NX-5948 for B-cell Cancer

Recruiting in Palo Alto (17 mi)

+47 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Nurix Therapeutics, Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Prolymphocytic leukemia, Richter's transformation, others

No Placebo Group

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.

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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.

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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.

Trial 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

Participant Groups

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.

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 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 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 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 13 in PCNSL Experimental Treatment 1 Intervention

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

Group XI: 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 cohort enrolling that disease with secondary CNS involvement of lymphoma

Group XII: 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 XIII: 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 XIV: 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 XV: 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)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Cleveland Clinic Cleveland, OH

Colorado Blood Cancer Institute Denver, CO

Florida Cancer Specialists Sarasota, FL

National Institute of Health Bethesda, MD

More Trial Locations

Who Is Running the Clinical Trial?

Nurix Therapeutics, Inc. Lead Sponsor

References

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

Inhibitors of B-cell receptor signaling for patients with B-cell malignancies. [2021] The B-cell receptor (BCR) complex and its associated protein tyrosine kinases play a critical role in the development, proliferation, and survival of normal or malignant B cells. Regulated activity of the BCR complex promotes the expansion of selected B cells and the deletion of unwanted or self-reactive ones. Compounds that inhibit various components of this pathway, including spleen tyrosine kinase, Bruton's tyrosine kinase, and phosphoinositol-3 kinase, have been developed. We summarize the rationale for use of agents that can inhibit BCR signaling to treat patients with either indolent or aggressive B-cell lymphomas, highlight early clinical results, and speculate on the future application of such agents in the treatment of patients with various B-cell lymphomas.

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

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review. [2022] Mantle cell lymphoma (MCL) accounts for nearly 2-6% of all non-Hodgkin lymphoma (NHL) cases, with a steady incidence increase over the past few decades. Although many patients achieve an adequate response to the upfront treatment, the short duration of remission with rapid relapse is challenging during MCL management. In this regard, there is no consensus on the best treatment options for relapsed/refractory (R/R) disease, and the international guidelines demonstrate wide variations in the recommended approaches. The last decade has witnessed the introduction of new agents in the treatment landscape of R/R MCL. Since the introduction of Bruton's tyrosine kinase (BTK) inhibitors, the treatment algorithm and response of R/R MCL patients have dramatically changed. Nevertheless, BTK resistance is common, necessitating further investigations to develop novel agents with a more durable response. Novel agents targeting the B-cell receptor (BCR) signaling have exhibited clinical activity and a well-tolerable safety profile. However, as the responses to these novel agents are still modest in most clinical trials, combination strategies were investigated in pre-clinical and early clinical settings to determine whether the combination of novel agents would exhibit a better durable response than single agents. In this report, we provide an updated literature review that covers recent clinical data about the safety and efficacy of novel therapies for the management of R/R MCL.

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

Mantle cell lymphoma: the promise of new treatment options. [2022] Though the expected overall survival (OS) for mantle cell lymphoma (MCL) has doubled in the last 30 years it is still in the range of only 4-5 years. Despite high response rates with current first-line treatments, most patients eventually relapse and become typically chemoresistant, leading to very poor outcome in the relapsed setting. Here, we summarize the clinical characteristics of MCL and frontline strategies used in MCL, and review a number of novel options that are currently being investigated in an effort to extend survival outcomes for this difficult-to-treat patient population. Among these novel options figure cytotoxics (bendamustine, cladribine), new biologicals/small molecules such as proteasome inhibitors (bortezomib 1st drug approved in the USA for MCL), mTOR inhibitors with temsirolimus (1st drug approved in EU for MCL), CDK inhibitors (flavopiridol); IMiDs (thalidomide, lenalidomide); HDAC inhibitors, Bcl-2 inhibitors and second or third generation monoclonal antibodies or immunotoxins. The panel of novel drugs approved or being tested offers new opportunities in the management of MCL from combination in the frontline setting (e.g. bortezomib-R-chemo) to post-induction strategies such as consolidation (e.g. radioimmunotherapy, bortezomib) or maintenance therapy (e.g. rituximab, lenalidomide).

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

B-cell receptor pathway modulators in NHL. [2018] With the recent success of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, and the phosphoinositide-3-kinase (PI3K) inhibitor, idelalisib, in the treatment of patients with relapsed or refractory non-Hodgkin's lymphoma (NHL), a number of new agents targeting the B-cell receptor (BCR) pathway are in clinical development. In addition, multiple trials combining these agents with conventional cytotoxic chemotherapy, immunomodulatory agents, monoclonal antibodies, or other kinase inhibitors are underway. This review will summarize the current data with the use of single agent and combination therapy with BCR inhibitors in NHL. In addition, commonly encountered as well as serious toxicities and hypothesized resistance mechanisms will be discussed. Lastly, this review will examine the future of these agents and opportunities to maneuver them into the front-line setting in selected NHL subtypes.

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

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma. [2023] Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-κB (NF-κB) pathway, whereas insensitive cell lines displayed activation of the alternative NF-κB pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-κB pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-κB pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-κB or NIK-NF-κB pathways in MCL and provide critical insights into patient stratification strategies for NF-κB pathway-targeted agents.

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] Dysregulated NF-κB signaling is critical for lymphomagenesis, however, the expression and clinical relevance of NF-κB subunit p50 in diffuse large B-cell lymphoma have not been evaluated. In this study, we analyzed the prognostic significance and gene expression signatures of p50 nuclear expression as a surrogate for p50 activation in 465 patients with de novo diffuse large B-cell lymphoma. We found that p50+ nuclear expression, observed in 34.6% of diffuse large B-cell lymphoma, predominantly composed of activated B-cell-like subtype, was an independent adverse prognostic factor in patients with activated B-cell-like diffuse large B-cell lymphoma. It was also an adverse prognostic factor in patients with wild-type TP53 independent of the activated B-cell-like and germinal center B-cell-like subtypes, even though p50 activation correlated with significantly lower levels of Myc, PI3K, phospho-AKT, and CXCR4 expression and less frequent BCL2 translocations. In contrast, in germinal center B-cell-like diffuse large B-cell lymphoma patients with TP53 mutations, p50+ nuclear expression correlated with significantly better clinical outcomes, and decreased p53, Bcl-2, and Myc expression. Gene expression profiling revealed multiple signaling pathways potentially upstream the p50 activation through either canonical or noncanonical NF-κB pathways, and suggested that immune suppression, including that by the immune checkpoint TIM-3 and that through leukocyte immunoglobulin-like receptors, but not antiapoptosis and proliferation, may underlie the observed poorer survival rates associated with p50+ nuclear expression in diffuse large B-cell lymphoma. In conclusion, these data show that p50 is important as a unique mechanism of R-CHOP-resistance in activated B-cell-like diffuse large B-cell lymphoma and in patients without TP53 mutations. The results also provide insights into the regulation and function of p50 in diffuse large B-cell lymphoma and its cross talk with the p53 pathway with important therapeutic implications.

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] PI3Kδ (phosphatidylinositol 3-kinase-δ), one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. This provides a rationale for the development of small molecule inhibitors that selectively target p110δ for patients with indolent non-Hodgkin lymphomas. Here in this paper, we comprehensively evaluated the in vitro and in vivo antitumor activity of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary chronic lymphocytic leukemia (CLL) cells. Scid mice were subcutaneously inoculated with the SU-DHL-6 cell line. SHC014748M was more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines and primary CLL cells. SHC014748M also inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in both lymphoma cells and primary CLL cells. In vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 in patient serum decreased sharply after SHC014748M treatment. According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL.

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

INCB040093 Is a Novel PI3Kδ Inhibitor for the Treatment of B Cell Lymphoid Malignancies. [2019] Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin's lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1β (MIP-1beta) and tumor necrosis factor-β (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin's lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.

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] Label="PURPOSE">SHC014748M is a potent, novel selective PI3Kδ isoform inhibitor and is proposed for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. This study investigated the pharmacokinetics, mass balance, metabolism and excretion of SHC014748M in Chinese male subjects following a single oral dose of 150 mg (100 μCi) [14C] SHC014748M.

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

[Study on PI3K inhibitor LY294002 for chemotherapeutic sensitization in diffuse large B cell lymphoma cell lines]. [2019] To investigate the effects on chemotherapeutic sensitization of the PI3K inhibitor LY294002 in diffuse large B cell Lymphoma (DLBCL) cell lines ly1, ly8, ly10.