Neurooncology clinical trial design for targeted therapies: lessons learned from the North American Brain Tumor Consortium

Abstract

The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study.

Fig. 1

Standard design of phase I toxicity study (to determine maximum tolerated dose [MTD] of drug) and phase II efficacy study in patients with recurrent malignant glioma. Abbreviation: PK, pharmacokinetic.

Fig. 2

Phase I/II clinical trial design that takes into account use of P450 hepatic enzyme inducing antiepileptic drugs (EIAEDs). Only if sufficient antitumor activity is seen in patients not taking EIAEDs (group A) would resources be committed to further study of the appropriate dose in patients taking EIAEDs (group B). Abbreviations: PK, pharmacokinetic; MTD, maximum tolerated dose.

Fig. 3

Phase I/II design for recurrent malignant glioma taking into account use of hepatic enzyme-inducing antiepileptic agents, with pilot tissue correlate study for targeted agents. Abbreviations: PK, pharmacokinetic; MTD, maximum tolerated dose.

Fig. 4

Ideal prospective analysis study of tissue correlates to identify populations of patients who may benefit from treatment with targeted agents. Abbreviation: PK, pharmacokinetic.

Fig. 5

Retrospective analysis of tissue correlates to identify populations of patients who may benefit from treatment with targeted agents.

Fig. 6

Integrated phase 0/I/II tissue correlate protocol designs for targeted therapies. The phase 0 protocol is used to determine the biologically optimal dose. The phase I protocol is a standard toxicity study. The phase II protocol is performed in a general population of patients with brain tumors to determine efficacy, and ultimately in an enriched population selected for their molecular characteristics. Abbreviation: PK, pharmacokinetic.

Fig. 7

Integrated phase 0/I/II surrogate marker protocol designs for targeted therapies.