A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies

Open to people ages 18 years and up

• 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, or Lugano Classification of Lymphoma response criteria)
• Patients with transformed lymphoma are eligible for the study with the exception of those who have 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
• Adequate organ and bone marrow function, in the absence of growth factors
• 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(grade 1 - 3b), or DLBCL
• Received at least 2 prior systemic therapies (or 1 prior therapy for patients with WM) 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 with no BTK C481 mutation whose disease has failed treatment with a BTKi;
• BTK C481 mutation-positive 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 (grade 1 - 3b) or MZL whose disease has failed treatment with anti-CD20 mAb-based regimen;
• DLBCL whose disease has failed treatment with an anti-CD20 mAb-based regimen and an anthracycline (either progressed post stem cell transplant or transplant-ineligible) or WM whose disease has failed treatment with BTKi

• History of CNS lymphoma/leukemia in remission for less than 2 years
• 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 chronic, therapeutic anticoagulation with warfarin or patients treated with dual anti-platelet therapy and vitamin K antagonists
• 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
• 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 (> 20 mg/day prednisone or equivalent) within 15 days, or other 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
• Patient is taking strong or moderate cytochrome P450 3A (CYP3A) inducers or inhibitors or inhibitors of P-glycoprotein