TAK-243 for Leukemia
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: OATP/BCRP inhibitors, CYP3A4/5 inducers
Disqualifiers: APL, Active infection, Cardiopulmonary disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This phase I trial studies the side effects and best dose of TAK-243 in treating patients with acute myeloid leukemia or myelodysplastic syndromes with increased blasts that has come back (relapsed) or that is not responding to treatment (refractory). TAK-243 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications, specifically organic anion transport protein (OATP) and BCRP inhibitors or strong inducers/inhibitors of cytochrome P450 (CYP)3A4/5, at least 14 days before starting TAK-243. It's important to discuss all your current medications with the study team to ensure there are no interactions.
Eligibility Criteria
This trial is for adults with acute myeloid leukemia or myelodysplastic syndromes that have relapsed or are not responding to treatment. Participants must meet specific health criteria, including a certain performance status and liver function. They should not have had recent chemotherapy or investigational therapy and cannot be allergic to the study drug TAK-243.Inclusion Criteria
My condition worsened or didn't improve after at least one treatment.
I am following the required birth control measures.
Minimum life expectancy of 1 month
+15 more
Exclusion Criteria
I do not have any severe infections or diseases.
Prolonged QTc interval
I have had major surgery recently.
+18 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive TAK-243 intravenously over 30 minutes on days 1, 4, 8, and 11 of each cycle. Cycles repeat every 21 days for up to 12 months.
12 months
4 visits per cycle (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment completion.
4 weeks
1 visit (in-person)
Participant Groups
The trial is testing TAK-243, which may inhibit cancer cell growth by blocking enzymes needed for cell growth. It involves procedures like bone marrow aspiration/biopsy and heart function tests to determine the best dose of TAK-243 and its side effects in patients.
1Treatment groups
Experimental Treatment
Group I: Treatment (TAK-243)Experimental Treatment6 Interventions
Patients receive TAK-243 IV over 30 minutes on days 1, 4, 8, and 11 of each cycle. Cycles repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients undergo urine sample collection, bone marrow aspiration and bone marrow biopsy, MUGA and ECHO during screening and on study, and blood sample collection throughout the trial.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University Health Network Princess Margaret Cancer Center LAOToronto, Canada
Virginia Commonwealth University/Massey Cancer CenterRichmond, VA
Northwestern UniversityChicago, IL
Moffitt Cancer CenterTampa, FL
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia. [2023]CD123, a subunit of the interleukin-3 receptor, is expressed on ~80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the anti-apoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 ug/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet (ELN) adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% CR, 19% CRi, 12% MLFS). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR=4, CRi=2, MLFS=1). Twelve of 17 (71%) tested responders had no flow measurable residual disease (MRD). Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations.
TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells. [2021]Acute myelogenous leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), which represent the ultimate therapeutic target for AML. Recent studies have identified several AML LSC-specific surface antigens as candidate targets of therapeutic molecules. T cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML, with the exception of acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). In xenograft models reconstituted with human AML LSCs or HSCs, an anti-human TIM-3 mouse IgG2a antibody with cytotoxic activities eradicates AML LSCs in vivo, but does not affect normal human hematopoiesis. Thus, TIM-3 is a promising therapeutic target for the eradication of AML LSCs.
Targeting CD123 in hematologic malignancies: identifying suitable patients for targeted therapy. [2021]Following the observation of interleukin 3 receptor α chain (IL-3Rα; CD123) upregulation on leukemia stem cells (LSCs) almost two decades ago, targeted treatment via CD123-diptheria toxin conjugates has now been tested in patients with diverse myeloid malignancies. Targeted eradication of LSCs could result in effective treatments for many challenging diseases initiated by these cells. Consequently, considerable effort has been directed toward targeting CD123 as a potential strategy for treating patients with hematologic malignancies in which CD123 is overexpressed. However, these therapies have had limited success so far, highlighting the need for suitable criteria to identify patients who could benefit from them. Given the diversity in CD123 expression across different hematologic malignancies, understanding CD123 expression patterns and the functional pathogenetic significance is crucial. Here, we review the methodologies available for CD123 assessment and discuss the biological and clinical characteristics of patients for whom CD123-targeting therapies may have a clinical impact.
Pathogenetic, Clinical, and Prognostic Features of Adult t(4;11)(q21;q23)/MLL-AF4 Positive B-Cell Acute Lymphoblastic Leukemia. [2021]Translocation t(4;11)(q21;q23) leading to formation of MLL-AF4 fusion gene is found in about 10% of newly diagnosed B-cell acute lymphoblastic leukemia (ALL) in adult patients. Patients expressing this chromosomal aberration present typical biological, immunophenotypic, and clinical features. This form of leukemia is universally recognized as high-risk leukemia and treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) could be a valid option to improve prognosis, but data obtained from the literature are controversial. In this review, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11)(q21;q23)/MLL-AF4 positive ALL and provide a review of the clinical outcome reported by the most important cooperative groups worldwide.
AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. [2021]PR-104, a phosphate ester of the nitrogen mustard prodrug PR-104A, has shown evidence of efficacy in adult leukemia clinical trials. Originally designed to target hypoxic cells, PR-104A is independently activated by aldo-keto-reductase 1C3 (AKR1C3). The aim of this study was to test whether AKR1C3 is a predictive biomarker of in vivo PR-104 sensitivity. In a panel of 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 showed significantly greater efficacy against T-lineage ALL (T-ALL) than B-cell-precursor ALL (BCP-ALL) xenografts. Single-agent PR-104 was more efficacious against T-ALL xenografts compared with a combination regimen of vincristine, dexamethasone, and l-asparaginase. Expression of AKR1C3 was significantly higher in T-ALL xenografts compared with BCP-ALL, and correlated with PR-104/PR-104A sensitivity in vivo and in vitro. Overexpression of AKR1C3 in a resistant BCP-ALL xenograft resulted in dramatic sensitization to PR-104 in vivo. Testing leukemic blasts from 11 patients confirmed that T-ALL cells were more sensitive than BCP-ALL to PR-104A in vitro, and that sensitivity correlated with AKR1C3 expression. Collectively, these results indicate that PR-104 shows promise as a novel therapy for relapsed/refractory T-ALL, and that AKR1C3 expression could be used as a biomarker to select patients most likely to benefit from such treatment in prospective clinical trials.