1 David R. Gandara, MD University of California, Davis Comprehensive Cancer Center Evaluating Well-designed vs Poorly- designed Randomized Trials Evaluating Good vs Poorly Designed Randomized Clinical Trials The Good, The Bad and the Ugly Why do you want to do the study? Who do you want to study? How are you going to study them? What is the study design & primary study endpoint? Where are you going to conduct the study? When do you want to look at interim results, if at all? Who, What, Where, Why, When and more Randomized Clinical Trials: The Basics Why do you want to do the study? What is the hypothesis? Will the results change SOC or lead to definitive trials? Who do you want to study? What patient population? All comer or Selected/Enriched? What stratifications (for prognostic groups)? How are you going to study them? Comparison of different treatments? (or against BSC) QOL or Comparative Effectiveness? Randomized Clinical Trials: The Basics (contd) What is the study design & primary study endpoint? Randomized Phase II, Phase II/III or Phase III? How big a patient sample size needed to address the hypothesis? If Phase II, new treatment vs SOC or pick the winner Primary Endpoint: Response, PFS, OS or Other (QOL)) Where are you going to conduct the study? Single institution, multi-site in your country or Global If Global: Will there be issues of population-related pharmacogenomics? When do you want to look at interim results, if at all? Planned interim analysis? Is the study a Phase II/III with go-no go decision? Randomized Clinical Trials: The Basics (contd) Example: QUARTZ Trial of Whole Brain Radiotherapy vs Optimal Supportive Care for NSCLC patients with brain metastases (ASCO 2015) Good, Bad or UGLY? Whole brain radiotherapy for brain metastases from non-small cell lung cancer: Quality of life and overall survival results from the UK MRC QUARTZ trial PM Mulvenna, MG Nankivell, R Barton, C Faivre-Finn, P Wilson, B Moore, E McColl, I Brisbane, D Ardron, B Sydes, C Pugh, T Holt, N Bayman, S Morgan, C Lee, K Waite, RJ Stephens, MKB Parmar, RE Langley Brain Metastases and NSCLC After radical treatment of primary Non Small Cell Lung Cancer (NSCLC), the brain remains a frequent and early site of distant relapse, affecting up to 40% of patients Patients with NSCLC and brain metastases fare poorly even if irradiated Median survival remains poor RTOG RPA prognostic classes RPA I7.1 months RPA II 4.2 months all patients received WBRT; 57% NSCLC RPA III 2.3 months In the face of modest prognosis, how do we ensure optimal quality of life? In spite of lack of randomised, controlled data, whole brain radiotherapy (WBRT) plus steroids standard care R R QUARTZ Trial Randomised Controlled Non-Inferiority Design Histologically proven NSCLC with brain metastases non-resectable and unsuitable for stereotactic radiosurgery Control Arm: Optimal Supportive Care Dexamethasone + Whole Brain Radiotherapy 20Gy in 5 daily # Investigational Arm: Optimal Supportive Care Dexamethasone Primary outcome quality adjusted life years (QALYS) Secondary outcomes overall survival symptom scores March August 2014 Main Inclusion Criteria Pragmatism, Inclusivity Histologically proven primary Non Small Cell Lung Cancer CT/MRI confirming brain metastases considered inoperable or ineligible for SRS by lung/neuro-oncology Multi-Disciplinary Teams (Tumour Boards) Previous systemic treatment allowed, at least 4 weeks prior to randomisation Subsequent/simultaneous (extra cranial) palliative RT permitted Subsequent systemic treatment permitted at clinicians discretion Adapted to changing landscape Statistical Design Non-inferiority design Aiming to exclude >1 week reduction in QALYs with omission of WBRT 80% power Sample size re-assessed in 2009 following poor recruitment Recalculated independently of results from interim analyses PatientsWBRT QALYHROne- sided Original (2006)10366 weeks1.22.5% Revised (2009)5345 weeks1.255% Challenges Treatment vs No Treatment Patient / Clinician Preferences Interim Data Release Oct 2010 538 Patients: Baseline characteristics 69 UK and 3 Australian centresOSC + WBRT (N=269) OSC Alone (N=269) AgeMedian (range)66 (38 84)67 (45 85) SexMale58% Karnofsky Performance Status 7062% 70 Controlled Primary Site Age