FDA Lifts Partial Clinical Hold on Trial Evaluating NX-2127 in R/R B-Cell Malignancies

FDA

The FDA has lifted the partial clinical hold on a phase 1a/b trial (NCT04830137) investigating NX-2127 for the treatment of adult patients with relapsed/refractory B-cell malignancies.¹

In November 2023, a partial clinical hold was placed on the study after the developer of NX-2127, Nurix Therapeutics, informed the regulatory agency of its intention to transition to an improved manufacturing process for the agent.²

With the clinical hold now lifted, Nurix announced that it plans to resume enrollment in the phase 1a dose-escalation portion of the trial.¹

“We are pleased with the timely resolution of the partial clinical hold, which allows us to reinitiate enrollment in the NX-2127 phase 1 study utilizing drug product from our new manufacturing process,” Paula G. O’Connor, MD, executive vice president and head of clinical development at Nurix, stated in a news release. “Following our clinical data disclosures at the [2023] ASH Annual Meeting and the recent scientific publication in the journal Science, we are seeing an acceleration of interest in our BTK degrader programs.”

NX-2127 is a novel bifunctional, orally bioavailable, investigational new drug designed to degrade BTK and IKZF1/3.

The phase 1 trial is enrolling patients at least 18 years of age with indolent forms of non-Hodgkin lymphoma meeting systemic treatment criteria, such as the International Workshop on Chronic Lymphocytic Leukemia (CLL), International Working Group, Lugano Classification of Lymphoma, or International Primary Central Nervous System Lymphoma (PCNSL) Collaborative Group response criteria.³

In phase 1a, patients are required to have histologically confirmed, relapsed/refractory CLL, small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), grade 1 to 3b follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), or PCNSL. At least 2 prior systemic therapies are required for all patients, except for those with Waldenström macroglobulinemia or PCNSL, in whom at least 1 prior therapy is needed.

Phase 1b will include patients with 1 of the following histologies:

• CLL/SLL with no BTK C481 mutation that has progressed after treatment with a BTK inhibitor;
• CLL/SLL harboring a BTK C481 mutation that has progressed after treatment with a BTK inhibitor;
• MCL that has progressed after treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody–based regimen (patients with blastoid morphology, pleomorphic morphology, or a known TP53 mutation are excluded);
• Grade 1 to 3b follicular lymphoma or MZL that has progressed after treatment with an anti-CD20 monoclonal antibody–based regimen;
• PCNSL that has progressed after at least 1 prior line of therapy;
• Waldenström macroglobulinemia that has progressed after treatment with a BTK inhibitor;
• or DLBCL that has progressed after an anti-CD20 monoclonal antibody–based regimen and either an anthracycline, an anti-CD19-based regimen, or another/palliative regimen. Patients with DLBCL need to have disease progression after a stem cell transplant or be ineligible for transplant.

All patients in both phases need to have measurable disease, adequate organ and bone marrow function, and an ECOG performance status of 0 or 1. Notably, patients with PCNSL are permitted to have an ECOG performance status of up to 2.

Those with a history of CNS lymphoma or leukemia in remission for less than 2 years for non-PCNSL indications; evidence of disease outside of the CNS other than ocular involvement; or disease involving the brain stem (PCNSL only) are not able to enroll. Other exclusion criteria include active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia and a history of known/suspected autoimmune disease.

Phase 1a features 1 cohort for all enrolled patients, where NX-2127 is being evaluated at multiple dose levels. Phase 1b consists of disease-specific cohorts for dose expansion.

The primary end points in phase 1a include examining dose-limiting toxicities and establishing the maximum tolerated dose and recommended phase 1b dose. Investigator-assessed overall response rate is the primary end point of the phase 1b portion of the trial. Examining the incidence of adverse effects is also a primary objective in both phases.

References

1. Nurix Therapeutics announces U.S. FDA lifts partial clinical hold on NX-2127 phase 1 trial. News release. Nurix Therapeutics. March 11, 2024. Accessed March 11, 2024. https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-announces-us-fda-lifts-partial-clinical-hold
2. Nurix Therapeutics announces partial clinical hold for NX-2127 phase 1 trial. News release. Nurix Therapeutics, Inc. November 1, 2023. Accessed March 11, 2024. https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-announces-partial-clinical-hold-nx-2127-phase
3. A study of NX-2127 in adults with relapsed/refractory B-cell malignancies. ClinicalTrials.gov. Updated November 7, 2023. Accessed March 11, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04830137