scholarly journals Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects

2018 ◽  
Vol 84 (8) ◽  
pp. 1821-1829 ◽  
Author(s):  
Manabu Kato ◽  
Hidetoshi Furuie ◽  
Takako Shimizu ◽  
Atsuhiro Miyazaki ◽  
Fumiaki Kobayashi ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Multiple Dose ◽  
Dose Escalation Study ◽  
Japanese Subjects

A phase I/II dose-escalation study of fractionated and multiple dose 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS188-TPS188
Author(s):  
Michael Sun ◽  
Jones T. Nauseef ◽  
Justin M Lebenthal ◽  
Muhammad Junaid Niaz ◽  
Sharon Singh ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Dose Escalation Study ◽  
Dose Cohort ◽  
Cell Counts ◽  
Psma Pet ◽  
Patient Reported ◽  
Pet Scans

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade > 3 heme toxicity or grade > 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had > 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.

scholarly journals A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors

2014 ◽  
Vol 20 (8) ◽  
pp. 2192-2204 ◽  
Author(s):  
Eric Angevin ◽  
Josep Tabernero ◽  
Elena Elez ◽  
Steven J. Cohen ◽  
Rastilav Bahleda ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Interleukin 6 ◽  
Multiple Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

Phase Ib Study of Recombinant Circularly Permuted TRAIL (CPT) in Relapsed or Refractory multiple Myeloma Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1857-1857 ◽  
Author(s):  
Wenming Chen ◽  
Lugui Qiu ◽  
Jian Hou ◽  
Xuejun Zhang ◽  
Xiaoyan Ke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Dose ◽  
Adverse Events ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Phase Ib ◽  
Refractory Multiple Myeloma ◽  
Significant Difference

Abstract Abstract 1857 Background: Circularly permuted TRAIL (CPT) is a recombinant mutant of human Apo2L/TRAIL developed by Beijing Sunbio Biotech Co. Ltd. as a targeted therapy for multiple myeloma and other hematologic malignancies. CPT is a dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). CPT selectively induces apoptosis in a variety of cancer cells, while sparing most normal cells in the preclinical models. Objective: The safety, pharmacokinetics and preliminary efficacy of CPT in relapsed or refractory multiple myeloma patients (Ral/Ref MM) has been evaluated. Methods: This is a phase Ib, multiple-center, open-label, single/multiple dose-escalation study,18 patients were enrolled in the single dose-escalation study, and 29 patients were recruited in multiple dose-escalation study (including some patients from single dose-escalation study of CPT). Five escalation dosage levels include 5.0, 6.5, 8.0, 10.0 and 15.0 mg/kg/day. Patients received single dose of CPT, or once daily for 5 consecutive days (multiple dose) of each 21-days cycle. Patients receiving multiple doses were treated up to 4 cycles. The clinical response was evaluated at the end of each cycle by an independent review committee according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Results: In single dose-escalation study, no dose limiting toxicity (DLT) and maximum tolerated dose (MTD) was observed. The most common treatment-related adverse events (≥10%) were elevated AST, fever, elevated LDH, leucopenia and shivers. In multiple dose-escalation study, the most common treatment-related adverse events(≥10%) were fever, leucopenia, elevated AST, fatigue and vomit. No significant difference of related adverse event was observed among the different dose groups. Two patients (33.3%) experienced laboratorial or clinical tumor lysis syndrome in 15.0 mg/kg multiple dose. The efficacy was evaluated in 27 patients, 1 patient achieved complete response (CR), 4 partial response (PR), 4 minor response (MR) and 12 no change (NC). No response better than MR was observed in 5.0mg/kg and 6.5mg/kg group. In 8.0mg/kg, 10.0mg/kg and 15.0mg/kg groups, the overall response rate (CR+PR %) was 33.33%, 16.67% and 33.33%, respectively. The disease control rate for five dose groups was 50.00%, 66.67%, 83.33%, 83.33% and 100% respectively, indicating that the optimal dose for CPT may be between 8.0 and 15.0mg/kg. PK results are linear at dose range from 5 mg/kg to 15 mg/kg with CL of 32.47±9.33 ml/h/kg, Vd of 51.89±9.20 ml/kg and t1/2 of 1.16±0.22h. No drug accumulation was observed in repeated administration. No anti-drug antibodies were detected after 1 to 4 cycle's treatment. Conclusion: CPT was well tolerated up to 15mg/kg with promising efficacy in patients with Ral/Ref MM. The MTD has not been reached. A randomized phase 2 trial in patients with Ral/Ref MM is ongoing. Disclosures: Yang: Beijing Sunbio Biotech Co., Ltd.: Employment. Zhu:Beijing Sunbio Biotech Co., Ltd.: Employment.

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