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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme; Gliosarcoma; Giant Cell Glioblastoma; Astrocytoma, Grade IV
• Intervention / Treatment: Radiation: Radiation

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 Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

  1. 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.

  2. Patients must be age greater than or equal to 18.
  3. Patients should have a KPS greater than or equal to 70%
  4. Prior standard radiation therapy to a dose ranging from 50 to 60 Gy at 1.8 to 2 Gy per fraction.
  5. Patients must be more than or equal to 14 days from previous cytotoxic treatment.

  6. 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.

  7. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
  8. 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:

1. Prior therapy < than 2 weeks since surgical re-resection or biopsy
2. Pregnant or breast feeding females are excluded due to potential mutagenic effects on the developing fetus or newborn
3. Preexisting grade 3 or 4 nervous system disorder as per CTCAE Version 4.0
4. 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.
5. 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.
6. Patients with preexisting known or suspected radiation sensitivity syndromes will be excluded due to potential confounding effect on outcome.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Kevin A Camphausen, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2016
• Primary Completion (Actual): December 16, 2022
• Study Completion (Actual): July 19, 2023

Study Registration Dates

• First Submitted: March 15, 2016
• First Submitted That Met QC Criteria: March 15, 2016
• First Posted (Estimated): March 16, 2016

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: September 28, 2023

More Information

Terms related to this study

• Keywords: Brain Tumor; GBM; Radiation Therapy; Astrocytoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Astrocytoma; Gliosarcoma
• Other Study ID Numbers: 160081; 16-C-0081

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No