BH-30236 for Acute Myeloid Leukemia and Myelodysplastic Syndrome
Recruiting in Palo Alto (17 mi)
+8 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: BlossomHill Therapeutics
Must not be taking: CLK inhibitors
Disqualifiers: Acute promyelocytic leukemia, others
No Placebo Group
Trial Summary
What is the purpose of this trial?Study BH-30236-01 is a first-in-human (FIH), Phase 1/1b, open-label, dose escalation and expansion study in participants with relapsed/refractory acute myelogenous leukemia (R/R AML) or higher-risk myelodysplastic syndrome (HR-MDS).
Phase 1 (Dose Escalation) will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of BH-30236 administered orally. Approximately 50 participants may be enrolled in Phase 1 of the study.
Phase 1b (Dose Expansion) will follow Phase 1 to further understand the relationships among dose, exposure, toxicity, tolerability, and clinical activity. Up to 24 participants may be enrolled in Phase 1b of the study.
The dose expansion part (Phase 1b) will be followed to understand the relationships among dose, exposure, toxicity, tolerability and clinical activity. Up to 24 participants may be enrolled in Phase 1b of the study.
Do I have to stop taking my current medications for this trial?
The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that you cannot have unresolved adverse effects from prior therapies or require systemic therapy for graft versus host disease within 4 weeks before starting the study drug. It's best to discuss your specific medications with the trial team.
What data supports the idea that the drug BH-30236 for Acute Myeloid Leukemia and Myelodysplastic Syndrome is an effective treatment?
The available research does not provide specific data on the effectiveness of BH-30236 for Acute Myeloid Leukemia and Myelodysplastic Syndrome. Instead, it discusses other drugs and therapies for these conditions, such as venetoclax, midostaurin, and gilteritinib, which have been approved for use. These alternatives have shown effectiveness in treating Acute Myeloid Leukemia by targeting specific genetic mutations or proteins in cancer cells. However, there is no direct mention of BH-30236 in the context of these conditions.
12345What safety data is available for BH-30236 in AML and MDS treatment?
The provided research does not contain specific safety data for BH-30236 in the treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The studies mention BH3 mimetics and other treatments but do not directly address BH-30236. Further investigation into clinical trial databases or specific studies on BH-30236 would be necessary to find relevant safety data.
13678Is the drug BH-30236 a promising treatment for Acute Myeloid Leukemia and Myelodysplastic Syndrome?
The drug BH-30236, also known as a BH3 mimetic, is promising because similar drugs have shown potential in targeting cancer cells by promoting cell death in leukemia. This approach could improve treatment outcomes for patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome.
19101112Eligibility Criteria
This trial is for people who have acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) that has come back or didn't respond to treatment. The study will involve about 74 participants in total.Inclusion Criteria
I can take care of myself but might not be able to do heavy physical work.
I am 18 years old or older.
I have relapsed AML or high-risk MDS with more than 5% bone marrow blasts.
+2 more
Exclusion Criteria
I have been treated with a CLK inhibitor before.
I have no other active cancers, with some exceptions.
I haven't needed strong medication for graft versus host disease in the last 4 weeks.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Participants receive ascending doses of BH-30236 to evaluate safety, tolerability, and determine the recommended dose for expansion
28 days per cycle
Multiple visits per cycle for dose administration and monitoring
Dose Expansion
Participants receive BH-30236 at selected recommended doses to further evaluate safety and anti-leukemic activity
28 days per cycle, up to 1 year
Regular visits for dose administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing BH-30236, a new oral medication. It's divided into two phases: Phase 1 tests safety and how the body reacts to different doses, while Phase 1b looks at how well it works and its effects at specific doses.
2Treatment groups
Experimental Treatment
Group I: Dose Expansion CohortExperimental Treatment1 Intervention
BH-30236 administered at a dose(s) determined form the data of dose escalation cohort
Group II: Dose Escalation CohortExperimental Treatment1 Intervention
BH-30236 monotherapy for Dose Escalation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Sarah Cannon Research InstituteNashville, TN
Memorial Sloan Kettering Cancer CenterNew York, NY
University of California Los AngelesLos Angeles, CA
Stanford Cancer CenterPalo Alto, CA
More Trial Locations
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Who Is Running the Clinical Trial?
BlossomHill TherapeuticsLead Sponsor
References
ABT-737, Synergistically Enhances Daunorubicin-Mediated Apoptosis in Acute Myeloid Leukemia Cell Lines. [2021]Intensive chemotherapy with daunorubicin (DNR) is associated with serious side effects in acute myeloid leukemia (AML) patients. In this study the effect of small-molecule BH3-mimetic, ABT-737, on the sensitivity of HL60 and U937 AML cell lines was investigated.
Harnessing the benefits of available targeted therapies in acute myeloid leukaemia. [2022]Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value. In this Review, we discuss ongoing research into combinations containing these commercially available targeted therapies for acute myeloid leukaemia.
Novel Therapeutics in Acute Myeloid Leukemia. [2022]In this review, we focus on three key areas in acute myeloid leukemia (AML) developmental therapeutics: FLT3 inhibitors, IDH inhibitors, and drugs that may be particularly beneficial in secondary AML.
[Progress in molecularly targeted therapies for acute myeloid leukemia]. [2015]Genetic abnormalities including specific point mutations have recently been confirmed by applying comprehensive genome sequencing analyses. Molecular targeting therapies, which focus on the mutated proteins and over-expressed proteins in acute myeloid leukemia (AML) cells, are now being developed in clinical studies and/or based on in vitro analyses. This manuscript summarizes the genetic abnormalities in AML cells and some of the current molecular targeting therapies including FLT3 inhibitors (e.g. AC220; Quizartinib), Polo like kinase 1 (PLK1) inhibitors (e.g. BI-6727; Volasertib), IDH2 inhibitors (e.g. AG-221), and XPO1 inhibitors (e.g. KPT-330; Selinexor).
Optimizing therapy for acute myeloid leukemia. [2019]The 10-year overall survival for younger patients with newly diagnosed acute myeloid leukemia has improved threefold in the past 2 decades. This improvement has occurred in large part because of advances in supportive care and efforts to optimize standard induction and consolidation therapies applied in a stratified approach based on predictors of individual patient risk. Innovations in diagnostic technologies have broadened the understanding of key prognostic factors, including cytogenetic and molecular status, which define the extensive interpatient heterogeneity of this clonal disease. Despite this progress, only approximately 25% of patients who experience a complete remission with cytotoxic chemotherapy (50%-70% of patients with newly diagnosed disease) remain disease-free. Efforts to develop novel agents are actively ongoing, particularly for older patients (age > or = 60), and targeted therapies, for specific subsets of patients are being based on a better understanding of the biology of the disease.
Lenalidomide treatment of Japanese patients with myelodysplastic syndromes with 5q deletion: a post-marketing surveillance study. [2023]Lenalidomide was approved in Japan for the treatment of patients with myelodysplastic syndromes associated with a 5q deletion (del 5q-MDS) in August 2010. A post-marketing surveillance (PMS) study enrolled 173 patients with del 5q-MDS who started lenalidomide treatment between August 2010 and September 2011 (mean ± standard deviation [SD] age 72.4 ± 9.0 years) and observed for up to 6 cycles or 6 months. Adverse drug reactions (ADRs) and serious ADRs were reported in 78.0% and 50.9% of patients. The most commonly observed ADRs were thrombocytopenia or platelet count decreased (46.2%), neutropenia or neutrophil count decreased (42.2%), and rash (23.1%). Of 114 patients who were red blood cell transfusion-dependent at baseline, 39 (34.2%) achieved transfusion independence during lenalidomide treatment. Of 173 patients, 19 (11.0%) had confirmed acute myeloid leukemia (AML) progression during the study. Moreover, long-term follow-up (3 years) was available for 68 of the 173 patients, of whom 12 (17.6%) progressed to AML during the additional period. This PMS study investigated the safety and effectiveness of lenalidomide in patients with del 5q-MDS. No new safety concerns were noted in routine clinical use in Japan and no evidence was found for an increased risk of AML progression following lenalidomide treatment.
Dynamic BH3 profiling method for rapid identification of active therapy in BH3 mimetics resistant xenograft mouse models. [2022]The clinical effectiveness of BH3 mimetics therapy is limited by the inevitable emergence of acquired resistance. We present a protocol to model in vivo acquired resistance to BH3 mimetics in patient-derived xenograft (PDX) mouse models of acute myeloid leukemia. Using resistant PDXs as a valuable model, we next introduce a protocol for dynamic BH3 profiling (DBP) method. DBP allows functional identification of effective drug therapies based on measurements of drug-induced apoptosis signaling to overcome in vivo BH3 mimetics resistance. For complete details on the use and execution of this protocol, please refer to Bhatt et al. (2020).
[Relationship between BH3 mimetic S1 and expression of BCL-2 family members in acute myeloid leukemia]. [2018]This study was to investigate the molecular biomarkers of apoptosis induced by BH3 mimetic S1 in human primary AML cells.
Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy. [2023]Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. We evaluated 415 patients with AML-MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML-MRC, therapy type and mutation profile. Criteria for AML-MRC included: cytogenetic abnormalities (AML-MRC-C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML-MRC-H) and 28 (7%) with previously treated MDS (AML-MRC-TS), and 97 (23%) with multilineage dysplasia (AML-MRC-M). Median age was 70 years (range 18-94). Among 95 evaluable patients, a total of 37 (39%) had secondary-type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML-MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML-MRC-M (HR 0.56, CI 0.38-0.84, P = .004) and AML-MRC-H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML-MRC-M/AML-MRC-H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML-MRC-M (HR 0.42, CI 0.19-0.94, P = .036) and with improved EFS in AML-MRC-M and AML-MRC-H (HR 0.26, CI 0.10-0.63, P = .003). This data suggests that not all diagnostic criteria for AML-MRC define high-risk patients and that specific subgroups may benefit from different therapeutic interventions.
Treatment of Low-Blast Count AML using Hypomethylating Agents. [2020]In 2002, the WHO classification reduced the proportion of blasts in the bone marrow (BM) necessary for the diagnosis of acute myeloid leukemia (AML) from 30% to 20%, eliminating the RAEB-t subtype of myelodysplastic syndromes (MDS). However, this AML subtype, defined as low-blast count AML (LBC-AML, with 20-30% BM-blasts) is characterized by peculiar features, as increased frequency in elderly individuals and after cytotoxic treatment for a different primary disease (therapy-related), poor-risk cytogenetics, lower white blood cell counts, and less frequent mutations of NPM1 and FLT3 genes. The clinical course of this entity is often similar to MDS with 10-19% BM-blasts. The hypomethylating agents azacitidine and decitabine have been shown to induce responses and prolong survival both in MDS and LBC-AML. The role of these agents has also been demonstrated in AML with >30% BM-blasts, particularly in patients with poor-risk cytogenetics and in AML with myelodysplasia-related changes. Most recent studies are evaluating strategies to improve outcome, including combinations of hypomethylating agents with immune-response checkpoint inhibitors, which have a role in cancer immune surveillance. Efforts are also ongoing to identify mutations which may predict response and survival in these patients.
Revised classification of acute myeloid leukemia. [2013]The traditional classification and model of acute myeloid leukemia (AML), in common usage for much of the twentieth century, correlates poorly with treatment outcome, biologic studies, and genetic markers in AML, fails to accommodate large subgroups such as typical AML in the elderly or AML following myelodysplastic syndrome (MDS), and (except for acute promyelocytic leukemia) is not used in clinical decisions. Available data suggest an alternative classification and model that initially divides AML into two groups not recognized by traditional classification: MDS-related (MDR)-AML and true de novo (TDN)-AML. MDR-AML includes most AML in the elderly, AML following MDS, AML complicating Fanconi's anemia, and a minor subset of AML in children; these subgroups appear to be linked by a common mutator phenotype, common genetic abnormalities, multilineage hematopoietic dysplasia, clonal hematopoiesis, and poor outcome with cytotoxic chemotherapy. TDN-AML includes AML with the common translocations seen in children and young adults; these subgroups lack features of a mutator phenotype, have approximately flat incidence throughout life, have similar genetic abnormalities, lack multilineage hematopoietic dysplasia and clonal hematopoiesis, and often have good outcome with cytotoxic chemotherapy. Progression in TDN-AML appears to consist predominantly of expansion of a transformed clone, while progression in MDR disease appears to consist initially of progressive accumulation of genetic damage, eventuating in malignant transformation to MDR-AML in some cases. This revised model and classification create therapeutically significant disease groups, allow rapprochement of clinical, morphologic, genetic, and biologic findings in AML, provide a rational model for AML, and frame questions that provide logical direction for future diagnostic, therapeutic, and biologic studies in AML.
Synergistic cooperation between ABT-263 and MEK1/2 inhibitor: effect on apoptosis and proliferation of acute myeloid leukemia cells. [2018]In spite of intensive research to improve treatment of acute myeloid leukemia (AML) more than half of all patients continue to develop a refractory disease. Therefore there is need to improve AML treatment. The overexpression of the BCL-2 family anti-apoptotic members, like BCL-2 or BCL-xL has been largely reported in lymphoid tumors but also in AML and other tumors. To counteract the anti-apoptotic effect of BCL-2, BH3 mimetics have been developed to target cancer cells. An increase in activity of ERK1/2 mitogen activated protein (MAP) kinase has also been reported in AML and might be targeted by MEK1/2 inhibitors. Hence, in the current work, we investigated whether the association of a BH3 mimetic such ABT-263 and the MEK1/2 inhibitor pimasertib (MEKI), was efficient to target AML cells. A synergistic increasing of apoptosis was observed in AML cell lines and in primary cells without affecting normal bone marrow cells. Such cooperation was confirmed on tumor growth in a mouse xenograft model of AML. In addition we demonstrated that MEKI sensitized the cells to apoptosis through its ability to promote a G1 cell cycle arrest. So, this combination of a MAP Kinase pathway inhibitor and a BH3 mimetic could be a promising strategy to improve the treatment of AML.