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

• ClinicalTrials.gov Identifier: NCT04830137
• Recruitment Status: Active, not recruiting
• First Posted: April 2, 2021
• Last Update Posted: November 7, 2023
• Sponsor: Nurix Therapeutics, Inc.
• Information provided by (Responsible Party): Nurix Therapeutics, Inc.

Tracking Information

• First Submitted Date: March 29, 2021
• First Posted Date: April 2, 2021
• Last Update Posted Date: November 7, 2023
• Actual Study Start Date: May 5, 2021
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 25, 2023)

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

Original Primary Outcome Measures (submitted: April 1, 2021)

• Number of Participants with Protocol Specified Dose-Limiting Toxicities [ Time Frame: 10 months ]
  Phase 1a
• To establish the MTD and/or recommended Phase 1b dose of NX-2127 [ Time Frame: 10 months ]
  Phase 1a
• To evaluate the clinical activity of NX-2127 at the recommended Phase 1b dose based on overall response rate (ORR) as assessed by the Investigator [ Time Frame: Up to 24 months ]
  Phase 1b
• Number of Participants with Adverse Events and Clinical Laboratory Abnormalities [ Time Frame: Up to 3 years ]
  Phase 1a/1b

Current Secondary Outcome Measures (submitted: August 25, 2023)

• Pharmacokinetic (PK) Profile of NX-2127: Maximum Serum Concentration [ Time Frame: 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 [ Time Frame: Up to 5 years ]
  Phase 1a/1b
• Progression-free survival (PFS) as assessed by the Investigator [ Time Frame: Up to 5 years ]
  Phase 1a/1b
• Overall survival (OS) as assessed by the Investigator [ Time Frame: 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 [ Time Frame: Up to 4 years ]
  Phase 1b
• Complete response (CR) rate / CR with incomplete marrow recovery as assessed by the Investigator [ Time Frame: Up to 5 years ]
  Phase 1a/1b

Original Secondary Outcome Measures (submitted: April 1, 2021)

• Pharmacokinetic (PK) Profile of NX-2127: Maximum Serum Concentration [ Time Frame: Up to 3 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 [ Time Frame: Up to 3 Years ]
  Phase 1a/1b
• Progression-free survival (PFS) as assessed by the Investigator [ Time Frame: Up to 3 Years ]
  Phase 1a/1b
• Overall survival (OS) as assessed by the Investigator [ Time Frame: Up to 24 months ]
  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 [ Time Frame: Up to 24 months ]
  Phase 1b

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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)

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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)

Intervention

Drug: NX-2127

Oral NX-2127

Study Arms

• Experimental: Phase 1a Dose Escalation
  Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose
  Intervention: Drug: 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
  Intervention: Drug: 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
  Intervention: Drug: 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
  Intervention: Drug: 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
  Intervention: Drug: 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
  Intervention: Drug: NX-2127

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: December 20, 2022): 160
• Original Estimated Enrollment (submitted: April 1, 2021): 130
• Estimated Study Completion Date: December 2025
• Estimated Primary Completion Date: December 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04830137
• Other Study ID Numbers: NX-2127-001
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Nurix Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Nurix Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Nurix Therapeutics, Inc.
• Verification Date: November 2023