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

Phase 1

Recruiting

• Conditions: Small Lymphocytic Lymphoma (SLL); Follicular Lymphoma (FL); Chronic Lymphocytic Leukemia (CLL); Waldenstrom Macroglobulinemia (WM); Mantle Cell Lymphoma (MCL); Marginal Zone Lymphoma (MZL); Diffuse Large B-cell Lymphoma (DLBCL); Primary Central Nervous System Lymphoma (PCNSL)
• Interventions: Drug: NX-2127

• Registration Number: NCT04830137
• Lead Sponsor: Nurix Therapeutics, Inc.

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2021-03-29
• Study First Submitted QC: 2021-04-01
• Study First Posted: 2021-04-02
• Study Start: 2021-05-05
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-22
• Last Update Posted: 2024-11-26
• Primary Completion: 2025-12
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 266

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)

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1a Dose Escalation	NX-2127	Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose
Phase 1b Dose Optimization Stage 1 in CLL or SLL (Dose A)	NX-2127	CLL/SLL patients whose disease has failed treatment with a BTK inhibitor
Phase 1b Dose Optimization Stage 1 in MCL (Dose A)	NX-2127	MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen
Phase 1b Dose Optimization Stage 1 in FL, MZL or WM (Dose A)	NX-2127	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
Phase 1b Dose Optimization Stage 1 in DLBCL (Dose A)	NX-2127	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
Phase 1b Dose Optimization Stage 1 in PCNSL (Dose A)	NX-2127	PCNSL patients whose disease has failed at least 1 prior line of treatment
Phase 1b Dose Optimization Stage 2 in CLL or SLL (Randomized to Dose A or Dose B)	NX-2127	CLL/SLL patients whose disease has failed treatment with a BTK inhibitor
Phase 1b Dose Optimization Stage 2 in MCL (Randomized to Dose A or Dose B)	NX-2127	MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen
Phase 1b Dose Optimization Stage 2 in FL, MZL or WM (Randomized to Dose A or Dose B)	NX-2127	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
Phase 1b Dose Optimization Stage 2 in DLBCL (Randomized to Dose A or Dose B)	NX-2127	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
Phase 1b Dose Optimization Stage 2 in PCNSL (Randomized to Dose A or Dose B)	NX-2127	PCNSL patients whose disease has failed at least 1 prior line of treatment

Primary Outcome Measures

Name	Time	Method
To evaluate the clinical activity of NX-2127 at the recommended Phase 1b dosage(s) based on overall response rate (ORR) as assessed by the Investigator	Up to 4 years	Phase 1b
Number of Participants with Adverse Events and Clinical Laboratory Abnormalities	Up to 5 years	Phase 1a/1b
To establish the MTD and/or recommended Phase 1b dosage(s) of NX-2127	Up to 24 months	Phase 1a
Number of Participants with Protocol Specified Dose-Limiting Toxicities	Up to 24 months	Phase 1a

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic (PK) Profile of NX-2127: Maximum Serum Concentration	Up to 5 years	Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment
Duration of response (DOR) as assessed by the Investigator	Up to 5 years	Phase 1a/1b
Progression-free survival (PFS) as assessed by the Investigator	Up to 5 years	Phase 1a/1b
Overall survival (OS) as assessed by the Investigator	Up to 4 years	Phase 1b
To further evaluate the safety and tolerability of NX-2127 by collecting adverse events, treatment emergent adverse events, and incidence of all deaths	Up to 4 years	Phase 1b
Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator	Up to 5 years	Phase 1a/1b

Trial Locations

Locations (16)

City of Hope; 🇺🇸 Duarte, California, United States

University of California Irvine; 🇺🇸 Orange, California, United States

University of California San Francisco Medical Center; 🇺🇸 San Francisco, California, United States

Sarah Cannon Research Institute at Colorado Blood Cancer Institute; 🇺🇸 Denver, Colorado, United States

Mount Sinai Comprehensive Cancer Center; 🇺🇸 Miami Beach, Florida, United States

Sarah Cannon Research Institute at Florida Cancer Specialists; 🇺🇸 Sarasota, Florida, United States

The University of Chicago Medical Center; 🇺🇸 Chicago, Illinois, United States

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

University of Cincinnati Medical Center; 🇺🇸 Cincinnati, Ohio, United States

OSU Wexner Medical Center; 🇺🇸 Columbus, Ohio, United States

Tennessee Oncology; 🇺🇸 Nashville, Tennessee, United States

Baylor University Medical Center; 🇺🇸 Dallas, Texas, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Huntsman Cancer Institute, University of Utah; 🇺🇸 Salt Lake City, Utah, United States

Swedish Cancer Institute; 🇺🇸 Seattle, Washington, United States