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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Department of Clinical Oncology, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain; 2 Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh, Scotland; and 3 PharmaMar R&D, Colmenar Viejo, Madrid, Spain
Requests for reprints: J.F. Smyth, Edinburgh Cancer Research Centre, Crewe Road South, Edinburgh, EH4 2XR United Kingdom. Phone: 44-131-777-3512; Fax: 44-131-777-3520; E-mail: john.smyth{at}ed.ac.uk.
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Abstract |
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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 
25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only 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.
The primary mechanism of action of plitidepsin in tumor cells is the subject of continuous investigations and several mechanisms have been proposed. Plitidepsin induces an early oxidative stress response, which results in a rapid and sustained activation of the epidermal growth factor receptor, the nonreceptor protein tyrosine kinase Src, and the serine threonine kinases c-Jun NH2-terminal kinase, and p38 mitogen-activated protein kinase. These early events rapidly trigger the induction of the mitochondrial apoptotic pathway via cytochrome c release, activation of the caspase cascade, and activation of protein kinase C, which seems to exert an important effector role in mediating cellular death induced by the drug (8–10). Recently, c-Jun-NH2-kinase activation in tumors has been found associated with plitidepsin treatment in vivo, suggesting that c-Jun-NH2-kinase phosphorylation is a potential biomarker of plitidepsin activity (11).
Plitidepsin acts in leukemic cells, at least in part, through Fas CD95 cell death receptor, a member of the tumor necrosis factor receptor family (12). Depending on the cell system, plitidepsin either induces a very rapid apoptotic death without previous cell cycle arrest or causes a block in G1 and/or a delay in the progression from S to G2 phases of the cell cycle (8, 9, 13). Further studies have shown that plitidepsin induces apoptosis by altering glutathione homeostasis, thereby increasing the levels of reactive oxygen species and inducing Rac1 GTPase activation and MKP-1 phosphatase down-regulation (14). In addition to the proapoptotic properties of plitidepsin, the molecule exhibits antiangiogenic activity (15, 16). The elucidation of a pharmacodynamic effect against the vascular endothelial growth factor receptor loop has also been studied in several preclinical in vitro and in vivo models. The results of these studies show that plitidepsin reduces the secretion of vascular endothelial growth factor from MOLT-4 human leukemia cells in vitro (17). Plitidepsin has also been shown to reduce the expression of vascular endothelial growth factor receptor 1 in the same cell line.
Different i.v. dose schedules were evaluated in a phase I program in patients with advanced solid tumors or non–Hodgkin's lymphoma. This program encompassed a range of dose schedules providing frequent or protracted exposure to plitidepsin (18). One of the dose schedules investigated in the phase I program was a 1-hour infusion, administered every week for three consecutive weeks of a 4-week treatment cycle. The main objectives of this phase I clinical trial were to define the maximum tolerated dose (MTD) and the recommended dose for phase II studies (RD) with plitidepsin given as a weekly 1-hour i.v. infusion on days 1, 8, and 15 every 4 weeks. In addition, the study aimed to describe the toxicity profile, to document any tumor response, and to provide an initial description of the pharmacokinetic profile of this plitidepsin schedule in cancer patients.
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Materials and Methods |
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Patients. Eligible patients were ages 
18 y old and had a histologically or cytologically confirmed diagnosis of solid tumor or non–Hodgkin's lymphoma not amenable to conventional therapies. Furthermore, they were required to have an Eastern Cooperative Oncology Group performance status of 
2 and a life expectancy of 3 mo. The following laboratory values were required within 7 d of registration: neutrophils of 1.5 x 109/L, platelets of 100 x 109/L, hemoglobin of 10 g/dL, prothrombin time and thrombotest within normal limits, calculated creatinine clearance of 50 mL/min, bilirubin of <25 µmol/L (1.5 mg/dL), aspartate aminotransferase (AST) and alanine aminotransferase of 3 x upper limit of normal (5 x upper limit of normal, if documented liver metastases), and alkaline phosphatase of 3 x upper limit of normal (5 x upper limit of normal if documented liver and/or bone metastases). Patients must have recovered from any prior therapy, have a left ventricular ejection fraction of > 45% and have an electrocardiogram within normal limits. Exclusion criteria were those usually applied in phase I trials of cytotoxic anticancer agents. Patients known to be hypersensitive to Cremophor were excluded because plitidepsin is reconstituted in a Cremophor-containing solvent. Concomitant anticoagulant therapy was prohibited.
Drug administration. Plitidepsin was supplied by Pharma Mar as a lyophilized product in glass vials (500 µg of plitidepsin per vial), which was reconstituted in a mixture of Cremophor EL/ethanol/water (15/15/70% v/v/v; ref. 19). The content of one vial of solution was reconstituted in 1 mL of the reconstitution solution, and the resultant clear, colorless solution was diluted in normal saline to a volume suitable for i.v. infusion (100-500 mL) over 1 h.
The starting dose of plitidepsin, derived from preclinical toxicology studies in mice and rats, was 0.133 mg/m2/wk or 0.4 mg/m2/cycle. The dose was escalated in consecutive cohorts of patients, according to the modified Fibonacci dose escalation scheme and considering the worst toxicity reported in the previous dose level, until dose-limiting toxicity (DLT) was encountered. DLT was defined as grade 4 neutropenia lasting 5 d or fever 38.5°C, grade 4 thrombocytopenia, grade 3 or 4 transaminase increase (nonreversible within 15 d from last infusion, as specified in a protocol amendment), or any other grade 3 or 4 nonhematologic toxicity, excluding severe emesis that emerged without prophylaxis, alopecia, and hypersensitivity reactions. The MTD was defined by the occurrence of a DLT in at least two of three, or two of six patients entered at a given dose level.
Study assessments. Prestudy assessments and assessments during and after treatment included medical history, physical examination, standard hematologic and biochemical laboratory evaluation, and radiological (chest X-ray and tumor evaluation), cardiological (electrocardiogram and left ventricular ejection fraction), and neurologic assessments. Toxicities were assessed at baseline and at regular intervals during treatment. Safety variables evaluated were the frequency and severity of adverse events (AE), serious AEs, the occurrence of study drug-related treatment discontinuations, and the frequency and severity of abnormal laboratory variables. Toxicity was assessed before each cycle/infusion and graded according to the NCI-Common Toxicity Criteria (v.2.0; ref. 20). Any tumor responses to treatment were assessed by radiological evaluation (chest X-ray, computer tomography scan, or magnetic resonance imaging) and graded according to WHO criteria (21) as complete response, partial response, stable disease, or progressive disease based on tumor size measurements made at least 4 wk apart.
Pharmacokinetic evaluations. Serial blood samples for the analysis of plitidepsin in whole blood, plasma, and blood cell pellets were taken before, during, and after the first infusion of the first treatment cycle in all patients. Blood samples were taken before the start of infusion; at the end of 1-h infusion; and 10, 20, 30, and 45 min, and 1, 1.5, 2, 3, 4,6, 8, 12, and 24 h from the end of infusion (from the arm contralateral to the arm into which plitidepsin was infused) and collected into heparinized plastic tubes. Urine was collected over the intervals 0 to 24 h and 24 to 48 h after the start of the infusion.
Blood and urine samples were stored at –20°C on dry ice until shipment to the Mario Negri Institute for assaying plitidepsin concentrations. Briefly, the assay method used high-performance liquid chromatography followed by tandem mass spectrometry. This assay has a lower limit of quantitation of 0.5 ng/mL and is linear up to 64.0 ng/mL. The bioanalytical method showed enough stability in blood, plasma, cell pellets, and urine for the validity of all analytic procedures (22).
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Results |
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3 chemotherapeutic agents.
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Patients received a total of 88 treatment cycles at doses ranging from 0.133 to 3.6 mg/m2/week (Table 2 ), with a median of 2 cycles per patient (range, 1-4 cycles). Three patients received only one infusion due to early disease progression (one patient at dose levels VI, VII, and VIII). Twenty-five patients (52.1%) had at least one treatment dose delay, with seven of these patients having dose delays in more than one cycle. The median duration of dose delay was 1 day (range, 1-102 days), but most of these delays (74.3%) were unrelated to the study drug. For instance, the delay of 102 days occurred in one patient (second cycle, first infusion) due to reactivation of viral C hepatitis with grade 3 transaminitis from which the patient recovered later on. This patient was retreated after showing signs of clinical benefit. The median relative dose intensity across all dose levels was 100% (range, 24.8-107.7%).
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No DLTs were observed until dose level VII (2.7 mg/m2/week) was reached. The first DLT encountered at this dose level was grade 3 biochemical hepatotoxicity (i.e., sustained grade 3 increase in AST, and grade 3 elevation of both bilirubin and alkaline phosphatase) in 1 patient from 8 studied. At the next dose level (dose level IX, 3.6 mg/m2/week), muscular toxicity was observed in cycle 2 in 2 patients. This toxicity consisted of grade 3 myalgia with grade 2 creatine phosphokinase (CPK) increase in 1 patient, and grade 4 CPK elevation in 1 patient. These DLTs defined this dose as the MTD for this plitidepsin schedule.
An intermediate dose level (dose level VIII, 3.2 mg/m2/week) was evaluated as the potential RD in a total of 14 patients. Grade 3/4 toxicity was reported in several patients (see Tables 3 and 4 ). In particular, one patient had a grade 3 increase in alkaline phosphatase, which was declared a DLT. However, no further DLTs were noted at this dose level, and it was considered the RD for plitidepsin administered as a 1-hour weekly infusion weekly for 3 consecutive weeks of a 4-week cycle.
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The most frequent nonhematologic, nonbiochemical AEs related to plitidepsin treatment were constitutional symptoms, gastrointestinal events, injection site reactions, pain, and muscular events (Table 3). Fatigue, including asthenia and malaise, was the most frequently reported AE, affecting 36 patients (75%), although only 9 patients (19%) experienced grade 3/4 fatigue. Vomiting, nausea, and anorexia were the most frequent gastrointestinal AEs, but grade 3 severity was rare (vomiting, n = 1 patient; anorexia, n = 1; no grade 4 gastrointestinal AEs were reported). Other gastrointestinal AEs infrequently reported (e.g., diarrhea, dyspepsia/dysgeusia, or constipation) were only of grade 1/2 severity.
Different types of pain (e.g., abdominal, back, chest, or tumor pain) were reported by 11 patients (22%) across various dose levels. All episodes of pain related to the study drug reached a maximum severity of grade 1/2. Injection site reactions of grade 1/2 severity occurred in 14 patients (29%) and included phlebitis, bruising, and inflammation. Treatment-related myalgia was observed in 12 patients (25%). Nine of these patients were treated at dose levels VIII and IX. Grade 3 myalgia was considered a DLT in one patient at dose level IX. Mild to moderate muscle weakness was the second most frequent treatment-related muscular AE (n = 3 patients).
Hematologic and biochemical abnormalities, regardless of their relationship to plitidepsin, are shown in Table 4. The most frequent hematologic abnormalities of any grade were anemia and lymphocytopenia, occurring in 42 (87%) and 35 patients (73%), respectively. However, most of these toxicities were only grade 1 or 2. Only 3 patients (6%) experienced grade 3 (2 patients) or grade 4 (1 patient) anemia. Five patients (10%) had grade 3 or 4 lymphocytopenia with lack of clinical relevance (i.e., concomitant fungal infections, comorbidity, etc.). Only mild (grade 1 or 2) neutropenia and thrombocytopenia were observed in 3 (6%) and 17 (35%) patients, respectively, with no episodes of febrile neutropenia.
Biochemical abnormalities of any grade were observed in patients at all dose levels (Table 4). The most frequent biochemical abnormalities of any grade were increased lactate dehydrogenase (40 patients, 70 cycles) and 
-glutamyltransferase (37 patients, 63 cycles). These two types of biochemical abnormalities did not show any cumulative trend and occurred frequently in conjunction with disease progression, without any obvious dose-effect relationship. Elevations of alanine aminotransferase occurred in 33 patients (68.7%; 4 patients, grade 3; 2 patients, grade 4) or in 54 cycles. Elevations of AST levels were reported in 32 patients (66.7%; 5 patients, grade 3; 1, patient grade 4) or in 49 cycles. Transaminase elevations were reversible. Notwithstanding the limitation of the small number of patients treated at each dose level, a trend toward a greater incidence appeared at the highest dose levels. Mild CPK elevations occurred in 7 patients (14.6%), and grade 3 or grade 4 in 1 patient (2.1%) each. CPK elevations were observed at the highest dose levels of plitidepsin, supporting a drug and dose relationship.
Antitumor activity. Ten patients treated with plitidepsin were not evaluable for tumor response because either they did not receive one complete cycle of treatment (n = 8) or because they withdrew prematurely before tumor assessment (n = 2). None of the 38 evaluable patients had a confirmed objective response. One patient with medullary thyroid carcinoma treated with plitidepsin 3.2 mg/m2/week had an unconfirmed partial response in bulky laterocervical nodes (52% overall decrease in the size of lesions). The response could not be confirmed due to early death of the patient unrelated to tumor progression or plitidepsin (Fig. 1 ). In addition, one patient with metastatic renal cancer treated with plitidepsin 2.7 mg/m2/week had major tumor reduction of multiple lung metastases but overall stable disease in abdominal and pleural disease. This patient discontinued plitidepsin due to reactivation of viral C hepatitis, and time to progression was 3.8 months (Fig. 1). At that time, the patient received plitidepsin again without additional evidence of clinical benefit. Three additional patients had disease stabilization as best response, including a patient with gastric cancer (1.2 mg/m2/week), 1 patient with a colonic carcinoid tumor (3.2 mg/m2/week), and 1 patient with colon cancer (3.6 mg/m2/week). Time to progression in the 5 patients with disease stabilization ranged from 1.2 to 3.8 months.
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A model-independent analysis of the data indicates that plitidepsin has a relatively long half-life, a low clearance, and a high volume of distribution in plasma (Table 5
). At the dose levels of 2.7 mg/m2/week and above, mean plasma half-life values ranged from 17 to 30 h. Over the same dose range, mean plasma clearance values ranged from 22 to 34 L/h, and corresponding mean volume of distribution in steady state values from 508 to 538 L. At the 3.2 mg/m2/week dose level, for which the most extensive data were available, whole blood and blood cell pellet plitidepsin concentrations and area under the curve values tended to be higher than those in plasma (blood cell pellet; data not shown). Mean volume of distribution in steady state was larger and mean clearance was higher in plasma compared with whole blood and blood cell pellets. Elimination half-lives in plasma, whole blood, and cell pellets were similar with mean values of 17, 24, and 17 hours, respectively.
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Urinary excretion of plitidepsin was very low, with a mean recovery over the first 48 hours of 4.3% (range, 0.02-10.2%) and <11% in all patients. These findings exclude renal excretion as a clinically relevant elimination route for plitidepsin.
There were no significant correlations between pharmacokinetic variables (e.g., plasma clearance, distribution volume, or half-life) and demographic variables (e.g., age, weight, or body surface area). Furthermore, plasma pharmacokinetic variables of plitidepsin were not significantly correlated with abnormalities in hepatic and renal function, as assessed by means of the absolute continuous value of alkaline phosphatase, alanine aminotransferase, AST, total bilirubin, and creatinine, except for a statistically significant negative correlation between clearance and elevated AST levels. For the blood cell pellet data, there were statistically significant negative correlations between the volume of distribution and clearance of plitidepsin and elevated creatinine levels. The significant results were not considered relevant due to the inconsistency (significant for AST but not for the other liver function tests; urinary excretion of unchanged plitidepsin plays a minor role in the total elimination of plitidepsin) and the multiplicity of retrospectively done tests.
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Discussion |
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Plitidepsin-induced muscular DLT constitutes transient muscular pain and weakness with late increases in CPK. Asymptomatic and severe CPK elevation was also observed as a DLT in this trial. Optical microscopy defined plitidepsin-related muscular toxic events as type II diffuse muscular atrophy (18). Early evidence from the phase I program evaluating different plitidepsin schedules showed that L-carnitine allowed further dose escalation in one of these phase I trials (25). However, a phase II trial comparing plitidepsin 5 mg/m2 for 24 hours every 2 weeks versus 7 mg/m2 plus L-carnitine has failed to show an improvement of the therapeutic index at the highest dose level. A clear protective effect of L-carnitine was not supported in this phase II trial as the worst muscular toxicity was observed with the highest dose of plitidepsin plus L-carnitine (26).
Having defined the MTD, an intermediate dose level (3.2 mg/m2/week) between the two highest dose levels in the dose escalation was evaluated as RD in 14 patients. The safety data in patients treated with plitidepsin 3.2 mg/m2/week indicate that this schedule is feasible in advanced pretreated cancer patients and can be considered for further clinical development. Phase II studies in which patients will likely receive a larger number of cycles may provide further confirmation of the appropriateness of this dose, taking into account potential cumulative toxicities not detected in the present phase I trial.
The general toxicity profile of plitidepsin over the dose levels investigated was primarily characterized by constitutional events, in particular, fatigue, asthenia and malaise, mild gastrointestinal events, namely nausea/vomiting, and various types of pain (abdominal, back, chest, or tumor pain). No toxic deaths were reported. In this phase I trial, the overall toxicity profile did not differ as a function of the number of cycles administered. 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. Muscular events such as myalgia, rigors, and muscle weakness were observed less frequently, but it cannot be excluded that some of the more frequent AEs such as pain, asthenia, and fatigue had underlying muscular causes. Nevertheless, as in most previous studies, the majority of CPK increases reported during this clinical trial were transient and did not require further intervention. The muscular toxicity of plitidepsin may be somewhat schedule dependent because a lower incidence was found in the daily for 5 days every 3 weeks schedule even in patients treated with multiple cycles (23). This needs to be taken with caution because CPK was only evaluated at baseline in that study, and CPK elevations anticipating muscular events might have been missed.
Biochemical abnormalities were observed at all dose levels. Elevations of lactate dehydrogenase and -glutamyltransferase did not show any dose relationship or a cumulative trend and were mostly observed in the context of progressive disease. Phase I studies evaluating other plitidepsin schedules did not report the incidence of these two laboratory abnormalities (23, 24). Transaminase elevations were also frequent and reached grade 3/4 severity. With the limitations of the data set, a dose relationship seemed to emerge. However, even at the RD, transaminase elevations were reversible and noncumulative, although the number of patients treated for a high number of cycles was insufficient to assess a potential cumulative liver toxicity. In addition, at this point, no recommendations regarding dose adjustments or exclusion criteria based on liver toxicity or liver variables are warranted. These aspects will need to be further assessed in phase II trials. No clear predisposing factor (e.g., particular prior chemotherapy, liver metastases, concomitant medication) for liver toxicity was found. The incidence of transaminase elevations with this weekly schedule was higher than that reported for other plitidepsin schedules (23, 24). This finding may point to a schedule-dependent liver toxicity. However, this may also be due, at least in part, to the higher percentage of patients with liver metastases (52%) in the present study compared with prior studies (23).
As anticipated in experimental models, this study has also confirmed a remarkable lack of bone marrow toxicities. Grade 3/4 toxicities were limited to anemia and lymphopenia in 6% and 10% of patients, respectively, with no clear dose relationship. No instances of severe neutropenia or thrombocytopenia were observed. Only mild neutropenia and thrombocytopenia was reported in 6% and 35% of patients, respectively. Other phase I studies of plitidepsin, using different dose schedules, have confirmed the lack of serious hematologic toxicity after plitidepsin treatment (23, 24). The lack of clinically relevant hematologic toxicity will facilitate the development of combination regimens with other cytotoxic agents, although liver toxicity will need to be considered in performing such combination studies.
No confirmed objective tumor responses were found. However, there were indications of treatment-related clinical benefit as evidenced by disease stabilization from 1.2 up to 3.8 months duration in 5 patients. Evidence of drug-induced tumor shrinkage was noted in two patients with renal cancer and medullar thyroid carcinoma (including an unconfirmed partial response). In prior phase I studies, stable disease ranging from 2 to 23 months was observed in various tumor types, including patients with documented progression at study entry (23, 24). In addition, two patients (one with non–small cell lung cancer and one with colorectal cancer) had evidence of tumor shrinkage without reaching partial response criteria (23).
Pharmacokinetic evaluations in plasma, whole blood, blood cell pellets, and urine indicate that plitidepsin has favorable characteristics for a drug that has been reported to induce optimal antitumor activity at prolonged exposure (3, 4). According to initial data collected in the current study and other phase I studies (24), plitidepsin seems to have a long half-life, low clearance, and a high volume of distribution. Thus, noncompartmental pharmacokinetic evaluation ascertained to date has shown that plitidepsin is widely distributed, with apparent volumes of distribution in steady state of 500 to 1,350 L, and has a prolonged elimination with terminal half-lives of 25 to 40 hours. Urinary excretion of unchanged compound is a minor elimination route, with average recoveries of 2% to 5% over 48 hours and maximum values below 15%. The major routes of elimination have not been determined yet. Preliminary population pharmacokinetic analysis has shown a good fit using a three-compatment model with first-order elimination and distribution constants, and that exposure increased proportionally with the dose. Nonlinear distribution, shown for other drugs formulated with cremophor (e.g., paclitaxel), has not been shown for plitidepsin. Pharmacokinetic samples will be obtained during the phase II studies at the RD suggested in this phase I study. This will allow for a better understanding of the pharmacokinetic and progressive disease characteristics of plitidepsin in this schedule, such as intrapatient variability, dose proportionality, exposure/toxicity, or exposure/efficacy relationships.
In conclusion, plitidepsin 3.2 mg/m2/week is proposed as the safe starting dose when given as 1-hour i.v. infusion weekly for 3 weeks on and a week off. Although the overall phase I data with plitidepsin do not allow to definitively select the most appropriate plitidepsin schedule in terms of potential benefit/risk ratio, they certainly warrant further exploration. A phase II exploratory program further evaluating the weekly and other schedules in various types of solid and hematologic malignancies is ongoing. This program will provide the data for selecting the most appropriate schedule and tumor type(s) for full clinical development.
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: M.A. Izquierdo is currently an employee of PharmaMar. J.A. López-Martín is currently working at the Hospital Ramon y Cajal, Madrid, Spain.
Received 7/ 6/07; revised 11/ 1/07; accepted 2/27/08.
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References |
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. Oncogene 2002;21:7533–44.[CrossRef][Medline]
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