A Tale of Two Trials

As I read through the November 10 issue of the Journal of Clinical Oncology there were two very different but highly instructive reports.

They first examined the impact of gemtuzumab ozogamicin for patients with acute myeloid leukemia. The second involved the incorporation of bevacizumab and erlotinib into the treatment of Stage III NSCLC in combination with radiation.

By way of introduction, gemtuzumab ozogamicin (GO) is an anti CD33 antibody linked to the highly toxic chemical calicheamicin. Calicheamicin, a member of enendyne class, is among the most toxic substances known to man. By linking this poison to an antibody directed against leukemia cells, it was reasoned that this novel conjugant would provide an effective therapy for leukemia. And indeed it did. But despite compelling science and what appeared to be initially good results (particularly in older patients with AML), and FDA approval for the agent, the drug was withdrawn from the market. Now, with the publication of a new study from the United Kingdom, GO is once again in the limelight as its inclusion in induction therapy resulted in a statistically significant three-year relapse-free survival advantage (p=.0007) and three year overall survival advantage (p=.05).

It appears, with regard to GO, that the clinical trial process failed to identify the clinical utility of an active and novel form of therapy for a potentially lethal disease.

The second article of interest regards a pilot study that incorporated an anti-VGEF antibody (bevacizumab) with EGFR TKI (erlotinib) along with chemotherapy and radiation. In this trial the objective response rate of 39 percent, median progression-free survival of 10.2 months and median overall survival of 10.4 months, were not demonstrably superior to contemporary results, yet toxicity was significantly enhanced. The investigators recommended against further exploration of this combination. Here the aggressive integration of targeted and conventional therapies proved a misadventure.

While these two reports are very different, they represent similar failings of the contemporary clinical trial process. The GO experience reflects the failure to identify efficacy due to contemporary clinical trial’s dilution of the benefit in select candidates, mixed in the overall population, with limited responsiveness to the agent. The second trial represents clinicians’ desire to engage in theoretically attractive clinical trials only to find that they reflect ineffective and/or more toxic treatment regimens.

On one hand, laboratory models that accurately identify responders can segregate those most likely to benefit from those who will not. GO represents just one of many interesting new classes of drugs for whom selective methodologies could prove highly valuable. The lung cancer experience reflects the failure of the research community to dedicate adequate resources to predictive clinical models.

Combinations of chemotherapy with target therapies have been the subject of investigation in our laboratory for more than a decade. For example, we observed antagonism between platins and the EGFR antagonists (gefitinib and erlotinib) two years before publication of the unsuccessful INTACT I and II Trials and three years before the unsuccessful TALENT and TRIBUTE trials.

All four of these trials combined platin based doublets with EGF-TKI’s. More recently we successfully identified favorable interactions between erlotinib and VGEF inhibitors in individual patients that have provided durable responses in our NSCLC patients as first line therapy, now out to four and five years since diagnosis. These experiences represent opportunities to explore novel therapies and avoid inadvertent antagonisms and misadventures.  In the recent JCO, a good treatment was missed while a bad treatment was advanced.

Functional profiling through use of the EVA-PCD® assay may represent the “critical path” from bench to bedside that the deputy director of the Center for Drug Evaluation and Research at the Food and Drug Administration, Janet Woodcock has described as a crying need.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

One Response to A Tale of Two Trials

  1. I remember when the anti-body drug conjugate (ADC) Mylotarg (gemtuzumab ozogamicin) was approved in AML in 2000. Mylotarg was removed from the market in 2010 after newer studies showed it did not prolong lives and had safety problems. At initial approval, Mylotarg (gemtuzumab ozogamicin) was associated with ven-occlusive disease (VOD), which can be fatal.

    Is T-DM1 (trastuzumab emtansine) another Mylotarg (gemtuzumab ozogamicin)? Mertansine is a cytotoxic agent also known as DM1. DM1 is added to trastuzumab (Herceptin) to make T-DM1. The chemistry wizards found a way to bind the trastuzumab to the maytansine derivative. The “theory” is that the trastuzumab can hone in on the breast cancer cells with the HER2 receptor and the attached chemotherapy drug could find its way into the cancer cell where it could do its damage.

    Maytansine was a drug evaluated in the 1970s and found to be effective in treating breast cancer, but its side effects were so severe that it could not be used clinically. As a result, it became a laboratory curiosity, banned from patient care.

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