Mathematical Model-Adapted Radiation In Glioblastoma

• ClinicalTrials.gov Identifier: NCT03557372
• Recruitment Status: Completed
• First Posted: June 15, 2018
• Results First Posted: June 11, 2021
• Last Update Posted: October 26, 2023
• Sponsor: Dana-Farber Cancer Institute
• Information provided by (Responsible Party): Shyam Tanguturi, MD, Dana-Farber Cancer Institute

Tracking Information

• First Submitted Date: May 23, 2018
• First Posted Date: June 15, 2018
• Results First Submitted Date: May 17, 2021
• Results First Posted Date: June 11, 2021
• Last Update Posted Date: October 26, 2023
• Actual Study Start Date: November 12, 2018
• Actual Primary Completion Date: November 9, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 24, 2023)

Number of Participants to Complete Model Adapted Radiations Fractionation Scheduled [ Time Frame: 10 Days ]

Successful completion of radiotherapy is defined as receipt of all scheduled fractions of daily radiotherapy within 24 hours of once daily fractions and within 1 hour of three-times daily fractions.

Original Primary Outcome Measures (submitted: June 4, 2018)

Number of Participants to complete Model Adapted Radiations Fractionation scheduled [ Time Frame: 10 Days ]

Feasibility is defined as successful completion of radiation therapy for at least 13 of 14 patients. Successful completion of radiotherapy is defined as receipt of all scheduled fractions of daily radiotherapy within 24 hours of once daily fractions and within 1 hour of three-times daily fractions.

Current Secondary Outcome Measures (submitted: October 24, 2023)

• Number of Participants With Radiation Necrosis [ Time Frame: 6 months ]
  Radiation necrosis (RN) was defined by clinical assessment including imaging features of an expansile, centrally hypointense lesion with increasing surrounding vasogenic edema and typically without features of high grade recurrence (restricted diffusion, elevated cerebral blood volume). Symptomatic RN included patients with radiographic RN requiring intervention such as corticosteroid therapy for neurologic symptoms, headaches, or signs of elevated intracranial pressure.
• Number of Participants With Seizures [ Time Frame: 6 months ]
  Count of number of patients developing new/worsening seizures within 6 months of receiving protocol radiation therapy
• Overall Survival (OS) [ Time Frame: range of follow-up from date of registration was 1.2 - 38.6 months ]
  Overall Survival (OS) based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
• Grade 3-5 Treatment-related Toxicity Rate [ Time Frame: 6 Months ]
  All grade 3-5 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv5 as reported on case report forms were counted. Rate is the proportion of treated participants experiencing at least one treatment-related grade 3-5 AE of any type during the time of observation.
• Median Progression-Free Survival (PFS) [ Time Frame: Disease evaluated on visit 4,5,6 and every 2-4 months in long-term. The range of follow-up from date of registration was 1.2 - 38.6 months and the median was 7.3 months. ]
  Progression-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented disease progression (PD) (defined protocol section 12.7) or death, or is censored at time of last disease assessment.
• Median Local Recurrence-free Survival [ Time Frame: Disease evaluated on visit 4,5,6 and every 2-4 months in long-term. The range of follow-up from date of registration was 1.2 - 38.6 months and the median was 7.3 months. ]
  Local recurrence-free survival based on the Kaplan-Meier method is defined as the duration between randomization and documented Local recurrence or death, or is censored at time of last disease assessment.
• Number of Participants Undergoing Salvage Craniotomy [ Time Frame: 6 Months ]
  Count of patients undergoing salvage craniotomy for resection or decompression of progressively enlarging tumor within 6 months of receipt of protocol radiation therapy.
• Number of Participants Receiving Additional Systemic Treatments After Reirradiation [ Time Frame: 6 Months ]
  Count of patients undergoing systemic therapies for presumed recurrence or progression of disease within 6 months after receipt of protocol radiation therapy

Original Secondary Outcome Measures (submitted: June 4, 2018)

• Quality of Life [ Time Frame: Baseline and 4 weeks after Completion of Reirradiation ]
  MDASI-BT index
• Quality of Life [ Time Frame: 6 months ]
  MDASI-BT index
• Incidence of radiation necrosis [ Time Frame: 6 months ]
  Kaplan-Meier plot, Cox regression
• Time to development of radiation necrosis [ Time Frame: 6 months ]
  Kaplan-Meier plot, Cox regression
• Incidence of seizures [ Time Frame: 6 months ]
  Kaplan-Meier plot, Cox regression
• Time to the development of seizures [ Time Frame: 6 months ]
  Kaplan-Meier plot, Cox regression
• Overall Survival [ Time Frame: 6 months ]
  Kaplan-Meier plot, Cox regression
• Karnofsky Performance Status [ Time Frame: 6 months ]
  Longitudinal regression
• Incidence of Grade 3+ Acute or Delayed CNS toxicity [ Time Frame: 6 Months ]
  CTCAEv5.0; Exact binomial distribution with 95% confidence intervals
• Time to the development of Grade 3+ acute or delayed CNS toxicity [ Time Frame: 6 Months ]
  CTCAEv5.0
• Progression-free survival [ Time Frame: 6 Months ]
  Kaplan-Meier plot, Cox regression
• Local recurrence [ Time Frame: 6 Months ]
  Kaplan-Meier plot
• Incidence of salvage craniotomy [ Time Frame: 6 Months ]
  Kaplan-Meier plot, Cox regression
• Time to salvage craniotomy [ Time Frame: 6 Months ]
  Kaplan-Meier plot, Cox regression
• Incidence of additional systemic treatments after reirradiation [ Time Frame: 6 Months ]
  Kaplan-Meier plot, Cox regression
• Time to additional systemic treatments after reirradiation [ Time Frame: 6 Months ]
  Kaplan-Meier plot, Cox regression
• Tumor Volumes [ Time Frame: 6 Months ]
  Based on the intended radiation administration times and actual radiation administration times) will be compared to the measured tumor volumes obtained from the MRI data that will be collected for the RANO response criteria using residual sum of squares

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Mathematical Model-Adapted Radiation In Glioblastoma
• Official Title: Mathematical Model-Adapted Radiation Fractionation Schedule for Patients With Recurrent Glioblastoma (MARS-Glio)

Brief Summary

This research study is studying a new schedule of radiation therapy for recurrent glioblastoma as a possible treatment for this diagnosis. This radiation schedule is based on a new model for radiation resistance in glioblastoma.

The name of the radiation schedule involved in this study is:

- Re-irradiation for glioblastoma using a novel Mathematical Model-Adapted Radiation Fractionation Schedule

Detailed Description

This research study is a Feasibility Study, which means that this is the first time that investigators are examining this new radiation schedule for recurrent glioblastoma.

• The FDA (the U.S. Food and Drug Administration) has approved radiation therapy as a treatment option for your disease.
• This is the first time that this particular radiation schedule will be tested in humans. There many other studies which have tested different radiation schedules in glioblastoma.

In this research study, investigators are adapting a standard two-week schedule of radiation commonly used for recurrent glioblastoma using a mathematical model. This study uses the same total dose of radiation as standard treatments but breaks up the dose into different amounts daily to maximize tumor kill. investigators have used a new mathematical model to create this schedule of radiation. This model was created to better represent how glioblastoma cells can escape the damaging effects of radiation. Based on the results of several laboratory studies, it is possible that this model may result in improved outcomes compared to standard radiation schedules.

The primary question of this study is to see whether participants can complete this new radiation schedule at the scheduled times. In addition, investigators will follow participants to ensure that this treatment is safe. If this treatment proves feasible, investigators hope to compare this treatment directly with standard radiation schedules for newly diagnosed and recurrent glioblastoma.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Recurrent Glioblastoma

Intervention

Radiation: Mathematical Model-Adapted Radiation Fractionation Schedule

• Re-irradiation with 35 Gy delivered over 2 weeks, based upon reference dosing of 35 Gy in 10 Fractions over 2 weeks
• Radiation therapy is delivered on Monday-Friday during standard clinic hours in our department. Each treatment may take 20-40 minutes.
• Treatment will be once daily for the first 7 days of treatment and then three-times daily for the last three days of treatment.

Study Arms

Experimental: Mathematical Model-Adapted Radiation

Mathematical Model-Adapted Radiation Fractionation Schedule

Intervention: Radiation: Mathematical Model-Adapted Radiation Fractionation Schedule

• Publications *: Dean JA, Tanguturi SK, Cagney D, Shin KY, Youssef G, Aizer A, Rahman R, Hammoudeh L, Reardon D, Lee E, Dietrich J, Tamura K, Aoyagi M, Wickersham L, Wen PY, Catalano P, Haas-Kogan D, Alexander BM, Michor F. Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity. Neuro Oncol. 2023 Jun 2;25(6):1100-1112. doi: 10.1093/neuonc/noac253.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 4, 2018): 14
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: November 9, 2022
• Actual Primary Completion Date: November 9, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participants must have recurrent glioblastoma (WHO Grade IV), as defined on brain imaging with CT or MRI, after prior receipt of definitive therapy including neurosurgical biopsy or resection and radiation therapy with or without systemic therapy.
• Participants must be deemed appropriate candidates for re-irradiation
• Histopathologic confirmation of disease as part of routine clinical care is required either at the time of initial diagnosis and/or at the time of recurrent disease. There is no requirement for central pathologic review.
• Age ≥ 18 years at the time of enrollment
• Karnofsky Performance Status (KPS) of at least 70
• Exclusion Criteria
• Participants who have received more than one prior course of radiotherapy to the local site of progressive disease
• Participants who have received prior radiotherapy to the local site of progressive disease within < 3 months of the anticipated start of re-irradiation
• Participants with recurrent tumor extensively abutting or involving the optic structures or brainstem, as assessed by the treating radiation oncologist
• Participants without a definable tumor cavity on MRI or CT obtained at study enrollment
• Participants receiving concurrent cytotoxic chemotherapy (i.e. temozolomide, CCNU, vincristine, procarbazine) or concurrent immunotherapy (i.e. pembrolizumab, nivolumab); however, participants may receive sequential chemotherapy before or after radiation without limitation. Participants may receive concurrent corticosteroid and/or anti-angiogenic therapy (i.e. bevacizumab) if clinically indicated.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03557372
• Other Study ID Numbers: 18-105
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Shyam Tanguturi, MD, Dana-Farber Cancer Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: Dana-Farber Cancer Institute
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Shyam Tanguturi, MD; Brigham and Women's Hospital

• PRS Account: Dana-Farber Cancer Institute
• Verification Date: October 2023