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RAPid SimPLE Targeted Radiation Treatment for Brain Metastases (RAPPLE)

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ClinicalTrials.gov Identifier: NCT05050929
Recruitment Status : Not yet recruiting
First Posted : September 21, 2021
Last Update Posted : September 21, 2021
Sponsor:
Collaborator:
Varian Medical Systems
Information provided by (Responsible Party):
Alan Nichol, British Columbia Cancer Agency

Brief Summary:
The aim of the study is to show that rapid, simple targeted radiotherapy to brain metastases with 8 Gy / 1 is non-inferior to 20 Gy / 5 in terms of overall survival for patients with poor prognosis.

Condition or disease Intervention/treatment Phase
Brain Metastases, Adult Radiation: Targeting All Brain Metastases Phase 2 Phase 3

Detailed Description:

Hypothesis For selected patients with limited life expectancy, a single targeted fraction of 8 Gy / 1 to brain metastases will provide equivalent survival as targeted radiotherapy with 20 Gy / 5 to brain metastases.

Justification The QUARTZ study randomized patients with brain metastases and poor prognosis between 20 Gy / 5 whole brain radiotherapy (WBRT) and best supportive care. The median survival in both arms of the study was 9 weeks. The quality of life in both arm was also the same. It is known that WBRT significantly diminishes quality of life. The investigators interpretation of the QUARTZ trial is that the unchecked growth of brain metastases in the best supportive care arm diminishes quality of life as much as WBRT. To control brain metastases without giving WBRT, targeted treatment with 20 Gy / 5 to the metastases alone is standard care at BC Cancer. Numerous randomized trials have compared the efficacy of 20-30 Gy / 5-10 fractions and 8 Gy / 1 for palliative treatment of pain from bone metastases. In addition, there is a randomized trial showing that 20 Gy / 5 and 8 Gy /1 are equally effective for the treatment of symptoms from spinal cord compression. This study will test the use of this shorter, one-visit treatment schedule against the standard 5-visit treatment schedule for patients with brain metastases.

Research Design Randomized Phase II Non-Inferiority Study. The estimated median survival for this cohort, based upon a prior cohort study from 2012-2016 at BC Cancer is 3 months (13 weeks). The investigators would regard a study median survival of less than the 9-week median survival observed in the QUARTZ trial as unacceptable. Hence, the hazard ratio for the experimental arm and the control arm is: 13 weeks / 9 weeks = 1.44. With one-sided Type I error set at alpha = 0.2 and power = 0.8, the investigators calculated a theoretical sample size of 86 patients. Based on prior experience with clinical trials for patients with brain metastases, a 15% risk of drop-out and loss to follow up is expected. Hence the final sample size will be 100 patients. Stratification by the diagnosis-specific graded prognostic assessment (DS-GPA) ranges of 0.0 - 1.0 and 1.5 - 2.0 and lung cancer versus other histologies will help to ensure baseline characteristics that predict for equal survival are equally distributed in both arms of the study.

Statistical Analysis The primary endpoint is overall survival. The study will be considered to be a positive phase II non-inferiority study if the median survival in the experimental arm is within 4 weeks of the median survival in the standard arm.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Equal arms (1:1)
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Non-Inferiority Study of 5-Day Versus 1-Day RAPid SimPLE (RAPPLE) Targeted Radiation Treatment for Brain Metastases
Estimated Study Start Date : November 1, 2021
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : July 1, 2026

Arm Intervention/treatment
Active Comparator: 20 Gy in 5 Fractions Volumetric Modulated Arc Therapy to Brain Metastases
Five treatments of 4 Gy will be delivered using volumetric modulated arc therapy on a conventional linear accelerator in a conventional head shell without the use of stereotactic radiosurgery technique.
Radiation: Targeting All Brain Metastases
Volumetric Modulated Arc Therapy

Experimental: 8 Gy in 1 Fraction Volumetric Modulated Arc Therapy to Brain Metastases
A single treatment of 8 Gy will be delivered using volumetric modulated arc therapy on a conventional linear accelerator in a conventional head shell without the use of stereotactic radiosurgery technique.
Radiation: Targeting All Brain Metastases
Volumetric Modulated Arc Therapy




Primary Outcome Measures :
  1. Survival Time [ Time Frame: 1 year ]
    The median time from randomization to death


Secondary Outcome Measures :
  1. Median Time to Decline in Karnofsky Performance Status [ Time Frame: 1 year ]
    The time from randomization to a 20-point decline in Karnofsky Performance Status

  2. Control of treated brain metastases [ Time Frame: 1 year ]
    Cumulative incidence of local recurrence of treated metastases

  3. Corticosteroid use [ Time Frame: 6 weeks ]
    Proportion of patients taking corticosteroids

  4. Control of brain disease [ Time Frame: 1 year ]
    Cumulative incidence of (local recurrence of treated metastases OR new metastases)

  5. Retreatments for brain metastases [ Time Frame: 1 year ]
    Proportion of patients with retreatment for brain metastases after radiotherapy

  6. Adverse Events [ Time Frame: 1 year ]
    Cumulative incidence of adverse events, graded using CTCAE Version 5.0

  7. Health-Related Quality of Life [ Time Frame: 1 year ]
    Median time to a minimum clinically important decline in Health-Related Quality of Life



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects must meet all of the following criteria to be eligible for participation in this study:

  • Age ≥ 18
  • Pathological diagnosis of a non-hematopoietic malignancy
  • Brain metastases of any size
  • Any number of brain metastases that can all be contoured and targeted
  • Anticipated median survival insufficient for surgery or stereotactic radiosurgery
  • Presence of extracranial disease
  • Estimated Glomerular Filtration Rate (eGFR) > 30 ml/min within 90 days
  • Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) ≤ 2.0
  • Able to complete the EuroQOL (EQ-5D-5L) questionnaire
  • Willing and able to have regular imaging follow up
  • Feasible to start protocol treatment within 14 days of patient enrolment
  • Karnofsky Performance Score (KPS) ≥ 40
  • Willing to provide email address on the informed consent form, if unable to attend in-person follow-up assessments
  • Signed a consent form prior to enrolment in the trial

Exclusion Criteria:

Subjects are excluded from the study if any of the following criteria apply:

  • Inability to have a brain MRI.
  • Craniotomy less than 3 months prior to randomization
  • Whole brain radiotherapy less than 6 months prior to randomization
  • Immunotherapy, targeted therapy or hormone therapy planned after RT
  • Disseminated leptomeningeal disease
  • Multiple sclerosis
  • Neurologically declining despite corticosteroids
  • Requiring craniotomy to relieve mass effect
  • Systemic lupus erythematosis, scleroderma, or other connective tissue disorders not in remission
  • Active alcohol or drug abuse
  • History of epilepsy or seizures, and not currently taking anti-epileptic medication
  • Any other serious intercurrent illness or medical condition judged by the local investigator to compromise the patient's safety, preclude safe administration of the planned protocol treatment, or prevent the patient from being managed according to the protocol guidelines
  • Pregnancy
  • Potentially fertile men or women of childbearing potential who are unwilling to employ highly effective contraception

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05050929


Locations
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Canada, British Columbia
BC Cancer - Vancouver
Vancouver, British Columbia, Canada, V5Z 4E6
Contact: Alan Nichol, MD    1-800-663-3333    anichol@bccancer.bc.ca   
Principal Investigator: Alan Nichol, MD         
Sponsors and Collaborators
British Columbia Cancer Agency
Varian Medical Systems
Investigators
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Principal Investigator: Alan Nichol, MD BC Cancer Vancouver
Publications:
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Responsible Party: Alan Nichol, Radiation Oncologist, British Columbia Cancer Agency
ClinicalTrials.gov Identifier: NCT05050929    
Other Study ID Numbers: H21-01343
First Posted: September 21, 2021    Key Record Dates
Last Update Posted: September 21, 2021
Last Verified: September 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alan Nichol, British Columbia Cancer Agency:
radiotherapy
randomized clinical trial
phase II
non-inferiority
overall survival
Additional relevant MeSH terms:
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Neoplasm Metastasis
Brain Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases