Rethinking clinical trial design for rare tumors

Today, February 29th is celebrated World Rare Disease Day with the aim of raising awareness in society about these pathologies that affect less than five people in every 10,000. It is estimated that there are more than 7,000 rare diseases that affect more than 300 million people around the world.

Nature Medicine* published a Comment article first authored by César Serrano, Group Leader of VHIO’s Sarcoma Translational Research Group and a Medical Oncologist at the Vall d’Hebron University Hospital (HUVH), explores novel options for clinical trial design rare neoplasms using gastrointestinal stromal tumor (GIST) as a test case.

To understand the natural history of placebo-treated metastatic GIST, the investigators conducted pooled meta-analyses of five landmark phase III clinical studies performed between 2003 and 2020. Based on their findings, the authors set out new directions for the optimization of clinical trial design for GIST and other rare cancers to facilitate the development and approval of new anticancer therapies for these patient populations who have very few treatment options available.

The investigators suggest a rethink of using placebos in future phase III clinical studies comparing the efficacy of experimental therapies and recommend the use of synthetic control arms designed with data from previous clinical studies or systematic collection of real-world data as comparators.

Challenges in current clinical trial design for rare cancers

There are 198 rare and less frequent tumor types. Although individually uncommon, collectively they account for approximately one quarter of all cancers. Population-based studies have consistently shown that patients with rare tumors have worse outcomes than those diagnosed with more common cancers.

“Although various factors contribute to poor survival rates in these patients, this is most likely linked to the inherent difficulties in clinical drug development for rare cancers. Conventional clinical trial designs typically demand large numbers of participants to reach conclusive results, which poses a significant challenge in less common tumor types,” said César Serrano, first and corresponding author of the article.

For the regulatory approval of a new agent or treatment combination, current randomized controlled trials compare experimental therapy with the best treatment option available which is usually the standard-of-care for a given tumor type or subgroup of patients. In rare cancers, when no active therapy is available as a comparator, placebo is used in the control group.

In clinical trials comparing a given experimental therapy versus placebo, approximately half of the patients are randomized to receive the study treatment and the other half are assigned to placebo. “Cancer patients participate in clinical trials with the hope that treatment could be effective, but the use of placebos in study designs can represent a source of anguish for patients, along with the ethical debate that this can raise,” observed Serrano.

In the meta-analyses now published in Nature Medicine*, the investigators studied the placebo groups of five phase III clinical trials in GIST, results of which show that patients who were administered placebo exhibited poorer outcomes compared to those treated with the experimental therapy.

“As an example, in the INVICTUS trial one third of patients who originally received placebo were unable to cross over to ripretinib, the experimental treatment arm, mainly due to rapid clinical disease progression. Previous studies indicated that the experimental therapy could be clinically beneficial in these patients,” added César Serrano, corresponding author of this present study.

These outcomes, added to their observation that the natural history of disease in these patients does not vary, led the investigators to propose a change in clinical trial design for rare cancers. “We strongly believe in putting our patients at the center of clinical trial design and modifying the rigidity of current studies. These trials are devised for more common tumors where the number of patients enrolled is sufficient to compare effective treatment options and thus avoid the use of placebo.”

Pointing to a paradigm shift

The authors recommend a rethink of current clinical trial designs which, in the absence of an effective standard-of-care as a comparator, use placebo as control. They propose that future phase III randomized clinical trials in patients with metastatic GIST and other rare cancers use external comparators designed with data from previous clinical studies or systematic collection of real-world data, but only where strong clinical efficacy has been clearly shown in the early phases of drug development.

“Not only would this approach leave behind the ethical debate regarding treating patients with placebo who could potentially benefit from the experimental treatment option, but fewer study participants would be required in order to study the antitumor efficacy of a given therapy and thus help to resolve one of the greatest challenges in clinical trials for rare cancers.”

“Our suggested shift in clinical trial design must naturally involve patients, investigators, sponsors, and regulatory agencies. Any discussions regarding the removal of placebo and the introduction of a given external comparator, where appropriate, must consider all viewpoints and aspects as we collectively strive to improve outcomes for patients with rare tumors, for whom treatment options are currently very limited,” concluded Serrano.

This study was carried out in collaboration with the Life Raft Group (LRG), the largest GIST patient advocacy group in the world. Based in the U.S., LRG’s mission is to enhance survival and quality of life for people living with GIST through patient-powered research, education and empowerment, and global advocacy efforts.

Reference: Serrano C, Rothschild S, Villacampa G, Heinrich MC, George S, Blay JY, Sicklick JK, Schwartz GK, Rastogi S, Jones RL, Rutkowski P, Somaiah N, Navarro V, Evans D, Trent JC. Rethinking placebos: embracing synthetic control arms in clinical trials for rare tumors. Nat Med. 2023 Oct 12. doi: 10.1038/s41591-023-02578-z.