Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How do Phase 1 Clinical Trials for Cancer Drugs Work?

Razelle Kurzrock, MD, Chief, Division of Hematology and Oncology,UCSD School of Medicine; Senior Deputy Director, Clinical Science; Director, Center for Personalized Cancer Therapy; Director, Clinical Trials Office, UCSD Moores Cancer Center, San Diego, California

Q: How is it determined that an investigational cancer drug is ready for entrance into Phase 1 clinical trials? And, how is that transition accomplished?
A: Phase 1 oncology studies encompass clinical trials wherein a new drug or combination of drugs is given to patients for the first time. These studies may include: (i) new combinations of FDA-approved or investigational drugs; and (ii) a first-in-human drug.
For this commentary, I will concentrate on first-in-human phase 1 studies. The main objectives of first-in-human studies include elucidating: (i) safety/toxicity; (ii) pharmacokinetics; (iii) optimal dose; and (iv) response signals.
These studies are designed with dose-escalation steps. The most efficient and, hence, most popular design is termed 3 + 3. Three patients are entered on a dose level, and depending on the side effects or lack thereof, the next cohort receives a higher dose (if there is no toxicity greater than grade 2) or there is an expansion of the current dose (if there is > grade 3 toxicity). The degree to which the doses are escalated can be predetermined by a variety of mathematical schemes.
How is a drug readied for Phase 1? It must go through multiple steps (outlined below) that often take 7 to 8 years. Once the steps are complete, the drug can be granted an Investigational New Drug (IND) by the FDA and given to humans.
The process starts with target discovery and then documenting in vitro and in vivo efficacy. But there is much more. Here are a few examples of the studies that must be done.

  • Formulation/drug stability
  • Pharmacology/pharmacokinetic in animals
  • ADME (absorption, distribution, metabolism, excretion)
  • P450 inhibition or induction
  • Short and long-term safety—often in 2 species
    • Single dose toxicity
    • Repeat dose toxicity
  • Teratogenicity in animals
  • Carcinogenicity in animals
  • Establish manufacturing processes meeting FDA guidelines

A key step is determining the starting dose for the first patient. While a primary concern is prevention of toxicity, an initial dose that is too conservative is also undesirable and can lead to a large proportion of patients being treated at sub-therapeutic doses.
Measures such as the no-observed-adverse-effect-level (NOAEL), maximum tolerated dose and lethal dose (LD) are determined in animals. Well-established algorithms convert these numbers to a suggested safe dose in humans. Sometimes a measure such as 10% of the LD10 (one tenth of the lethal dose to 10% of mice) is used, especially for cytotoxics, to define the first dose in humans. There is abundant evidence that Phase 1 oncology trials are exceedingly safe, with deaths that are even possibly due to drug being in the 1.5 % range. In contrast, ~50% of patients with cancer who enroll on Phase 1 trials will have succumbed to their disease by nine months.
Developing a new drug, from target discovery through preclinical to clinical testing and then to FDA approval, costs about one billion dollars and takes 10 to 15 years. For every 5,000 to 10,000 compounds that enter the pipeline, only one receives approval. And even drugs that reach clinical trials have only about a 15% chance of being approved. Drug development is a long and expensive process.


Dr. Kurzrock has research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant fees from Sequenom and Actuate Therapeutics and an ownership interest in Novena, Inc. and Curematch, Inc.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.