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Journal of Pharmaceutical and... Oct 2017Plitidepsin is an anti-cancer drug currently evaluated in phase I/II/III clinical trials. This article describes the development and validation of a bioanalytical assay...
Plitidepsin is an anti-cancer drug currently evaluated in phase I/II/III clinical trials. This article describes the development and validation of a bioanalytical assay to quantify plitidepsin in human plasma, urine and whole blood using HPLC-MS/MS. The analyte was extracted from the matrix by liquid-liquid extraction using tert-butyl methyl ether. Final extracts were injected onto a C18 column, gradient elution was applied for chromatographic separation and detection was performed on a triple quadrupole mass spectrometer operating in the positive ion mode. The assay was linear over the range 0.1-100ng/mL, with acceptable accuracy and precision values. This is the first reported bioanalytical assay quantifying plitidepsin using a stable isotopically labelled standard, achieving a lower limit of quantification of 0.1ng/mL in all three matrices, allowing the quantification of trace levels of plitidepsin, and accomplishing this in an analysis time of two minutes only. The presented method was successfully applied in a mass balance study with plitidepsin in patients with advanced cancer.
Topics: Chromatography, High Pressure Liquid; Depsipeptides; Humans; Methyl Ethers; Peptides, Cyclic; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 28662481
DOI: 10.1016/j.jpba.2017.06.013 -
Anti-cancer Drugs Nov 2016This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab...
This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m, n=3; 3.8 mg/m, n=4; and 4.8 mg/m, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Colorectal Neoplasms; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasms; Peptides, Cyclic; Prospective Studies; Uterine Cervical Neoplasms
PubMed: 27610894
DOI: 10.1097/CAD.0000000000000409 -
European Journal of Cancer (Oxford,... Feb 2012To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered...
AIMS
To determine the maximum tolerated dose, the recommended dose (RD) for phase II studies, dose-limiting toxicities and pharmacokinetics (PK) for plitidepsin administered as a 3-h intravenous infusion every 2weeks (one cycle) to children with refractory or relapsed solid tumours.
METHODS
Consecutive cohorts of patients were treated according to a standard '3+3' design with escalating doses of plitidepsin at 4, 5 and 6mg/m(2). Additional 15 patients were recruited at the RD to further evaluate safety and pharmacokinetic associations with respect to age, dose level and toxicity.
RESULTS
Thirty-eight of 41 patients registered received plitidepsin. Dose-limiting toxicities during the first three treatment cycles related to myalgia, elevated creatine phosphokinase, transaminase increase and nausea/vomiting. The RD for plitidepsin is 5mg/m(2). PK analyses revealed high inter-patient variability in plasma, but a similar clearance of plitidepsin in children and adolescents. One partial response confirmed at 4weeks in a patient with neuroblastoma and one unconfirmed partial response in a pancreatoblastoma were observed; four other patients with neuroblastoma, medulloblastoma, glioblastoma and rhabdoid tumour had disease stabilisations lasting ⩾3months.
CONCLUSION
Plitidepsin administered to children as a 3-h infusion every 2weeks is received with manageable toxicity for children with cancer, and the RD is 5mg/m(2). Pharmacokinetic parameters in children and adolescents are comparable to adults. Future phase II studies of plitidepsin are warranted, and our results suggest that plitidepsin could be appropriately developed in combination with other antitumour where myelosuppression is dose-limiting.
Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Cohort Studies; Depsipeptides; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infant; Infusions, Intravenous; Male; Maximum Tolerated Dose; Neoplasms; Peptides, Cyclic
PubMed: 22119199
DOI: 10.1016/j.ejca.2011.10.036 -
Scientific Reports Oct 2016eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties,...
eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties, favoring tumor cell proliferation while inhibiting apoptosis. We demonstrate that plitidepsin, an antitumor agent of marine origin that has successfully completed a phase-III clinical trial for multiple myeloma, exerts its antitumor activity by targeting eEF1A2. The drug interacts with eEF1A2 with a K of 80 nM and a target residence time of circa 9 min. This protein was also identified as capable of binding [C]-plitidepsin in a cell lysate from K-562 tumor cells. A molecular modelling approach was used to identify a favorable binding site for plitidepsin at the interface between domains 1 and 2 of eEF1A2 in the GTP conformation. Three tumor cell lines selected for at least 100-fold more resistance to plitidepsin than their respective parental cells showed reduced levels of eEF1A2 protein. Ectopic expression of eEF1A2 in resistant cells restored the sensitivity to plitidepsin. FLIM-phasor FRET experiments demonstrated that plitidepsin localizes in tumor cells sufficiently close to eEF1A2 as to suggest the formation of drug-protein complexes in living cells. Altogether, our results strongly suggest that eEF1A2 is the primary target of plitidepsin.
Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Depsipeptides; HeLa Cells; Humans; Multiple Myeloma; Peptide Elongation Factor 1; Peptides, Cyclic; Protein Domains; Rabbits
PubMed: 27713531
DOI: 10.1038/srep35100 -
Haematologica Mar 2013This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m(2) administered as a 1-hour intravenous infusion weekly on days...
This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m(2) administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks in 67 adult patients with relapsed/refractory aggressive non-Hodgkin's lymphoma. Patients were divided into two cohorts: those with non-cutaneous peripheral T-cell lymphoma (n=34) and those with other lymphomas (n=33). Efficacy was evaluated using the International Working Group criteria (1999). Of the 29 evaluable patients with non-cutaneous peripheral T-cell lymphoma, six had a response (overall response rate 20.7%; 95% confidence interval, 8.0%-39.7%), including two complete responses and four partial responses. No responses occurred in the 30 evaluable patients with other lymphomas (including 27 B-cell lymphomas). The most common plitidepsin-related adverse events were nausea, fatigue and myalgia (grade 3 in <10% of cases). Severe laboratory abnormalities (lymphopenia, anemia, thrombocytopenia, and increased levels of transaminase and creatine phosphokinase) were transient and easily managed by plitidepsin dose adjustments. The pharmacokinetic profile did not differ from that previously reported in patients with solid tumors. In conclusion, plitidepsin monotherapy has clinical activity in relapsed/refractory T-cell lymphomas. Combinations of plitidepsin with other chemotherapeutic drugs deserve further evaluation in patients with non-cutaneous peripheral T-cell lymphoma. (clinicaltrials.gov identifier: NCT00884286).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Depsipeptides; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Peptides, Cyclic; Recurrence; Treatment Outcome; Tumor Burden; Young Adult
PubMed: 23065525
DOI: 10.3324/haematol.2012.069757 -
Investigational New Drugs Dec 2011This dose-escalating phase I clinical trial was designed to determine the recommended dose (RD) and to assess the safety and feasibility of weekly plitidepsin (1-hour...
This dose-escalating phase I clinical trial was designed to determine the recommended dose (RD) and to assess the safety and feasibility of weekly plitidepsin (1-hour i.v. infusion, Days 1, 8 and 15) combined with carboplatin (1-hour i.v. infusion, Day 1, after plitidepsin) in 4-week (q4wk) cycles given to patients with advanced solid tumors or lymphomas. Twenty patients were enrolled and evaluable for both safety and efficacy. The starting dose was plitidepsin 1.8 mg/m(2) and carboplatin area under the curve (AUC) = 5 min*mg/ml; dose escalation proceeded based on worst toxicity in the previous cohort. The maximum tolerated dose (MTD) was plitidepsin 3.0 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with grade 3 transaminase increases as the most common dose-limiting toxicities (DLTs). The RD for phase II studies was plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml, with fatigue, myalgia and nausea as the most common drug-related adverse events (AEs). No unexpected toxicity was seen. Twelve patients (60%), ten of whom were heavily pretreated (≥2 previous chemotherapy lines) showed stable disease (SD), with a median time to progression (TTP) of 4.4 months. In conclusion, plitidepsin 2.4 mg/m(2) and carboplatin AUC = 5 min*mg/ml is a safe dose for future phase II studies evaluating the use of this combination in cancer patients potentially sensitive to platinum-based therapy.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carboplatin; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Lymphoma; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Peptides, Cyclic; Treatment Outcome
PubMed: 20623160
DOI: 10.1007/s10637-010-9488-1 -
Clinical Cancer Research : An Official... May 2008Plitidepsin, 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...
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/m2/week). Dose-limiting toxicities (defining 3.6 mg/m2/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/m2/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 approximately 25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only approximately 10% 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 +/- 7.7 hour) and a high volume of distribution value (525.2 +/- 219.3 L).
CONCLUSIONS
The recommended dose for plitidepsin given as a weekly 1-hour schedule was 3.2 mg/m2/week. Muscular and liver toxicity were dose limiting at 3.6 mg/m2/week. Additional evaluation of this dose dense schedule is warranted.
Topics: Adult; Aged; Antineoplastic Agents; Depsipeptides; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Peptides, Cyclic
PubMed: 18483378
DOI: 10.1158/1078-0432.CCR-07-1652 -
Biochemical Pharmacology Feb 2020Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory...
Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory authorities for the treatment of multiple myeloma patients. Plitidepsin binds to eEF1A2 and induces oxidative stress, Rac1 activation and JNK1 phosphorylation, triggering a rapid apoptotic program in tumor cells. Since oxidative stress is one of the known sources of endoplasmic reticulum stress, we investigated whether PLD was inducing a bona fide ER stress in HeLa cells and whether this process was essential in the mechanism of action of the compound. Indeed, PLD activated an ER stress-induced unfolded protein response (UPR), including the alternative splicing of XBP1, the proteolytic processing of ATF6 and the phosphorylation of eIF2α and JNK. Interestingly, though PLD induced a strong phosphorylation of eIF2α in all the analyzed cell lines, it did not elicit an increased expression of ATF4 and CHOP, a transcription factor involved in launching UPR-mediated apoptosis. On the contrary, a clear reduction of CHOP protein levels was observed after PLD treatment, most probably due to both the lack of transactivation by ATF4 and its rapid degradation by the ubiquitin/proteasome machinery. Using fibroblasts devoid of each one of the four possible kinases involved in eIF2α phosphorylation, we observed that only PKR was involved in the response to PLD treatment and, accordingly, PKR fibroblasts are shown to be resistant to the apoptogenic activity of the compound. Furthermore, eIF2α phosphorylation itself was shown to be irrelevant for the induction of cell death by PLD. Instead, we reveal that PLD induces an increase in the levels of misfolded proteins while simultaneously inhibiting the autophagic flux. These two effects combined prevent PLD-treated cells from reducing proteotoxic stress and lead to apoptosis. Other anti-myeloma drugs like bortezomib, which target the proteasome, also inhibit the degradation of misfolded proteins through alternate pathways and a synergistic anticancer effect of the PLD plus bortezomib combination has been previously disclosed. The present results extend this synergy to in vivo experiments and provide a mechanistic rationale for this synergy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Depsipeptides; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, SCID; Multiple Myeloma; Neoplasms, Experimental; Oxidative Stress; Peptides, Cyclic; Phosphorylation; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Transcription Factor CHOP
PubMed: 31812675
DOI: 10.1016/j.bcp.2019.113744 -
Clinical Cancer Research : An Official... Jun 2010This trial evaluated the antitumor activity and safety of the marine-derived cyclodepsipeptide plitidepsin in patients with relapsed/refractory multiple myeloma.
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.
Topics: Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Depsipeptides; Dexamethasone; Drug Administration Schedule; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Male; Middle Aged; Multiple Myeloma; Peptides, Cyclic; Recurrence
PubMed: 20530693
DOI: 10.1158/1078-0432.CCR-10-0469 -
Marine Drugs Feb 2021The latest chapter of the historic battle of humans against pathogenic microbes is the severe acute respiratory syndrome (SARS)-like coronavirus-2 (SARS-CoV-2),...
The latest chapter of the historic battle of humans against pathogenic microbes is the severe acute respiratory syndrome (SARS)-like coronavirus-2 (SARS-CoV-2), responsible for COVID-19, a respiratory disease declared a global pandemic by the WHO on March 11, 2020 [...].
Topics: Anti-Inflammatory Agents; Antimicrobial Cationic Peptides; Antiviral Agents; Aquatic Organisms; Biological Products; COVID-19; COVID-19 Vaccines; Depsipeptides; Humans; Pandemics; Peptides, Cyclic; SARS-CoV-2; Seawater; Virus Attachment; COVID-19 Drug Treatment
PubMed: 33670191
DOI: 10.3390/md19020104