© 2006 European Society for Medical Oncology
phase I and pharmacokinetics |
Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115
1 The Ottawa Hospital Regional Cancer Centre, Ottawa, Ontario, Canada
2 Centre Hospitalier Université de Montréal, Pavillon Notre-Dame, Montréal, Québec, Canada
3 NCIC Clinical Trials Group, Kingston, Ontario, Canada
4 MD Anderson Cancer Centre, Houston, Texas, USA
5 Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
6 Northeastern Ontario Oncology Program, Sudbury, Ontario, Canada
7 Pharma-Mar R&D, Colmenar Viejo, Madrid, Spain
*Correspondence to: Dr J. Maroun, Ottawa Hospital Regional Cancer Centre, 501 Smyth Road, Box #911, Ottawa, Ontario K1H 8L6, Canada. Tel: +1 (613) 737-7700 x70181; Fax: +1 (613) 247-3511; E-mail: jmaroun{at}ottawahospital.on.ca
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Abstract |
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Background: Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans.
Methods: This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose.
Results: Thirty-seven patients were accrued on study. Doses ranged from 80 µg/m2 to 1500 µg/m2/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 µg/m2 and 1350 µg/m2/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 µg/m2 daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer.
Conclusions: Aplidine given at a dose of 1200 µg/m2 daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.
Key words: Aplidine, phase I clinical trial
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introduction |
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Didemnins have been of interest as potential cancer therapeutics for some years; the parent compound, didemnin B (DB) was incorporated into clinical development in the early 1980s [1]. Phase I/II studies involving DB were hampered by the onset of unpredictable severe muscular events with muscular necrosis, neurological toxicity with axonal neuropathy, neuromotor, neurophysiological and neuroclinical grade 3/4 toxicity [2, 3] and severe gastrointestinal toxicity [4] that precluded the administration of effective doses in multiple cycles. In spite of promising results in patients with advanced pretreated lymphoma [3] the clinical development of DB was stopped to seek for second generation didemnins harbouring a better therapeutic index. Aplidine (dehydrodidemnin B) is a novel cyclic depsipeptide derived from the Mediterranean marine tunicate Aplidium albicans, which is structurally related to the didemnins. Aplidine has been shown to have in vitro activity against several human hematological and solid tumor cell lines [4–8]. It has also been shown to be more active in vivo versus murine B16 melanoma and other human xenografts in athymic nude mice [9]. Aplidine appears to exert its anticancer activity via a number of different mechanisms. Aplidine inhibits protein synthesis via GTP-dependent elongation factor 1-
[10]. It inhibits DNA synthesis and ornithine decarboxylase activity and has an effect on palmitoyl thioesterase that is involved in signal transduction process of cellular proliferation [11]. Aplidine inhibits VEGF-RI gene expression and blocks cell cycle progression in G1 phase. Finally Aplidine has antiviral and immunosuppressive properties [12]. Preclinical toxicology studies demonstrated expected toxicity for this class of agent and included lymphocyte necrosis and thymic atrophy, gastric ulceration, hepatic damage, cardiotoxicity and muscular toxicity with neurological components. However, these toxicities were less severe, and occurred at higher doses, compared with didemnin B, suggesting that Aplidine had a better therapeutic index [1, 4]. Preclinical models also demonstrated that prolonged exposure with dose dense schemas of Aplidine had a significant activity and that this activity is schedule dependent [13]. Phase I studies addressed this observation by proposing weekly or daily schedules [14].
We report here on an open-label Phase I study conducted in two centres. The purpose of the study was to evaluate the toxicity and pharmacokinetics of Aplidine when given as a one hour intravenous infusion daily for 5 days every three weeks, and to define the dose limiting toxicities (DLT), the maximal tolerated dose (MTD), and the recommended phase II dose (RP2D) for further study. As neuromuscular events were limiting factors in the development of the parent compound [2], this study aimed, in addition, to characterize Aplidine's muscular and related neurological toxicities by using clinical and instrumental tests.
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material and methods |
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eligibility
Patients with histological or cytological proof of solid tumors or low/intermediate grade Non-Hodgkin's lymphomas with advanced or metastatic disease, refractory to or not suitable for conventional therapy, were eligible. Other eligibility criteria included age
18, an ECOG performance status of 2 or less, clinically or radiologically assessable disease and adequate hematological and biochemical functions (normal renal function, bilirubin within normal limits, hepatic transaminases and alkaline phosphatase 
3 times upper limit of normal, or 5 times upper limit of normal in the presence of known liver metastases). Prior radiation therapy was acceptable if it involved < 30% of bone marrow reserves. Patients had adequate cardiac function (left ventricular ejection fraction > 45%), neurotoxicity no worse than grade 1, and no evidence of symptomatic CNS metastases. Patients must have recovered from previous chemotherapy (no limits were placed on the number of prior regimens) and radiation therapy. Concomitant therapy with Coumadin or investigational agents was not permitted; patients who had experienced hypersensitivity reactions with Cremophor, or pregnant or lactating women were ineligible. All patients signed an informed consent and the study was approved by each institutional Ethics Review Board.
evaluations
Pretreatment evaluation included: medical history; physical examination including weight, body surface area and performance status; complete blood cell count; electrolytes, creatinine, total protein, albumin, bilirubin, alkaline phosphatase, glucose, AST, ALT, BUN, uric acid, calcium, phosphate, creatine phosphokinase, aldolase, prothrombin time, partial thromboplastin time; urinalysis; ECG; chest x-ray; left ventricular ejection fraction; imaging of all measurable and/or evaluable disease. All patients were re-assessed every 3 weeks; toxicity was graded using the Common Toxicity Criteria version 2.0. Hematology and coagulation tests were repeated twice weekly for the first two cycles and weekly thereafter. Biochemistry was done weekly for cycles 1 and 2 and then every 3 weeks. Imaging studies were repeated every 6 weeks. After the last treatment each patient was observed at one month, then every 3 months until disease progression, for documentation of late toxicity and disease status. Neurological evaluation was carried out using objective testing (determination of reflexes, tandem walking, Romberg test etc.) and two questionnaires assessing physical ability and symptoms of paraesthesia. Muscular evaluation included physical exams to determine the degree of myalgia, strength tests (dynamometer readings) and vibration perception threshold (vibrameter readings).
All patients who had received at least one cycle of therapy and had their measurable disease re-assessed were considered evaluable for response; patients with objective progression in cycle 1 were also considered evaluable for response. Response was classified as follows:
- Complete response. Disappearance of all clinical and radiological evidence of tumor, determined by two observations not less than 4 weeks apart with no tumor related symptoms.
- Partial response. 50% or greater decrease in the overall sum of measurable lesions determined by two observations not less than 4 weeks apart with no simultaneous increase in the size of any lesion nor the appearance of any new lesions. Non-measurable lesions must have remained stable or regressed.
- Response duration. This was measured from the time measurement criteria for response were first met until disease progression was objectively documented.
- Stable disease. Steady state of disease less than partial response or progression less than progressive disease present for at least 4 weeks from the start of therapy, with no new lesions.
- Stable disease duration. This was measured from the time of start of therapy until disease progression.
- Progressive disease. An unequivocal increase of at least 25% in the overall sum of measurable lesions as compared to baseline, or the nadir sum of lesions. Appearance of new lesions also constituted progressive disease.
starting dose and escalation schedule
Aplidine was given at a starting dose of 80 µg/m2 IV daily x5 days every 3 weeks. The dose selected was 1/10th of the MTD defined in preclinical rodent and canine toxicology studies. Doses were escalated according to a modified Fibonacci scheme. Cohorts of three patients were entered at each dose level; escalation to the next dose level occurred if none of the three patients demonstrated DLT during the first cycle of treatment. If one of the first three patients exhibited a DLT, three more patients were treated at that dose level for a total of six patients. If < two of six patients experienced a DLT, accrual was initiated at next higher dose level. If two patients experienced a DLT, then the dose was declared the maximum tolerated dose and the next lower dose was recommended for future phase II/III studies using Aplidine in this schedule.
DLT was defined as neutropenia grade 4 for 5 days, thrombocytopenia grade 3, febrile neutropenia, thrombocytopenic bleeding, grade 3 or 4 non-hematologic toxicity (excluding hypersensitivity reactions or unpremedicated nausea or vomiting) or persistent grade 2 neurotoxicity.
drug administration
Aplidine was supplied by Pharma Mar (Madrid, Spain). Each vial contained 500 µg of lyophilized powder. Ampoules were reconstituted with 15/15/70% v/v/v Cremophor EL/Ethanol/water to a concentration of 0.5 mg/ml. Aplidine was further diluted in normal saline (0.9% NaCl) and infused over 60 min through a PVC-free, low absorption tubing set.
Patients were not routinely premedicated for nausea and vomiting or for hypersensitivity reactions. If patients experienced nausea and/or vomiting, anti-emetics were introduced prophylactically in subsequent cycles; prophylactic premedication for nausea or vomiting or hypersensitivity could be introduced for all patients if the incidence of such events were felt to warrant this. Doses of Aplidine were reduced by 25% for subsequent cycles if DLT occurred, with the exception of grade 4 non-hematologic toxicity, when Aplidine was permanently discontinued. Treatment with Aplidine was to be continued until disease progression, the occurrence of unacceptable toxicity, for two cycles after confirmation of complete response or a partial response, or, in the event of stable disease, for a maximum of six cycles.
The study was conducted in two centres: the Ottawa Regional Cancer Centre and the CHUM-Pavillon Notre-Dame, Montreal.
clinical pharmacokinetics
Clinical pharmacokinetic studies (PK) were performed in consenting patients during the first cycle of therapy. The purpose was to estimate the individual patient's plasma level of drug and to derive the main pharmacokinetic parameters of Aplidine. Blood samples were collected prior to the start of the daily 1-h infusion from day 1 to 5 and also at the end of the infusion on days 1 and 5. Ten additional blood samples were taken at different time points over 8 hours post infusion on days 1 and 5. Plasma and blood concentrations of Aplidine were determined at the Mario Negri Institute using a validated high performance liquid chromatography system coupled to a mass spectrometer (HPLC/MS) method [1]. The lower limit of quantification (LLOQ) was 0.25 ng/ml in general, but for some assay runs, it was increased to 0.5 or 1.0 ng/ml depending on the assay performance for that run.
Due to logistic reasons such as the need for week-end sampling, some key samples were not obtained thus precluding model-dependent pharmacokinetic analysis. Analysis was therefore limited to the model-independent parameters of Cmax and AUC0
7hrs (from the beginning of infusion through to 7 h after the start of the infusion on days 1 and 5 of cycle 1 of therapy).
All derived individual PK parameters were tabulated and summarized for each treatment and sample matrix for the evaluable PK population using count per cohort (n = number of available PK samples per dose level), mean, median, minimum and maximum values. The relationship between the PK parameters Cmax and AUC07hrs and dose was depicted for both plasma and whole blood. For all parameters, 95% CI were used.
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results |
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Between February 15, 1999 and February 2, 2002, 37 patients were entered on the study. There were 12 females and 25 males, 31 patients had a performance status of 0–1 and six patients a performance status of 2. The median age was 54 years (range 18–77). The most commonly treated tumors were colorectal, lung, renal, head and neck, sarcomas and mesotheliomas. Six patients had no prior treatment, 19 patients had prior radiation therapy and 31 patients had received 1–6 prior chemotherapy regimens, with 12 and nine patients receiving two and three prior regimens respectively. Eighteen patients previously received at least one type of neurotoxic drugs (15 patients received vincas, nine taxanes and 15 patients platin salts). Demographic data is shown in Table 1. A total of 104 evaluable cycles of Aplidine were administered with a range of 1–14 cycles per patient. Eleven patients (30%) received more than three cycles of therapy and four patients (11%) were exposed to six or more courses of therapy. Dose levels ranged from 80 µg/m2 to 1500 µg/m2 given daily for 5 days and repeated every 3 weeks (Table 2).
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toxicity
All patients were evaluable for toxicity.
non-hematological toxicity.
The main toxicities encountered with Aplidine were non-hematological. Drug related severe ( grade 3) events included fatigue (13.5%), nausea (5.4%), hypersensitivity reactions and skin rash (5.4% each), myalgia, vomiting, anorexia and diarrhea (2.7% each) (Table 3). Prophylactic anti-emetics (including dopamine- and 5HT3 antagonists and dexamethazone) were introduced at the 1200 µg/m2 dose level following the observation of an increase in the incidence of severe nausea and vomiting at the previous dose levels. Hypersensitivity reactions (all grades) occurred in 16 patients; they consisted mainly of flushing, rash, chest tightness and allergy-like symptoms. These were due to Cremophor, a known cause of hypersensitivity, with no relationship between the dose of Aplidine and the severity of the event.
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neuromuscular toxicity.
There were neuromotor and neurosensory changes recorded at all dose levels. These were generally grade 1 or 2 in severity, short lasting and reversible. Of note, at the fourth dose level (360 µg/m2), one patient previously treated with non neurotoxic drugs experienced grade 4 muscle weakness and dyspnoea considered related to the progression of the disease and not to the study drug. Another patient at this same dose level experienced some grade 2 neuro-motor changes (abnormal tandem walking) at the end of cycle 1 but these were transient. Also, at the ninth dose level (1500 µg/m2), one patient had grade 3 myalgia in cycle 2 and this was considered dose limiting. Data from dynamometer and vibrameter tests measuring the maximum change from baseline in hand strength and perception and extinction of vibration in both hands and feet are presented in Table 4. For dynamometer readings only, lower scores represent higher toxicity.
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The results derived from the two questionnaires assessing physical ability and paresthesia and from the objective neurological testing (tandem walking, Romberg test etc.) are presented in Table 5. Higher scores represent a maximal change from baseline and reflect higher toxicity. Overall neurological evaluations did not reveal any obvious dose related effects.
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hematological toxicity.
No drug related granulocytopenia or thrombocytopenia were noted; Anemia was more frequent, although predominantly grade 1 or 2. Anemia did not appear to be dose dependent. Lymphocytopenia was the most common hematological abnormality, with grades 2 and 3 documented in 65% of the patients. Median nadirs ranged from 0.40 to 1.2 (x 109/L). This finding might be consistent with the known immunosuppressive effects of Aplidine. This specific drug related effect did not lead to clinically relevant complications and was considered a laboratory event.
biochemical toxicity.
Biochemical toxicities were uncommon; few grade 1 and 2 changes were documented and included mainly abnormalities in liver function tests, aldolase, AST. One patient at starting dose 1200 µg/m2 had a grade 1 rise in creatine phosphokinase levels and another one at 1500 µg/m2 had a grade 2 rise with grade 3 myalgia. One patient experienced a grade 3 elevation of alkaline phosphatase at the highest dose level at 1500 µg/m2.
dose limiting toxicity and recommended phase II dose.
At the 9th dose level of 1500 µg/m2, two out of three accrued patients experienced a DLT; one patient had grade 3 nausea and vomiting leading to dehydration despite adequate pretreatment with standard anti-emetics (Prochlorperazine) and a grade 3 skin rash. Treatment with Granisetron HCl and Dexamethazone was introduced on days 3 and 4, but this was ineffective. Patient was hospitalized for rehydration on Day 5, nausea and vomiting improved and he was discharged the following day. The second patient had grade 3 myalgia in cycle 2, with grade 2 creatinine phosphokinase elevation. This was considered a DLT despite the fact that it occurred in cycle 2, as manifestations of muscular toxicity only occur 4–5 weeks after treatment initiation. It was considered that the MTD had been reached at the dose level of 1500 µg/m2.
Since the 1200 µg/m2 dose level was well tolerated, an intermediate dose level of 1350 µg/m2 was chosen. However, two other patients experienced DLTs in this cohort: first patient had grade 3 erythematous skin rash and grade 3 fatigue. The DLTs resolved within a week. The other patient had grade 3 diarrhea and grade 3 fatigue. He was not hospitalized and toxicity resolved within a week. The two events indicated that 1350 µg/m2 was also a maximal tolerated dose. It was concluded that the DLT of Aplidine given in this schedule consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea and the recommended dose for phase II studies was 1200 µg/m2 daily for 5 days, given every 3 weeks.
The proposed recommended dose appears to harbour an appropriate safety profile with lack of severe toxicities. At this dose level, grade mild to moderate fatigue and vomiting appeared to be the most prevalent drug related side effects.
pharmacokinetics
Pharmacokinetic evaluation was performed in all 37 patients on study. During the study it was realized that concentrations of Aplidine in whole blood were higher than in plasma. Therefore, whole blood based sampling was performed in the late patients. Results of whole blood PK parameters are shown in Table 6. Full plasma profiles were available in 13 patients on day 1 and 14 on day 5, and whole Aplidine AUC07 hrs and Cmax values generally increased with dose. In plasma, the statistical analysis revealed that dose-proportionality was inconclusive over the dose range 80 to 540 µg/m2/day, most probably due to the limited sample size for all dose levels, and a high interpatient variability. In whole blood AUC07 hrs and Cmax were not dose-proportional over the dose range 540 to 1500 µg/m2/day. There were no statistically significant gender differences in Aplidine AUC07hrs and Cmax in plasma or whole blood. Though model dependent pharmacokinetic parameters of Aplidine including clearance, volume of distribution and half life were not obtained due to limited sampling schedules in this study, pharmacokinetics in the other phase I studies demonstrated that PKs of Aplidine were compatible with dose linearity up to the recommended dose levels and follows a tri-compartmental model; the distribution is extensive with a median terminal life of 34 h [4]. A representative plot of the whole blood Aplidine PK distribution at the recommended dose (1200 µg/m2/day) at day 1 and 5 of the first cycle is presented in Figure 1. It is important to note that based on preclinical data, therapeutic plasma concentrations (>1 µg/µl) were achieved well below the recommended dose level.
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anti-tumor activity
Thirty-three patients were evaluable for response. In two patients, disease was not re-evaluated with repeat imaging, one patient died before disease re-evaluation and one patient had no measurable disease. Nine patients with various tumor types (three colorectal, two lung, one renal, head and neck, mesothelioma, sarcoma respectively) had stable disease with a median duration of 5.3 months (range 2.2–23.0 months). Of note, two of these patients were chemonaive at study start; the others had had between two and five lines of therapy prior to study start. Stable disease was observed at six different dose levels of Aplidine. Three of these patients had stable disease for 7, 10 and 11 months respectively. Two patients had a minor response without reaching partial response criteria: one patient with NSCLC at 1500 µg/m2 had a 36% decrease in tumor measurements at cycle 3 and another patient with colorectal cancer at 720 µg/m2 had a 22% decrease in cycle 4. Both patients progressed subsequently at cycle 5 and 6 respectively and were taken off study.
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discussion |
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This phase I study is one of six previously reported schedules selected for evaluation. Other schedules included 24 h continuous infusion weekly for 3 weeks, repeated every 4 weeks (Recommended Phase II Dose (RP2D) 3750 µg/m2) [15], a 1-h infusion weekly for 3 weeks repeated every 4 weeks (RP2D 3200 µg/m2) [16], 24 or 3-h continuous infusion given on alternate weeks (RP2D 5000 µg/m2) [17, 18]. Another study used Carnitine as a protector against muscular toxicity with a 24-h infusion of Aplidine given every 2 weeks. (RP2D 7000 µg/m2).
Interestingly, the reported toxicities of Aplidine in all schedules tested appeared to be somewhat schedule dependent. Nausea, vomiting and fatigue were common to all schedules [14], and were similar to that reported for didemnin B [12]; based on this data, appropriate prophylactic anti-emetics is recommended for all patients treated with Aplidine. However, dose limiting muscular toxicity was observed in almost all schedules other than the daily times five schedule, while dose limiting hepatotoxicity was seen in two regimens, the weekly 24-h continuous infusion and the 3-h infusion given every second week schedules.
Muscular toxicity noted in other studies was characterized by muscle cramps and weakness associated with an increase in creatine kinase with normal MB fraction. Pathological changes were characterized by type II fiber atrophy, minimal changes on optic microscopy and specific accumulation of glycogen and autophagocytic vacuoles on electron microscopy. The mechanism of muscular toxicity was postulated to be related to carnitine palmitoyl transferase deficiency that could be treated with carnitine supplements. L-carnitine was incorporated in the alternate week 24-h continuous infusion schedule leading to a decrease in muscular toxicity and allowing an increase in the recommended dose of Aplidine to 7000 µg/m2 [19, 20].
Our study evaluated a 1-hour infusion given for 5 days every 3 weeks. Thirty-seven patients were accrued at 10 dose levels from a starting dose of 80 µg/m2 to 1500 µg/m2 daily for 5 days. Overall this schedule was well tolerated with no significant hematological or biochemical toxicities. Non-hematological toxicities were more common and consisted mainly of fatigue, nausea, vomiting and anorexia. In our study muscular toxicity was not dose limiting and not noted to be a prevalent drug related toxicity even in patients treated with multiple cycles. As we only conducted evaluation of CPK and aldolases at baseline there is the possibility that laboratory abnormalities anticipating muscular events have been missed in our trial. However, as muscular toxicity is historically significant, it is recommended to be carefully assessed with biochemical changes, although no instrumental testing may be necessary.
The characterization of the potential neurotoxic effects of Aplidine has been one of the objectives of our study; based on the results, we estimate that neurological evaluation is no longer mandatory in patients treated with Aplidine in a daily time five schedule. However, further studies might be needed if Aplidine is combined with neurotoxic anticancer agents. Neurosensory abnormalities, taste disturbance and stomatitis were not significant. DLTs consisted of fatigue, nausea and vomiting, diarrhea and rash. The dose recommended for further study is 1200 µg/m2 daily for 5 days repeated every 3 weeks.
In our study there was evidence of stability of disease in various tumor types and evidence of tumor shrinkage in pretreated/progressive non-small cell lung cancer and colorectal cancer where two minor responses were documented. Previous animal studies suggested that prolonged exposure to Aplidine is required for anti-tumor activity. Interestingly, this schedule displayed prolonged half life of Aplidine in humans supporting the use of this schedule in clinical trials. In other phase I studies objective evidence of anti-tumor activity and clinical benefit has been noted in different tumor types such as malignant melanoma, gastric carcinoma, renal cell carcinoma, medullary thyroid cancers, bronchial carcinoids and non-Hodgkin lymphoma [14].
Phase II studies incorporating the every other week and the weekly schedules are underway in solid tumors and hematological malignancies. Early phase II data are producing evidence of activity in advanced pretreated melanoma [21] and multiple myeloma [22].
In conclusion, Aplidine given at a dose of 1200 µg/m2 daily for five days, every three weeks is generally well tolerated, has some evidence of anti-tumor activity, and appears to be associated with less muscular toxicity when compared to other treatment schedules tested. This schedule is being incorporated into a phase I combination study with Cytosine Arabinoside in patients with refractory leukemia and lymphoma [23]. Phase II studies of this regimen in solid tumors and in other hematological malignancies are ongoing.
Received for publication August 24, 2005. Revision received May 30, 2006. Revision received June 19, 2006. Accepted for publication June 20, 2006.
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