Multiparametric MR-Guided High Dose Adaptive Radiotherapy With Concurrent Temozolomide in Patients With Newly Diagnosed Glioblastoma

• ClinicalTrials.gov Identifier: NCT04574856
• Recruitment Status: Recruiting
• First Posted: October 5, 2020
• Last Update Posted: December 17, 2021
• Sponsor: University of Michigan Rogel Cancer Center
• Information provided by (Responsible Party): University of Michigan Rogel Cancer Center

Study Description

Brief Summary:

This study will investigate whether or not intensified radiation therapy adapted during the radiation treatment course to high-risk, treatment-resistant tumor regions will improve overall survival in patients with newly diagnosed glioblastoma (GBM) compared to conventional chemoradiotherapy.

Condition or disease	Intervention/treatment	Phase
Glioblastoma	Radiation: Dose-Intensified Radiotherapy; Drug: Temozolomide; Drug: Adjuvant temozolomide	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Multiparametric MR-Guided High Dose Adaptive Radiotherapy With Concurrent Temozolomide in Patients With Newly Diagnosed Glioblastoma
• Actual Study Start Date: November 4, 2020
• Estimated Primary Completion Date: January 2024
• Estimated Study Completion Date: January 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Patients with Newly Diagnosed Glioblastoma; Patients will receive dose-intensified, adaptive photon radiation therapy

Radiation: Dose-Intensified Radiotherapy; Adaptive, dose-intensified radiotherapy targeting an advanced imaging signature, with a target, nominal radiotherapy dose of 80 Gy.; Drug: Temozolomide; Temozolomide chemotherapy (75 mg/m2 daily for 6 weeks); Drug: Adjuvant temozolomide; Adjuvant temozolomide will be delivered at 150-200 mg/m2 days 1-5 every 28 days for 6 cycles, with additional cycles delivered at the discretion of the investigator.

Outcome Measures

Primary Outcome Measures :

1. 12-month overall survival rate [ Time Frame: 12 months post radiation therapy (RT) ]
   12-month overall survival rate of study participants (failure defined as death due to any cause)

Secondary Outcome Measures :

1. Overall survival [ Time Frame: 2 years ]
   Overall survival (failure defined as death due to any cause)
2. Progression-free survival rate [ Time Frame: 2 years ]
   Progression-free survival (failure defined as progression or death due to any cause) will be evaluated using standard response assessment in neuro-oncology (RANO) criteria.
3. Proportion of failures classified by relation to the high-dose radiation region [ Time Frame: 2 years ]

   Patterns of failure (tumor growth) will be classified as follows:

   • Central: >95% of the tumor volume is within the high-dose radiation region
   • In-field: >80% to 95% of the tumor volume is within the high-dose radiation region
   • Marginal: 20-80% of the tumor volume is within the high-dose radiation region
   • Distant: <20% of the tumor volume is within the high-dose radiation region
4. Advanced MRI Gross tumor volume (GTV) and its association with overall survival [ Time Frame: 3 months post-RT ]
   GTV is defined as the combined hypercellularity tumor volume and hyperperfused tumor volume, assessed by high b-value diffusion MRI and dynamic contrast-enhanced perfusion MRI, respectively. Patients will be grouped into those with less than 2.5 cc GTV and those with 2.5 cc or more GTV. This measure will be used to determine whether advanced MRI metrics can be used to distinguish pseudoprogression from true tumor progression, and to determine whether advanced MR-identified tumor volume 3 months post-chemoradiation is associated with survival.
5. Patient-reported quality of life (QOL) using EORTC QLQ-C30 and BN20 [ Time Frame: Up to 12 months post-RT ]
   The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) is a validated questionnaire developed to assess the quality of life of cancer patients, with the EORTC QLQ-BN20 specifically for brain tumor patients. Patients will be classified as having deterioration if there is a clinically meaningful change (10 point drop from baseline) in the QOL scales. The percentage of patients with deterioration in each survey will be reported.
6. Patient-reported symptom burden using MDASI-BT [ Time Frame: Up to 12 months post-RT ]
   The MD Anderson Symptom Inventory for Brain Tumor (MDASI-BT) is a validated questionnaire developed to assess the symptom burden of brain tumor patients. Severity of symptoms is scored on a scale of 0-10, with 0 being "not present" and 10 being "as bad as you can imagine." Patients will be classified as having deterioration if there is a clinically meaningful change (1 point increase in symptom severity from baseline). The percentage of patients with deterioration will be reported.
7. Patient objective neurocognitive function [ Time Frame: Up to 12 months post-RT ]
   Objective neurocognitive function (NCF) testing using Hopkins Verbal Learning Tests, Controlled Oral Word Association, and Trail Making Tests A and B. Test results will be reported as a composite, using the reliable change index (RCI) to categorize patients as improved, stable, or declined from baseline.
8. Grade 3 or higher treatment-related toxicities [ Time Frame: 12 months post-RT ]
   Rate of grade 3 or higher toxicities (neurologic and non-neurologic) of dose-intensified, adaptive chemoradiotherapy. Toxicity assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Newly diagnosed, histologically-confirmed supratentorial WHO grade IV gliomas including glioblastoma (all variants) and gliosarcoma. Prior low-grade glioma without prior RT, now with malignant progression are eligible.
• Karnofsky performance status >=70
• Minimal life expectancy of 12 weeks
• Adequate bone marrow reserve (Hemoglobin ≥ 10 g/dL, absolute neutrophils ≥ 1500/mm3, platelet count ≥ 100,000/mm3), acceptable liver function (total bilirubin ≤ 2 x upper limit of normal (ULN) (unless elevated bilirubin is related to Gilbert syndrome), and ALT/AST ≤ 5 x ULN) and renal function (serum creatinine ≤ 2.0 mg/dL) within 14 day prior to registration. Eligibility level for hemoglobin may be reached by transfusion.
• Maximal contiguous diameter of tumor based on high b-value diffusion MRI and DCE perfusion MRI ≤5 cm
• Patients must be registered within 6 weeks of most recent resection
• Females of child-bearing potential must have a negative pregnancy test within 14 days prior to registration. Patients with reproductive potential must agree to use an effective contraceptive method during treatment and study participation.

Exclusion Criteria:

• Recurrent glioma, or tumor involving the brainstem or cerebellum
• Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment is not permitted. Prior chemotherapy for a different cancer is allowable if interval since last treatment cycle completion is >3 years.
• Evidence of CSF dissemination (positive CSF cytology for malignancy or MRI findings consistent with CSF dissemination)
• Evidence of severe concurrent disease requiring treatment
• Prior invasive malignancy (except non-melanoma skin cancer or non-life limiting invasive malignancy that may not require treatment, such as low-risk prostate cancer) unless disease free for a minimum of 3 years (for example, carcinoma in situ of breast, oral cavity or cervix are all permissible)
• Patients unable to undergo MRI exams (i.e. patients with non-compatible devices such as cardiac pacemakers, other implanted electronic devices, metallic prostheses, or ferromagnetic prostheses [e.g. pins in artificial joints and surgical pins/clips], or unable to receive gadolinium for MRI, as per the standard Department of Radiology MRI screening criteria)
• Patients treated with previous cranial or head/neck radiotherapy leading to significant radiation field overlap as determined by treating physician
• Multifocal disease (>1 lobe of involvement) of discontiguous contrast enhancing disease as seen on conventional MRI
• Pregnancy or lactation

Contacts and Locations

Contacts

Contact: Michelle Kim, MD; 734-936-4300; michekim@med.umich.edu

Locations

United States, Michigan

University of Michigan Rogel Cancer Center; Recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Michelle Kim, MD

Sponsors and Collaborators

University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: Michelle Kim, MD; University of Michigan

More Information

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT04574856
• Other Study ID Numbers: UMCC 2020.033; HUM00179427 ( Other Identifier: University of Michigan )
• First Posted: October 5, 2020
• Last Update Posted: December 17, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents