RAPid SimPLE Targeted Radiation Treatment for Brain Metastases (RAPPLE)

Randomized Phase II Non-Inferiority Study of 5-Day Versus 1-Day RAPid SimPLE (RAPPLE) Targeted Radiation Treatment for Brain Metastases

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.

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.

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.

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.

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

Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. doi: 10.1016/S0140-6736(16)30825-X. Epub 2016 Sep 4.