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

Study Overview
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Brief Summary
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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
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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)

Official Title
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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

Conditions
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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 / Treatment
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* Drug: NX-2127


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)