Dose Escalated MRSI Guided Radiation Therapy in Glioblastoma

Phase 2

Terminated

Conditions: Glioblastoma

Interventions: Radiation: Intensity Modulated Radiation Therapy
Drug: Temozolomide
Behavioral: Functional Assessment of Cancer Therapy-Brain (FACT-Br)
Radiation: Simultaneous Integrated Boost
Radiation: Stereotactic Radiosurgery Boost
Device: 3D MRSI

Registration Number: NCT02394665

Lead Sponsor: University of Miami

Brief Summary: In summary, the overall prognosis of glioblastoma (GBM) patients remains poor. Although clinical gains have been achieved in the past, these have been modest, with a majority of patients succumbing to local disease progression within 2 years. New strategies for treatment need to be identified which enhance local control above the current treatment regimen in order to achieve further clinical gains in this disease. Favorable early experience with magnetic resonance spectroscopy imaging (MRSI) demonstrates that metabolic imaging can identify active tumor beyond standard MRI as well as high risk regions at risk for local failure. There is also clinical evidence that limited field dose escalation with either simultaneous integrated boost (SIB) or stereotactic radiosurgery (SRS) is feasible and safe. Coupling these findings provide the rationale for this proposed Phase II trial designed to define efficacy and toxicity of the novel treatment approach of whole brain volumetric 3D MRSI guided dose-escalated radiation therapy (RT) in newly diagnosed GBM patients.

Detailed Description: This phase II study will investigate efficacy and safety of volumetric 3D MRSI-directed treatment for newly diagnosed GBM patients. This study will enroll 48 patients in order to obtain at least 40 patients receiving RT and temozolomide. Depending on the size and number of HTVs, a patient will receive either simultaneous integrated boost (SIB) with IMRT (Group 1) or SRS boost followed by IMRT 1 week later (Group 2). Duration of enrollment will be 2 years and minimum follow-up will be 2 years.

The duration of treatment and follow-up will occur as follows:

* Six weeks of RT with concurrent Temozolomide treatment;

* 3D MRSI at week 3 and at the end of RT;

* 28 day break;

* Adjuvant treatment with Temozolomide administered daily on days 1-5 of each cycle, for up to 12 cycles (one cycle = 28 days) which will include standard gadolinium enhanced MRI and 3D MRSI prior to cycle 1, 5, 9, and post cycle 12 of adjuvant Temozolomide;

* Active follow-up at least every three months for one year after the end of adjuvant Temozolomide treatment;

* After one year follow-up for survival will occur every three months for one year.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

Inclusion Criteria

Histologically proven diagnosis of glioblastoma (WHO grade IV). Since gliosarcoma is a variant of glioblastoma, gliosarcoma is also an eligible diagnosis.
The tumor must have a supratentorial component
Patients must have recovered from the effects of surgery, postoperative infection and other complications
Karnofsky performance status > 70
Age > 18 years
Adequate bone marrow function defined as follows:
- Absolute neutrophil count (ANC) >/= 1500 cells/mm^3
- Platelet count > 100,000 cells/mm^3
- Hemoglobin > 10.0 g/dL (Note: the use of transfusion or other intervention to achieve Hgb > 10.0 g/dL is acceptable.)
Patients on full-dose anticoagulants (e.g., warfarin or low-molecular weight (LMW) heparin) must meet both of the following criteria:
- No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
- In-range international normalized ratio (INR) (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin
Adequate renal function, defined as follows:
- Blood urea nitrogen (BUN) < 30 mg/dL
- Serum creatinine < 1.5 x upper limit of normal (ULN)
Adequate hepatic function, as defined below:
- Bilirubin < 1.5 normal range
- Alanine transaminase (ALT) < 3x normal range
- Aspartate transaminase (AST) < 3x normal range
Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy test must be done within 7 days prior to registration. Effective contraception (men and women) must be used in patients of child-bearing potential while on study treatment and for 6 months after.
Ability to understand and the willingness to sign a written informed consent document
Ability to have MRI Scans
Ability to swallow capsules

Exclusion Criteria

Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of the breast, oral cavity or cervix are all permissible)
Recurrent malignant glioma or evidence of leptomeningeal spread
Metastases detected below the tentorium or beyond the cranial vault
Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment
Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation therapy fields
Prior radiation therapy or chemotherapy for glioblastoma
Severe, active co-morbidity, defined as follows:
- Symptomatic congestive heart failure of New York heart Association Class III or IV
- Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within the last 6 months, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
- Severely impaired lung function as defined as spirometry and diffusing capacity of the lung for carbon monoxide (DLCO) that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
- Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
- Active (acute or chronic) or uncontrolled severe infections requiring intravenous antibiotics
- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
- Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition or known HIV seropositivity. Note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with HIV/AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
- Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity
- Other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy
Pregnancy
Women who are breast feeding
Prior allergic reaction to temozolomide
Treatment on any other therapeutic clinical protocol
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter their absorption of temozolomide (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Contraindications to MRI including but not limited to, pacemaker, aneurysm clips, neurostimulators, cochlear implants, metal in eyes, steelworker or other implants
Need to continue treatment with any prohibited medication (e.g. antioxidants) or have not completed the appropriate washout period.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 1: SIB + IMRT	Functional Assessment of Cancer Therapy-Brain (FACT-Br)	* Simultaneous Integrated Boost (SIB) plus Fractionated Intensity Modulated Radiation therapy (IMRT), with concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 1: SIB + IMRT	Intensity Modulated Radiation Therapy	* Simultaneous Integrated Boost (SIB) plus Fractionated Intensity Modulated Radiation therapy (IMRT), with concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 1: SIB + IMRT	3D MRSI	* Simultaneous Integrated Boost (SIB) plus Fractionated Intensity Modulated Radiation therapy (IMRT), with concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 1: SIB + IMRT	Simultaneous Integrated Boost	* Simultaneous Integrated Boost (SIB) plus Fractionated Intensity Modulated Radiation therapy (IMRT), with concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 2: SRS Boost + IMRT	Functional Assessment of Cancer Therapy-Brain (FACT-Br)	For patients with High-Risk Tumor Volumes (HTV) \<= 4cm; or multiple HTVs \<= 3 cm: * Stereotactic Radiosurgery Boost (SRS Boost) followed one week later by Fractionated Intensity Modulated Radiation therapy (IMRT), and concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 2: SRS Boost + IMRT	Stereotactic Radiosurgery Boost	For patients with High-Risk Tumor Volumes (HTV) \<= 4cm; or multiple HTVs \<= 3 cm: * Stereotactic Radiosurgery Boost (SRS Boost) followed one week later by Fractionated Intensity Modulated Radiation therapy (IMRT), and concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 2: SRS Boost + IMRT	3D MRSI	For patients with High-Risk Tumor Volumes (HTV) \<= 4cm; or multiple HTVs \<= 3 cm: * Stereotactic Radiosurgery Boost (SRS Boost) followed one week later by Fractionated Intensity Modulated Radiation therapy (IMRT), and concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 2: SRS Boost + IMRT	Intensity Modulated Radiation Therapy	For patients with High-Risk Tumor Volumes (HTV) \<= 4cm; or multiple HTVs \<= 3 cm: * Stereotactic Radiosurgery Boost (SRS Boost) followed one week later by Fractionated Intensity Modulated Radiation therapy (IMRT), and concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 1: SIB + IMRT	Temozolomide	* Simultaneous Integrated Boost (SIB) plus Fractionated Intensity Modulated Radiation therapy (IMRT), with concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.
Group 2: SRS Boost + IMRT	Temozolomide	For patients with High-Risk Tumor Volumes (HTV) \<= 4cm; or multiple HTVs \<= 3 cm: * Stereotactic Radiosurgery Boost (SRS Boost) followed one week later by Fractionated Intensity Modulated Radiation therapy (IMRT), and concurrent Temozolomide therapy for 6 weeks; * 3D MRSI during week 3, end of RT and other protocol-defined time points during adjuvant Temozolomide therapy; * Functional Assessment of Cancer Therapy-Brain (FACT-Br) questionnaire administered at protocol-defined time points; * Adjuvant Temozolomide Therapy for up to 12 cycles.

Primary Outcome Measures

Name	Time	Method
Rate of Overall Survival (OS) in Study Patients	Up to 2 years	The efficacy of 3D MRSI-guided, dose escalated radiation in newly diagnosed glioblastoma (GBM) patients as measured by overall survival (OS). Overall survival (OS) is defined as the time elapsed from the start of study treatment until death. Surviving patients (including patients lost to follow up) will be censored at the date of last contact.

Secondary Outcome Measures

Name	Time	Method
Rate of Progression-Free Survival (PFS) in Study Patients	Up to 2 years	Rate of progression-free survival in study participants. Progression-free survival (PFS) is defined as the time elapsed from the start of study treatment to the date of documented progression events. For progression-free patients (without progression events), PFS will be censored at the last date of documented PF status.
Rate of Grade 3 or Higher Toxicity as a a Consequence of Study Therapy.	2 years	Rate of Grade 3 of Higher Toxicity in study participants as a consequence of study therapy.
Change in Quality of Life From Baseline in Study Participants	Up to 2 years	Change in quality of life during radiation and across the longitudinal progression-free interval compared to baseline. Change of quality of life will be assessed and scored via the FACT-Br behavioral questionnaire.
Patterns of Failure in Study Participants Post-Protocol Therapy	Up to 2 years	Patterns of Failure will be assessed by determining the number of failures that arise in-field compared to the number that arise out-of-field. In-field failure will be defined as those where greater than 80% of the recurrence volume was encompassed by the 95% prescription isodose line. In addition, we will also describe failures by three types: unifocal, multifocal and diffuse (multicentric including leptomeningeal dissemination).