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SRS Compared With FSRS for Treatment of Intact Metastatic Brain Disease, FRACTIONATE Trial

Primary Purpose

Metastatic Malignant Neoplasm in the Brain

Status

Recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Questionnaire Administration

Stereotactic Radiosurgery

About this trial

This is an interventional treatment trial for Metastatic Malignant Neoplasm in the Brain

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age >= 18 years old
Presence of presumed brain metastases from an extra-cerebral tumor site (e.g. lung, breast, prostate, etc.)
- Note: Dural based metastases (e.g. commonly seen in breast cancer) are eligible
Size of brain metastases
- At least one intact metastasis (not previously treated with radiosurgery) must measure >= 2.0 cm and =< 4.0 cm in maximal extent on the contrasted pre-treatment magnetic resonance imaging (MRI) brain scan obtained =< 28 days prior to registration
- If the largest lesion measures >= 2.0 to =< 4.0 cm in maximal extent the patient will be randomized
Able to undergo contrast enhanced MRI brain
Negative urine or serum pregnancy test completed =< 7 days prior to registration, for women of childbearing potential only
Patient willing and able to provide written informed consent
Karnofsky performance status (KPS) >= 50
Eastern Cooperative Oncology Group (ECOG) performance score of (PS) >= 2
Past radiosurgery or resection is allowed as long as no definitive evidence of progression in these locations
- Note: Repeat radiosurgery to the same location/lesion is not allowed on this protocol

Exclusion Criteria:

Any patient who has received previous whole brain radiation
Any brain metastasis that is located in the brainstem measuring >= 2.0 cm in maximal extent
Any patient with definitive evidence of leptomeningeal metastasis (LMD)
- NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion
Any patient with an intact brain metastasis measuring > 4.0 cm

Sites / Locations

Mayo Clinic in ArizonaRecruiting
Mayo Clinic in FloridaRecruiting
Mayo Clinic in RochesterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

Arm A (single fraction SRS)

Arm B (fractionated SRS)

Arm Description

Patients undergo single fraction SRS.

Patients undergo fractionated SRS.

Outcomes

Primary Outcome Measures

Time to local failure or symptomatic radiation brain necrosis of large brain metastasis

Will determine if the composite endpoint of time to local failure or symptomatic radiation brain necrosis of a large brain metastasis [cumulative treatment failure (CTF)] is increased with fractionated stereotactic radiosurgery (FSRS) compared to single fraction stereotactic radiosurgery (SSRS).

Secondary Outcome Measures

Overall survival (OS)

OS will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms. Medians and 95% confidence intervals will be reported.

Incidence of adverse events

The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The frequency and percentage of grade 3+ adverse events will be compared between the 2 treatment arms. Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test.

Rates of radiation necrosis

Will compare rates of radiation necrosis in patients who receive FSRS to patients who receive SSRS. Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test.

Central nervous system (CNS) failure patterns (Fractionation)

Will evaluate if there is any difference in CNS failure patterns (e.g. local, distant brain failure) in patients who receive FSRS compared to patients who receive SSRS. Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test.

Time to neurologic death

Will ascertain whether FSRS prolongs time to neurologic death as compared to SSRS. This will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms. Medians and 95% confidence intervals will be reported.

Quality of life (QOL)

Will determine whether there are improved patient reported outcomes (Functional Assessment of Cancer Therapy [FACT]-Brain Symptom Index [FBrSI]-24) including quality of life for patients who receive FSRS compared to patients who receive SSRS. Changes over time in QOL from baseline will be compared between arms using the 2-sample t-test (or Wilcoxon Rank-Sum test for non-normal data). Box-plots will be used to show differences between arms graphically.

CNS failure patterns (Gamma Knife)

Will evaluate if there is any difference in CNS failure patterns (e.g. local, distant brain failure) and symptomatic radiation necrosis rates in patients who are treated with Gamma Knife compared to patients who are treated with a linear accelerator platform. Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test.

Per lesion analysis between treatment arms: time to local failure

Will determine whether differences in time to local failure differs between treatment arms (or other patient or treatment factors) when analyzed on a "per lesion" basis rather than the per patient basis utilized for the primary endpoint. Time-to-event models (Cox and Kaplan- Meier) with sandwich estimators for covariance will be utilized to in treatment comparisons, with model comparisons completed through log-likelihood and Akaike Information Criterion.

Per lesion analysis between treatment arms: time to necrosis

Will determine whether differences in time to necrosis differs between treatment arms (or other patient or treatment factors) when analyzed on a "per lesion" basis rather than the per patient basis utilized for the primary endpoint. Time-to-event models (Cox and Kaplan- Meier) with sandwich estimators for covariance will be utilized to in treatment comparisons, with model comparisons completed through log-likelihood and Akaike Information Criterion.

Per lesion analysis between treatment arms: endpoint CTF

Will determine whether differences in the composite endpoint CTF differs between treatment arms (or other patient or treatment factors) when analyzed on a "per lesion" basis rather than the per patient basis utilized for the primary endpoint. Time-to-event models (Cox and Kaplan- Meier) with sandwich estimators for covariance will be utilized to in treatment comparisons, with model comparisons completed through log-likelihood and Akaike Information Criterion.

Full Information

NCT ID

NCT05222620

First Posted

January 11, 2022

Last Updated

October 4, 2023

Sponsor

Mayo Clinic

1. Study Identification

Unique Protocol Identification Number

NCT05222620

Brief Title

SRS Compared With FSRS for Treatment of Intact Metastatic Brain Disease, FRACTIONATE Trial

Official Title

Phase IIR Trial of Single Fraction Stereotactic Radiosurgery (SRS) Compared With Fractionated SRS (FSRS) for Intact Metastatic Brain Disease (FRACTIONATE)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

March 14, 2022 (Actual)

Primary Completion Date

February 15, 2027 (Anticipated)

Study Completion Date

February 15, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mayo Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

This phase II trial compares the effect of single fraction stereotactic radiosurgery to fractionated stereotactic radiosurgery for the treatment of patients with cancer that has spread to the brain (metastatic brain disease). Stereotactic radiosurgery (SRS) is a form of radiation therapy that focuses high-power energy on a small area of the body. This trial is being done to determine if single (one) fraction stereotactic radiosurgery is better than fractionated stereotactic radiosurgery or vice versa in controlling tumor and side effects in patients with tumors that have spread to the brain.

Detailed Description

PRIMARY OBJECTIVE: I. To ascertain if the composite endpoint of cumulative treatment failure, defined by time to either local failure or symptomatic radiation brain necrosis of the largest brain metastasis (target lesion), is increased with fractionated stereotactic radiosurgery (FSRS) compared to single fraction stereotactic radiosurgery (SSRS). SECONDARY OBJECTIVES: I. To ascertain whether there is improved overall survival in patients who undergo FSRS compared to patients who receive SSRS. II. To tabulate and descriptively compare the post-treatment adverse events associated with the interventions, including the potential impact of immunotherapy and targeted therapy. III. To compare rates of radiation necrosis in patients who receive FSRS to patients who receive SSRS. IV. To evaluate if there is any difference in central nervous system (CNS) failure patterns (e.g. local, distant brain failure) in patients who receive FSRS compared to patients who receive SSRS. V. To ascertain whether FSRS prolongs time to neurologic death as compared to SRS. VI. To determine whether there is improved patient reported outcomes (Functional Assessment of Cancer Therapy [FACT]-Brain Symptom Index [FBrSI]-24) including quality of life for patients who receive FSRS compared to patients who receive SSRS. VII. To evaluate if there is any difference in CNS failure patterns (e.g. local, distant brain failure) and symptomatic radiation necrosis rates in patients who are treated with gamma knife compared to patients who are treated with a linear accelerator platform. VIII. To determine whether differences in time to local failure, time to necrosis, or their composite endpoint cumulative treatment failure differs between treatment arms (or other patient or treatment factors) when analyzed on a "per lesion" basis rather than the per patient basis utilized for the primary endpoint. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients undergo single fraction SRS. ARM B: Patients undergo fractionated SRS. After completion of study treatment, patients are followed up at 3 months, every 3 months for 2 years, and then every 6 months for 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Malignant Neoplasm in the Brain

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

69 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm A (single fraction SRS)

Arm Type

Other

Arm Description

Patients undergo single fraction SRS.

Arm Title

Arm B (fractionated SRS)

Arm Type

Other

Arm Description

Patients undergo fractionated SRS.

Intervention Type

Other

Intervention Name(s)

Questionnaire Administration

Intervention Description

Ancillary studies

Intervention Type

Radiation

Intervention Name(s)

Stereotactic Radiosurgery

Other Intervention Name(s)

Stereotactic External Beam Irradiation, stereotactic external-beam radiation therapy, Stereotactic Radiation Therapy, Stereotactic Radiotherapy, stereotaxic radiation therapy, stereotaxic radiosurgery

Intervention Description

Undergo single fraction SRS

Intervention Type

Radiation

Intervention Name(s)

Stereotactic Radiosurgery

Other Intervention Name(s)

Intervention Description

Undergo fractionated SRS

Primary Outcome Measure Information:

Title

Time to local failure or symptomatic radiation brain necrosis of large brain metastasis

Description

Time Frame

Up to 5 years

Secondary Outcome Measure Information:

Title

Overall survival (OS)

Description

OS will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms. Medians and 95% confidence intervals will be reported.

Time Frame

From study entry to death from any cause, assessed up to 5 years

Title

Incidence of adverse events

Description

Time Frame

Up to 2 years post radiation therapy

Title

Rates of radiation necrosis

Description

Will compare rates of radiation necrosis in patients who receive FSRS to patients who receive SSRS. Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test.

Time Frame

Up to 5 years

Title

Central nervous system (CNS) failure patterns (Fractionation)

Description

Time Frame

Up to 5 years

Title

Time to neurologic death

Description

Time Frame

Up to 5 years

Title

Quality of life (QOL)

Description

Time Frame

Up to 5 years

Title

CNS failure patterns (Gamma Knife)

Description

Time Frame

Up to 5 years

Title

Per lesion analysis between treatment arms: time to local failure

Description

Time Frame

Up to 5 years

Title

Per lesion analysis between treatment arms: time to necrosis

Description

Time Frame

Up to 5 years

Title

Per lesion analysis between treatment arms: endpoint CTF

Description

Time Frame

Up to 5 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age >= 18 years old Presence of presumed brain metastases from an extra-cerebral tumor site (e.g. lung, breast, prostate, etc.) Note: Dural based metastases (e.g. commonly seen in breast cancer) are eligible Size of brain metastases At least one intact metastasis (not previously treated with radiosurgery) must measure >= 2.0 cm and =< 4.0 cm in maximal extent on the contrasted pre-treatment magnetic resonance imaging (MRI) brain scan obtained =< 28 days prior to registration If the largest lesion measures >= 2.0 to =< 4.0 cm in maximal extent the patient will be randomized Able to undergo contrast enhanced MRI brain Negative urine or serum pregnancy test completed =< 7 days prior to registration, for women of childbearing potential only Patient willing and able to provide written informed consent Karnofsky performance status (KPS) >= 50 Eastern Cooperative Oncology Group (ECOG) performance score of (PS) >= 2 Past radiosurgery or resection is allowed as long as no definitive evidence of progression in these locations Note: Repeat radiosurgery to the same location/lesion is not allowed on this protocol Exclusion Criteria: Any patient who has received previous whole brain radiation Any brain metastasis that is located in the brainstem measuring >= 2.0 cm in maximal extent Any patient with definitive evidence of leptomeningeal metastasis (LMD) NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion Any patient with an intact brain metastasis measuring > 4.0 cm

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Paul D. Brown, M.D.

Organizational Affiliation

Mayo Clinic in Rochester

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Arizona

City

Scottsdale

State/Province

Arizona

ZIP/Postal Code

85259

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Clinical Trials Referral Office

Phone

855-776-0015

mayocliniccancerstudies@mayo.edu

First Name & Middle Initial & Last Name & Degree

Sujay A. Vora, M.D.

Facility Name

Mayo Clinic in Florida

City

Jacksonville

State/Province

Florida

ZIP/Postal Code

32224

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Clinical Trials Referral Office

Phone

855-776-0015

mayocliniccancerstudies@mayo.edu

First Name & Middle Initial & Last Name & Degree

Jennifer L. Peterson, M.D.

Facility Name

Mayo Clinic in Rochester

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Clinical Trials Referral Office

Phone

855-776-0015

mayocliniccancerstudies@mayo.edu

First Name & Middle Initial & Last Name & Degree

Paul D. Brown, M.D.

12. IPD Sharing Statement

Links:

URL

https://www.mayo.edu/research/clinical-trials

Description

Mayo Clinic Clinical Trials

Learn more about this trial

SRS Compared With FSRS for Treatment of Intact Metastatic Brain Disease, FRACTIONATE Trial

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