Considerations for the development of novel chemotherapies and antibody drug conjugates in phase I trials

The notion of using chemicals to treat diseases has been around since the turn of the twentieth century, with early discoveries coming serendipitously. By the 1950s, a Cancer Chemotherapy National Service Center (CCNSC) had begun to screen compounds for antitumor activity. It was from this effort that we derive our modern clinical trials methods in oncology as well. Modern chemotherapy is predominantly based on our understanding of the cell cycle, and most active agents interfere with pre-mitotic phases or mitosis. Models such as the "log-kill" hypothesis explained tumor kinetics and were based on leukemia cell growth. Based on this early understanding, chemotherapy was pushed to a maximal tolerated dose (MTD) and this became the benchmark endpoint for early phase clinical trials. The "log-kill" hypothesis proved inadequate for describing behavior of solid tumors. Norton and Simon showed that a Gompertzian curve was more representative of solid tumor kinetics. Based on this observation, chemotherapy "dose-density" was developed with investigators giving less recovery time between cycles of chemotherapy to maximize tumor volume reduction. Many of today's most recognized chemotherapeutic agents were developed in the mid-twentieth century under the CCNSC. New agents have continued to be developed in the twenty-first century, as alternative formulations of old chemotherapies or entirely new compounds derived from unusual places such as the ocean. Alternative formulations have been especially successful, improving patient convenience or reducing toxicity with oral, long-lasting (PEGylation), or liposomal formulations. Antibody-drug conjugates (ADCs) are novel chemotherapies and delivery mechanisms. They allow for the targeted delivery of extremely potent chemotherapeutic agents directly to the tumor, sparing the patient from significant toxicity. The development of ADCs combines targeting of specific tumor cell surface markers by antibodies with super-potent chemotherapeutic agents, such as auristatins. Joining the antibody with the chemotherapeutic payload is a stable linker mechanism that releases the agent upon entry into the cancer cell. Future development of chemotherapies will take many forms and continues to be a vibrant and exciting area of cancer research.