A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton*s Tyrosine Kinase (BTK) Degrader, in Adults with Relapsed/Refractory B-cell Malignancies

Non-Hodgkin*s lymphoma (NHL) accounts for 3% of both cancer diagnoses and
deaths worldwide. There are approximately 509,000 new cases of NHL worldwide
and 248,700 deaths (Thanda 2021) B-cell NHL accounts for 85% of all NHL cases.
In the UK, the incidence of NHL is approximately 12 per 100,000 and the
mortality is 3 per 100,000 (Thanda 2021). Patients with R/R NHL have extremely
poor prognosis, especially after two prior therapies. Even when approved
therapies exist, the median Overall Survival (OS) is low:
• 12.4 months median OS for polatuzumb vedotin with bendamustine and rituximab
in DLBCL (Sehn 2019).
• 20.3 months median OS for idelalisib in FL (Gopal 2014).
• 19.0 months median OS for lenalidomide in MCL (Goy 2013).
Thus, there remains a high unmet medical need to develop novel and efficacious
agents for patients with relapsed and refractory B-cell malignancies.

Lymphoid neoplasms of mature B-cells are classified in part based upon a
comparison of the immunophenotype and genotype of the tumor cells to normal
stages of B-cell development as well as other characteristic immunophenotypic
and genetic features.
These tumors can be derived from any stage of mature B-cell development,
including naive B-cells, germinal center B-cells, post-germinal center memory
B-cells, or plasma cells. The most common B-cell neoplasms derive from cells
that have experienced a germinal center reaction, which is initiated when
antigen stimulated B-cells migrate into the germinal centers (or follicles) of
secondary lymphoid organs (e.g., lymph nodes, spleen, and mucosa associated
lymphoid tissues). Germinal center B-cells proliferate and undergo two events
that permit the diversification of immunoglobulin genes, somatic hypermutation
and heavy chain class switching. Most tumors of mature B-cells, including
plasma cell neoplasms, show evidence of somatic hypermutation, and it is
thought that "mistakes" that occur during somatic hypermutation and class
switching are responsible for many of the acquired mutations that lead to
B-cell transformation. The latest World Health Organization classification,
updated in 2016, identifies more than 40 major B-cell malignancy subtypes with
distinct genetic, morphologic, and clinical features.
BTK is a key component of the B-cell receptor (BCR) signaling pathway and has
been clinically validated as a target in the treatment of B-cell malignancies.
BTK inhibition has been shown to be safe and effective for several B-cell
malignancies, but acquired resistance to currently approved agents leads to
poor outcomes and has been difficult to overcome. BTK degradation may provide a
promising mechanism of overcoming such resistance.
BCR signaling is indispensable for the adhesion, survival, and growth of human
B-cells. Chronic activation of the BTK-mediated BCR signaling is a hallmark of
many B-cell lymphoid malignancies making it an attractive therapeutic target.
Therapies targeting BTK are approved for the treatment of various B-cell
lymphomas, including MCL, CLL, SLL, WM, and MZL. These BTKi*s bind covalently
to cysteine 481 (C481) of the BTK protein and profoundly impair BCR signaling,
however, acquired mutations of C481 are associated with clinical resistance to
these agents and subsequent relapse. There are several noncovalent BTKi that do
not require binding to C481, which are currently being investigated in clinical
trials as potential therapies for patients with relapsed/refractory disease.
However, other mutations have been shown to decrease the in vitro activity of
these non-covalently bound BTKi suggesting that mutations may ultimately limit
the effectiveness of these compounds as well.
Small molecule-induced protein degradation of BTK offers a unique approach to
overcome such resistant mutations. NX-5948 is a chimeric targeting molecule
that induces the degradation of BTK in cells through recruitment of cereblon,
an adaptor protein of the E3 ubiquitin ligase complex, and promotes the
formation of a ternary complex of CRBN, NX-5948, and BTK. Within this complex,
ubiquitin is transferred to BTK directing it for degradation by the proteasome.
Nurix has generated data demonstrating that NX-5948 degrades both wild type
(DC50 of 1.81 nM in primary human B-cells) and ibrutinib-resistant forms of the
BTK protein in a lymphoma cell line, representing a potential approach to
targeting both wild-type and mutant pathways. In addition, NX-5948 demonstrates
potent tumor growth inhibition across orally delivered doses in BTK-dependent
mouse xenograft tumor models expressing either wild type or ibrutinib-resistant
C481S BTK mutant protein. This therapeutic modality (i.e., targeted
degradation) may also be beneficial in BTK-driven malignancies bearing non-C481
mutations arising in patients treated with non-covalent second-generation BTKi.

This study has been transitioned to CTIS with ID 2023-510541-25-00 check the CTIS register for the current data.

This study*s phase 1a primary objectives are:
• To evaluate the safety and tolerability of BTK degrader NX-5948, when taken
orally, in adult patients with R/R B cell malignancies
• To establish the Maximum Tolerated Dose (MTD) and/or recommended Phase 1b
dose (s) of NX 5948 in adult patients with R/R B-cell malignancies.

This study*s phase 1a secondary objectives are:
• To characterize the PK profile of NX-5948
• To characterize the PD profile of NX-5948
• To assess preliminary anti-tumor activity of NX-5948

This study*s phase 1b primary objectives are:
• To evaluate the anti-tumor activity of NX 5948 in least 2 DLs in patients
with CLL/SLL selected for Phase 1b safety expansion.
• To evaluate the anti-tumor activity of NX-5948 in patients with NHLs (MCL,
MZL, DLBCL/HGBL, FL, PCNSL/SCNSL) or WM based on the DLs selected for Phase 1b
safety expansion.
• To further characterize and compare the safety and tolerability of at least 2
DLs of NX-5948 in patients with CLL/SLL based on the dose(s) selected in Phase
1a for Phase 1b safety expansion.
• To further characterize the safety and tolerability of NX-5948 in patients
with NHLs (MCL, MZL, DLBCL/HGBL, FL, PCNSL/SCNSL) or WM based on the DLs
selected in Phase 1a for Phase 1b safety expansion.
To establish the optimal dose for patients with CLL/SLL based on safety,
tolerability, anti-tumor activity, and PK/PD profile for further evaluation of
dose expansion arms.


This study*s phase 1b secondary objectives are:
• To further characterize the PK profile of at least 2 DLs of NX-5948
• To further characterize the PD profile of at least 2 DLs of NX-5948
• To further assess anti-tumor activity of NX-5948 in at least 2 DLs selected
for Phase 1b safety expansion.

This is a first-in-human, open-label, multicenter, Phase 1a/1b study evaluating
the safety, tolerability, and anti-tumor activity of NX-5948 in adult patients
with relapsed/refractory B-cell malignancies. The study will be divided into 2
parts: dose escalation (Phase 1a) followed by safety expansion (Phase 1b).

phase1a:
Subjects in this phase who meet all inclusion criteria and do not meet any of
the exclusion criteria are assigned to 1 dose of the dose escalation period.
The subjects are given one or more capsules to match a dose of 50, 100, 200,
300, 450, 600, 800 or 1000 mg/day. A higher dose can be decided. Each dose
escalation cohort will include 3-6 patients and may enroll a maximum of 12
backfill subjects per previously clear dose level.
The study drug is a capsule taken with water in the morning. Fasting is
required for 2 hours both before and after taking the capsules.
The night before the intensive PK visits (Cycle 1 Day 1 and Cycle 2 Day 1), the
subject must be fasted, for at least 8 hours before study drug intake, up until
2 hours after study drug intake.

phase 1b:
In the second part of the study (the expansion), different groups of subjects
receive the selected dose from the dose escalation part (1a) with a maximum of
20 subjects per arm.

Nonclinical data available for NX-5948 support possible toxicities, including
reversible subcutaneous hemorrhage, mucosal effects, and decreased red cell
mass (anemia/cytopenia). The toxicity profile of NX-5948 in non human primates,
at doses up to 100 mg/kg for 28 consecutive days is generally consistent with
BTK inhibition.
Toxicities associated with BTKi include an increased risk of bleeding,
particularly for patients receiving concurrent anticoagulation. Additional AEs
associated with use of BTKi include serious and opportunistic infections,
cytopenias, cardiovascular complications such as cardiac arrhythmias and
hypertension, and tumor lysis syndrome.
The study protocol contains entry criteria, DLT definitions, and Safety Review
Committee oversight to minimize risk to study participants. Patients will be
monitored for signs and symptoms of toxicities throughout the study.
The study will utilize an Safety Review Committee. Decisions on dose escalation
will be made by the SRC. The Safety Review Committee will be comprised of
representatives of the Sponsor, the Sponsor*s Medical Monitor, the CRO*s
Medical Monitor (if applicable), and at a minimum, a quorum of Investigators
with subjects under review.
Given that the main expected adverse effects of NX-5948 are anticipated to be
similar to BTKi, NX-5948 has an acceptable risk/benefit profile for use in
patients with treatment relapsed/refractory malignant disease.