NCCN Working Group report: designing clinical trials in the era of multiple biomarkers and targeted therapies

Abstract

Defining treatment-susceptible or -resistant populations of patients with cancer through the use of genetically defined biomarkers has revolutionized cancer care in recent years for some disease/patient groups. Research continues to show that histologically defined diseases are diverse in their expression of unique mutations or other genetic alterations, however, which presents opportunities for the development of personalized cancer treatments, but increased difficulty in testing these therapies, because potential patient populations are divided into ever smaller numbers. To address some of the growing challenges in biomarker development and clinical trial design, NCCN assembled a group of experts across specialties and solid tumor disease types to begin to define the problems and to consider alternate ways of designing clinical trials in the era of multiple biomarkers and targeted therapies. Results from that discussion are presented, focusing on issues of clinical trial design from the perspective of statisticians, clinical researchers, regulators, pathologists, and information developers.

Figure 1. I-SPY2 trial design

Abbreviations: AC, anthracycline; ECHO, echocardiogram; ERBB2(HER2), human epidermal growth factor receptor 2; I-SPY2, Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2; MUGA, multi gated acquisition scan; pCR, pathologic complete response. ^aHER2+ participants will also receive trastuzumab. An investigational agent may be used instead of trastuzumab.

Figure 2. Lung Master Protocol (Lung MAP) trial design

Exp 1–4 are different TT/TTC regimens. SoC 1–5 depends on biomarker and TT/TTC/NMT regimen. Abbreviations: Exp, experimental therapy (TT or TTC); NMT, non-match study experimental therapy or combinations; SoC, standard of care (docetaxel or erlotinib); TT, targeted therapy; TTC, targeted therapy combination. ^aSubstudies assigned based on biomarker results; patients with multiple biomarkers randomly assigned to substudy.

Figure 3. CONSORT diagram, PREDICT program

^aRegional therapy, 18; ineligible for study participation, 26; too early, 44. ^bRegional therapy, 8; ineligible for participation, 10; too early, 2. From Tsimberidou AM, Iskander NG, Hong DS, et al. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clin Cancer Res 2012;18:6373–6383; with permission.