The new generation of cancer drugs behave quite differently than cytotoxic therapies, and that may mean phase 1 trials need to be updated. That’s the message of a recent study reviewing the dose-response relationship in phase 1 trials of therapies including targeted small-molecule inhibitors, targeted antibodies, and immunotherapies. For these types of drugs, the authors report, the dose-response relationship isn’t linear, and some have significant activity outside the recommended phase 2 dose.

“Now that we have more types of cancer therapies, not just traditional chemotherapy, we started to wonder: Do our traditional phase 1 trials fit today’s new therapeutic agents in oncology?” said Emerson Chen, MD, assistant professor of medicine at Oregon Health and Science University (OHSU) in Portland, and the paper’s corresponding author.

The study, published in the Journal of the National Comprehensive Cancer Network, reviews results from 93 phase 1 trials that specifically reported patient response data corresponding to the dose administered. Unlike in traditional chemotherapies, here they observed significant response rates at lower doses, even doses lower than 40% of the eventual recommended phase 2 dose (RP2D).


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“What the authors did is something that a lot of us have been interested [in looking] at,” said Lillian Siu, MD, director of the Phase 1 Program at Princess Margaret Cancer Centre in Toronto. “They are raising the point that for some of these classes of drugs, we could see some biological activity even at the lower dose levels.”

With cytotoxic chemotherapy, side effects are often immediate, and they increase as dose goes up. In phase 1 trials, then, the goal is to find the maximum dose, then determine the appropriate dose based on toxicity.

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“In the old era, we would stop because we hit a toxicity,” said Dr Siu. “That’s becoming less true of the biologics and immunotherapy, because we often don’t see toxicity that stops us from going higher.”

The current paper doesn’t consider toxicity specifically, instead it focuses on efficacy at various dosages, reported as a percentage of the RP2D. Because the studies encompassed a wide variety of tumor types and genetic profiles, tumor response was a more appropriate comparison than survival. Tumor response did increase with dose, but even at low doses, certain types of therapies generated a significant response.

“This tells us the field is changing, in the sense that people are setting the bar higher to take more promising molecules into patient testing,” she said. “As a phase 1 trialist, we almost dread putting the first patient [in] a trial, because the chances of that patient getting a benefit is very low. This shows that maybe it’s not so futile.”

“Patients are often entering phase 1 trials in the hopes of having a response to new treatment,” said Jonathan Kimmelman, PhD, director of the biomedical ethics unit at McGill University. “Ideally, we would like to give them a level that’s going to give them a shot at having a response.”