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

A Phase 1, Dose Escalation, Safety and Tolerability Study of NX-2127, a Bruton's Tyrosine Kinase (BTK) Degrader, 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL); Mantle Cell Lymphoma (MCL); Diffuse Large B-cell Lymphoma (DLBCL); Follicular Lymphoma (FL); Primary Central Nervous System Lymphoma (PCNSL); Marginal Zone Lymphoma (MZL); Waldenstrom Macroglobulinemia (WM)
• Intervention / Treatment: Drug: NX-2127

Detailed Description

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 (or at least 1 prior therapy for patients with WM or PCNSL) and for whom no other therapies are known to provide clinical benefit. Phase 1b will investigate the efficacy of NX-2127 at the dosage(s) 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 (or at least 1 prior therapy for patients with WM or PCNSL):

• Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with no BTK C481 mutation
• BTK C481 mutation-positive CLL/SLL
• Mantle Cell Lymphoma (MCL)
• Follicular lymphoma (FL) or Marginal Zone Lymphoma (MZL); or Primary Central Nervous System Lymphoma (PCNSL)
• Diffuse Large B-cell Lymphoma (DLBCL) or Waldenstrom Macroglobulinemia (WM)

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Patient Outreach; Phone Number: 7806 (415)-230-7806; Email: nx2127001@nurixtx.com

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Orange, California, United States, 92868
      • University of California Irvine
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon Research Institute at Colorado Blood Cancer Institute
  • Florida
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Comprehensive Cancer Center
    • Sarasota, Florida, United States, 34203
      • Sarah Cannon Research Institute at Florida Cancer Specialists
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • National Institutes of Health Clinical Center
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Columbus, Ohio, United States, 43210
      • OSU Wexner Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute at Tennessee Oncology
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute, University of Utah
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 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 (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(grade 1 - 3b), 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 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, excluding patients with blastoid morphology, pleomorphic morphology, or a known TP53 mutation
  • FL (grade 1 - 3b) or MZL whose disease has failed treatment with anti-CD20 mAb-based regimen; or 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, an anti-CD19-based regimen, or another/ palliative regimen (either progressed post stem cell transplant or transplant-ineligible); or WM whose disease has failed treatment with a BTKi

Exclusion Criteria:

• History of central nervous system (CNS) lymphoma/leukemia in remission for less than 2 years (non-PCNSL indications) or evidence of disease outside of the CNS (other than ocular involvement) or disease involving the brain stem (PCNSL patients)
• 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
• 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 or moderate inducers of CYP3A for 7 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1a Dose Escalation; Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose	Drug: NX-2127; Oral NX-2127
Experimental: Phase 1b Dose Expansion in CLL or SLL with no BTK C481 mutation; CLL/SLL patients with no BTK C481 mutation whose disease has failed treatment with a BTK inhibitor	Drug: NX-2127; Oral NX-2127
Experimental: Phase 1b Dose Expansion in BTK C481 mutation-positive CLL/SLL; BTK C481 mutation-positive CLL/SLL patients whose disease has failed treatment with a BTK inhibitor	Drug: NX-2127; Oral NX-2127
Experimental: Phase 1b Dose Expansion in MCL; MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen	Drug: NX-2127; Oral NX-2127
Experimental: Phase 1b Dose Expansion in FL, MZL or PCNSL; FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or PCNSL whose disease has failed at least 1 prior line of treatment	Drug: NX-2127; Oral NX-2127
Experimental: Phase 1b Dose Expansion in DLBCL or WM; DLBCL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen and either an anthracycline, an anti-CD19-based regimen, or another/palliative regimen; or WM patients whose disease has failed treatment with a BTK inhibitor	Drug: NX-2127; Oral NX-2127

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Protocol Specified Dose-Limiting Toxicities	Phase 1a	Up to 24 months
To establish the MTD and/or recommended Phase 1b dosage(s) of NX-2127	Phase 1a	Up to 24 months
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	Phase 1b	Up to 4 years
Number of Participants with Adverse Events and Clinical Laboratory Abnormalities	Phase 1a/1b	Up to 5 years

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Nurix Therapeutics, Inc.
• Investigators: Study Director: Paula O'Connor, MD, Nurix Therapeutics, Inc.

Publications and helpful links

General Publications

• Zhang D, Harris HM, Chen J, Judy J, James G, Kelly A, McIntosh J, Tenn-McClellan A, Ambing E, Tan YS, Lu H, Gajewski S, Clifton MC, Yung S, Robbins DW, Pirooznia M, Skanland SS, Gaglione E, Mhibik M, Underbayev C, Ahn IE, Sun C, Herman SEM, Noviski M, Wiestner A. NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts. Blood. 2023 Mar 30;141(13):1584-1596. doi: 10.1182/blood.2022016934.

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: March 29, 2021
• First Submitted That Met QC Criteria: April 1, 2021
• First Posted (Actual): April 2, 2021

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Pomalidomide; IMiD; Lymphoma; Lenalidomide; BTK Inhibitor; C481S; Bruton's Tyrosine Kinase; C481; BTK Degrader; Targeted Protein Degradation; Chimeric Targeting Molecule (CTM); B-cell Malignancy; NX-2127
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease Attributes; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma, B-Cell; Chronic Disease; Neoplasms; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Waldenstrom Macroglobulinemia; Leukemia, Lymphocytic, Chronic, B-Cell
• Other Study ID Numbers: NX-2127-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No