a study of nx-2127 in adults with relapsed/refractory b-cell malignancies

Conditions: Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL); Waldenstrom Macroglobulinemia (WM); Mantle Cell Lymphoma (MCL); Marginal Zone Lymphoma (MZL); Follicular Lymphoma (FL); Diffuse Large B-cell Lymphoma (DLBCL); Primary Central Nervous System Lymphoma (PCNSL)

Summary: this is a first-in-human phase 1a/1b multicenter, open-label oncology study designed to evaluate the safety and anti-cancer activity of nx-2127 in patients with advanced b-cell malignancies.

phase 1a (dose escalation) will evaluate the safety and tolerability of nx-2127 in adult patients with relapsed/refractory (r/r) b-cell malignancies, who have required and received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with wm or pcnsl) and for which no other therapies are known to provide clinical benefit. phase 1b (dose optimization) will use a 2-stage design to further investigate the safety, tolerability, and preliminary efficacy of nx-2127 in r/r b-cell malignancies based on the dosage(s) selected in phase 1a. stage 1 will enroll approximately 10 participants per group based on b-cell lymphoma/leukemia indication at a specific dose selected from the first part of the study. the sponsor may decide to open stage 2 for any given group after review of safety and anti-tumor activity data from stage 1. in stage 2, an additional 10 participants will be enrolled at the dose from stage 1 as well as 20 additional participants at a second alternative dose. participants will be randomly assigned to one of the 2 dose levels in stage 2.

Eligibility criteria:
inclusion criteria: * patients must be ≥ 18 years of age * patients must have measurable disease per disease-specific response criteria * patients with indolent forms of nhl must meet the criteria requiring systemic treatment (i.e., iwcll, iwg, lugano classification of lymphoma response criteria, or international pcnsl collaborative group response criteria) * patients with transformed lymphoma are eligible for the study with the exception of those detailed in exclusion criteria #1: prolymphocytic leukemia, mcl with blastoid histology, mcl with pleomorphic morphology, or mcl with known tp53 mutation * eastern cooperative oncology group (ecog) performance status of 0 or 1 (non-pcnsl indications) or 0 - 2 (pcnsl patients) * adequate organ and bone marrow function * patients of child-bearing potential must use adequate contraceptive measures to avoid pregnancy for the duration of the study as defined in the protocol inclusion criteria for patients in phase 1a: * have histologically confirmed r/r cll, sll, wm, mcl, and mzl, fl, dlbcl, or pcnsl * received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with wm or pcnsl) and have no other therapies known to provide clinical benefit * must require systemic therapy inclusion criteria for patients in phase 1b: * must have one of the following histologically documented r/r b-cell malignancies: * cll/sll whose disease has failed treatment with a btki; * mcl whose disease has failed treatment with btki and an anti-cd20 mab-based regimen * fl or mzl whose disease has failed treatment with an anti-cd20 mab-based regimen; or wm whose disease has failed treatment with a btki * pcnsl whose disease failed at least 1 prior line of treatment * dlbcl whose disease has failed treatment with an anti-cd20 mab-based regimen and either: an anthracycline-based regimen; or an anti-cd19-based regimen, or another/ palliative regimen (either progressed post stem cell transplant or transplant-ineligible) exclusion criteria: * active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia * history of known/suspected other autoimmune disease (exception(s): patients with alopecia, vitiligo, resolved childhood atopic dermatitis, hypothyroidism, or hyperthyroidism that is clinically euthyroid at screening are allowed.) * unable to swallow capsules or have a condition that may interfere in the delivery, absorption, or metabolism of the study drug * bleeding diathesis, or other known risk for acute blood loss * patients requiring ongoing treatment with warfarin or an equivalent vitamin k antagonist and within 7 days prior to the first dose of study drug * prior radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation) * toxicities from previous anticancer therapies must have resolved to baseline levels or to grade 1 (except for alopecia, hypothyroidism with adequate replacement therapy, hypopituitarism with adequate replacement therapy, peripheral neuropathy or hematologic parameters meeting inclusion criteria). * active known second malignancy. exception: patients with non-metastatic, non-melanoma skin cancer are eligible * patient has had major surgery (e.g. requiring general anesthesia) within 4 weeks before the planned first dose of study drug * infection with human immunodeficiency virus (hiv)-1 or hiv-2. exception: patients with well-controlled hiv (e.g., cd4 \> 350/mm3 and undetectable viral load) are eligible. * current active liver disease from any cause * active viral reactivation (e.g., cmv or ebv) * use of systemic corticosteroids exceeding 20 mg/day prednisone (or equivalent) for non-pcnsl indications within 15 days prior to the planned start of study drug. pcnsl patients may not exceed corticosteroid doses of 40 mg/day prednisone (or equivalent) and should be on a stable or decreasing dose for 7 days prior to planned study start. * use of non-steroidal immunosuppressive drugs within 30 days prior to start of the study * clinically significant, uncontrolled cardiac, cardiovascular disease, or history of myocardial infarction within 6 months of planned start of study drug * administration of any strong cytochrome p450 3a (cyp3a) inducers or inhibitors for 14 days prior to the first dose of study drug, and any p-glycoprotein inhibitors (for 2 days) or moderate inducers of cyp3a for 7 days

Keywords: btk degrader btk inhibitor b-cell malignancy lymphoma imid lenalidomide pomalidomide bruton's tyrosine kinase nx-2127 targeted protein degradation chimeric targeting molecule (ctm) c481 c481s