The US Food and Drug Administration (FDA) has issued a draft guidance to help sponsors identify the optimal dosage for cancer drugs in clinical development and in it, the agency recommends a new approach in selecting such dosages for modern, targeted oncology drugs.
Historically, dose-finding trials for cytotoxic chemotherapy drugs have been designed to determine the maximum tolerated dose (MTD). The MTD paradigm applies to drugs that have a steep dose-response, have limited drug target specificity and involve the willingness of patients and providers to accept substantial toxicity to treat serious, life-threatening diseases.
Yet this approach may not be a match for modern oncology drugs, including kinase inhibitors and monoclonal antibodies, which are designed to interact with a molecular pathway unique to an oncologic disease. FDA states that “these targeted therapies demonstrate different dose-response relationships compared to cytotoxic chemotherapy, such that doses below the MTD may have similar efficacy to the MTD but with fewer toxicities.”
The MTD paradigm “can result in a recommended dosage that is poorly tolerated, adversely impacts functioning and quality-of-life, and moreover, affects a patient’s ability to remain on a drug and thereby derive maximal clinical benefit. Additionally, patients who experience adverse reactions from one treatment may have difficulty tolerating future treatments, especially if there are overlapping toxicities.”…
