NX-5948 for B-cell Cancer

Recruiting at 59 trial locations

Overseen By Additional Site Contact Information

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Nurix Therapeutics, Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Prolymphocytic leukemia, Richter's transformation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

572 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a first-in-human Phase 1a/1b multicenter, open-label study designed to evaluate the safety and anti-cancer activity of NX-5948 in patients with advanced B-cell malignancies.

Will I have to stop taking my current medications?

The trial requires that you stop certain medications before starting the study drug. Specifically, you must not have had radiotherapy, systemic chemotherapy, monoclonal antibody therapy, or small molecule therapy within a specified period before starting the study drug. Additionally, there are restrictions on the use of systemic corticosteroids and immunosuppressive drugs.

What data supports the effectiveness of the drug NX-5948 for B-cell cancer?

Research shows that drugs targeting the B-cell receptor (BCR) pathway, like NX-5948, have been effective in treating B-cell cancers, as similar drugs have shown success in conditions like non-Hodgkin's lymphoma by inhibiting key proteins involved in cancer cell growth and survival. ^{1 2 3 4 5}

What makes the drug NX-5948 unique for treating B-cell cancer?

NX-5948 is unique because it is a selective inhibitor of PI3Kδ, a molecule important for B-cell development, which makes it specifically target B-cell cancers like non-Hodgkin lymphoma and chronic lymphocytic leukemia. This selectivity may offer a more focused treatment with potentially fewer side effects on non-B-cell functions compared to less selective treatments. ^{6 7 8 9 10}

Research Team

Paula O'Connor, MD

Principal Investigator

Nurix Therapeutics, Inc.

Eligibility Criteria

Adults over 18 with certain advanced B-cell malignancies, measurable disease, and in good physical condition (ECOG 0-1) can join. They must have tried at least two prior treatments without success. Excluded are those recently treated with chemotherapy, monoclonal antibodies, small molecules or immunosuppressives; have heart issues, uncontrolled blood pressure or bleeding disorders; received CAR T-cell therapy or stem cell transplant too recently.

Inclusion Criteria

I have a confirmed diagnosis of a specific type of blood cancer.

My cancer can be measured on scans, with visible tumors.

I can care for myself and perform daily activities.

Exclusion Criteria

I haven't taken immunosuppressive drugs, except for corticosteroids, in the last 30 days.

I haven't had CAR T-cell therapy in the last 100 days (30 days for Phase 1b) or I have evidence of B-cell recovery after such therapy.

I haven't taken small molecule therapy in the last 4 weeks or 5 half-lives.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Phase 1a involves dose escalation to evaluate the safety and tolerability of NX-5948 in adult patients with relapsed/refractory B-cell malignancies.

Up to 24 months

Safety Expansion

Phase 1b Part 1 investigates the safety and anti-tumor activity of NX-5948 at the dose(s) selected in Phase 1a in up to 13 expansion cohorts.

Up to 3 years

Cohort Expansion

Phase 1b Part 2 further investigates the anti-tumor activity of NX-5948 at the dose(s) selected in Phase 1b Part 1 in one additional expansion arm of CLL/SLL patients.

Up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment.

Up to 6 years

Treatment Details

Interventions

• NX-5948

Trial Overview The trial is testing NX-5948's safety and effectiveness against various B-cell cancers. It's a first-in-human study that includes an initial phase to find the right dose and a second phase to see how well it works on specific cancer types.

Participant Groups

Group I: Phase 1b Part 2 in CLL or SLL with prior BTKi and BCL-2i Experimental Treatment 1 Intervention

CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor

Group II: Phase 1b Part 1 Cohort 9 in WM (2L) Experimental Treatment 1 Intervention

WM following upfront therapy with a BTKi

Group III: Phase 1b Part 1 Cohort 8 in WM (3L+) Experimental Treatment 1 Intervention

WM with prior exposure to a BTKi and at least an additional line of therapy

Group IV: Phase 1b Part 1 Cohort 7 in MZL Experimental Treatment 1 Intervention

MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy

Group V: Phase 1b Part 1 Cohort 6 in MCL Experimental Treatment 1 Intervention

Non-blastoid MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemoimmunotherapy regimen

Group VI: Phase 1b Part 1 Cohort 5 in CLL/SLL with 2L+, prior BTKi Experimental Treatment 1 Intervention

Patients with at least 1 prior line of therapy that included a BTKi and are BCL-2i naïve.

Group VII: Phase 1b Part 1 Cohort 4 in CLL/SLL with TP53 or 17p deletion, 2L, prior BTKi Experimental Treatment 1 Intervention

Patients with documented TP53 mutation or 17p deletion and 1 prior line of therapy that included a BTKi and are BCL-2i naïve.

Group VIII: Phase 1b Part 1 Cohort 3 in CLL/SLL with prior non-covalent BTKi Experimental Treatment 1 Intervention

CLL/SLL with prior exposure to ncBTKi and are BCL-2i naïve.

Group IX: Phase 1b Part 1 Cohort 2 in CLL/SLL with non-C481S BTK mutations Experimental Treatment 1 Intervention

Prior exposure to both BTKi and BCL-2i (unless deemed ineligible for BCL-2i by Investigator at the time of study enrollment) and documented BTK mutation other than C481S within 6 months prior to study entry

Group X: Phase 1b Part 1 Cohort 17 in CLL/SLL with CNS involvement Experimental Treatment 1 Intervention

BTKi-exposed R/R CLL or SLL with CNS involvement

Group XI: Phase 1b Part 1 Cohort 16 in CLL/SLL with secondary warm autoimmune hemolytic anemia (wAIHA) Experimental Treatment 1 Intervention

BTKi-exposed R/R CLL or SLL with secondary wAIHA

Group XII: Phase 1b Part 1 Cohort 15 in BTKi-naive CLL/SLL Experimental Treatment 1 Intervention

First-line (1L) or second-line+ (2L)+ CLL/SLL with no prior exposure to a BTKi

Group XIII: Phase 1b Part 1 Cohort 14 in first-line WM Experimental Treatment 1 Intervention

Treatment-naïve WM deemed unfit for chemoimmunotherapy

Group XIV: Phase 1b Part 1 Cohort 13 in PCNSL Experimental Treatment 1 Intervention

PCNSL following upfront therapy and with no prior exposure to a BTKi (2L).

Group XV: Phase 1b Part 1 Cohort 12 in PCNSL/SCNSL Experimental Treatment 1 Intervention

PCNSL following at least 1 prior line of therapy that included a BTKi (2L+) or following 2 or more prior lines of therapy (3L+), or SCNSL patients meeting criteria for a non-CLL/SLL cohort enrolling that disease with secondary CNS involvement of lymphoma

Group XVI: Phase 1b Part 1 Cohort 11 in FL Experimental Treatment 1 Intervention

FL (grade 1-3a) with prior exposure to an anti-CD20 mAb-based chemoimmunotherapy regimen and an additional line of therapy

Group XVII: Phase 1b Part 1 Cohort 10 in DLBCL Experimental Treatment 1 Intervention

DLBCL which transformed from indolent lymphoma or Richters transformation with prior exposure to an anthracycline (unless previously deemed ineligible to receive), an anti-CD20 mAb-based chemoimmunotherapy regimen, and an additional line of therapy

Group XVIII: Phase 1b Part 1 Cohort 1 in CLL or SLL with prior BTKi and BCL2i Experimental Treatment 1 Intervention

CLL or SLL with prior exposure to both a Bruton's tyrosine kinase inhibitor (BTKi) and BCL-2 inhibitor, unless previously deemed ineligible for a BCL-2i. Patients enrolled in CLL/SLL arm will be randomized to one of two dose levels.

Group XIX: Phase 1a Dose Escalation Experimental Treatment 1 Intervention

Multiple dose levels of NX-5948 to be evaluated; determination of Maximum Tolerated Dose/Phase 1b recommended dose(s)

Who Is Running the Clinical Trial?

Nurix Therapeutics, Inc.

Lead Sponsor

Trials

7

Recruited

1,100+

Findings from Research

Inhibiting the B-cell receptor (BCR) signaling pathway, which is crucial for the growth and survival of B cells, can be a promising strategy for treating both indolent and aggressive B-cell lymphomas.

Early clinical results suggest that compounds targeting key components of the BCR pathway, such as spleen tyrosine kinase and Bruton's tyrosine kinase, show potential in improving treatment outcomes for patients with B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibitors of B-cell receptor signaling for patients with B-cell malignancies. Choi, MY., Kipps, TJ.[2021]

Mantle cell lymphoma (MCL) is a challenging type of non-Hodgkin lymphoma with a rising incidence and often leads to rapid relapse after initial treatment, highlighting the need for effective management strategies for relapsed/refractory (R/R) cases.

Recent advancements, particularly the introduction of Bruton's tyrosine kinase (BTK) inhibitors, have significantly changed treatment approaches for R/R MCL, but resistance to these therapies is common, prompting research into novel agents and combination strategies to improve treatment durability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review. Al-Mansour, M.[2022]

Mantle cell lymphoma (MCL) has seen an improvement in overall survival rates over the past 30 years, now averaging 4-5 years, but patients often relapse and become resistant to chemotherapy, leading to poor outcomes.

Novel treatment options, including various cytotoxics, biologicals, and small molecules like bortezomib and temsirolimus, are being explored to improve survival rates and manage MCL more effectively, particularly in combination therapies and maintenance strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mantle cell lymphoma: the promise of new treatment options. Goy, A., Kahl, B.[2022]

Ibrutinib and idelalisib, both targeting the B-cell receptor pathway, have shown success in treating relapsed or refractory non-Hodgkin's lymphoma, leading to the development of new agents and combination therapies.

The review highlights the importance of understanding the toxicities and resistance mechanisms associated with BCR inhibitors, which is crucial for optimizing their use in future treatments for specific subtypes of NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

B-cell receptor pathway modulators in NHL. Blum, KA.[2018]

A study of over 100 hematological cell line models revealed that certain mantle cell lymphoma (MCL) cell lines are highly sensitive to B cell receptor (BCR) signaling inhibitors like ibrutinib and sotrastaurin, linked to chronic activation of the classical NF-κB pathway.

In contrast, MCL cell lines that are insensitive to these inhibitors often have genetic mutations affecting the alternative NF-κB pathway, suggesting that targeting the protein kinase NIK could be a promising new treatment strategy for patients with refractory MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. Rahal, R., Frick, M., Romero, R., et al.[2023]

In a study of 465 patients with diffuse large B-cell lymphoma, nuclear expression of the NF-κB subunit p50 was found to be an independent adverse prognostic factor, particularly in the activated B-cell-like subtype, indicating its potential role in poor patient outcomes.

Interestingly, in patients with TP53 mutations, p50 nuclear expression was associated with better clinical outcomes, suggesting that p50 may have a complex role in lymphoma biology and could influence treatment resistance, especially in the context of R-CHOP therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NF-κB p50 activation associated with immune dysregulation confers poorer survival for diffuse large B-cell lymphoma patients with wild-type p53. Cai, Q., Tu, M., Xu-Monette, ZY., et al.[2023]

SHC014748M, a selective inhibitor of PI3Kδ, demonstrated significant antitumor activity in both in vitro and in vivo studies, effectively targeting B-cell lymphomas and chronic lymphocytic leukemia (CLL).

The compound showed high selectivity for PI3Kδ over other class I PI3K enzymes and successfully inhibited downstream signaling pathways, leading to reduced lymphoma cell growth in treated mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia. Fan, L., Wang, C., Zhao, L., et al.[2021]

INCB040093 is a novel small-molecule inhibitor of PI3Kδ that shows strong selectivity and efficacy in inhibiting B cell functions, making it a promising candidate for treating B cell malignancies like Hodgkin's lymphoma.

In preclinical studies, INCB040093 not only inhibited tumor growth in models of non-Hodgkin's lymphoma but also enhanced the effectiveness of the chemotherapy drug bendamustine, indicating its potential as a valuable addition to cancer treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies. Shin, N., Li, YL., Mei, S., et al.[2019]

In a study involving six healthy Chinese male subjects, the novel PI3Kδ inhibitor SHC014748M showed a median time to peak concentration (Tmax) of 1.6 hours and was primarily eliminated through fecal excretion, accounting for about 90.68% of the administered dose.

The main metabolic pathways for SHC014748M included monooxidation and glucuronide conjugation, with unchanged SHC014748M being the primary component found in plasma after oral administration, indicating effective absorption and metabolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [14C] SHC014748M in healthy Chinese subjects following oral administration. Guo, F., Liu, B., Li, X., et al.[2023]

The PI3K inhibitor LY294002 effectively reduced phospho-AKT levels in three diffuse large B cell lymphoma (DLBCL) cell lines, indicating its role in targeting the AKT signaling pathway.

When used sequentially with doxorubicin, LY294002 significantly increased apoptosis rates in DLBCL cells, suggesting it could enhance the effectiveness of doxorubicin as a treatment for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Study on PI3K inhibitor LY294002 for chemotherapeutic sensitization in diffuse large B cell lymphoma cell lines]. Zhang, TC., Chu, HJ., Zhao, JQ., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Inhibitors of B-cell receptor signaling for patients with B-cell malignancies. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Mantle cell lymphoma: the promise of new treatment options. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

B-cell receptor pathway modulators in NHL. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

NF-κB p50 activation associated with immune dysregulation confers poorer survival for diffuse large B-cell lymphoma patients with wild-type p53. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

SHC014748M, a novel selective inhi-bitor of PI3Kδ, demonstrates promising preclinical antitumor activity in B cell lymphomas and chronic lymphocytic leukemia. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies. [2019]

9. Germany pubmed.ncbi.nlm.nih.gov

Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [14C] SHC014748M in healthy Chinese subjects following oral administration. [2023]

10. China pubmed.ncbi.nlm.nih.gov

[Study on PI3K inhibitor LY294002 for chemotherapeutic sensitization in diffuse large B cell lymphoma cell lines]. [2019]