FDA Places Partial Hold on NX-2127 Phase 1 Trial in B-Cell Malignancies
While screening and enrollment of new study participants has been temporarily halted, patients currently receiving treatment can continue to do so following study protocols until the FDA resolves the clinical hold.
The FDA announced that it has placed a partial clinical hold on the phase 1 NX-2127-001 study (NCT04830137) evaluating the Bruton tyrosine kinase (BTK) degrader NX-2127 in various B-cell malignancies, according to a press release from Nurix Therapeutics, Inc.1
While screening and enrollment of new study participants has been temporarily halted, patients currently receiving treatment can continue to do so following study protocols until the FDA resolves the clinical hold. The hold was placed due to the manufacturing company’s intention of transitioning to a different manufacturing process.
“The initial NX-2127 manufacturing process produced a phase 1 drug product that has yielded important proof-of-concept results with meaningful clinical responses in patients with advanced B-cell malignancies,” Arthur T. Sands, MD, PhD, president and chief executive officer of Nurix, said in the press release.
“While the partial hold is in effect, we will supply the current drug product for patients who continue on therapy in the phase 1 study and will work expeditiously with FDA to introduce the improved NX-2127 manufacturing process and drug product into our clinical development plan.”
The first-in-human, multicenter, open-label NX-2127-001 study includes patients with advanced B-cell malignancies, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and primary central nervous system lymphoma (PCNSL).2
The phase 1a portion of the study is designed to analyze the dose escalation of the drug, and phase 1b is designed to analyze the safety, efficacy, and tolerability of NX-2127 in patients with advanced B-cell malignancies.Patients in the study are predominantly male (64.3%) with a median age of 76 years (61-92). To enroll, patients needed to have received at least 2 previous systematic therapies or at least 1 previous therapy for patients with Waldenström macroglobulinemia or PCNSL with no clinical benefit. Patients were initially given 100 mg of oral NX-2127 once daily for 28 days. Patients were then enrolled into dose levels of 200 or 300 mg.
NX-2127 is a bifunctional molecule that targets and degrades BTK, as well as cereblon neosubstratesAiolos (IKZF3) and Ikaros (IKZF1). The degradation of this pathway has proven to be beneficial for patients with CLL. Researchers observed an average degradation of 86% of BTK in all patients within 22 days, and a mean degradation of 83% in patients with CLL. Immunomodulatory activity was observed at all dose levels as well. The overall response rate (ORR) was 33%. Data show that ORR increased with longer follow up; ORR was 16.7% at 2 months, 42.9% at 4 months, and 50.0% at 6 months.
Frequent adverse effects (AE) that occurred in patients receiving treatment included fatigue, decreased neutrophil count, anemia, contusion, hypertension, dyspnea, pruritis, maculopapular rash, increased blood creatinine, diarrhea, petechiae, and decreased platelet count.
The data support further development of NX-2127 in CLL, and Nurix is working with the FDA to lift the partial clinical hold. Other drug studies led by Nurix are unaffected by the FDA’s decision.
References
- Nurix Therapeutics announces partial clinical hold for NX-2127 phase 1 trial. News release. Nurix Therapeutics. November 1, 2023. Accessed November 6, 2023. https://bit.ly/3FNeJbV
- Mato AR, Wierda WG, Ai WZ, et al. NX-2127-001, a first-in-human trial of NX-2127, a bruton’s tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies. Blood. 2022;140(suppl 1):2329-2332. doi:10.1182/blood-2022-164772
