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 Richter's transformation, prolymphocytic leukemia, or blastoid lymphoma prior to planned start of study drug
• 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), and DLBCL (High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements and high-grade B-cell lymphoma NOS)
• 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 or MZL whose disease has failed treatment with BTKi and an anti-CD20 mAb-based regimen or WM whose disease has failed treatment with BTKi
• FL (grade 1 - 3b) 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)
• DLBCL histologies include high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements and high-grade B-cell lymphoma NOS

• 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 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 with the exception of any of the following:
• Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer;
• Adequately treated Stage I cancer from which the patient is currently in remission and has been in remission for ≥ 2 years;
• Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 ng/mL; or
• Any other cancer from which the patient has been disease-free for ≥ 2 years
• 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)
• 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