Phase I and Pharmacokinetic Study of Aplidine, a New Marine Cyclodepsipeptide in Patients With Advanced Malignancies

Faivre, Sandrine; Chièze, Stéphanie; Delbaldo, Catherine; Ady-vago, Nora; Guzmán, C.; López-Lázaro, Luis; Lozahic, Stéphanie; Jimeno, J.; Pico, Fernando; Armand, J.P.; Lopez-Martin, Jose A.; Raymond, Éric

doi:10.1200/jco.2005.09.357

Cited by 90 publications

(89 citation statements)

References 16 publications

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“…However, the lack of patients treated with multiple cycles precludes an accurate analysis of the potential dose cumulative toxicities. Nausea, vomiting, and fatigue are common in other previously tested plitidepsin schedules (23,24). Based on these data, appropriate prophylactic antiemetic medication is recommended for all patients treated with plitidepsin.…”

Section: Discussionmentioning

confidence: 99%

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Phase I Clinical and Pharmacokinetic Study of Plitidepsin as a 1-Hour Weekly Intravenous Infusion in Patients with Advanced Solid Tumors

Izquierdo

Bowman

García

et al. 2008

Clinical Cancer Research

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Purpose: Plitidepsin, given as a 1-hour weekly i.v. infusion for 3 consecutive weeks during a 4-week treatment cycle, was investigated in patients with solid tumors to determine the maximum tolerated dose and the recommended dose (RD) using this administration schedule. Experimental Design: Consecutive cohorts of patients with metastatic solid tumors or non^Hodgkin's lymphomas were to be treated at escalating doses of plitidepsin in a conventional phase I study including pharmacokinetic analyses of plitidepsin in plasma, whole blood, and blood cell pellets. Results: Forty-nine patients with solid tumors were enrolled, and 48 were treated with plitidepsin (doses from 0.133 to 3.6 mg/m 2 /week). Dose-limiting toxicities (defining 3.6 mg/m 2 /week as the maximum tolerated dose) included myalgia, increased creatine phosphokinase levels, and sustained grade 3/4 increases of hepatic enzyme levels. The RD was established at 3.2 mg/m 2 /week. The most common toxicities were fatigue, vomiting/nausea, anorexia, injection site reaction, and pain, mostly of mild or moderate severity. Muscular toxicity manifested by mild-moderate myalgia, weakness, and/or creatine phosphokinase elevations occurred in f25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only f10% of patients. Plitidepsin lacked significant hematologic toxicity. No complete or partial tumor responses were observed; however, five patients had disease stabilization (including one patient with medullary thyroid carcinoma with an unconfirmed partial response and one patient with renal carcinoma with major tumor shrinkage in lung metastases). Pharmacokinetic results for the RD indicated a long plasma half-life give value (16.8 F 7.7 hour) and a high volume of distribution value (525.2 F 219.3 L). Conclusions: The recommended dose for plitidepsin given as a weekly 1-hour schedule was 3.2 mg/m 2 /week. Muscular and liver toxicity were dose limiting at 3.6 mg/m 2 /week. Additional evaluation of this dose dense schedule is warranted.

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Section: Discussionmentioning

confidence: 99%

“…Previous phase I trials with other plitidepsin i.v. schedules have also reported muscular toxicity as DLT (23,24), whereas skin rash and diarrhea were also reported to be DLTs in other phase I trial evaluating a 1-hour i.v. infusion daily for 5 days every 3 weeks (23).…”

Section: Discussionmentioning

confidence: 99%

Phase I Clinical and Pharmacokinetic Study of Plitidepsin as a 1-Hour Weekly Intravenous Infusion in Patients with Advanced Solid Tumors

Izquierdo

Bowman

García

et al. 2008

Clinical Cancer Research

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“…In phase I studies, the main side effects noted were myalgia and muscle weakness, prevented by administration of L-carnitine. 1 Bone marrow toxicity was not dose limiting. 2 Phase II clinical studies are being carried out in solid and hematologic tumors with preliminary evidence of activity in advanced melanoma and multiple myeloma.…”

Section: Introductionmentioning

confidence: 98%

Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity

et al. 2007

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Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G 1 and G 2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.

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“…Before the amendment, 23 patients received a median of 4 cycles of single-agent plitidepsin (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. A median of 6 cycles (range, 3-18) of study treatment were given to the 19 patients in which dexamethasone was added because of suboptimal response to single-agent plitidepsin.…”

Section: Patients and Treatmentmentioning

confidence: 99%

“…A total of 278 plitidepsin cycles were administered during the study, with a median of 4 cycles per patient (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Before the amendment, 23 patients received a median of 4 cycles of single-agent plitidepsin (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

Section: Patients and Treatmentmentioning

confidence: 99%

Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma

Mateos

Cibeira

Richardson

et al. 2010

Clinical Cancer Research

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Purpose: This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.Experimental Design: This was a prospective, multicenter, open-label, single-arm, phase II trial with plitidepsin at 5 mg/m 2 as a 3-hour i.v. infusion every two weeks. The protocol was amended to allow patients with suboptimal response to single-agent plitidepsin to add 20 mg/day on days 1 to 4 of oral dexamethasone every two weeks. Results: Fifty-one patients started treatment with plitidepsin and 47 were evaluable for efficacy. The overall response rate (complete response plus partial response plus minimal response) was 13% with plitidepsin alone and 22% in the cohort of patients with the addition of dexamethasone (n = 19, 18 evaluable). Both plitidepsin alone and with dexamethasone were feasible and well tolerated. Anemia (29%) and thrombocytopenia (18%) were the most frequent grade 3/4 hematologic toxicities. Fatigue (16%), muscular toxicity (6%), and transient alanine aminotransferase/aspartate aminotransferase (27%) and creatine phosphokinase (23%) increases were the most relevant nonhematologic side effects. A prolonged plasma half-life was observed in responding patients as compared with nonresponding patients (P = 0.009).Conclusions: Single-agent plitidepsin has limited but reproducible activity in relapsed/refractory multiple myeloma patients. Activity observed after dexamethasone addition merits further study. Both regimens were well tolerated in this heavily pretreated population. Clin Cancer Res; 16(12); 3260-9. ©2010 AACR.Multiple myeloma is the second most common hematologic malignancy after non-Hodgkin's lymphoma. In the Western hemisphere, about 1% of cancer-related deaths are due to myeloma. The disease primarily affects aged individuals, with a median age of 60 years at diagnosis. Despite recent advances in the treatment of multiple myeloma and the availability of novel agents, few patients, if any, can be considered cured, as the vast majority will eventually relapse (1). Thus, new active agents without known cross-resistance with other well-established anti-multiple myeloma agents are needed.Plitidepsin is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans and is currently produced by chemical synthesis. The doselimiting toxicities (DLT) at the phase II recommended dose of 5.0 mg/m 2 over a 3-hour i.v. infusion every two weeks (2-7) included myalgia, muscular weakness, transient and reversible transaminases increase, and fatigue both in patients with solid tumors and in those

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Phase I and Pharmacokinetic Study of Aplidine, a New Marine Cyclodepsipeptide in Patients With Advanced Malignancies

Abstract: Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m(2) without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.

Cited by 90 publications

References 16 publications

Phase I Clinical and Pharmacokinetic Study of Plitidepsin as a 1-Hour Weekly Intravenous Infusion in Patients with Advanced Solid Tumors

Phase I Clinical and Pharmacokinetic Study of Plitidepsin as a 1-Hour Weekly Intravenous Infusion in Patients with Advanced Solid Tumors

Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity

Phase II Clinical and Pharmacokinetic Study of Plitidepsin 3-Hour Infusion Every Two Weeks Alone or with Dexamethasone in Relapsed and Refractory Multiple Myeloma

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