With the growth of genomic testing and personalised medicine, a traditional clinical trial with one intervention for one indication is no longer considered the optimal design for all studies. Two nontraditional study designs—basket and umbrella trials—are shaking up the drug development space, with at least eight trials that adopt these approaches set to complete or have data in H1 2023.

Basket trials, which test a single intervention in “baskets” of different indications, are gaining popularity as a Phase II approach in oncology. In H1 2023, six Phase II basket trials, including studies assessing drugs for Eli Lilly, Merck, Roche, and Elevation Oncology, are expected to complete or have results. Many of these trials test multiple tumour types associated with similar underlying genetic alterations.

Meanwhile, there are at least two Phase II investigator-sponsored umbrella trials, also in oncology, that are expected to conclude in H1 2022. Umbrella trials are like an inverted basket, testing multiple interventions within a single indication.

The popularity of basket and umbrella trials fits within pharma’s broader push for adaptive clinical trials that can meet the demands of more personalised medicines. Heading into 2023, the increase in flexible clinical trials could open the door for greater patient participation, explains Liz Beatty, Chief Strategy Officer of the clinical operations company Inato, which connects trial sites and sponsors. “Patients who want to take part in clinical research will not only have more flexibility, but also have more options with respect to trials for more serious conditions like cancer,” she says.

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Four basket trials focus on gene mutations

Among the six basket trials with major events in the next six months, two are testing cancers involving human epidermal growth factor receptor 2 (HER2) alterations. HER2 is expressed in normal cells, but its overexpression is thought to drive cancerous growth.

Seagen is assessing Tukysa (tucatinib) and Herceptin (trastuzumab) in a 270-patient Phase II study (NCT04579380) for various solid tumours with HER2 alterations—including uterine neoplasms, biliary tract neoplasms, and non-small-cell lung cancer (NSCLC). The study includes specific cohorts for cancers characterized by HER2 amplification and overexpression, and HER2 mutations. Meanwhile, RemeGen is testing RC48-ADC in a 120-patient Phase II study (NCT04965519) for gynecological malignancies with HER2 alterations, including vulvar cancer and vaginal cancer. Both trials use a primary endpoint of objective response rate (ORR) assessed over two years.

Next up, an investigator-sponsored Phase II trial out of Indiana University (NCT04534283) is testing Eli Lilly’s LY3214996 with Verzenio (abemaciclib) in cohorts involving a series of cancer-associated gene alterations. These include mutations to MEK1, MEK2, ERK, and RAF1—all of which are kinase proteins involved in the same cellular cascade. LY3214996 inhibits the signal transduction protein ERK implicated in this cascade, and the study’s primary endpoint is evaluating ORR for up to one year.

Meanwhile, Elevation Oncology is testing seribantumab in a 75-patient Phase II trial (NCT04383210) for various solid tumours with neuregulin 1 (NRG1) fusions. The trial also uses ORR over one year as the primary endpoint. Seribantumab is an agonist of HER3, which is activated by binding to NRG1 and can lead to unregulated cell proliferation.

Two baskets of cancer types

Two more basket trials are targeting clusters of cancer types without focusing on specific genetic mutations. First up, IO Biotech is testing IO102-IO103 alongside Merck’s Keytruda (pembrolizumab) in a 90-patient Phase II study (NCT05077709). The trial is focusing on metastatic NSCLC, squamous cell carcinoma of head or neck, and metastatic urothelial bladder cancer.

IO102-IO103 is a peptide vaccine targeting programmed death ligand 1 (PD-L1), and indoleamine 2, 3-dioxygenase (IDO), which can cause immune tolerance in cancer. Keytruda is an FDA-approved PD-1 inhibitor, used to treat several types of cancers including the three indications tested in IO Biotech’s trial. As a primary endpoint, the trial is measuring ORR or progression free survival (PFS) over six months.

Next up, a 137-patient Phase II trial sponsored by MD Anderson Cancer Center (NCT03074513) is testing Roche’s PD-L1 inhibitor Tecentriq (atezolizumab) and Genentech's anti-VEGF Avastin (bevacizumab) in patients with rare solid tumours, including pancreatic neuroendocrine tumour, recurrent Merkel cell carcinoma, and nasopharyngeal carcinoma. As a primary endpoint, the trial is testing ORR for up to four years.

Umbrella trials home in on single cancer types

Two large investigator-sponsored oncology trials with readouts in H1 2023 are utilising the umbrella study approach. The University of Birmingham, UK, is leading a 423-patient study (NCT02664935), dubbed the National Lung Matrix Trial, in collaboration with Cancer Research UK alongwith other organisations.

The multi-center study consists of several single-arm Phase II trials testing a separate drug in a pre-specified NSCLC patient population stratified by biomarkers. Study drugs include candidates from AstraZeneca, Pfizer, and Mirati Therapeutics, and the trial has three primary endpoints: ORR over 18 months, PFS over 18 months, and durable clinical benefit (DCB) after 24 weeks.

Finally, Fudan University, China, is sponsoring a 319-patient umbrella trial (NCT04355858) for patients with hormone receptor (HR) positive HER2-negative endocrine-resistant advanced breast cancer. The study includes multiple drug candidates from Jiangsu, as well as three approved drugs: capecitabine, everolimus, and nab-paclitaxel. The study’s objective is to screen treatment options for subsequent Phase III randomised control trials, according to the study listing. As a primary endpoint, this study investigates ORR for up to five years.

Basket and umbrella trials on the rise

In the past decade, basket and umbrella trials have seen a notable uptick. The results and insights from these studies are likely to drive further innovation in the field. Already, pharma is pursuing novel strategies to test and develop cancer drugs in early-stage clinical trials.

According to GlobalData’s Clinical Trials database, basket and umbrella trials that are anticipated to start in 2023 will account for 2.33% of planned oncology trials that year. This represents a tenfold increase from almost a decade earlier, when basket and umbrella trials comprised just 0.22% of oncology trials initiated in 2014. GlobalData is the parent company of Clinical Trials Arena.

A byproduct of this growth in clinical trials, and in particular studies utilising innovative designs, is the likely surge of investments into companies that fuel the trial enablement ecosystem, Beatty explains. “As life science organizations launch more research, the cottage industry that supports them will explode - perhaps even rivaling the digital health boom of 2021,” she notes.