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1.
Leuk Lymphoma ; : 1-9, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38952054

ABSTRACT

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

2.
Cancer Chemother Pharmacol ; 93(4): 341-352, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38086998

ABSTRACT

PURPOSE: Imaradenant is a novel potent and selective adenosine A2A receptor antagonist that is hypothesized to reduce immune suppression in the tumor microenvironment. This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and anti-tumor activity of imaradenant. METHODS: Japanese patients with advanced solid malignancies received imaradenant 50 mg (n = 3) or 75 mg (n = 7) once daily (QD). The primary objective was safety and tolerability, and the secondary objectives were pharmacokinetics and anti-tumor activity. RESULTS: The median treatment duration was 2.10 months and 2.14 months for the 50- and 75-mg QD cohorts, respectively. The most common adverse events were nausea, malaise, decreased appetite, and vomiting. Five patients (50%) reported adverse events that were considered causally related to imaradenant; three patients had Grade 2 adverse events of malaise, nausea, and diarrhea. No deaths or serious adverse events occurred. The median times of maximum observed concentrations sampled after a single dose in the 50- and 75-mg QD cohorts were 1.08 h (range, 0.95-1.95) and 2.00 h (range, 0.92-5.52), respectively. There was little accumulation after multiple dosing, with geometric mean accumulation ratios of maximum concentration of 1.3 (50-mg QD) to 1.4 (75-mg QD) and area under the concentration-time curve 0-24 of 1.4 (50-mg QD) to 1.5 (75-mg QD). The best objective response was stable disease (3/10). CONCLUSION: No new or unexpected safety concerns were identified, and imaradenant had an acceptable safety profile at both 50- and 75-mg QD. CLINICALTRIALS: gov identifier NCT03980821 (June 10, 2019).


Subject(s)
Neoplasms , Humans , Japan , Neoplasms/drug therapy , Neoplasms/pathology , Nausea/chemically induced , Vomiting/chemically induced , Diarrhea/chemically induced , Tumor Microenvironment
3.
Cancer Sci ; 112(6): 2405-2415, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33728735

ABSTRACT

This multicenter, open-label, phase I study assessed the safety and antitumor activity of acalabrutinib in Japanese patients with relapsed/refractory (r/r) B-cell malignancies. Parts 1 (dose confirmation) and 2 (dose expansion) of this three-part study are reported. Treatment was a single dose of 100 mg acalabrutinib (day 1), followed by a washout period and then twice daily 100 mg acalabrutinib in part 1, or twice daily 100 mg acalabrutinib in part 2. Patients from parts 1 and 2 with r/r chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and r/r mantle cell lymphoma (MCL) were assessed as r/r CLL/SLL and r/r MCL cohorts, respectively. Twenty-five patients received treatment (part 1, n = 6). Median age was 71.0 years. Nine (one patient from part 1) and 13 (two patients from part 1) patients were included in the r/r CLL/SLL and r/r MCL cohorts, respectively. Treatment-related adverse events (AEs) occurred in 88% of patients (grade ≥3, 36%); the most common were headache (28%) and purpura (24%), both grade 1/2. No AEs resulted in treatment discontinuation or death. Median duration of treatment was 31, 20, and 7 months for part 1, r/r CLL/SLL cohort, and r/r MCL cohort, respectively. Overall response rate (ORR) was 89% and 62% for the r/r CLL/SLL and r/r MCL cohorts, respectively. The median progression-free survival (PFS) was not reached for the r/r CLL/SLL cohort and was 7 months for the r/r MCL cohort. Acalabrutinib (100 mg twice daily) was generally safe and well-tolerated in adult Japanese patients with B-cell malignancies.


Subject(s)
Antineoplastic Agents/administration & dosage , Benzamides/administration & dosage , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Mantle-Cell/drug therapy , Neoplasm Recurrence, Local/drug therapy , Pyrazines/administration & dosage , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Benzamides/adverse effects , Benzamides/pharmacokinetics , Drug Administration Schedule , Female , Headache/chemically induced , Headache/epidemiology , Humans , Japan , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Lymphoma, Mantle-Cell/blood , Male , Middle Aged , Neoplasm Recurrence, Local/blood , Purpura/chemically induced , Purpura/epidemiology , Pyrazines/adverse effects , Pyrazines/pharmacokinetics , Survival Analysis , Treatment Outcome
4.
J Pharmacol Sci ; 103(2): 222-33, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17299242

ABSTRACT

The cardioprotective effect of caldaret, a novel intracellular Ca(2+) handling modulator that acts through reverse-mode Na(+)/Ca(2+) exchanger inhibition and potential sarcoplasmic reticulum (SR) Ca(2+) uptake enhancement, against reperfusion injury was investigated. We employed a canine model of myocardial infarction induced by 90-min occlusion of left circumflex (LCX) coronary artery followed by 4 h of reperfusion. Intravenously infused caldaret (3 or 30 microg/kg per hour) for 30 min at LCX-reperfusion markedly reduced infarct size (by 51.3% or 71.9%, respectively). This cardioprotection was accompanied by an acceleration of left ventricular (LV) contraction and relaxation during reperfusion, but not by an increase in ischemic regional transmural myocardial blood flow (TMBF) or endocardial/epicardial blood flow ratio (Endo/Epi ratio) or a reduction in double-product throughout the protocol. Diltiazem (2000 microg/kg per hour) also reduced infarct size (by 36.1%), but unlike caldaret, was accompanied by the significant increase in Endo/Epi ratio in the ischemic region and decrease in double-product. There were significant inverse relationships between infarct size and ischemic regional TMBF in all groups. Caldaret, but not diltiazem shifted the regression line downward with a flatter slope. These results suggest that the amelioration of intracellular Ca(2+) handling dysfunction achieved by caldaret leads to cardioprotective effects against reperfusion injury following prolonged ischemia.


Subject(s)
Benzenesulfonates/pharmacology , Calcium/metabolism , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/pathology , Piperazines/pharmacology , Algorithms , Animals , Blood Pressure/drug effects , Calcium Channel Blockers/pharmacology , Coronary Circulation/drug effects , Diltiazem/pharmacology , Dogs , Heart/drug effects , Myocardial Infarction/etiology , Myocardial Reperfusion Injury/complications , Myocardium/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Sodium-Calcium Exchanger/metabolism
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