Also called an umbrella or basket trial, the master trial allows for a more targeted approach to cancer treatment, faster patient enrollment and the flexibility to pivot.
Pictured, from left: Susan Powers and Cheryl Spile/Steven Buckwalter
When Susan Powers went in for surgery to replace her hip in 2018, the last thing on her mind was cancer. But Powers’ pre-surgery blood work alarmed doctors enough that they recommended she see an oncologist immediately. Her daughter, Cheryl Spile, drove her to the hospital, where her worst fears were confirmed. Soon after, Spile told BioSpace, doctors confirmed that 75-year-old Powers had acute myeloid leukemia, one of the most aggressive cancers.
“The doctor sat across the table from the two of us and said, ‘You need to get your affairs in order. You’ve got about six months to live,’” Spile recalled.
But a first-of-its-kind master clinical trial gave her a lifeline. As opposed to the more traditional trial format that tests one intervention or one group, a master trial protocol tests multiple drugs and patient groups at once. Master trials are gaining in popularity, and experts say their unconventional design is contributing to their success in cancer drug development.
Beat AML, the Leukemia & Lymphoma Society (LLS) master trial in which Powers participated, began in 2016. Since then, more than 1,300 patients have been enrolled and over 10 acute myeloid leukemia (AML) treatments have been approved by the FDA, said Alice Mims, a hematologist at Ohio State University and a senior medical director for the trial. She told BioSpace that before Beat AML started, the treatment options for this disease in older patients had been very limited.
“There weren’t a lot of treatment options for [older] patients who weren’t candidates for really intensive chemotherapy,” Mims said. “Treatment was very palliative, and patients didn’t live very long.”
A blood and bone marrow cancer, AML is the most common type of leukemia in adults. Approximately 20,000 Americans are diagnosed with AML each year, and while the National Cancer Institute puts the five-year survival rate at 31.7%, it’s half of that for adults diagnosed at 60 or older. A combination of factors drives the poor prognosis in older people, including weaker immune systems and lower medication tolerance compared to younger adults, and the biology of the cancer itself.
Faced with these odds, participating in Beat AML was a no-brainer for Powers and her family. “For us, it was an easy decision—six months to live or a clinical trial,” Spile said.
Accelerated Drug Development
Master trials, also known as umbrella or basket trials, have risen in popularity over the past decade in the cancer space, alongside increases in targeted treatment options and the availability of genomic sequencing. In these trials, patients are assigned to a treatment arm based on a genetic, immunological or other biological marker.
This trial design is meant to speed up late-stage drug development, as investigators can remove a drug shown to be ineffective or add new therapies to investigate. And fewer patients are required in order to demonstrate significant effects: Instead of enrolling control groups for each investigational treatment, FDA guidelines published in 2022 recommend the use of a shared standard-of-care control arm.
Early master trials have proven their benefits compared to traditional approaches. Launched in 2013, Novartis’ Signature Program—a basket trial for multiple cancer types with a particular set of mutations— set up sites for its master trial in an average of 3.6 weeks. In comparison, the median start-up time of a traditional trial was 10.4 months. Novartis was able to shave more than nine months off this timeline by providing treatment sites and clinicians with pre-approved start-up packages that included a standard protocol, budget and informed consent forms.
“The Signature Program was a successful approach,” wrote the authors of a 2018 study summarizing the trial’s findings. The program, they said, led to rapid identification of signals, reduced patients’ exposure to toxic drugs, and saved time and money compared to conventional designs.
A Successful Treatment Pivot
In 2016, LLS started Beat AML to expand targeted treatment options for 15 distinct types of AML. Once a patient is diagnosed and enrolled, they undergo genomic sequencing in order to match them to one of the study’s treatment arms. The sequencing takes a week, giving patients time to confer with family and take in their diagnosis. This is a significant departure from the traditional approach to treating AML, where the mantra was “don’t let the sun set” before beginning treatment like chemotherapy, Mims said. “It definitely gives people time to wrap their head around the diagnosis.”
Then, doctors start patients on a targeted therapy that may be coupled with chemotherapy. Powers began with a combination treatment but developed infections and a complication from the chemotherapy that sent her to the hospital for weeks. “I lost a lot of weight,” she told BioSpace. “I had a hard time even getting out of bed and standing on my two feet, so that took a while to overcome.”
When her care team made the decision to place Powers on the targeted therapy, which consisted of a once-a-day pill, her condition improved. She was discharged, and nearly seven years after her initial diagnosis, she is cancer-free. Powers, who was featured with Spile in a recent documentary produced by the LLS about this master trial, enjoys spending time with her family—which now includes 10 grandchildren and two great-grandchildren.
Spile is the mother of two of these grandchildren, whom she drops off twice a week to visit with “Meemaw,” as they call Powers. Going from the sobering conversation with the oncologist at the time of her diagnosis to a successful treatment regimen that involves only a daily pill has been surreal, Spile said. “I still pinch myself. I cannot believe I still have her here.”
Maddie Bender is a freelance science journalist based in Honolulu, HI. You can contact her through her website, maddiebender.com.
