MRSI in Predicting Early Response in Patients Treated with Radiation Therapy and Temozolomide with or without Belinostat for Newly-Diagnosed Glioblastoma or Gliosarcoma
This phase II trial studies magnetic resonance spectroscopic imaging (MRSI) in predicting early response in patients treated with radiation therapy and temozolomide with or without belinostat for newly-diagnosed glioblastoma or gliosarcoma. Diagnostic procedures, such as MRSI, may help doctors predict a patient's response to belinostat, to see how well belinostat works to kill glioblastoma or gliosarcoma cells, and allow doctors to plan better treatment.
Inclusion Criteria
- Patients must have a newly-diagnosed glioblastoma or gliosarcoma that has been confirmed pathologically
- Patients must be able to have magnetic resonance imaging (MRI) scans
- Patients must have measurable contrast-enhancing supratentorial tumor (>= 0.2 cc [current resolution of MRSI is 0.108 cc]) in a region amenable to MRSI
- White blood cells (WBC) >= 3,000/uL
- Absolute neutrophil count (ANC) >= 1,500/uL
- Platelet count of >= 100,000/uL
- Hemoglobin >= 10 gm/dL (transfusion is allowed to reach minimum level)
- Serum glutamic oxaloacetic transaminase (SGOT) =< 2.0 x upper normal limit (UNL)
- Bilirubin =< 2 x UNL
- Creatinine =< 1.5 mg/dL
- Patients must have a life expectancy of >= 12 weeks
- Patients must have a Karnofsky performance status (KPS) >= 60
- Patients who are women of childbearing potential must have a negative beta-human chorionic gonadotropin (HCG) pregnancy test documented =< 7 days prior to registration
- All men and women of childbearing potential must agree to use adequate barrier contraception for the duration of study participation and for 12 weeks after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while participating in this study, she needs to inform her treating physician immediately
- Patients must be able to understand and provide written informed consent
- Both men and women, and members of all races and ethnic groups are eligible for this trial; subjects will be approximately representative of the demographics of the referral base for the participating institutions
- Patient must be able to swallow capsules
- Patient must be willing to provide mandatory tissue samples (unstained slides) for research purposes
- Patients must be willing to forego other cytotoxic and non-cytotoxic therapies against the tumor while being treated on this protocol
Exclusion Criteria
- Patients with pacemakers, non-titanium aneurysm clips, neurostimulators, cochlear implants, non-titanium metal in ocular structures, history of being a steel worker, or other incompatible implants which makes MRI safety an issue are excluded
- Patients that have any significant medical illnesses that in the investigator’s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient’s ability to tolerate this therapy are excluded
- Patients with a history of any other invasive cancer (except non-melanoma skin cancer and excluding carcinomas in-situ), unless in complete remission and off of all therapy for that disease for >= 3 years, are ineligible
- Patients with an active infection or serious intercurrent medical illness are ineligible
- Patients with any disease that will obscure toxicity or dangerously alter drug metabolism are excluded
- Patients receiving any other investigational agents are excluded
- Patients who have received prior cytotoxic, non-cytotoxic or experimental drug therapies for brain tumor are excluded
- Patients with a history of prior cranial radiation are ineligible
- Patients with a history of myocardial infarction or unstable angina =< 6 months prior to registration or congestive heart failure (CHF) requiring use of ongoing maintenance therapy, or life-threatening ventricular arrhythmias
- Patients with congenital long QT syndrome (for cohort 2a and 2b [belinostat cohorts] only, electrocardiogram [ECG] not required for cohort 1)
- Patients with prolonged corrected QT (QTc) interval (> 450 msec) (for cohort 2a and 2b [belinostat cohorts] only, electrocardiogram [ECG] nor required for cohort 1)
- Patients taking any of the following category I drugs that are generally accepted to have a risk of causing Torsades de Pointes =< 7 days prior to registration (for cohort 2a and 2b [belinostat cohort] only) * Quinidine, procainamide, disopyramide * Amiodarone, sotalol, ibutilide, dofetilide * Erythromycin, clarithromycin * Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide * Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine
- Patients taking valproic acid =< 2 weeks prior to initiation of belinostat therapy (for cohort 2a and 2b [belinostat cohort] only)
- Patients with residual enhancing tumor that lies completely within 1-2 cm of the inner table of the skull
- Patients may not be enrolled on any other therapeutic trial for which they are receiving an anti-tumor therapy; (Note: patients on the standard therapy arm of another GBM trial that otherwise meet eligibility requirements for this trial remains eligible for cohort 1)
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02137759.
PRIMARY OBJECTIVES:
I. To utilize machine learning (eg. a support vector machine approach) to determine an MRSI 5-metabolite profile that is predictive of prolonged progression-free survival (PFS at 9 months) at week 3 (during chemoradiation therapy [chemoRT]) (Cohort 1).
II. To find the maximum tolerated dose (MTD) of belinostat (up to 1000 mg/day x 5 days every [q] 3weeks x 3) used with standard radiation therapy (RT)/temozolomide for newly diagnosed glioblastoma (GBM) patients (Cohort 2a).
III. To determine whether MRSI is useful as an early biomarker by comparing progression-free survival (PFS at 9 months) of belinostat-responders versus non-responders based changes in MRSI metabolite maps (spectroscopic restoration index [SRI] > 0.8) at week 3 (during chemoRT) (Cohort 2b).
SECONDARY OBJECTIVES:
I. To determine whether changes in MRSI metabolite maps at week 3 are useful as an early biomarker for predicting improved overall survival (OS) at 18 months (Cohorts 1 and 2b).
II. To determine whether changes in MRSI metabolite maps predict for mood alterations as measured by a self-reported depression survey (Inventory of Depressive Symptomatology-Self Report [IDS-SR]) (Cohorts 1 and 2b).
III. To determine whether changes in MRSI metabolite maps at day 8 (after initial belinostat window) and week 11 (4 weeks post-concurrent chemotherapy and radiation therapy) correlate with PFS at 9 months and OS at 18 months (Cohorts 1 and 2b).
IV. To compare the OS and PFS of patients treated with belinostat/temozolomide (TMZ)/RT versus TMZ/RT (Cohorts 1 and 2b).
TERTIARY OBJECTIVES:
I. To determine whether changes in MRSI metabolite maps correlate with changes in subjects’ quality-of-life as measured by validated self-assessment instruments (Cohorts 1 and 2b).
II. To determine whether changes in MRSI metabolite maps correlate with changes in subjects’ overall neurocognitive function (Cohorts 1 and 2b).
III. To determine whether pretreatment molecular characteristics of the tumor can predict improved MRSI response and/or outcomes with belinostat/TMZ/RT therapy (Cohort 2b).
IV. To determine a good SRI cutoff for a positive response to belinostat.
OUTLINE: Patients are assigned to 1 of 2 treatment groups.
COHORT I: Patients undergo MRSI up to 14 days prior to receiving therapy. Patients then undergo radiation therapy 5 days a week over 6 weeks for up to 30 treatments and receive temozolomide orally (PO) once daily (QD) for 6 weeks. Patients undergo MRSI after completing 2 weeks of therapy and again 1 week before beginning adjuvant therapy. Beginning 4-10 weeks after completion of radiation therapy, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
COHORT II: Patients receive belinostat intravenously (IV) over 30-45 minutes on days 1-5, 15-19, and 36-40 and then undergo MRSI on day 8. Patients then undergo radiation therapy 5 days a week over 6 weeks for up to 30 treatments and receive temozolomide PO QD for 6 weeks. Patients undergo MRSI after completing 2 weeks of therapy and again 1 week before beginning adjuvant therapy. Beginning 4-10 weeks after completion of radiation therapy, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks, every 2 months for up to 1 year, and then every 3 months for approximately 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationEmory University Hospital/Winship Cancer Institute
Principal InvestigatorHui-Kuo George Shu
- Primary IDWINSHIP2434-13
- Secondary IDsNCI-2014-01432, IRB00065425
- ClinicalTrials.gov IDNCT02137759