Toxicities in Phase I Clinical Trials
As many of you know, Phase I clinical trials are all about safety in humans. Of course, by the time a drug is approved for testing, it has been in the lab and studied in animals for quite some time. This is the first human exposure, and there is always the chance of unexpected toxicities. In Phase I trials, the researchers are really not wondering about the efficacy of the drugs or even the right doses, but, instead, is this drug safe in people?
This rather arcane topic is either of little interest or, if relevant to you, enormous interest. Here is more from Reuters:
From Reuters Health Information
Toxicities in Phase 1 Trials of Targeted Therapies Are Common
By Gabriel Miller
NEW YORK (Reuters Health) Apr 19 - Drug trials for the new classes of cancer treatments known as targeted therapies have overlooked a life-altering issue for many cancer patients -- chronic toxicity -- according to a new study.
"Most of these treatments are administered orally over a long period," said the study's lead author, Dr. Xavier Paoletti of the Institut Curie in Paris in an email to Reuters Health. "Moderate toxicities lasting for several days or weeks are then just unbearable."
Unlike traditional cytotoxic therapies, which broadly interfere with all rapidly dividing cells, targeted therapies interact with specific molecules involved in cancer growth, typically proteins involved in cellular signaling pathways.
Despite their different mechanism of action and administration, these new drugs have been developed and tested in the same way cancer drugs have always been tested -- for shorter-term use.
"What's important and often times neglected in the development phase is how the drug is anticipated to be used," Dr. Walter Stadler, an oncologist and associate dean for Clinical Research at the University of Chicago, told Reuters Health by email. He was not involved in the study.
Currently many phase I trials look only at short-term adverse events, even though acute toxicity "is far more tolerable to patients than chronic toxicity," Dr. Stadler said. "We need to think a lot more about chronic, low-level toxicities that may be quite life-altering if the therapy is anticipated to be utilized on a more chronic basis."
Dr. Paoletti's study, which was published online March 28 in the Journal of Clinical Oncology, describes late toxicities by looking retrospectively at all patients enrolled in phase I trials of molecular targeted drugs at two hospitals, the Royal Marsden Hospital in the United Kingdom and the Institut Gustave-Roussy in France.
Four hundred and forty five patients from 36 phase I trials were included, all of whom had taken molecularly targeted agents (MTAs) either alone or combination, but always without traditional chemotherapy. There were a broad range of tumor types. Patients received a median of two cycles (range, one to 33) of therapy, and half received 75% of the maximum tolerated dose.
The study analyzed all NCI grade 1 or worse events, however these were limited to gastrointestinal, skin, and clinical renal problems.
Overall, 82.7% of patients experienced some toxicity, 46% of which were grade 2 and 8.3% of which were either grades 3 or 4. More than half of the grades 3 and 4 toxicities occurred after cycle 1.
The median duration of toxicity was 15 days (range, 1 to 641 days), although it wasn't associated with any specific cycle number.
The study also found that the percentage of patients experiencing at least one toxicity didn't vary according to the dose received. Patients given oral drugs had more toxicities compared to patients given intravenous drugs (median, 5 vs. 2) and had almost three times the odds of developing a grade 3 or 4 toxicity (P=0.0045).
"Toxicities were more frequent, were more severe, and occurred later with oral agents, contrary to the common view that oral drugs are less toxic," the investigators reported.Because the majority of grade 3 or 4 toxicities occurred in the studies after their period of measuring dose-limiting toxicities, they were not used to develop maximum doses or the doses recommended for later phase II trials. To account for these, investigators suggest a new model -- the "chronic dose-limiting toxicity" -- that takes into account moderate to severe toxicities occurring later in phase I trials.
The new method, which uses a weighted system based on when toxicity occurs, would account for later toxicities without increasing the duration of phase I trials, Dr. Paoletti said.
SOURCE: http://bit.ly/eL4GTg JCO 2011