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

Primary Purpose

Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Waldenstrom Macroglobulinemia (WM)

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
NX-2127
Sponsored by
Nurix Therapeutics, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia (CLL) focused on measuring BTK Degrader, BTK Inhibitor, B-cell Malignancy, Lymphoma, C481, C481S, IMiD, Lenalidomide, Pomalidomide, Bruton's Tyrosine Kinase, NX-2127, Targeted Protein Degradation, Chimeric Targeting Molecule (CTM)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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 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), non-GCB 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
    • FL (grade 1 - 3b) or MZL whose disease has failed treatment with anti-CD20 mAb-based regimen; or PCNSL whose disease failed treatment with a BTKi
    • Non-GCB 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) or WM whose disease has failed treatment with 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

Sites / Locations

  • City of HopeRecruiting
  • University of California IrvineRecruiting
  • University of California San Francisco Medical CenterRecruiting
  • Sarah Cannon Research Institute at Colorado Blood Cancer InstituteRecruiting
  • Mount Sinai Comprehensive Cancer CenterRecruiting
  • Sarah Cannon Research Institute at Florida Cancer SpecialistsRecruiting
  • The University of Chicago Medical CenterRecruiting
  • National Institutes of Health Clinical CenterRecruiting
  • Memorial Sloan Kettering Cancer CenterRecruiting
  • University of Cincinnati Medical CenterRecruiting
  • OSU Wexner Medical CenterRecruiting
  • Sarah Cannon Research Institute at Tennessee OncologyRecruiting
  • Baylor University Medical CenterRecruiting
  • MD Anderson Cancer CenterRecruiting
  • Huntsman Cancer Institute, University of UtahRecruiting
  • Swedish Cancer InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase 1a Dose Escalation

Phase 1b Dose Expansion in CLL or SLL with no BTK C481 mutation

Phase 1b Dose Expansion in BTK C481 mutation-positive CLL/SLL

Phase 1b Dose Expansion in MCL

Phase 1b Dose Expansion in FL, MZL or PCNSL

Phase 1b Dose Expansion in DLBCL or WM

Arm Description

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

CLL/SLL patients with no BTK C481 mutation whose disease has failed treatment with a BTK inhibitor

BTK C481 mutation-positive CLL/SLL patients whose disease has failed treatment with a BTK inhibitor

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

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

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

Outcomes

Primary Outcome Measures

Number of Participants with Protocol Specified Dose-Limiting Toxicities
Phase 1a
To establish the MTD and/or recommended Phase 1b dosage(s) of NX-2127
Phase 1a
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
Number of Participants with Adverse Events and Clinical Laboratory Abnormalities
Phase 1a/1b

Secondary Outcome Measures

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
Duration of response (DOR) as assessed by the Investigator
Phase 1a/1b
Progression-free survival (PFS) as assessed by the Investigator
Phase 1a/1b
Overall survival (OS) as assessed by the Investigator
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
Phase 1b
Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator
Phase 1a/1b

Full Information

First Posted
March 29, 2021
Last Updated
August 25, 2023
Sponsor
Nurix Therapeutics, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04830137
Brief Title
A Study of NX-2127 in Adults With Relapsed/Refractory B-cell Malignancies
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 5, 2021 (Actual)
Primary Completion Date
December 2024 (Anticipated)
Study Completion Date
December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nurix Therapeutics, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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 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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Waldenstrom Macroglobulinemia (WM), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), Follicular Lymphoma (FL), Diffuse Large B-cell Lymphoma (DLBCL), Primary Central Nervous System Lymphoma (PCNSL)
Keywords
BTK Degrader, BTK Inhibitor, B-cell Malignancy, Lymphoma, C481, C481S, IMiD, Lenalidomide, Pomalidomide, Bruton's Tyrosine Kinase, NX-2127, Targeted Protein Degradation, Chimeric Targeting Molecule (CTM)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
160 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 1a Dose Escalation
Arm Type
Experimental
Arm Description
Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose
Arm Title
Phase 1b Dose Expansion in CLL or SLL with no BTK C481 mutation
Arm Type
Experimental
Arm Description
CLL/SLL patients with no BTK C481 mutation whose disease has failed treatment with a BTK inhibitor
Arm Title
Phase 1b Dose Expansion in BTK C481 mutation-positive CLL/SLL
Arm Type
Experimental
Arm Description
BTK C481 mutation-positive CLL/SLL patients whose disease has failed treatment with a BTK inhibitor
Arm Title
Phase 1b Dose Expansion in MCL
Arm Type
Experimental
Arm Description
MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen
Arm Title
Phase 1b Dose Expansion in FL, MZL or PCNSL
Arm Type
Experimental
Arm Description
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
Arm Title
Phase 1b Dose Expansion in DLBCL or WM
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
NX-2127
Intervention Description
Oral NX-2127
Primary Outcome Measure Information:
Title
Number of Participants with Protocol Specified Dose-Limiting Toxicities
Description
Phase 1a
Time Frame
Up to 24 months
Title
To establish the MTD and/or recommended Phase 1b dosage(s) of NX-2127
Description
Phase 1a
Time Frame
Up to 24 months
Title
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
Description
Phase 1b
Time Frame
Up to 4 years
Title
Number of Participants with Adverse Events and Clinical Laboratory Abnormalities
Description
Phase 1a/1b
Time Frame
Up to 5 years
Secondary Outcome Measure Information:
Title
Pharmacokinetic (PK) Profile of NX-2127: Maximum Serum Concentration
Description
Phase 1a/1b - Sampling following the first dose, pre and post-dose at selected cycles, and at the end of treatment
Time Frame
Up to 5 years
Title
Duration of response (DOR) as assessed by the Investigator
Description
Phase 1a/1b
Time Frame
Up to 5 years
Title
Progression-free survival (PFS) as assessed by the Investigator
Description
Phase 1a/1b
Time Frame
Up to 5 years
Title
Overall survival (OS) as assessed by the Investigator
Description
Phase 1b
Time Frame
Up to 4 years
Title
To further evaluate the safety and tolerability of NX-2127 by collecting adverse events, treatment emergent adverse events, and incidence of all deaths
Description
Phase 1b
Time Frame
Up to 4 years
Title
Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator
Description
Phase 1a/1b
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Patient Outreach
Phone
(415)-230-7806
Ext
7806
Email
nx2127001@nurixtx.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paula O'Connor, MD
Organizational Affiliation
Nurix Therapeutics, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
City of Hope
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Name
University of California Irvine
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Individual Site Status
Recruiting
Facility Name
University of California San Francisco Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Individual Site Status
Recruiting
Facility Name
Sarah Cannon Research Institute at Colorado Blood Cancer Institute
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Individual Site Status
Recruiting
Facility Name
Mount Sinai Comprehensive Cancer Center
City
Miami Beach
State/Province
Florida
ZIP/Postal Code
33140
Country
United States
Individual Site Status
Recruiting
Facility Name
Sarah Cannon Research Institute at Florida Cancer Specialists
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34203
Country
United States
Individual Site Status
Recruiting
Facility Name
The University of Chicago Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Individual Site Status
Recruiting
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20814
Country
United States
Individual Site Status
Recruiting
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Cincinnati Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Individual Site Status
Recruiting
Facility Name
OSU Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Name
Sarah Cannon Research Institute at Tennessee Oncology
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Individual Site Status
Recruiting
Facility Name
Baylor University Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Individual Site Status
Recruiting
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Name
Huntsman Cancer Institute, University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Individual Site Status
Recruiting
Facility Name
Swedish Cancer Institute
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
36375120
Citation
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.
Results Reference
derived

Learn more about this trial

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

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