UCSF-led clinical trial model may present a better way to test new breast cancer drugs

In In The News by Barbara Jacoby

By Josh Baxt

From: medcitynews.com

Clinical trials have a long rap sheet: expensive, slow, inaccurate, prone to failure. Patients, researchers, and investors wait impatiently for that elusive signal to show up – often in vain. But now, a UC San Francisco-led group may be developing a better way.

Their solution is a platform trial called I-SPY – which stands for Investigating Series Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis. This public-private partnership, which includes the NIH, FDA and pharma companies, is working to match breast cancer patients with the most effective drugs and rapidly amass evidence to get those drugs (agents) approved. A single study with multiple arms, I-SPY is revisiting which patients get enrolled in a trial – frontloading treatment to avoid complications later.

“Instead of testing first in a metastatic setting – phase 1, 2, 3 –  and then a neoadjuvant setting, how about getting phase 1 safety data and bringing these agents in for women with bad cancers who are at high risk of dying of their disease,” said Laura Esserman, who directs the Carol Franc Buck Breast Care Center at the UCSF Helen Diller Family Comprehensive Cancer Center, in a phone interview.

Esserman was touting the benefits of this model at the Precision Medicine World Conference earlier this week in Mountain View, California.

Nearly 20 years old, the I-Spy effort grew from the realization that breast cancer patients respond differently to the same treatments. Starting with breast MRI, the team added new imaging and molecular diagnostics to identify women who could benefit most from neoadjuvant therapy. By testing these drugs early in a patient’s progression, they can eliminate some of the complications associated with metastasis and failed treatments.

“Most patients (enrolled in the trial’s various arms) are pretty healthy,” said Julie Sudduth-Klinger, Business Development Director at Quantum Leap, which helps administer the trial, in a phone interview. “They have intact immune responses, intact bone marrow, their livers are usually pretty good.”

Catching patients before their immune systems sustain damage can produce eye-opening results. One of I-Spy’s recent successes has been Merck’s Keytruda. Early administration has increased the drug’s effectiveness against some of the most deadly forms of breast cancer.

“We’ve demonstrated that pembrolizumab triples the chance of a complete response in triple negative and nearly doubles it in hormone positive,” Esserman said.

Frontloading therapies is just one of the trial’s many refinements. The team has also shown that pathologic complete response – when pathologists can no longer find cancer cells in breast or lymph nodes – is highly predictive of three-year survival without reoccurrence.

“The FDA has accepted that endpoint, and companies can get early approval for their drug if they go into the neoadjuvant patient population and show their drug has a significant increase in pathologic complete response,” Sudduth-Klingersaid.”

Perhaps the most significant improvement has been I-Spy’s adaptive approach. In other words, how patients respond to a drug informs the randomization machine.

“If you are in the trial and someone with the same subtype responds to a drug, you are more likely to get that drug,” Esserman said. “If they didn’t respond, you’re less likely to get it. It learns over time how to assign the therapy.”

As I-Spy succeeds, other researchers are taking note. These ideas are being disseminated into trials for glioblastoma, melanoma, pancreatic cancer and possibly even Alzheimer’s disease. Meanwhile, Esserman and colleagues are working with the FDA to develop new regulatory frameworks to produce better safety and outcome data and get drugs to market faster. Ultimately, they want to completely remake how patients are treated for breast cancer.

“Our goal is to get 90 percent of patients to a complete response without chemotherapy in five years,” she said. “We want to take a high-risk breast cancer and get it to a place where it’s easy to cure.”