Phase 2 Trial in Multiple Brain Metastases Outcomes With HA-SIB-WBRT

Sponsor

National Cancer Centre, Singapore (Other)

Overall Status

Recruiting

CT.gov ID

NCT04452084

Collaborator

Singhealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP) (Other), Singapore General Hospital (Other)

100

Enrollment

Location

Arms

Anticipated Duration (Months)

2.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Recently, the evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT) as the recommended treatment option in patients with good prognosis and multiple brain metastases as it gives better neurocognitive preservation compared to historical whole brain radiotherapy controls. There is however often poor tumour control with this technique due to the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is given to patients who have a limited number of brain metastases, gives a higher radiation dose to the metastases resulting in better target lesion control. With improvements in radiation technology, advanced dose-painting techniques now allow a simultaneous integrate boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve brain tumour control and preserve cognitive outcomes (HA-SIB-WBRT).

The Investigators believe that the SIB in HA-SIB-WBRT (experimental) will result in better functional and survival outcomes compared to HA-WBRT (control). Patients who are fit, have multiple brain metastases (5-25 lesions) and reasonable life expectancy (>6 months) will be recruited from NCCS over 2 years. Patients will be followed up the over the following year with imaging, toxicity data, quality of life, activities of daily living and cognitive measurements at set time points. The results will be compared across the 2 arms.

Patients with brain metastases are living longer. Maintaining functional independence and brain metastases control is thus increasingly important. Improved radiotherapy treatment techniques could provide better control and survival outcomes whilst maintain QoL and functional capacity.

Condition or Disease	Intervention/Treatment	Phase
Brain Metastases	Radiation: HA-WBRT Radiation: HA-SIB-WBRT	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Masking Description:

Blinding is not feasible in this study and will not be performed.

Primary Purpose:

Treatment

Official Title:

Randomised Prospective Phase 2 Trial in Multiple Brain Metastases Comparing Outcomes Between Hippocampal Avoidance Whole Brain Radiotherapy With or Without Simultaneous Integrated Boost

Actual Study Start Date :

Jun 15, 2020

Anticipated Primary Completion Date :

Jun 14, 2023

Anticipated Study Completion Date :

Jun 14, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Control	Radiation: HA-WBRT The accepted standard HA-WBRT doses in the control arm are 30Gy in 10 fractions.
Experimental: Experimental Procedure	Radiation: HA-SIB-WBRT The doses selected for experimental HA-SIB-WBRT arm are 30Gy in 10 fractions to the whole brain with 40 to 45Gy in 10 fraction SIB doses to tumours.

Arm

Intervention/Treatment

Active Comparator: Control

Radiation: HA-WBRT

The accepted standard HA-WBRT doses in the control arm are 30Gy in 10 fractions.

Experimental: Experimental Procedure

Radiation: HA-SIB-WBRT

The doses selected for experimental HA-SIB-WBRT arm are 30Gy in 10 fractions to the whole brain with 40 to 45Gy in 10 fraction SIB doses to tumours.

Outcome Measures

Primary Outcome Measures

Target lesion progression [From time of randomisation to target lesion progression, up to 6 months after last day of radiotherapy.]

Secondary Outcome Measures

Time to symptomatic brain metastases [From time of randomisation to symptomatic brain progression, up to 12 months after last day of radiotherapy.]
Incidences of treatment-emergent adverse events (AE) [From time of randomisation to 12 months after last day of radiotherapy.]
Identified and graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria.
Overall Survival [From time of randomisation to death from any cause, up to 12 months after last day of radiotherapy.]
Progression Free Survival [From time of randomisation to overall progression, up to 12 months after last day of radiotherapy.]
Cognitive function [From time of randomisation to 12 months after last day of radiotherapy.]
Assessed using Hopkins Verbal Learning Test

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

21-80 years old patients with radiological confirmed brain metastases (5-25 lesions)
Histologically proven malignancy of primary cancer
ECOG performance status ≤ 2
Maximum lesion or cavity size ≤ 5cm
For patients with large (≥ 3cm) lesions, a neurosurgical consult is recommended as the risk of cerebral oedema and hydrocephalus is higher with RT. A Ventricular-peritoneal shunt/ surgical excision may be required prior to planning of RT
If brain surgery or other invasive procedures are performed, the treatment can only begin at least 2-weeks post-procedure
Life expectancy of at least 6 months
Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential
Women of childbearing potential and male participants who are sexually active must agree to use a medically effective means of birth control throughout protocol treatment
Not recommended or does not want Stereotactic Radiosurgery (SRS)
Agrees to be randomised to either HA-WBRT or HA-SIB-WBRT

Exclusion Criteria:

Prior whole brain radiotherapy

o Prior SRS is not an exclusion. Details of treatment must be recorded.

Concurrent systemic cytotoxic treatment.

o If patient is on systemic treatment a treatment break of at least 7 days for immunotherapy or chemotherapy and 3 days for targeted therapy is required before and after radiotherapy.

Leptomeningeal disease
Extensive extracranial disease, not controlled by systemic treatment
Severe, active co-morbidity, defined as follows:
Major medical or psychiatric illness, which in the investigator's opinion would interfere with the completion of therapy and follow up or with full understanding of the risks and potential complications of the therapy;
Unstable angina and/or uncontrolled congestive heart failure;
Myocardial infarction within the last 6 months;
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; note that patients switched from IV antibiotics and currently on oral antibiotics whose infection is assessed to be adequately treated or controlled are eligible.
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days prior to registration;
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
Dementia, ongoing psychotic episodes or moderate-severe depression (PHQ-9).
Recent stroke in the past 3 months
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception;
ECOG performance status >2 despite a duration of high dose steroids
Symptomatic brain metastases limiting ADLs
Rapid brain progression
Patients unable to give informed consent
Total tumour planning target volume (PTV) >60cc
Radiological evidence of hydrocephalus
Contraindication to Gadolinium contrast-enhanced MRI brain
Patients who are unable to meet expected follow-up schedule (e.g. non-resident patients)
Patients with diagnoses of small cell carcinoma, lymphoma or primary brain tumour