, most people s tumors come back after therapy. When the tumor grows back, surgery or chemotherapy may not be possible or may no longer work. Repeat radiation therapy or re-irradiation, is an option for treating these tumors when they regrow. Objective: To find out the safety and highest tolerated dose of re-irradiation for people who have recurrent glioblastoma. Eligibility: People ages 18 50 who have glioblastoma that has been treated with radiation but has regrown. Design: Participants will be screened with: Medical history Physical exam MRI of the brain: They will lie in a machine that takes pictures of the brain. Participants will have baseline tests before they start therapy. These will include: Blood tests Neuropsychological tests: These test things like memory, attention, and thinking. Quality of life questionnaire Eye and hearing tests Participants will get a CT of the brain prior to radiation start in order to plan the radiation treatment. Once the plan is completed, they will receive radiation once a day Monday Friday for a total of 10 17 treatments. They will lie on their back for about 10 minutes while they get the treatment. Participants will be monitored for side effects. After they finish treatment, participants will have visits 1, 2, and 3 months later. Then they will have them every 2 months for 3 years. These will include: Medical history Physical exam Blood tests MRI of the brain. Quality of life questionnaire Neuropsychological tests (at some visits) After 3 years, participants will be contacted by phone each month.

Detailed Description
-----------------
Background Although the survival of gliomas has improved, most high grade gliomas will recur in field or adjacent to the treatment field within months to years of the original treatment. In newly diagnosed GBM, the concurrent use of radiation and temozolomide is standard of care. Surgical resection upon recurrence is possible in less than 50% of patients. For a significant proportion of recurrent glioma patients in whom reresection is not favourable and for whom systemic options have been exhausted, re-irradiation has emerged as a possible treatment option. Using modern precision RT techniques (stereotactic radiosurgery (SRS), stereotactic radiotherapy (SRT) or intensity modulated radiation therapy (IMRT), Rapid Arc techniques), re-irradiation has proven a feasible option with possible benefit in outcome as these techniques are often able to minimize dose to previously treated organs at risk in the field (OAR) and treat the recurrence safely. Data from multiple retrospective studies has indicated that not only is re-irradiation feasible, but it may actually improve survival in the appropriately selected patient. Objective The primary objective of this phase I study is to determine maximum tolerated re-irradiation dose (MTD). Eligibility Recurrent glioblastoma or gliosarcoma Prior standard radiation therapy to a dose ranging from 50 to 60 Gy at 1.8 to 2 Gy per fraction. Prior irradiation > 12 months from enrollment on protocol. Age greater than or equal to 18. KPS greater than or equal to 70 Design Radiation therapy will be administered daily Monday-Friday at Radiation Oncology Branch (ROB), NCI. All the protocol related follow-up appointments will occur at NCI ROB. Radiation therapy dose will be administered on consecutive treatment days, 5 fractions per week via a linear accelerator using 6 MV photons or greater. Using a 3 plus 3 design , and three dose escalation levels, with 6 patients per dose level with 9 total patients at the MTD (provided no DLT), a maximum of 21 evaluable patients will be enrolled. Time to progression will be determined by the interval from initiation of treatment on protocol to progression as per RANO criteria. Neurologic decline without radiographic evidence of tumor will be designated as treatment related toxicity. Survival duration will be determined by the interval from initiation of treatment on protocol to date of death.

Official Title
-----------------
A Phase I Dose Escalation Trial of Re-Irradiation in Good Prognosis Recurrent Glioblastoma

Conditions
-----------------
Astrocytoma, Grade IV, Giant Cell Glioblastoma, Glioblastoma Multiforme, Gliosarcoma

Intervention / Treatment
-----------------
* Radiation: Radiation


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: Histological diagnosis Previous histologic diagnosis of glioblastoma, transformation to glioblastoma or gliosarcoma established by biopsy or resection prior to enrollment as evident on NIH or outside pathology. Patients must be age greater than or equal to 18. Patients should have a KPS greater than or equal to 70% Prior standard radiation therapy to a dose ranging from 50 to 60 Gy at 1.8 to 2 Gy per fraction. Patients must be more than or equal to 14 days from previous cytotoxic treatment. Concurrent therapy The concurrent use of bevacizumab is allowed if previously initiated for tumor progression or symptomatic management. Prior temozolomide or other cytotoxic chemotherapy is allowed. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. EXCLUSION CRITERIA: Prior therapy < than 2 weeks since surgical re-resection or biopsy Pregnant or breast feeding females are excluded due to potential mutagenic effects on the developing fetus or newborn Preexisting grade 3 or 4 nervous system disorder as per CTCAE Version 4.0 Clinically significant unrelated systemic illness (including but not limited to active life threatening infection, cardiac or neurologic events, current hospital admission for a coexisting comorbid illness), which would make it impossible for the patient to tolerate re-irradiation or systemic chemotherapy or likely to interfere with the results. Patients exhibiting baseline grade 3 or 4 by CTCAE criteria are excluded due to difficulty in assigning these to the study intervention as treatment related DLT. Patients with preexisting known or suspected radiation sensitivity syndromes will be excluded due to potential confounding effect on outcome.

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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Radiation<br>Dose escalation is as follows: dose level 1 (DL1) 3.5 Gy x 10; dose level 2 (DL2) 3.5 Gy x 12; dose level 3 (DL3) 3.5 Gy x 14. If 2 DLTs are observed in the second dose level a step down dose of 3.0 Gy x 14 fractions will be tested. If 2 DLTs are observed in the third dose level a step down dose of 3.0 Gy x 17 fractions will be tested. The study will have 3 planned re-irradiation dose levels, with 1 to 6 patients per dose level using the 3+3 design to define the MTD. The number of patients may be increased to 9 total patients at the MTD ( provided no DLT) with a maximum of 21 evaluable patients enrolled. | Radiation: Radiation<br>* Radiation therapy will be administered daily Monday-Friday at NCI, ROB unless the treatment schedule requires amendment in the event of inclement weather or federal holidays. Radiation therapy dose will be administered as per on consecutive treatment days, 5 fractions per week via a linear accelerator using 6 MV photons or greater. Dose escalation is as follows: dose level 1 (DL1) 3.5 Gy x 10; dose level 2 (DL2) 3.5 Gy x 12; dose level 3 (DL3) 3.5 Gy x 14. If 2 DLTs are observed in the second dose level a step down dose of 3.0 Gy x 14 fractions will be tested. If 2 DLTs are observed in the third dose level a step down dose of 3.0 Gy x 17 fractions will be tested. The study will have 3 planned re-irradiation dose levels, with 1 to 6 patients per dose level using the 3+3 design to define the MTD. The number of patients may be increased to 9 total patients at the MTD ( provided no DLT) with a maximum of 21 evaluable patients enrolled.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine maximum tolerated re-irradiation dose (MTD). | The MTD will be based on the assessment of DLT within one month following the re-irradiation, and will be defined as the dose level at which less than one-third of patients (0/3 or 0-1/6 patients) treated at that dose experience a DLT, with the next higher dose level demonstrating a one-third or greater number of patients (>= 2/3 or >= 2/6 patients) having DLT. | 1 month after completion of re-irradiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine QOL and impact on neurocognition in the setting of re-irradiation of recurrent glioblastoma | QOL scores will be summarized at baseline and for each visit. Changes from baseline of health-related quality of life questionnaire mean scores will be evaluated | baseline and at each visit | 
| To determine progression free survival and overall survival. | interval from initiation of treatment on protocol to progression as per RANO criteria Survival duration will be determined by the interval from initiation of treatment on protocol to date of death | time of progression; time of death | 
| To determine late toxicity secondary to re-irradiation | listing of adverse events | completion of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Brain Tumor, Astrocytoma, GBM, Radiation Therapy