A Look at I-SPY 2: Novel Trial Design May Expand the Scope of Oncology Drug Development

Jane de Lartigue, PhD
Published Online: Wednesday, April 2, 2014
Breast Cancer Amid a growing recognition of the need to improve the process of developing oncology drugs, the novel I-SPY 2 clinical trial in breast cancer has demonstrated the potential to deliver new, effective treatment options more rapidly to patients who would most benefit while dramatically reducing the time and costs currently required to evaluate experimental therapies.

The I-SPY 2 program employs an adaptive clinical trial design that allows for a new agent to be tested among smaller groups of patients identified as likely candidates for the therapy through detailed screening, and then uses statistical modeling to determine the probability of success in a larger study.

News of the first successful “graduations” from I-SPY 2 emerged as one of the major developments from the 2013 San Antonio Breast Cancer Symposium (SABCS) in December. Thus far, two compounds, the PARP inhibitor veliparib and the pan-ErbB inhibitor neratinib, are poised for phase III testing as a result of the program.

Need for Reforms Recognized

Currently, clinical trials in oncology are designed to test just one drug at a time, and generally are focused on treating patients with advanced, metastatic disease, with success in metastatic disease followed by investigations in the adjuvant setting. The process of getting a drug to market can take a decade or more, hundreds of millions of dollars, thousands of patients—and still face a high likelihood of failure.

Only 1 in 10 drugs moves successfully from a phase I clinical trial to FDA approval, and oncology agents have the lowest likelihood of approval, according to a recent industry study of approval trends from 2011-2013. In fact, only 45% of phase III trials of oncology drugs result in FDA approvals.

Although there are numerous reasons for these failures, there is a growing suspicion among those involved in drug development that good drugs are being lost to inefficient clinical trial designs that are unable to appropriately test novel anticancer agents. It has been increasingly recognized that the neoadjuvant setting has significant potential to provide a unique platform to test new treatments much more rapidly. It offers a powerful opportunity to examine the effects of an experimental agent on a tumor before it is surgically removed, to codevelop biomarkers, and to individualize therapy.

However, there are significant safety and ethical considerations associated with testing investigational agents, with limited safety data, in the neoadjuvant setting in patients who are potentially curable. In the current model of drug development, the only way that these issues can be addressed is by ensuring that the drug has already undergone significant phase II studies in patients with advanced-stage disease. This is a time-consuming and expensive process that limits the potential for accelerated drug development.

I-SPY 1 Establishes Concept

The I-SPY trials represent a significant example of efforts under way to address the need for fundamental change in the clinical trial system. The program is sponsored by the Biomarkers Consortium, a public-private biomedical research partnership managed by the Foundation for the National Institutes for Health (FNIH), and involves a collaboration among stakeholders from industry, academia, government, and others. These are phase II trials in the neoadjuvant setting in patients with locally advanced, stage II/III breast cancer, designed to rapidly codevelop novel agents and biomarker signatures.

The I-SPY 1 trial was an initial study of neoadjuvant chemotherapy (NAC; doxorubicin/cyclophosphamide followed by paclitaxel) in women with high-risk breast cancer, with a principal objective of identifying indicators of response to NAC in this patient population.

I-SPY 2 At a Glance

Criteria for drug inclusion
  • Evidence of potential efficacy from preclinical/clinical studies
  • Tested and found safe in at least 1 phase I study with a taxane (or a taxane in combination with trastuzumab in patients with HER2-positive tumors)
  • Only 1 representative drug from a particular class
Criteria for “graduation”
  • Meet a threshold of 85% for predicted likelihood of success in a phase III trial of at least 300 patients
  • Double the log odds of achieving pathologic complete response
Active Clinical Investigations
Agent/Regimen Target (s) Company
Trebananib (AMG 386) ± trastuzumab (Herceptin) Angiopoietin 1/2-neutralizing peptibody + HER2-targeting agent Amgen
Ganitumab (AMG 479) + metformin Insulin-like growth factor 1 receptor inhibitor + anti hyperglycemic agent Amgen
MK-2206 ± trastuzumab Akt inhibitor + HER2-targeting agent Merck
Pertuzumab (Perjeta) + trastuzumab HER2-targeting agents Genentech
Pertuzumab + T-DM1 (Kadcyla) HER2-targeting agents Genentech
Graduated Agents
Veliparib (ABT-888) + carboplatin PARP inhibitor with platinum compound AbbVie
Neratinib Pan-ErbB inhibitor Puma Biotechnology


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