The FDA has placed a partial clinical hold on the phase 1 NX-2127-001 trial investigating the novel BTK degrader NX-2127 in patients with relapsed/refractory B-cell malignancies.
The FDA has placed a partial clinical hold on the phase 1 NX-2127-001 trial (NCT04830137) investigating the novel BTK degrader NX-2127 in patients with relapsed/refractory B-cell malignancies, according to an announcement from Nurix Therapeutics, Inc.1
The FDA’s decision follows Nurix’s communication of its intention to improve its manufacturing process.
As a result of this partial clinical hold, the screening and enrollment of new patients into the NX-2127-001 trial have been paused. Patients currently enrolled in the trial who are deriving clinical benefit may continue to receive the study treatment in accordance with the trial protocol.
“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, stated in a 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.”
NX-2127 is a novel bifunctional molecule that degrades BTK, as well as the cereblon neosubstrates Aiolos (IKZF3) and Ikaros (IKZF1).
The first-in-human, multicenter, open-label NX-2127-001 trial is evaluating the agent’s safety and efficacy in adult patients with the following advanced B-cell malignancies: chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia (WM), 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 dose-escalation portion of the trial is evaluating the safety and tolerability of NX-2127 at multiple dose levels in patients who have received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL) and for whom no other known therapies provide clinical benefit. The primary end points of this portion of the study are to determine the incidence of protocol-specified dose-limiting toxicities and establish the maximum tolerated dose and/or recommended phase 1b dosage(s) of NX-2127.
The phase 1b dose-expansion portion of the trial will evaluate the efficacy of NX-2127 at the dose selected in the phase 1a portion in a maximum of 5 cohorts of patients who have received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL), including those with CLL or SLL with or without BTK C481 mutations whose disease has progressed on a BTK inhibitor; those with MCL whose disease has progressed on a BTK inhibitor and an anti-CD20 monoclonal antibody–based regimen; those with FL or MZL whose disease has progressed on an anti-CD20 monoclonal antibody–based regimen; those with PCNSL whose disease has progressed on 1 or more prior lines of therapy; those with DLBCL whose disease has progressed on an anti-CD20 monoclonal antibody–based regimen and either an anti-CD19–based regimen, an anthracycline, or another regimen; and those with WM whose disease has progressed on a BTK inhibitor. The primary end points of the phase 1b portion of the trial are overall response rate and safety.
Eligible patients include those with measurable disease per disease-specific response criteria who have an ECOG performance score of 0 or 1 (or 0 to 2 for patients with PCNSL) and adequate bone marrow and organ function. Patients are excluded if they have a history of CNS lymphoma or leukemia that has been in remission for less than 2 years (or evidence of disease outside the CNS, other than ocular involvement, or disease involving the brain stem for patients with PCNSL); a history of known or suspected autoimmune disease; known risks for acute blood loss; prior radiotherapy within 2 weeks of the planned start of the study drug; or an active known second malignancy.
The other drug programs led by Nurix are unaffected by the manufacturing process improvements for NX-2127.1 Nurix is working with the FDA to lift the partial clinical hold.