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

Nurix Therapeutics

Status and phase: Enrolling; Phase 1

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

Treatments: Drug: NX-2127

Study type: Interventional

Funder types: Industry

Identifiers

NCT04830137

NX-2127-001

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 248 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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248 participants in 11 patient groups

Phase 1a Dose Escalation

Experimental group

Description:

Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 1 in CLL or SLL (Dose A)

Experimental group

Description:

CLL/SLL patients whose disease has failed treatment with a BTK inhibitor

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 1 in MCL (Dose A)

Experimental group

Description:

MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 1 in FL, MZL or WM (Dose A)

Experimental group

Description:

FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTK inhibitor

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 1 in DLBCL (Dose A)

Experimental group

Description:

DLBCL patients 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

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 1 in PCNSL (Dose A)

Experimental group

Description:

PCNSL patients whose disease has failed at least 1 prior line of treatment

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 2 in CLL or SLL (Randomized to Dose A or Dose B)

Experimental group

Description:

CLL/SLL patients whose disease has failed treatment with a BTK inhibitor

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 2 in MCL (Randomized to Dose A or Dose B)

Experimental group

Description:

MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 2 in FL, MZL or WM (Randomized to Dose A or Dose B)

Experimental group

Description:

FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTK inhibitor

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 2 in DLBCL (Randomized to Dose A or Dose B)

Experimental group

Description:

DLBCL patients 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

Treatment:

Drug: NX-2127

Phase 1b Dose Optimization Stage 2 in PCNSL (Randomized to Dose A or Dose B)

Experimental group

Description:

PCNSL patients whose disease has failed at least 1 prior line of treatment

Treatment:

Drug: NX-2127