BTM-3566 for B-Cell Lymphoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Bantam Pharmaceuticals
Disqualifiers: Primary CNS lymphoma, Neurologic disease, Second malignancy, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The goal of this clinical trial is to learn if BMT-3566 can safety be given to adult patients with relapsed or refractory mature b cell lymphomas. It will also learn how well BTM-3566 works to treat relapsed or refractory mature b cell lymphomas. The main questions it aims to answer are:
What are the side effects of BTM-3566 at different doses? What are the levels of BTM-3566 in the blood at different timepoints around dosing? What is the clinical benefit of BTM-3566 in treating cancer (i.e. how well does it slow or stop disease progression)?
Participants will:
Take BTM-3566 in 14-day periods with 7 days of dosing followed by 7 days of no dosing Visit the clinic regularly for checkups and tests Keep a diary of their dosing and weight
Do I need to stop my current medications to join the trial?
The trial information does not specify if you need to stop taking your current medications. However, it does mention that you cannot have received any anti-cancer therapy within 28 days before starting the trial.
What safety data exists for BTM-3566 or similar treatments in humans?
Bruton's tyrosine kinase inhibitors, similar to BTM-3566, have been studied for safety in B-cell malignancies. New-generation inhibitors show fewer heart-related side effects but more blood and stomach issues compared to older ones. In a trial with a similar drug, M7583, common side effects included diarrhea, fatigue, and vomiting, but no severe dose-limiting toxicities were reported.
12345How is the drug BTM-3566 different from other treatments for B-cell lymphoma?
BTM-3566 is unique because it targets the BCL6 protein, which is crucial for the survival of certain B-cell lymphomas. This approach is different from conventional treatments as it specifically inhibits BCL6, a protein involved in the development and maintenance of these cancer cells, offering a new strategy for treating lymphomas that rely on BCL6 for growth.
678910Eligibility Criteria
Adults over 18 with relapsed or refractory mature B cell lymphoma can join this trial. They should have measurable disease, be able to perform daily activities (ECOG PS 0-2), and likely live at least another 3 months. Participants must use birth control during the study and for 90 days after.Inclusion Criteria
I am 18 years old or older.
Must have measurable disease per response evaluation criteria in lymphoma (Lugano classification)
Must have a predicted life expectancy of ≥3 months
+3 more
Exclusion Criteria
Is pregnant or breastfeeding
I have been diagnosed with lymphoma in my brain or spinal cord.
I have side effects from cancer treatment that are mild or worse.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-3 weeks
Treatment
Participants receive BTM-3566 in 14-day cycles with 7 days of dosing followed by 7 days off
24 months
Regular clinic visits for checkups and tests
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 months
Imaging every 3 months, then every 6 months
Participant Groups
The trial is testing BTM-3566's safety and effectiveness in treating mature B cell lymphomas that have come back or didn't respond to treatment. It involves taking the drug for a week, then pausing for a week, while attending regular clinic visits and tracking dosing.
1Treatment groups
Experimental Treatment
Group I: BTM-3566 TreatmentExperimental Treatment1 Intervention
BTM-3566 Oral Solution
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
MD Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
Bantam PharmaceuticalsLead Sponsor
References
The safety of Bruton's tyrosine kinase inhibitors in B-cell malignancies: A systematic review. [2022]B-cell malignancies, most notably lymphomas, make up most of the non-Hodgkin lymphomas in the United States. There are limited randomized data comparing first- and second-generation Bruton tyrosine kinase (BTK) inhibitors. Our aim was to compare the safety profiles of first versus second-generation BTK inhibitors. A systematic search was performed from database inception to January 13, 2020. Studies with BTK inhibitor monotherapy for the treatment of B-cell malignancies in the adult population (>18 years old) were utilized and the adverse events (AEs) were extracted. Fifty-five studies that met the inclusion criteria were included in the systematic review with 41 studies with first generation and 14 studies with second generation. The review included both clinical trials and retrospective studies with average time of follow-up of 2 years for the first-generation group and 18 months for the second-generation group. We found that the incidence of cardiovascular AEs was significantly higher in the first-generation group (20.8%) as compared to the second-generation group (6.3%). However, there was a higher incidence of hematologic/oncologic and gastrointestinal side effects in the second-generation group compared to the first (62.3% compared to 39.2% and 36.9% compared to 28.9%). The number of Grade 5 cardiovascular events (death) was same in the first-generation group compared to the second generation. Further research is needed to develop highly selective BTK inhibitors to avoid unwanted AEs by minimizing off-targets.
[Clinical features and prognosis of children with lymphoblastic lymphoma]. [2018]To evaluate the clinical characteristics of childhood lymphoblastic lymphoma (LBL) and therapeutic efficacy of BCH-LBL-2003 regimen modified from BFM-90 protocol. The drug-related toxicities and prognostic factors were explored at the same time.
Improved treatment outcome in Chinese children and adolescents with Burkitt's lymphoma and large cell lymphoma by using the modified B-non-Hodgkin's lymphoma-Berlin-Frankfurt-Münster-90 protocol. [2015]This study was designed to evaluate the efficacy and toxicity of the modified B-Non-Hodgkin's Lymphoma (NHL)-Berlin-Frankfurt-Münster (BFM)-90-based protocol in Chinese children and adolescents with Burkitt's lymphoma and large cell lymphoma.
Efficacy and safety of new-generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and meta-analysis. [2023]Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a type of mature B lymphocyte clonal proliferative tumor with a specific immunophenotype. Bruton tyrosine kinase inhibitors (BTKi) have been approved for the treatment of CLL/SLL. However, the efficacy and safety of new-generation BTKi-based regimens have not been systematically studied. In this systematic review, we evaluated the efficacy and safety of new-generation BTKi-based regimens for the treatment of patients with CLL/SLL. A comprehensive search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. up to January 31, 2023, was conducted by us. Studies reporting data on CLL/SLL patients treated with new-generation BTKi were included. We assessed the overall response rate (ORR), complete response (CR) rate, and 24-month OS/PFS rates for efficacy analysis. For safety analysis, we evaluated the incidence of grade ≥ 3 adverse events (AEs). The meta-analysis included twenty studies. The pooled ORR for new-generation BTKi was 92% (95% CI, 89-95%, I2 = 80.68%, P = 0.00), while the pooled CR rate was 10% (95% CI, 6-14%, I2 = 88.11%, P = 0.00). Research has found that the new-generation BTKi-based therapy had higher efficacy under the following treatment conditions: < 65 years old, treatment-naive (TN)-CLL, and BTKi combination therapy. The ORR/CR rates and 24-month OS/PFS rates of BTKi combination therapy were higher than that of BTKi monotherapy. Compared to acalabrutinib monotherapy, zanubrutinib monotherapy demonstrated higher ORR/CR rates and 24-month OS/PFS rates. Common grade ≥ 3 AEs included cytopenia and hypertension. The new-generation BTKi-based therapy has good tolerance and provides incremental benefits for CLL/SLL patients. Despite the superior efficacy of BTKi combination therapy compared to monotherapy, its AEs rates are relatively high. Compared to acalabrutinib, Zanubrutinib may be the preferred monotherapy for CLL. However, randomized-controlled studies are still needed.
Phase I, first-in-human trial of Bruton's tyrosine kinase inhibitor M7583 in patients with B-cell malignancies. [2021]M7583 is a potent, highly selective, covalent BTK inhibitor in development. In this phase I, first-in-human, open label, multicenter dose-escalation trial, M7583 was given at 80 mg (three days)/160 mg (full 28-day cycle), then 300 mg/day, 600 mg/day, 900 mg/day, and 300 mg twice daily to 18 patients (median age 63 years) with refractory/resistant, stage III/IV B-cell malignancies who failed prior therapy (NCT02825836). No dose-limiting toxicities were reported. Treatment-emergent adverse events (AEs) occurred in 89% of patients, treatment-related AEs in 78%, and treatment-related grade ≥3 AEs in 17%. Common AEs were diarrhea (33%), fatigue (22%), and vomiting (17%). M7583 was rapidly absorbed and exposure was dose-proportional. BTK occupancy was >95% in the 300 mg twice daily and 900 mg/day cohorts. Objective response rate was 50% and disease control rate 78%, supporting a favorable benefit:risk profile. Fasted doses up to 900 mg once daily and 300 mg twice daily were well tolerated and may be tested in future clinical studies.
BCL6 as a therapeutic target for lymphoma. [2018]B cell lymphoma 6 (BCL6) is a transcriptional repressor critical for the development and maintenance of germinal centers (GCs), which are required for generation of an effective humoral immune response. Genomic aberrations of BCL6, including mutations and translocations that occur during the GC reaction, as well as alterations of genes that regulate BCL6 expression, lead to sustained activity of BCL6, which promotes the development of GC-derived lymphomas. Since many types of B cell non-Hodgkin lymphomas (B-NHL) arise from neoplastic transformation of GC B cells and a high proportion harbor genetic lesions that deregulate BCL6 expression, inhibition of BCL6 has emerged as an attractive therapeutic strategy for lymphomas. Areas covered: This review examines the rationale for and challenges in therapeutic targeting of BCL6 in lymphomas. We describe approaches that have been used and are currently being considered for inhibition of BCL6. Expert opinion: Several BCL6 inhibiting agents, including peptidomimetics, small molecules, and natural compounds, most of which target the BTB domain of the protein at the corepressor binding site, have been developed with demonstration of anti-lymphoma activity in preclinical models. Future clinical trials will be important to investigate the efficacy of targeting BCL6 in B-NHL (and other neoplasms), particularly in combination with other therapies.
The role of BCL6 in lymphomas and routes to therapy. [2016]BCL6 is a transcription factor that has essential B-cell and T-cell roles in normal antibody responses. It is involved in chromosomal translocations in diffuse large B-cell lymphoma (DBCL; including primary mediastinal B-cell lymphoma) and nodular lymphocyte predominant Hodgkin lymphoma, and is expressed in follicular lymphoma and Burkitt's lymphoma. The neoplastic T-cells of angioimmunoblastic T-cell lymphoma also express BCL6. BCL6 prevents terminal B-cell differentiation largely through repression of PRDM1. In the "cell of origin" classification of DLBCL BCL6 is associated with the germinal centre subtype, which carries a good response to modern treatments. More recently, specific BCL6 antagonists, including small molecule inhibitors, have been developed. These antagonists have demonstrated that DLBCL cells, in which BCL6 is transcriptionally active, are dependent on this gene for survival. BCL6 antagonists are active against primary DLBCL and may find future application in the treatment of lymphomas.
Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin's lymphoma. [2021]The pathogenesis of non-Hodgkin's lymphoma (NHL) with a large cell component (DLLC, including diffuse large cell, DLCL; diffuse mixed cell, MX-D; and immunoblastic, IMB) is unknown. A novel candidate proto-oncogene, BCL6, that is involved in chromosome band 3q27 aberrations in NHL has been recently identified. We have investigated the incidence and disease-specificity of BCL6 rearrangements in a large panel of lymphoid tumors, including acute and chronic lymphoid leukemias (96 cases), various NHL types (125 cases), and multiple myelomas (23 cases). BCL6 rearrangements were found in 16/45 (35.5%) DLLC, more frequently in DLCL (15/33, 45%) than in MX-D (1/10, 10%), in 2/31 (6.4%) follicular NHL, and in no other tumor types. BCL6 rearrangements represent the first genetic lesion specifically and recurrently associated with DLLC and should prove useful for understanding the pathogenesis as well as for the clinical monitoring of these tumors.
DSF/Cu induces antitumor effect against diffuse large B-cell lymphoma through suppressing NF-κB/BCL6 pathways. [2022]The B-cell lymphoma 6 (BCL6) oncogene is required for the survival of diffuse large B-cell lymphoma (DLBCL), which is incurable using conventional chemotherapy. Thus, it is imperative to improve the survival of patients with DLBCL. Disulfide (DSF) has been shown to have anticancer effects, but its effect on DLBCL remains unclear.
Molecular features of a new human lymphoma cell line carrying both BCL2 and BCL6 gene rearrangements. [2015]Chromosomal translocations and/or their molecular equivalents involving the BCL6 gene on 3q27 band have been suggested to be involved in the development of non-Hodgkin's lymphoma of B-cell type (B-NHL). The rearrangement of BCL6 sometimes coexists with other translocations specific to B-NHL. Here, we report a novel B-cell lymphoma cell line, YM, established from a patient with diffuse large cell lymphoma. The YM cells expressed B-cell-associated antigens in addition to mu delta/kappa monoclonal immunoglobulin. Southern blot analysis of DNA from YM cells demonstrated rearrangement of the BCL2 gene within the 5' flanking region (5'-BCL2). Polymerase chain reaction (PCR) using primer pairs for the BCL2 exons 1 and 2, and for the constant region of the immunoglobulin kappa light chain gene (IGkappa) revealed PCR products encompassing the 5'-BCL2/IGkappa fusion, indicating that the YM cells had a t(2;18)(p11;q21) translocation. The BCL6 gene was rearranged at a point within the first intron, and cloning of the rearranged BCL6 revealed unidentified sequences juxtaposed to the 5' side of the gene. The isolated clones were mapped to 16p11.2 by high resolution fluorescence in situ chromosomal hybridization. Thus, the YM cells carried a 3q27 translocation involving 16p11.2 as a partner. Chromosome painting of metaphase spreads confirmed that the YM cells had both t(2;18) and t(3;16). Northern blot analysis using a fragment immediately adjacent to the breakpoint on 16p11.2 revealed transcriptional activity within this locus. The YM cells expressed abundant transcripts with aberrant sizes from BCL2 and BCL6, indicating deregulated overexpression of the two genes resulting from the t(2;18) and t(3;16). The YM cell line will therefore be useful to study whether BCL2 and BCL6 genes collaborate in the pathogenesis of B-NHL.