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Dose Escalated MRSI Guided Radiation Therapy in Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02394665
Recruitment Status : Terminated (Lack of Accrual/Enrollment)
First Posted : March 20, 2015
Results First Posted : January 5, 2017
Last Update Posted : January 5, 2017
Sponsor:
Information provided by (Responsible Party):
University of Miami

Tracking Information
First Submitted Date  ICMJE March 16, 2015
First Posted Date  ICMJE March 20, 2015
Results First Submitted Date  ICMJE November 8, 2016
Results First Posted Date  ICMJE January 5, 2017
Last Update Posted Date January 5, 2017
Study Start Date  ICMJE March 2015
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 8, 2016)
Rate of Overall Survival (OS) in Study Patients [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 16, 2015)
Rate of Overall Survival (OS) in Study Patients [ Time Frame: 2 years ]
The efficacy of 3D MRSI guided, dose escalated radiation in newly diagnosed GBM patients as measured by overall survival (OS)
Change History Complete list of historical versions of study NCT02394665 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 8, 2016)
  • Rate of Progression-Free Survival (PFS) in Study Patients [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 16, 2015)
  • Number of patients experiencing adverse events as a consequence of study therapy [ Time Frame: 2 years ]
    To assess acute grade 3 or higher toxicity as a consequence of study therapy
  • Rate of Progression-Free Survival (PFS) in Study Patients [ Time Frame: 2 years ]
    To determine progression-free survival (PFS) in study patients
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Escalated MRSI Guided Radiation Therapy in Glioblastoma
Official Title  ICMJE Phase II Study of Dose Escalated, Targeted Radiation Therapy Using 3D Magnetic Resonance Spectroscopy Imaging (MRSI) in Newly Diagnosed Glioblastoma
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Glioblastoma
Intervention  ICMJE
  • Radiation: Intensity Modulated Radiation Therapy
    IMRT treatment will consist of 60 Gy in 30 fractions to PTV 60
    Other Names:
    • IMRT
    • Fractionated RT
  • Drug: Temozolomide

    Concurrently during radiation therapy. Adjuvant therapy administered daily on days 1 - 5 for 12 cycles. One cycle = 28 days:

    • Concurrent during Radiation Therapy: 75 mg/m^2 orally for 6 weeks;
    • Post-radiation, adjuvant therapy: 150 mg/m^2 - 200 mg/m^2 orally daily on days 1 - 5 of each cycle.
    Other Names:
    • Temodar
    • Temodal
  • Behavioral: Functional Assessment of Cancer Therapy-Brain (FACT-Br)
    FACT-Br Quality of Life (QOL) questionnaire to be completed by study patients as protocol specific timepoints
    Other Name: FACT-Br
  • Radiation: Stereotactic Radiosurgery Boost

    Patients will undergo SRS boost in a single fraction dose prior to IMRT treatment:

    HTV Maximum dimension vs. Prescribed Dose to HTV: ≤ 20 mm = 21 Gy; 21 mm - 30 mm = 18 Gy; 31 mm - 40 mm = 15 Gy.

    Other Name: SRS Boost
  • Radiation: Simultaneous Integrated Boost
    Treatment shall consist of 60 Gy in 30 fractions to planning target volume (PTV) 60 and 75 Gy in 30 fractions to PTV 75.
    Other Name: SIB
  • Device: 3D MRSI
    Three Dimensional Magnetic Resonance Spectroscopy Imaging (MRSI) during pre-treatment, week 3 during radiation therapy, end of radiation therapy; will include standard gadolinium enhanced MRI prior to cycle 1, 5, 9, and post cycle 12 of adjuvant temozolomide therapy, per protocol.
    Other Name: 3D Magnetic Resonance Spectroscopy Imaging
Study Arms  ICMJE
  • Experimental: Group 1: SIB + IMRT
    • 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.
    Interventions:
    • Radiation: Intensity Modulated Radiation Therapy
    • Drug: Temozolomide
    • Behavioral: Functional Assessment of Cancer Therapy-Brain (FACT-Br)
    • Radiation: Simultaneous Integrated Boost
    • Device: 3D MRSI
  • Experimental: Group 2: SRS Boost + IMRT

    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.
    Interventions:
    • Radiation: Intensity Modulated Radiation Therapy
    • Drug: Temozolomide
    • Behavioral: Functional Assessment of Cancer Therapy-Brain (FACT-Br)
    • Radiation: Stereotactic Radiosurgery Boost
    • Device: 3D MRSI
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 29, 2016)
1
Original Estimated Enrollment  ICMJE
 (submitted: March 16, 2015)
48
Actual Study Completion Date  ICMJE September 2016
Actual Primary Completion Date September 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Histologically proven diagnosis of glioblastoma (WHO grade IV). Since gliosarcoma is a variant of glioblastoma, gliosarcoma is also an eligible diagnosis.
  2. The tumor must have a supratentorial component
  3. Patients must have recovered from the effects of surgery, postoperative infection and other complications
  4. Karnofsky performance status > 70
  5. Age > 18 years
  6. 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.)
  7. 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
  8. Adequate renal function, defined as follows:

    • Blood urea nitrogen (BUN) < 30 mg/dL
    • Serum creatinine < 1.5 x upper limit of normal (ULN)
  9. Adequate hepatic function, as defined below:

    • Bilirubin < 1.5 normal range
    • Alanine transaminase (ALT) < 3x normal range
    • Aspartate transaminase (AST) < 3x normal range
  10. 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.
  11. Ability to understand and the willingness to sign a written informed consent document
  12. Ability to have MRI Scans
  13. Ability to swallow capsules

Exclusion Criteria:

  1. 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)
  2. Recurrent malignant glioma or evidence of leptomeningeal spread
  3. Metastases detected below the tentorium or beyond the cranial vault
  4. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment
  5. Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation therapy fields
  6. Prior radiation therapy or chemotherapy for glioblastoma
  7. 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
  8. Pregnancy
  9. Women who are breast feeding
  10. Prior allergic reaction to temozolomide
  11. Treatment on any other therapeutic clinical protocol
  12. 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)
  13. Contraindications to MRI including but not limited to, pacemaker, aneurysm clips, neurostimulators, cochlear implants, metal in eyes, steelworker or other implants
  14. Need to continue treatment with any prohibited medication (e.g. antioxidants) or have not completed the appropriate washout period.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02394665
Other Study ID Numbers  ICMJE 20140540
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of Miami
Study Sponsor  ICMJE University of Miami
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Fazilat Ishkanian, MD, PhD University of Miami
PRS Account University of Miami
Verification Date November 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP