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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT02709226

Collaborator

(none)

Enrollment

Location

Arm

124.5

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Astrocytoma, Grade IV Giant Cell Glioblastoma Glioblastoma Multiforme Gliosarcoma	Radiation: Radiation	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 15, 2016

Anticipated Primary Completion Date :

Oct 30, 2024

Anticipated Study Completion Date :

Oct 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1/Radiation 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 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.

Arm

Intervention/Treatment

Experimental: 1/Radiation

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

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.

Outcome Measures

Primary Outcome Measures

To determine maximum tolerated re-irradiation dose (MTD). [1 month after completion of re-irradiation]
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.

Secondary Outcome Measures

To determine QOL and impact on neurocognition in the setting of re-irradiation of recurrent glioblastoma [baseline and at each visit]
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
To determine progression free survival and overall survival. [time of progression; time of death]
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
To determine late toxicity secondary to re-irradiation [completion of study]
listing of adverse events

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.