Like Raising a Child
Authors: Mark S. Berger
Journal: Journal of Clinical Oncology (2012)

DOI: 10.1200/JCO.2011.40.1695 Clinical drug development is like raising a child, I was told. At the time, I had three young children, all girls, so I could easily identify with that analogy. I had just made the leap from academic medicine to clinical research and development at a pharmaceutical company—an important step in my career—to work on a phase I trial of a new agent for acute myeloid leukemia (AML). Only 2 weeks into my involvement in the development of this “child,” the more senior physician supervising the program left, turning it over to me. It felt like the birth of my own first daughter, when I had no idea what I was supposed to do, comforted only by the knowledge that others with no greater experience had somehow succeeded. The drug was gemtuzumab ozogamacin, later better known as Mylotarg (Pfizer, New York, NY), an antibody targeted to AML cells with a highly toxic chemical, calichiamycin, attached to the antibody. A group of superb chemists had produced a linker that kept the antibody-linker-calichiamycin complex together in the serum but allowed it to fall apart once it was internalized in the cell and entered the lower pH environment of the lysozyme. Gemtuzumab ozogamacin was an unruly child being developed in a tough environment. The previous physician left the program in part because he was a rheumatologist, and it was difficult to visualize the course of the patients with relapsed AML in the phase I trial without having been intimately involved in the care of similar patients. As every oncologist knows, all kinds of difficult clinical problems arise during the care of patients with AML—even more so in those patients with AML in relapse, who were the focus of the clinical trials. As a result, it was not always easy to tell the difference between the effects of gemtuzumab ozogamacin and those of AML. The phase I trial was almost derailed by CNS symptoms in one patient until a relatively new test diagnosed a rare type of CNS herpes infection in the spinal fluid. It was like trying to know whether a child’s skin rash is part of a routine viral infection or the earliest sign of chicken pox. (One of my daughters still teases me for not being able to diagnose her chicken pox until she came downstairs one morning and defiantly showed me the vesicular lesions all over her stomach.) In addition to those problems, the drug did cause significant myelosuppression and, infrequently, hepatic veno-occlusive disease. Unruly indeed. The key was to find a patient population sick enough to benefit from the drug but not too sick to respond, which was not easy in relapsed AML, for which no other drugs had been US Food and Drug Administration approved. Patients with AML in first relapse who had relapsed after at least 6 months of complete remission (CR) were whom we settled on for the phase II trial, and this choice proved to be a wise one. Early in the trial, it seemed that patients with AML in first relapse with at least 6 months of CR were hard to find. There was a lot of pressure to enlarge the population and include patients in second relapse or patients in first relapse with fewer than 6 months of CR. The debate sounded like the discussion my wife and I had had before the start of school, when one of our children was assigned a teacher we did not think was very good. Did we demand that she be switched to a different class? Did we wait and see how the class turned out and defer any request? Should the child be shielded from some teachers who may not be as inspiring as others? In the end, we toughed it out, and so did she, and although the school year was not the best, it was not nearly as bad as we had feared. In the phase II trial, as word circulated among the small group of physicians who routinely treated AML that there was a new treatment with some promising results, the tide turned, and patient enrollment markedly improved. Gemtuzumab ozogamacin development was exciting and creative. We defined a new category of clinical benefit in relapsed AML— complete response without full platelet recovery—and we were able to pull together the single-arm phase II data to apply for an early accelerated approval in the United States. Not only did we believe our child was extraordinary, we also had proof, because our drug gained US Food and Drug Administration approval when others did not. Although gemtuzumab ozogamacin was the first to be approved, there are now a number of antibodytargeted chemotherapy agents in development. US Food and Drug Administration approval was a significant milestone, but it was merely the JOURNAL OF CLINICAL ONCOLOGY A R T O F O N C O L O G Y VOLUME 30 NUMBER 10 APRIL 1 2012