A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies
A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies
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 is a dose escalation to 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 and for whom no other therapies are known to provide
 clinical benefit. Phase 1b will investigate the efficacy of NX-2127 at the dose selected in
 Phase 1a in up to 5 cohorts of patients with R/R B-cell malignancy indications who have
 received at least 2 prior systemic therapies:

 -  Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with no BTK C481
 mutation

 -  BTK C481 mutation-positive CLL/SLL

 -  Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL) or Waldenstrom
 Macroglobulinemia (WM)

 -  Follicular lymphoma (FL)

 -  Diffuse Large B-cell Lymphoma (DLBCL)
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, 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 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, MZL or WM whose disease has failed treatment with BTKi and an anti-CD20
 mAb-based regimen [Where BTKi-treatment failed is defined as: i.) Best response
 of stable disease (SD) during treatment with BTKi and then subsequently had
 progressive disease (PD); ii.) Any response with secondary progression; or iii)
 Best response of PD at any time while on 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) [see exclusion #6 for prior CAR-T therapy]

 -  High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements and
 high-grade B-cell lymphoma NOS

 Exclusion Criteria:

 -  History of CNS lymphoma/leukemia in remission for less than 2 years

 -  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

 -  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, 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