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

• Study Type: Interventional
• 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
• Enrollment: 14

Participant Flow

Recruitment Details
Pre-assignment Details	There are no details to report.

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Period Title: Overall Study
Started	14
Completed	14
Not Completed	0

Baseline Characteristics

Arm/Group Title		Mathematical Model-Adapted Radiation
Arm/Group Description		Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Baseline Participants		14
Baseline Analysis Population Description		Participants were counted for the primary endpoint of the study based on if they were able to complete the protocol specified course of radiation treatment or not.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	13 92.9%
	>=65 years	1 7.1%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	Female	4 28.6%
	Male	10 71.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	14 100.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	14 participants
		14

Outcome Measures

1. Primary Outcome

Title	Number of Participants to Complete Model Adapted Radiations Fractionation Scheduled
Description	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.
Time Frame	10 Days

Outcome Measure Data

Analysis Population Description

All 14 participants were analyzed for the primary endpoint.

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: Participants
	14 100.0%

2. Secondary Outcome

Title	Number of Participants With Radiation Necrosis
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

3. Secondary Outcome

Title	Number of Participants With Seizures
Description	Count of number of patients developing new/worsening seizures within 6 months of receiving protocol radiation therapy
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: Participants
	1 7.1%

4. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	range of follow-up from date of registration was 1.2 - 38.6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Median (95% Confidence Interval); Unit of Measure: Months
	7.3; (4.7 to 10.7)

5. Secondary Outcome

Title	Grade 3-5 Treatment-related Toxicity Rate
Description	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.
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Measure Type: Number; Unit of Measure: proportion of treated participants
	0.29

6. Secondary Outcome

Title	Median Progression-Free Survival (PFS)
Description	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.
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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Median (95% Confidence Interval); Unit of Measure: Months
	4.3; (2.4 to 5.2)

7. Secondary Outcome

Title	Median Local Recurrence-free Survival
Description	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.
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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Median (95% Confidence Interval); Unit of Measure: Months
	6.2; (5.2 to 30)

8. Secondary Outcome

Title	Number of Participants Undergoing Salvage Craniotomy
Description	Count of patients undergoing salvage craniotomy for resection or decompression of progressively enlarging tumor within 6 months of receipt of protocol radiation therapy.
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

9. Secondary Outcome

Title	Number of Participants Receiving Additional Systemic Treatments After Reirradiation
Description	Count of patients undergoing systemic therapies for presumed recurrence or progression of disease within 6 months after receipt of protocol radiation therapy
Time Frame	6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description:	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: Participants
	3 21.4%

Adverse Events

Time Frame	Time-frame for observation of adverse events was up to 6 months of clinical follow up, and for all cause-mortality, up to 38.6 months.
Adverse Event Reporting Description	Serious adverse events (AEs) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv5. All remaining events regardless of treatment attribution were classified as Other AEs. Maximum grade toxicity by type for a patient over time was calculated. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	Mathematical Model-Adapted Radiation
Arm/Group Description	Mathematical Model-Adapted Radiation Fractionation Schedule 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.
All-Cause Mortality
	Mathematical Model-Adapted Radiation
	Affected / at Risk (%)
Total	13/14 (92.86%)
Serious Adverse Events
	Mathematical Model-Adapted Radiation
	Affected / at Risk (%)	# Events
Total	8/14 (57.14%)
General disorders
Death NOS † 1	8/14 (57.14%)	8
Nervous system disorders
Seizure † 1	1/14 (7.14%)	1
Edema cerebral † 1	1/14 (7.14%)	1
Hydrocephalus † 1	1/14 (7.14%)	1
1 Term from vocabulary, CTCAE v5; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Mathematical Model-Adapted Radiation
	Affected / at Risk (%)	# Events
Total	8/14 (57.14%)
Gastrointestinal disorders
Nausea † 1	1/14 (7.14%)	1
General disorders
Fatigue † 1	2/14 (14.29%)	2
Infections and infestations
Infections and infestations - Other, specify † 1	1/14 (7.14%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness † 1	1/14 (7.14%)	1
Muscle weakness lower limb † 1	1/14 (7.14%)	1
Nervous system disorders
Ataxia † 1	1/14 (7.14%)	1
Edema cerebral † 1	1/14 (7.14%)	1
Headache † 1	1/14 (7.14%)	1
1 Term from vocabulary, CTCAE v5; † Indicates events were collected by systematic assessment

Limitations and Caveats

Quality of life assessment using MDASI-BT was incomplete due to patient preference and incomplete adherence. As such, assessment by this endpoint was not possible.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Shyam Tanguturi
• Organization: Dana Farber Cancer Institute
• Phone: 617-632-0000
• EMail: stanguturi@partners.org

Publications of Results:

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.

• Responsible Party: Shyam Tanguturi, MD, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03557372
• Other Study ID Numbers: 18-105
• First Submitted: May 23, 2018
• First Posted: June 15, 2018
• Results First Submitted: May 17, 2021
• Results First Posted: June 11, 2021
• Last Update Posted: October 26, 2023