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Phase I dose-escalating study of panobinostat (LBH589) Administered intravenously to Japanese patients with advanced solid tumors

Summary Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of...

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Published in:Investigational new drugs 2012-10, Vol.30 (5), p.1950-1957
Main Authors: Morita, Sachi, Oizumi, Satoshi, Minami, Hironobu, Kitagawa, Koichi, Komatsu, Yoshito, Fujiwara, Yutaka, Inada, Megumi, Yuki, Satoshi, Kiyota, Naomi, Mitsuma, Ayako, Sawaki, Masataka, Tanii, Hiromi, Kimura, Junko, Ando, Yuichi
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cited_by cdi_FETCH-LOGICAL-c344t-b3d4c46ec8d71088ba07b2fc72c478cca0becc0c9e4f04606b3c7cc86481b3a3
cites cdi_FETCH-LOGICAL-c344t-b3d4c46ec8d71088ba07b2fc72c478cca0becc0c9e4f04606b3c7cc86481b3a3
container_end_page 1957
container_issue 5
container_start_page 1950
container_title Investigational new drugs
container_volume 30
creator Morita, Sachi
Oizumi, Satoshi
Minami, Hironobu
Kitagawa, Koichi
Komatsu, Yoshito
Fujiwara, Yutaka
Inada, Megumi
Yuki, Satoshi
Kiyota, Naomi
Mitsuma, Ayako
Sawaki, Masataka
Tanii, Hiromi
Kimura, Junko
Ando, Yuichi
description Summary Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m 2 [three patients], Cohort 2: 15 mg/m 2 [three patients], Cohort 3: 20 mg/m 2 [eight patients]), according to a standard “3 + 3” design. One patient who received 20 mg/m 2 had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for >7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m 2 was the MTD and recommend as the starting dose for phase II clinical trials.
doi_str_mv 10.1007/s10637-011-9751-0
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As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m 2 [three patients], Cohort 2: 15 mg/m 2 [three patients], Cohort 3: 20 mg/m 2 [eight patients]), according to a standard “3 + 3” design. One patient who received 20 mg/m 2 had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for &gt;7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. 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One patient who received 20 mg/m 2 had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for &gt;7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. 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As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m 2 [three patients], Cohort 2: 15 mg/m 2 [three patients], Cohort 3: 20 mg/m 2 [eight patients]), according to a standard “3 + 3” design. One patient who received 20 mg/m 2 had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for &gt;7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m 2 was the MTD and recommend as the starting dose for phase II clinical trials.</abstract><cop>Boston</cop><pub>Springer US</pub><pmid>21964801</pmid><doi>10.1007/s10637-011-9751-0</doi><tpages>8</tpages></addata></record>
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identifier ISSN: 0167-6997
ispartof Investigational new drugs, 2012-10, Vol.30 (5), p.1950-1957
issn 0167-6997
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language eng
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source ABI/INFORM Global; Springer Nature
subjects Adult
Aged
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Cohort Studies
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Follow-Up Studies
Humans
Hydroxamic Acids - administration & dosage
Hydroxamic Acids - adverse effects
Hydroxamic Acids - pharmacokinetics
Indoles - administration & dosage
Indoles - adverse effects
Indoles - pharmacokinetics
Infusions, Intravenous
Japan
Male
Maximum Tolerated Dose
Medicine
Medicine & Public Health
Middle Aged
Neoplasms - drug therapy
Neoplasms - metabolism
Oncology
Pharmacology/Toxicology
Phase I Studies
Thrombocytopenia - chemically induced
title Phase I dose-escalating study of panobinostat (LBH589) Administered intravenously to Japanese patients with advanced solid tumors
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