When it comes to dosing in oncology clinical trials, the FDA thinks less is more.
The agency is launching Project Optimus from the FDA’s Oncology Center of Excellence, which will develop new guidance for cancer drug makers to test a wider range of doses early in development. The agency has long been pushing for a more thoughtful approach to dosing as cancer treatments get better and more precise. But now, they’re getting serious.
At least two companies—Amgen and Kura Oncology—have already experienced the new program firsthand. Both say they were ready. Investors, on the other hand, were not.
Kura’s Q1 announcement that it would run a new dose-optimization trial for the acute myeloid leukemia therapy KO-539—and a directive from the FDA for Amgen to do the same for the newly-approved KRAS inhibitor Lumakras—were met with “controversy and consternation among biotech investors,” Cowen analysts wrote.
“It really should not have caught them by surprise, because this is not new guidance from FDA,” said Kura Therapeutics CEO Troy Wilson in an interview. “This is simply FDA really saying, ‘Guys, the guidance we put out? Yeah, we mean that guidance.’”
Project Optimus—named for dose optimization—is tackling difficult questions, said Mirat Shah, M. D., a medical oncologist at the FDA’s Office of Oncologic Diseases at the Center for Drug Evaluation and Research (CDER). The FDA wants to bring together parties from across the drug pipeline including companies, researchers and patients, to come up with guidance to best select doses during drug development—and, “if necessary”—in post-approval studies, she added.
“What we understand is that these dosing issues are not limited to a few oncology drugs, but have more to do with the paradigm that has been applied in oncology over decades to select the doses of drugs,” Shah said. “Changing the current dosing paradigm, which heavily relies on the [maximum tolerated dose, or MTD], will require concerted effort from within the FDA and ... stakeholders outside the FDA.”
Setting the phase 2 dose is “the single most important decision a company makes in the drug development process,” according to Wilson, because it sets the dosing for every future study as well. The data resulting from "registration-enabling" trials can also be used to seek approval.
The MTD approach is unique to cancer. In other trials, companies tend to try harder to determine an effective, but still comfortable dose for patients, Shah said.
“Even in situations where there is no evidence to show that the MTD is more efficacious than a lower dose, we still see drug developers picking [it] to move forward in later phase trials,” she said.
Wilson and his company, Kura, are ready to engage. In fact, he says Kura pre-emptively decided to expand dosing considerations in an early-stage clinical trial for their lead program, which he calls “the poster child” for Project Optimus.
Late last year, Kura was conducting dose escalation to find that MTD sweet spot when the data began to show there was no maximum: Patients were not experiencing toxicity at any level, but the drug was proving effective. That got the team wondering whether they could try something new, so they went to the FDA and proposed a split phase 1 trial that would examine a high and low dose. The agency was thrilled, and the study is now enrolling.
“Now we're asking the question—that very thoughtful, logical question—is the high dose better, or is the low dose better?” Wilson said.
The CEO admits that the expanded dosing trials could slow down the KO-539 program for now, but they are also using the opportunity to further fine tune the type of patients who may benefit from the therapy.
Plus, Kura expects to roll the dosing patient groups right into a phase 2 trial, which will help speed things up later on. The company expects to have the dosing data in hand this year.
Better treatments, better results
The stereotypical cancer patient, complete with a bald head and other devastating side effects, is changing, and it’s time for the pharmaceutical world to get on board.
Cancer treatments have gotten so good, so targeted, that many patients no longer have to be pumped full of hazardous chemotherapies to slow or eliminate their disease that “would very nearly kill the patients,” Wilson said.
Pharmaceutical companies previously determined the MTD in early clinical research that was effective and safe enough. That means they noted the most serious or life-threatening of adverse events in an assessment of what was tolerable for patients, Shah said. The drug was then tested at that level in later trials and sent on to regulatory authorities once efficacy was proven.
Patients accepted a higher level of side effects because early chemotherapy drugs were their only hope and could provide at least some extra time. But Shah said that some of these adverse events, such as chronic diarrhea, impacted quality of life, meaning a patient would drop treatment. If a patient can't take a therapy, they can't benefit from it.
“Oncology traces its roots to chemotherapy,” Wilson said. “Historically what you did was you treated the patient with as much of a chemotherapeutic as she could tolerate, because you're looking to kill rapidly proliferating cells.”
And since then, the MTD method stuck, because companies were fearful that a lower dose wouldn’t be as effective.
But newer therapies are now pushing the boundaries on life expectancy for many devastating cancers and patients remain on them longer.
“Patients can take some of these drugs, and they don't even know they're on a drug,” Wilson said, if it weren’t for the occasional trip to the hospital to check a patient’s labs. “Some people say, ‘Well, if some is good, isn't more better?’ And this is where the investing world kind of got wrapped around the axle for several months.”
One key reason to ditch the MTD is that in the real world, cancer patients don’t have the clinical experience of just receiving one therapy, Wilson said. They can be on “a soup” of other drugs for related or non-related conditions, such as anti-microbials or anti-fungals, antidepressants or stomach treatments.
“It's dizzying how many drugs some of these patients are on,” Wilson said. “All these drugs interact. You wish they wouldn't but they do.” Keeping dosing as low as possible minimizes risk of complications for patients.
Instead, drug developers should evaluate a range of doses to determine which is best to maximize the benefits while minimizing side effects, Shah said.
The FDA wants clinical trial sponsors, often the companies developing the drugs, to develop a more comprehensive dosing strategy using data they generate before the clinic, according to Atiqur Rahman, Ph.D., director of the FDA’s Division of Cancer Pharmacology II in the Office of Clinical Pharmacology, Center for Drug Evaluation and Research.
Sponsors should consider how the drug interacts with the target, how it works and how safe it is. Once the drug is administered to patients in phase 1, the sponsors should evaluate whether the drug is actually spurring the response or any adverse events and to what degree; whether the target is receiving the therapy as intended; and whether the patient can tolerate treatment for more than one cycle.
Drugmakers should have a “solid rationale” for their selected dose before moving forward, Shah said. The agency is encouraging companies to test multiple doses in randomized trials to determine safety, efficacy and tolerability for pivotal trials.
The FDA is raising these issues at milestone meetings with companies, from early meetings before a therapy has even been taken by a human up to discussions about a new drug application. As in Amgen's case, a dosing trial request can come late, but the FDA is trying to ensure this is no longer a surprise.
'A philosophic evolution'
Wilson said the Amgen decision caused a “a bit of hubbub,” because the agency has rarely stepped in so late in the process to request a dosing study.
While Kura and Amgen made headlines, Wilson said there’s plenty of chatter among biotechs going on behind the scenes about the FDA’s increasing interest in dosing.
Lumakras moved extremely quickly through development, with Amgen settling on a dose of 960 mg early on after studies found an effect—but low toxicities—at a variety of doses, according to Greg Friberg, Amgen VP and Therapeutic Area Head, Oncology.
“We saw what appeared to be a numerically higher response rate at the higher dose than at the lower dose—now these are small numbers, and therein lies the challenge,” Friberg said in an interview.
Amgen needed more data and a bigger patient pool to determine a better range of possible doses for treating patients who have KRAS G12-mutated non-small cell lung cancer with Lumakras. Working with the FDA, Amgen embarked on the new post-marketing study with a high and low dose.
The FDA included the new trial as a condition of Lumakras’ accelerated approval and is requesting the study “further characterize serious adverse events,” such as gastrointestinal effects.
Friberg said there’s no concern about the 960 mg dose and a once-a-day schedule has worked well for patients, but they’re planning to keep probing the efficacy and patient experience with Lumakras for years to come anyway.
Amgen’s chief competitor in the KRAS inhibitor space, Mirati Therapeutics, could also find itself the subject of a late request from the FDA for more dose-optimization studies but has not yet received one, Cowen analysts said. Mirati told the firm they wouldn't be surprised if they got the 11th-hour request and that they were aware of the trend.
Friberg called the FDA’s new focus a “philosophic evolution” that's happening in conjunction with a broader debate that’s been going on in oncology for decades.
“There are different nooks and crannies of this question, but what's fair to say is, yes, I believe that this broader discussion is absolutely intertwined with what's being asked in terms of additional work with Lumakras,” Friberg said. “If the lower dose can offer the same safe and effective dose in the same way with a lower pill burden, philosophically, one could argue that that is … important for patients.”
He continued, “We're more than willing to prosecute that study, and we'll be looking forward to seeing how this data evolves.”
Treat it like a duck
Not all oncology drugs in development will need to go through a dose-optimization trial, but Wilson said any therapy that shows efficacy with different amounts of drug will land “squarely within the rubric of Project Optimus.”
“I would expect if it walks like a duck and it talks like a duck, you're going to have to treat it like a duck,” Wilson said.
Ultimately, better dosing will benefit patients.
“As patients with cancer are receiving novel therapeutics for potentially longer periods of time, an emphasis is being placed on safety and tolerability as this greatly impacts quality-of-life for patients and, ultimately, adherence to the drug, which may determine whether patients experience its full benefit,” Shah said.
Wilson has heard anecdotally that the AML patients in his company’s trials are “thrilled” with the new focus on optimization. This form of leukemia often afflicts older people and can cause anemia and deadly infections.
“Really the gold standard is, you want [the drugs] to take [patients] to a point where they don't think every minute of every day that they have a devastating disease,” Wilson said. The biotech industry should be striving to have patients barely notice they’re taking their drugs, he added.