March 2014 Edition Vol.11, Issue 3

New Clinical Trials Designed to Better Leverage Precision Medicine

New Clinical Trials Designed to Better Leverage Precision Medicine 

By Jennifer Levin Carter, MD, MPH, Chief Medical Officer and Founder, N-of-One

Next Generation Sequencing is leading to the discovery and approval of a growing number of effective targeted cancer therapeutics that are based on uncovering the molecular characteristics of tumors. Although the number of potential targets continues to grow, drug approvals for targeted therapies have lagged behind these biologic discoveries, in large part due to the need for new clinical trial designs. Historically, clinical trials have been designed to treat cancers classified by their anatomic location, without consideration of molecular alterations that may be present in subsets of such tumors.  

Oncology drug development is one of the largest therapeutic areas for pharmaceutical companies. To get a single oncology drug through clinical trials and the FDA approval process, pharmaceutical companies can spend over $1 billion, and the process can take12 to 15 years and require thousands of patient volunteers (Foundation for National Institutes of Health). In addition, clinical trial success rates have been very low: 70% of oncology drugs fail in Phase II and 59% of oncology drugs fail in Phase 3 (Kola, 2004).

A new paradigm is clearly needed. It has been hypothesized and demonstrated that using molecular markers to stratify patients into appropriate clinical trials can improve success rates of trials. While a study analyzing clinical trial drug development in breast cancer from 1998 to 2012 found that only 14% of drugs in clinical development for advanced disease were approved, when patients were selected based on HER2 status, the success rate increased to 23%. Using HER2 status to stratify patients also led to a 27% decrease in costs (Parker, 2012).

Similarly, clinical trial success rates in NSCLC during the same time period were six times higher for biomarker-targeted therapies and three times higher for receptor-targeted therapies than for trials that were not molecularly guided. The risk-adjusted cost for NSCLC clinical drug development was estimated to be nearly $2 billion (Parker, 2014).

Over the past few years, two new trial methodologies have emerged in order to address this growing need for a new clinical trial approach:

  1. The adaptive design and
  2. The biomarker-guided design. 

The goals of these two methods are three-fold:

  • More effectively match drugs to the populations most likely to benefit based on an individual patient’s molecular profile
  • Decrease trial costs
  • Decrease the time to drug approval. 

The strategies involved within these new designs include interim trial analyses of individual patient data, as well as pre-trial biomarker screening combined with a deeper analysis of the molecular variability within individual patient tumors. The FDA has drafted industry guidance outlining the use and importance of adaptive trials, and various biomarker status initiatives are underway or are being developed.

The Adaptive Design Clinical Trial

The purpose of the adaptive trial design is both to increase the likelihood of a study’s success as well as to deliver more in-depth data concerning the treatment’s effects. The FDA defines an adaptive trial as “a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study.”  

A key feature of this trial design is the use of interim analyses, which permit researchers to customize the trial, for example, by adjusting the randomization process or treatment dose or schedule, based on results from earlier participants in the study. This allows for potentially ineffective parameters within the trial to be minimized, instead of being locked into the study’s original design (FDA, 2010).

There are more than 20 ongoing adaptive trials in the pipeline. Two examples that have yielded recent positive results are the I-SPY 2 and BATTLE trials.

I-SPY 2
The I-SPY 2 trial, jointly conducted by the NCI, FDA and Biomarkers Consortium for patients with newly diagnosed, locally advanced breast cancer, was launched in 2010. The trial screens up to 12 cancer drugs from multiple pharmaceutical companies over the duration of the trial, by adding each individually to a standard neoadjuvant chemotherapy backbone. The adaptive approach in this study involves performing transcriptional profiling on patients’ tumor samples upon trial entry, and calculating incoming patients’ probable responses to the trial’s various therapies based on how previous patients’ tumors with similar genetic signatures responded to these treatments.  The outcomes are then used to weight the randomization that assigns each patient to a trial arm (Printz, 2013).

Attractive features of this trial’s design include the relatively rapid assessment of the primary endpoint (approximately five months after initiation of neoadjuvant treatment), the evaluation of multiple therapeutic agents with one control arm, and the ability to predict benefit in molecularly defined subsets, allowing the design of future larger trials within the molecularly defined group of patients (Berry et al, 2012 – Nat Rev Clin Oncol).

Recently, two of the drugs involved, veliparib (AbbVie Inc.) and neratinib (Puma Biotechnology Inc.), were found to have promising results in two different breast cancer subtypes. The veliparib-containing regimen was estimated to have a pathologic complete remission (pCR) rate of 52% in patients with triple negative disease, compared to 26% for patients treated with standard chemotherapy alone (SABCS, 2013). 

For the neratinib-containing regimen, it was predicted that if tested in a Phase 3 trial, this regimen has a 94.7% Bayesian probability of proving superior to standard therapy in women with HER2 positive/hormone receptor negative disease (Puma Biotech, 04/12/2013). On January 15, 2014, AbbVie initiated a Phase 3 trial for veliparib, and Puma Biotechnology is currently discussing plans for a Phase 3 trial for neratinib.

BATTLE
The MD Anderson Cancer Center’s Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial is another adaptive trial that recently reported positive data. However in this trial, multiple drugs are tested on multiple mutations within a single cancer type. In the first phase, ~40% of patients had biomarker testing and were randomly assigned to one of the 4 treatment arms. The second phase of the trial was adaptive, in which the remaining 60% were assigned to treatments based on their biomarker status and how patients with similar tumor profiles had responded in the first phase of the trial. 

In December 2013, the BATTLE investigators reported that sorafenib demonstrated clinical activity in NSCLC patients, particularly in those harboring wild-type EGFR: the eight-week disease control rate (DCR) was 58.2% (98 patients total), and the median progression-free survival (PFS) and overall survival (OS) were 2.83 and 8.48 months, respectively (Blumenschein, 2013).

By contrast, in May 2013 the vandetanib arm of the trial was reported to have results that were similar to those reported in the literature for unselected NSCLC populations (Tsao, 2013). The remaining two trials are currently in the pipeline. 

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