NX-2127 for B-cell Malignancies
Recruiting in Palo Alto (17 mi)
+7 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: Warfarin, Corticosteroids, Immunosuppressives, others
Disqualifiers: Autoimmune disease, Active liver disease, 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 oncology study designed to evaluate the safety and anti-cancer activity of NX-2127 in patients with advanced B-cell malignancies.
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications before starting, such as strong CYP3A inducers or inhibitors, P-glycoprotein inhibitors, and non-steroidal immunosuppressive drugs. If you are on warfarin or similar medications, you must stop them 7 days before the trial. Please consult with the trial team for specific guidance on your medications.
What data supports the effectiveness of the drug NX-2127 for B-cell malignancies?
Research on similar treatments shows that targeting specific pathways in B-cell malignancies, like the B-cell receptor signaling pathway, has been promising. Drugs targeting these pathways have shown activity in various types of lymphoma and leukemia, suggesting potential effectiveness for NX-2127.
12345How is the drug NX-2127 different from other treatments for B-cell malignancies?
NX-2127 is unique because it represents a shift from traditional chemotherapy to more selective agents that target specific cellular pathways involved in B-cell malignancies. This approach focuses on disrupting key pathways that drive cancer cell growth and survival, potentially offering more effective and targeted treatment options.
12467Eligibility Criteria
Adults with certain types of blood cancer who've had at least two prior treatments (or one for specific conditions) can join this trial. They must be over 18, not pregnant, and have a good performance status. People with uncontrolled diseases, recent major surgery or radiation, active infections like HIV or hepatitis, or autoimmune diseases aren't eligible.Inclusion Criteria
I am fully active or restricted in physically strenuous activity but can do light work.
My cancer is a confirmed type of blood or lymphatic system cancer.
Patients of child-bearing potential must use adequate contraceptive measures to avoid pregnancy for the duration of the study as defined in the protocol
+8 more
Exclusion Criteria
I have an active autoimmune condition affecting my blood.
I haven't taken strong medication affecting liver enzymes or certain drug transporters in the last 2 weeks.
I haven't had radiotherapy in the last 2 weeks, except for palliative care.
+14 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Phase 1a Dose Escalation
Evaluate the safety and tolerability of NX-2127 in adult patients with relapsed/refractory B-cell malignancies
Up to 24 months
Phase 1b Dose Optimization
Further investigate the safety, tolerability, and preliminary efficacy of NX-2127 in R/R B-cell malignancies
Up to 4 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 5 years
Participant Groups
The study is testing NX-2127's safety and effectiveness against advanced B-cell malignancies. It's an early-stage trial where all participants receive the same experimental drug to see how well it works and what side effects it may cause.
11Treatment groups
Experimental Treatment
Group I: Phase 1b Dose Optimization Stage 2 in PCNSL (Randomized to Dose A or Dose B)Experimental Treatment1 Intervention
PCNSL patients whose disease has failed at least 1 prior line of treatment
Group II: Phase 1b Dose Optimization Stage 2 in MCL (Randomized to Dose A or Dose B)Experimental Treatment1 Intervention
MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen
Group III: Phase 1b Dose Optimization Stage 2 in FL, MZL or WM (Randomized to Dose A or Dose B)Experimental Treatment1 Intervention
FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTK inhibitor
Group IV: Phase 1b Dose Optimization Stage 2 in DLBCL (Randomized to Dose A or Dose B)Experimental Treatment1 Intervention
DLBCL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen and either: an anthracycline-based regimen; or an anti-CD19-based regimen; or another/palliative regimen
Group V: Phase 1b Dose Optimization Stage 2 in CLL or SLL (Randomized to Dose A or Dose B)Experimental Treatment1 Intervention
CLL/SLL patients whose disease has failed treatment with a BTK inhibitor
Group VI: Phase 1b Dose Optimization Stage 1 in PCNSL (Dose A)Experimental Treatment1 Intervention
PCNSL patients whose disease has failed at least 1 prior line of treatment
Group VII: Phase 1b Dose Optimization Stage 1 in MCL (Dose A)Experimental Treatment1 Intervention
MCL patients whose disease has failed treatment with a BTK inhibitor and an anti-CD20 monoclonal antibody (mAb) based regimen
Group VIII: Phase 1b Dose Optimization Stage 1 in FL, MZL or WM (Dose A)Experimental Treatment1 Intervention
FL or MZL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTK inhibitor
Group IX: Phase 1b Dose Optimization Stage 1 in DLBCL (Dose A)Experimental Treatment1 Intervention
DLBCL patients whose disease has failed treatment with an anti-CD20 mAb-based regimen and either: an anthracycline-based regimen; or an anti-CD19-based regimen; or another/palliative regimen
Group X: Phase 1b Dose Optimization Stage 1 in CLL or SLL (Dose A)Experimental Treatment1 Intervention
CLL/SLL patients whose disease has failed treatment with a BTK inhibitor
Group XI: Phase 1a Dose EscalationExperimental Treatment1 Intervention
Multiple dose levels of NX-2127 to be evaluated; determination of MTD/Phase 1b recommended dose
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sarah Cannon Research Institute at Tennessee OncologyNashville, TN
Tennessee OncologyNashville, TN
Huntsman Cancer Institute, University of UtahSalt Lake City, UT
MD Anderson Cancer CenterHouston, TX
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Nurix Therapeutics, Inc.Lead Sponsor
References
[Clinical observation on 112 cases with non-Hodgkin's lymphoma treated by Chinese herbs combined with chemotherapy]. [2016]To seek for the effective therapeutical method in treating non-Hodgkin's lymphoma (NHL).
Developing novel strategies to target B-cell malignancies. [2021]In the past several years we have seen the identification and validation of several key pathways that drive malignant B-cell development. In addition, the effect nonmalignant effector cells within the immune microenvironment have on tumor survival, proliferation, and possibly chemotherapy resistance is increasingly understood. Although there is still much to be learned, this improved understanding combined with rapid advances in medicinal chemistry focusing on structure-based drug design have resulted in a shift in the development of new agents away from traditional chemotherapy to more selective agents targeting key cellular pathways. Examples of "hot" new therapeutic targets include the B-cell receptor signaling pathway, PI3K/mTOR/AKT pathway, histone deacetylases (HDAC), regulators of apoptosis such as the BCL-2 family, the proteasome, and cell-cell interactions within the tumor environment. Many drugs that target specific agents in early clinical development have demonstrated activity in various subtypes of lymphoma and leukemia. Monoclonal and conjugated antibodies targeting cell surface proteins such as CD19, CD22, CD37, and different epitopes of CD20 have also shown promise in relapsed B-cell malignancies and are rapidly moving into efficacy studies. This review will focus on a few of the new nonantibody-based targeted agents in development, their respective pathways, and their activity in various B-cell malignancies.
Rituximab in combination with CNOP chemotherapy in patients with previously untreated indolent non-Hodgkin's lymphoma. [2016]Rituximab, a chimeric monoclonal antibody, produces response rates of up to 73% in patients with previously untreated indolent non-Hodgkin's lymphoma (NHL), and has high activity when combined with chemotherapy. The purpose of this phase II study was to determine the efficacy and safety of rituximab plus cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) chemotherapy in patients with indolent NHL. In all, 42 patients (median age 67 years) with previously untreated follicular, marginal zone or small lymphocytic/lymphoplasmacytic NHL received six infusions of rituximab (375 mg/m(2)) in combination with six cycles of CNOP. The overall response rate was 90% comprising 30 complete (71%) and eight partial (19%) responses. Although patients with marginal zone lymphoma or International Prognostic Index (IPI) score 3 had lower complete response rates, no significant difference in overall response rate was observed between the histological groups (P=0.24) or between patients stratified according to IPI score (P>0.05). Median overall survival, time-to-progression and response duration had not been reached after a median 19.5-month follow-up. In all, 31 patients (74%) are currently free from progression and 38 (90%) remain alive. Treatment was well tolerated. One patient (2%) experienced grade 3/4 infusion-related toxicity; 13 (31%) grade 3/4 leukopenia and 18 (43%) grade 3/4 neutropenia. Infection was observed in nine patients: eight (19%) grade 1/2 and one (2.4%) grade 3. This study demonstrates that combining rituximab with CNOP achieves high remission rates without significant additional toxicity in patients with previously untreated indolent NHL. Further follow-up will determine response duration and survival.
Rituximab: clinical development and future directions. [2019]The availability of effective monoclonal antibodies (mAbs) has revolutionised the management of patients with B-cell malignancies. The most widely studied of these agents is rituximab (Rituxan, IDEC Pharmaceuticals, San Diego, CA), a chimeric anti-CD20 antibody. Using the standard 4-weekly administration schedule, rituximab induces responses in almost half of patients with relapsed follicular/low-grade (F/LG) non-Hodgkin's lymphoma (NHL) with complete remissions in 6%. Lower response rates (RRs) have been noted in chronic lymphocytic leukaemia (CLL) using the standard dose and schedule. The drug has been well tolerated in most patients with common adverse events including mild to moderate fevers and chills and rare occurrences of a serious syndrome related to cytokine release and rapid tumour clearance. This antibody is also active against aggressive NHL, mantle cell NHL, post-transplant lymphoproliferative disorder (PTLD), lymphoplasmacytic NHL and hairy cell leukaemia and is also being evaluated in autoimmune disorders. Combinations of rituximab with chemotherapy regimens such as CHOP (cyclophosphamide, adriamycin, vincristine, predinisone) may alter the therapeutic paradigm for these diseases. The future promise of this antibody is a foundation on which to develop new strategies to increase the cure of patients with lymphoid malignancies.
Lomustine (chloroethylnitrosourea [CCNU]), ifosfamide, bleomycin, vincristine, and cisplatin (CIBO-P) is an effective regimen for patients with poor prognostic refractory or multiple disease recurrent aggressive non-Hodgkin lymphoma. [2015]The current study was designed to assess the activity and safety of a novel combination therapy for patients with recurrent or refractory aggressive non-Hodgkin lymphoma (NHL).
New targeted therapies for malignant lymphoma based on molecular heterogeneity. [2017]Owing to tremendous advances in the understanding of mechanisms involved in the pathogenesis of malignant tumors an emerging field of novel targeted drugs has evolved within the last decade. This is of particular interest also for malignant lymphomas, constituting a heterogeneous tumor category with substantial variation in clinical outcome, ranging from indolent forms that do not require treatment over years to aggressive cases for which an immediate treatment is mandatory. The elucidation of different molecular strategies adopted by malignant cells has led to a profound profiling of tumor-specific features and consequently resulted in the development of new targeted therapies. Areas covered: A review of currently tested tailored approaches, in particular in B-cell lymphomas (B-NHL), ranging from monoclonal antibodies to inhibition of intrinsic and extrinsic effector molecules. These approaches are currently tested in several subtypes of B-NHL both in preclinical studies and in clinical trials and are summarized within this review. Expert commentary: Considering how quickly basic scientific discoveries could meanwhile be transferred to clinical trials and approvals, future perspectives for novel tailored therapeutic strategies are promising.
Therapeutic potential of SGN-CD19B, a PBD-based anti-CD19 drug conjugate, for treatment of B-cell malignancies. [2021]Patients with relapsed/refractory B-cell malignancies such as non-Hodgkin lymphoma (B-NHL) or acute lymphoblastic leukemia have a poor prognosis. Despite measurable clinical activity with new targeted therapies, many patients do not achieve a complete or durable response suggesting an opportunity to improve upon existing therapies. Here we describe SGN-CD19B, a pyrrolobenzodiazepine (PBD)-based anti-CD19 antibody drug conjugate (ADC) being investigated for treatment of B-cell malignancies, which has improved potency compared with other ADCs. CD19-expressing tumor cells rapidly internalize SGN-CD19B, and the released PBD drug induces DNA damage, resulting in G2/M cell cycle arrest and cell death. SGN-CD19B demonstrated activity against a broad panel of malignant B-cell lines and induced durable regressions in mice bearing xenografts derived from these B-cell malignancies. A single dose of SGN-CD19B induced durable regressions at 300 μg/kg (3 μg/kg drug equivalents); combination with rituximab decreased the curative dose to 100 μg/kg (1 μg/kg drug equivalents). These doses are significantly lower than the level of drug required with other ADC payloads. In cynomolgus monkeys, SGN-CD19B effectively depleted CD20+ B lymphocytes in peripheral blood and lymphoid tissues confirming that SGN-CD19B is pharmacodynamically active at well-tolerated doses. In summary, preclinical studies show SGN-CD19B is a highly active ADC, which releases a DNA cross-linking agent rather than a microtubule inhibitor. The distinct mechanism of action, broad potency, and potential to combine with rituximab suggest that SGN-CD19B may offer unique clinical opportunities in B-cell malignancies. A phase 1 clinical trial is in progress to investigate the therapeutic potential of SGN-CD19B in relapsed/refractory B-NHL. This trial was registered at www.clinicaltrials.gov as #NCT02702141.