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

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.

- 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 4.03

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.