A Phase 1 clinical trial evaluating Cleave Therapeutics’ experimental oral therapy CB-5339 as a treatment for people with relapsed or refractory acute myeloid leukemia (AML) or intermediate- to high-risk myelodysplastic syndrome (MDS) has dosed its first patient.
Enrollment in the trial is ongoing, with sites in the U.S. and Australia. More information can be found here.
CB-5339 is a potent and selective oral small molecule that blocks the VCP enzyme, also known as p97 — a key regulator of several cellular protein balance and stress processes that are essential for cancer cell growth and survival.
As a second-generation VCP inhibitor, CB-5339 overcomes the limitations of earlier compounds, including exposure and selectivity to the target. According to Cleave, there is compelling preclinical data supporting the therapy’s anti-cancer effects in AML, which has a significant unmet therapeutic need.
“We are pleased to begin patient enrollment of our clinical study in AML and MDS, which marks an important milestone in evaluating the initial safety and potential therapeutic benefit of VCP inhibitors for patients with cancer,” Amy Burroughs, Cleave’s president and CEO, said in a press release.
“Despite several new drug approvals in the last several years, there remains an urgent need for well-tolerated, effective therapies for patients with myeloid malignancies,” said Courtney DiNardo, MD, the trial’s principal investigator at the University of Texas MD Anderson Cancer Center.
“We are eager to study CB-5339 as a unique oral therapy that could benefit our AML and MDS patients — perhaps even regardless of their mutational status — by disrupting stress pathways that are critical to cancer cells,” added DiNardo, an associate professor in leukemia at MD Anderson.
The two-part, open-label Phase 1 clinical trial (NCT04402541) will evaluate the therapy’s safety, preliminary effectiveness, and pharmacokinetics — its movement into, through, and out of the body. The study will enroll up to 60 adults with relapsed or refractory AML or relapsed or refractory intermediate- to high-risk MDS. Refractory cancer is one that does not respond to treatment.
Of note, MDS is a type of blood cancer that often precedes AML.
Patients currently are being recruited at three sites across the U.S. and two in Australia. The participants’ tumor genetic profile will not be a selection or exclusion parameter.
The study’s first part comprises a dose-escalation phase to establish CB-5339’s maximum tolerated dose and/or recommended dose for Phase 2 studies. That dosage will be further evaluated in the second part of the trial, a dose-expansion phase.
In the first part, participants with AML or MDS will receive CB-5339 for four days, followed by a three-day treatment-free period each week. The treatment will be given in successive 28-day cycles.
In the second part, the established maximum tolerated dose will be given to additional AML patients, for whom there is no standard therapy likely to lead to disease remission. Additional patient groups may be added in the future.
The trial’s main goals are to assess the therapy’s safety, optimal dose, and schedule, while secondary goals include several pharmacokinetics measurements and an evaluation of CB-5339’s anti-tumor effects in AML patients.
CB-5339 also is being tested in people with solid tumors and lymphoma, another type of blood cancer, in a U.S.-only Phase 1 study (NCT04372641) sponsored by the National Cancer Institute, part of the National Institutes of Health. That trial is still recruiting in Maryland; more information on contacts and locations can be found here.
“This clinical program stems from more than a decade of research by scientists who have identified VCP/p97 as a pan-cancer core fitness target that is essential for cancer cell growth and survival,” Burroughs said.
Cleave also plans to evaluate the therapeutic potential of CB-5339 in neurodegenerative diseases, since VCP was shown to contribute to the function of mitochondria — the powerhouses of cells — whose impairment is associated with a number of such conditions.