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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Institut Català d'Oncologia and 2 Hospital Vall d'Hebron, Barcelona, Spain; and 3 Hospital Universitario 12 de Octubre and 4 PharmaMar R&D, Colmenar Viejo, Madrid, Spain
Requests for reprints: Beatriz Pardo, Institut Català d'Oncologia, Av. Gran Via s/n, km. 2.7, 08907-L'Hospitalet de Llobregat, Barcelona, Spain. Phone: 34932607744; Fax: 34932607741; E-mail: bpardo{at}ico.scs.es.
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Abstract |
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Experimental Design: Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 µg/m2, and dose escalation proceeded based on the worst toxicity found in the previous cohort.
Results: Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 µg/m2. Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 µg/m2, and the recommended dose for phase II studies was 650 µg/m2. No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent.
Conclusions: The maximum tolerated dose was 800 µg/m2. Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 µg/m2 was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.
Preclinical studies showed that kahalalide F is a COMPARE (National Cancer Institute)-negative compound that induces strong cytotoxic activity against solid tumor cell lines in vitro. Half maximal inhibitory concentration (IC50) values ranging from 200 nmol/L to 10 µmol/L were reported for kahalalide F against colon, central nervous system, melanoma, prostate, and breast cancer cell lines of human origin and, in general, against tumor cell lines overexpressing the Her2/neu gene, with hormone-independent prostate cancer cells being the most sensitive to kahalalide F (4). The cytotoxic effects of kahalalide F were confirmed in vitro using human tumor colony-forming units isolated from surgically removed samples of breast, colon, kidney, non–small cell lung, ovary, prostate, stomach, and uterine cancer (5). Kahalalide F was effective against several cell lines with strong multidrug resistance (e.g., PC-3 prostate, CACO-2 colon, UO-31 renal, or MCF7 breast) and against cell lines resistant to topoisomerase II inhibitors. No significant protection against cytotoxicity induced by kahalalide F was found with ectopic overexpression of the multidrug resistance protein, MDR1, or with inhibition of protein synthesis or caspase-dependent apoptosis (6). In vivo, total kahalalide F doses of 140 and 210 µg/kg administered i.p. once daily for 5 days resulted in treatment-to-control ratios of 15% and 5%, respectively, in athymic mice with human PC-3 prostate cancer samples implanted i.p. using hollow silastic fibers. Antitumor activity was also found against other human cell lines xenografted into athymic mice, including breast cancer (treatment-to-control ratio of 22%), non–small cell lung (treatment-to-control ratio of 37%), and colon cancer (treatment-to-control ratios of 41-47%). The feasibility of using multicourse schedules with kahalalide F was suggested by the finding of antitumor activity after each cycle in mice xenografted with human prostate tumors and treated with two cycles of kahalalide F at the maximum tolerated dose (MTD; 490 µg/kg) or the 1/2 MTD (245 µg/kg) levels (7).
The primary mechanism of action of kahalalide F remains to be elucidated, although multiple membrane-associated targets have been found that may be related to its hydrophobic nature, and evidence suggests that lysosomes may be a likely target. Incubation with kahalalide F even for short periods of time quickly induced loss of mitochondrial membrane potential and lysosomal integrity, severe cytoplasmic swelling and vacuolization, irregular clumping of chromatin within the cell nucleus, and finally, cell death in human breast and prostate cancer cells. These effects were independent of caspase activation and were not associated with DNA degradation or cell cycle block (6). Biologically relevant concentrations of kahalalide F induced similar effects, together with detachment from substrate and migration of large vacuoles from the cell periphery to a perinuclear location, both in normal kidney cells and in human epithelioid cervical carcinoma cells. Neither the cytoskeleton nor the morphology of the Golgi apparatus and the endoplasmic reticulum were affected by kahalalide F (8). In vitro tests have identified a cell cycle block in G0-G1 in several tumor cell lines sensitive to kahalalide F (IC50 values in the range of 1 µmol/L), including prostate, cervical, colon, head and neck, and non–small cell lung (7). Other studies found that kahalalide F also inhibits Her2/neu transmembrane tyrosine kinase activity, blocks the epidermal growth factor receptor, and inhibits transforming growth factor 
gene expression (9), all of which are growth factors that control the tyrosine kinase class I subfamily that normally mediates signal transduction in the Ras signaling pathway.
Several lines of evidence point to ErbB3 as a major determinant of kahalalide F action. The sensitivity to kahalalide F in a panel of tumor cell lines (including non–small cell lung, breast, ovarian, and hepatic carcinomas) significantly correlated with ErbB3 protein expression levels, whereas no correlation was found with the levels of epidermal growth factor receptor, ErbB2, and ErbB4. In contrast to the general down-regulation of ErbB family members observed after long-term exposure to kahalalide F, a 4-h treatment with kahalalide F resulted in the selective down-regulation of ErbB3 in a sensitive, high ErbB3-expressing cell line; moreover, ectopic expression of ErbB3 increased the kahalalide F sensitivity of a resistant cell line. The PI3K/Akt signaling pathway coupled to ErbB receptors was also affected by kahalalide F treatment. Kahalalide F decreased phosphorylated Akt levels, and the ectopic expression of a constitutively active Akt mutant reduced kahalalide F cytotoxicity in a sensitive cell line. Moreover, kahalalide F induced the redistribution of p27kip1, a marker for Akt activity, from the cytosol to the nucleus (10).
The toxicity profile of kahalalide F has been evaluated in mice, rats, and rabbits. Single i.v bolus injections of kahalalide F resulted in reversible alterations in liver function and, at doses greater than the MTD of 250 µg/kg, reversible nephrotoxicity and potentially fatal neurotoxicity in rodents (7). Fractionated administration of kahalalide F for 5 days did not result in drug-related mortality, histopathologic lesions, or clinical signs of toxicity in mice or rats (11).
A previous phase I clinical trial evaluated kahalalide F given daily for 5 days in cycles of 3 weeks in patients with advanced androgen-resistant prostate cancer. The dose-limiting toxicities (DLT) were reversible, and asymptomatic grade 3/4 increases in blood levels of transaminases. No other relevant toxicities, including severe hematologic toxicity, were observed, and the recommended dose was 560 µg/m2 (12).
The aim of this phase I study was to establish the MTD, and the recommended dose of kahalalide F administered as a weekly i.v. 1-h infusion to adult patients with advanced solid tumors.
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Materials and Methods |
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Objectives. The primary objective was to determine the MTD and the recommended dose for phase II studies of kahalalide F weekly i.v. 1-h infusion administered to adult patients with advanced solid tumors. The secondary objectives were to determine the safety and toxicity profile, and the corresponding DLTs, of kahalalide F; to study the pharmacokinetics of kahalalide F and its correlation with the toxicity of the drug; and to find preliminary evidence of antitumor activity in solid tumors.
Eligibility criteria. Patients were enrolled into the study if they had histologically or cytologically proven advanced malignant solid tumors for which no efficient standard treatment existed. The patients should have had evaluable disease during the last 4 weeks before entry into the study and should have recovered from any toxicities derived from previous anticancer radiotherapies and/or chemotherapies. Other eligibility criteria were as follows: Eastern Cooperative Oncology Group performance status, 0 to 2; life expectancy, 
3 months; age, >18 years and <70 years; adequate bone marrow reserve [absolute neutrophil count, 1.5 x 109/l; platelet count, 100 x 109/l; and hemoglobin, 9 g/dl; adequate hepatic function [serum bilirubin (
1.5) x the upper limit of normal (ULN), serum aspartate aminotransferase (AST), and alanine aminotransferase (ALT; 2.5) x ULN]; adequate renal function [creatinine clearance (calculated), 50 mL/min; and proteinuria, <100 mg/dl].
Patients were excluded if they fulfilled any of the following criteria: prior history of another malignant disease (other than cured nonmelanoma skin carcinoma, in situ carcinoma, and surface bladder cancer), history of serious cardiac disease (i.e., myocardial infarction, uncontrolled angina pectoris, and arrhythmia requiring medication), or serious liver disease. Patients with active bacterial infection, HIV infection, symptomatic brain involvement, ongoing grade of 2 neuropathy, and prior history of hypersensitivity to Cremophor were also excluded. No pregnant or nursing women were included in the study, and adequate contraceptive methods had to be used.
Study drug. Kahalalide F was supplied by PharmaMar as a sterile lyophilized product. Vials with two different kahalalide F strengths (50 or 150 µg) were reconstituted by adding 1 mL (50-µg vials) or 3 mL (150-µg vials) of reconstitution solution [Cremophor EL/Ethanol/Water at 5/5/90% (v/v/v)]. The resulting solution had a drug concentration of 50 µg/mL and was further diluted in normal saline solution (0.9% NaCl for injection) before i.v. administration, using an infusion set consisting of a glass container and silicon tubing.
Treatment plan. Kahalalide F was administered weekly, without any resting periods, as a 1-h i.v. infusion. The starting dose (266 µg/m2 per week) was chosen after the finding that kahalalide F total doses of up to 1,600 µg/m2 given every 3 weeks (in a fractionated daily x 5 schedule) were not associated with dose-limiting or drug-related toxicities in a previous phase I study (12). Initially, three patients were treated in each cohort. If none of these three patients had DLTs, dose escalation proceeded and the next patients enrolled into the study were given kahalalide F at a higher dose level, which was based on the worst toxicity found in the previous cohort (Table 1 ). If one of the first three patients in a cohort had a DLT, then the cohort was expanded to six patients; if no other patients in this cohort had a DLT, dose escalation proceeded as described above. If two or more patients at any cohort had a DLT, then that dose level was considered the MTD, and subsequent patients were treated at a lower dose level. The recommended dose for phase II studies was defined as the highest dose level at which less than two patients in a cohort of six patients experienced DLTs. Only DLTs occurring during the first 4 weeks of treatment were considered for establishing the MTD and the recommended dose. Once the recommended dose had been established, between 12 and 24 additional patients had to be enrolled into this cohort to provide more comprehensive safety and pyruvate kinase profiles at the recommended dose and preliminary data on the potential anticancer clinical effects of kahalalide F.
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1.5 x ULN; AST/ALT, 2.5 x ULN] before the next kahalalide F dose. If these criteria were not met at the time of evaluation, treatment was delayed for 1 week and the retreatment criteria were again evaluated. In case of no recovery within 2 weeks or in the event of a DLT, patients were withdrawn from the study unless the investigator felt that the patient had clinical benefit. In this case, treatment with kahalalide F could be continued at a reduced dose. Patients requiring more than two dose reductions without showing any signs of clinical benefit were withdrawn from the study. Evaluations. A complete medical history, an electrocardiogram, a chest X-ray, a physical examination (including neurologic examination), serum biochemistry tests, and a complete blood panel were obtained from all patients before receiving the first kahalalide F dose. During the study, some of these tests were repeated before each kahalalide F infusion (performance status, complete blood panel and, most serum biochemistry tests, including liver function tests), whereas others were repeated every four kahalalide F infusions (physical examination and the remaining serum biochemistry tests). Additional tests included a blood coagulation test (after the first infusion and then every four infusions) and a urinalysis (every four infusions). At the time of withdrawal from the study, the patients underwent a chest X-ray and an electrocardiogram.
Assessment of toxicity and DLTs. All toxicities were graded following the National Cancer Institute Common Toxicity Criteria, version 2.0. DLTs were defined as follows: absolute neutrophil count, <500/mm3 for >5 days; absolute neutrophil count, <500/mm3 with fever (at least 38.5°C); platelets, <25,000/mm3; any other grade 3/4 nonhematologic toxicity (except for nausea and/or vomiting without prophylaxis and/or treatment, grade 3 transaminase increase lasting for <14 days, or hypersensitivity reactions); and a delay of 2 consecutive weeks (missing two doses) due to persistent toxicity.
Assessment of response. Tumor response was assessed by evaluating unidimensionally or bidimensionally measurable lesions once every eight infusions. Response was determined using standard WHO criteria and, in case of response, confirmation was obtained 4 weeks later.
Pharmacokinetic analyses. Blood samples for pharmacokinetic evaluation were collected during the first kahalalide F infusion from all patients and during the second kahalalide F infusion from patients enrolled into the expanded cohort treated at the recommended dose level. Samples were collected at 12 time points: before infusion; 30 min after the beginning of infusion; at the end of infusion; and at 15, 30, 60, 90 min and 2, 4, 8, 10, and 24 h after the end of infusion. Blood samples (10 mL during the first extraction and 5 mL during all other extractions) were obtained using a peripheral catheter placed in a vein of the arm contralateral to that used for kahalalide F administration. Plasma was obtained by centrifugation and stored at –20°C.
Complete plasma concentration-time profiles of kahalalide F were analyzed by standard noncompartmental pharmacokinetic methods. Plasma drug concentrations were determined using a validated high performance liquid chromatography system coupled with electrospray ionization tandem mass spectrometry method. The lower limit of quantification was 1 ng/mL (13, 14), and predose values below the limit of quantification of the assay were set to zero; whereas values below the limit of quantification of the assay that occurred after maximum plasma concentration were set to missing. The pharmacokinetic variables derived from plasma kahalalide F concentrations were as follows: area under the plasma concentration-time curve from time zero to infinity (AUCinf), total body clearance (CL), observed maximum plasma concentration (Cmax), terminal phase half-life (t1/2), and apparent volume of distribution at steady-state (Vss). Each variable was tabulated and summarized per dose level using count (N), mean, SD, coefficient of variation, median, minimum and maximum. The relationship between plasma pharmacokinetic variables and total kahalalide F dose was depicted graphically. Acceptance ranges for linear dose proportionality were established after a power model–based method described by Smith et al. (15). The same method was used to establish acceptance ranges in a linear regression analysis that evaluated the relationship of pharmacokinetic variables with patient characteristics; this was complemented with a multivariate analysis that explored the mutual relationships and relative importance of the different baseline patient variables across all categories. The relationship between pharmacokinetic variables and adverse effects was evaluated using an analysis of covariance model. All calculations used the actual sampling times, and statistical analyses were done using SPSS, release 9.0 or the SAS SYSTEM, release 8.02.
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Results |
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5 h after kahalalide F infusion that triggered an early blood testing, which in turn showed a grade 4 increase in both AST and ALT levels that was reported as a DLT. No creatine phosphokinase elevation was observed, and a myocardial event was excluded. This suggested that the peak effect of kahalalide F on blood transaminase levels may take place shortly after administration and raised the possibility that this peak effect may have gone unnoticed in previous dose levels. Therefore, an intermediate lower dose level (1,000 µg/m2) was explored in the next study cohort, and extra blood samples were collected from these patients at 4 and 24 h postdose for ALT/AST determination. Two of the first three patients experienced DLTs in the form of acute transient grade 4 increases in blood AST and ALT. As a result, additional patients were recruited at the previously tested dose level of 800 µg/m2. Two of the three patients included in the expanded cohort had DLTs, which again consisted of acute transient grade 4 increases in blood AST and ALT levels, and dose was further reduced to a new intermediate level (650 µg/m2). Only one of the first three patients included at this dose level had a DLT (transient grade 4 increases in blood AST and ALT levels) that resolved within 6 days. Therefore, 800 µg/m2 was considered to be the MTD for kahalalide F administered weekly, and 650 µg/m2 was established as the recommended dose for further studies. Ten more patients were then recruited into the 650 µg/m2 cohort.
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All treatment-related adverse events found in the 13 patients who received a total of 109 cycles of weekly kahalalide F at the recommended dose of 650 µg/m2 were mild or moderate (Table 4 ). The most common of these events at the recommended dose were pruritus (5 patients in 41 cycles), fatigue (4 patients in 35 cycles), and hypersensitivity reactions (3 patients in 15 cycles). Pruritus occurred mostly, although not exclusively, in the palms as a tingling sensation, initiated during or shortly after the kahalalide F infusion, was mild in severity (grade 1 and 2 in 36 and 5 cycles, respectively), and resolved within a few hours. No patients required dose delays or reductions as a result of pruritus. Hypersensitivity reactions were mild in 13 cycles and moderate in 2 cycles. All cases appeared on the same day of kahalalide F infusion but resolved within 1 day without requiring any dose delays or reductions.
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IFN for 4 months, and when disease progression was detected, she received dacarbazine for nine cycles until disease progression was detected. The patient received up to 80 cycles of weekly kahalalide F (the initial dose of 800 µg/m2 was reduced to 600 µg/m2 after cycle 3 due to ALT/AST increase) and showed unconfirmed partial response after cycle 51. The second patient with response was a 56-year-old woman with metastatic lung adenocarcinoma who received four cycles of kahalalide F 1,000 µg/m2. Minor response was detected after cycle 1 and was maintained throughout the patient's participation in the study. The patient discontinued the study after cycle 4 due to clinical signs related to disease progression, and she died due to malignant disease 1 month after discontinuing kahalalide F treatment.
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Pharmacokinetics. Thirty-five patients were evaluable for noncompartmental pharmacokinetics. Table 7
summarizes the plasma pharmacokinetic variables measured in the first treatment cycle, grouped by dose level. Kahalalide F given as a once-weekly i.v. 1-h infusion was characterized by a narrow distribution and short body residence. After administration of the first kahalalide F infusion at the recommended dose of 650 µg/m2, the median volume of distribution at steady-state (Vss) was 5.55 liters (with values ranging from 4.25 to 10.86 liters), and the median half-life (t1/2) was 0.52 h (with values ranging from 0.22 to 1.48 h). Both AUC and Cmax values increased with dose, and although Cmax did so proportionally, AUC increased more than linearly at doses higher than the recommended dose for phase II studies. Interpatient variability was moderate, and the coefficients of variation for t1/2, Vss, and CL were, respectively, 52.4%, 33.2%, and 49.0%. Intrapatient variability was low, and variation between the pharmacokinetic variables of cycles 1 and 2 was <10%. Linear regression analysis of natural logarithm-transformed plasma pharmacokinetic values revealed that both CL and Vss increased with body size and were best predicted with body surface area and height, respectively. No significant correlation was found between CL, and baseline tests for renal function (creatinine) and liver function (total bilirubin, AST, ALT, 
-glutamyltransferase, and alkaline phosphatase). Increases in ALT levels reported by the patients after kahalalide F treatment were related to drug exposure (ALT versus AUC; P = 0.0383). The relationship between ALT/AST increases, and Cmax was close but did not reach statistical significance. No other conclusive predictors were found for other adverse events.
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Discussion |
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5 h after kahalalide F administration, and was detected incidentally in an unplanned blood test, thus suggesting that the peak effect of kahalalide F on blood transaminase levels might have gone unnoticed in previous dose levels. Dose level V (800 µg/m2) was the lowest at which at least two patients experienced DLTs during the first 4 weeks of treatment, and thus was declared the MTD. The recommended dose for phase II clinical trials with this schedule was 650 µg/m2, the dose immediately below the MTD.
Once-weekly, kahalalide F was generally well-tolerated. Severe blood transaminase increases were the only DLT reported, and involved 3 of 13 patients treated at the recommended dose of 650 µg/m2. At this dose level, grade 3/4 increases in AST and/or ALT levels appeared during the 1st or 2nd day after kahalalide F administration but were transient and reversible, as they returned to grade 1/2 toxicity values within 6 to 9 days. No evidence of cumulative hepatic toxicity was found. Additionally, no patients treated at the recommended dose level showed signs of hepatic dysfunction. Grade 3 increases in the blood levels of -glutamyltransferase were also detected in 35 cycles but were not dose limiting. Severe hematologic toxicities were uncommon and included two patients with grade 3/4 anemia and two with grade 3 lymphopenia; however, these effects were transient and showed no clear relationship with the kahalalide F dose level. Of note, no relevant neutropenia or thrombocytopenia was observed after kahalalide F treatment.
Mild pruritus initiated typically as a tingling sensation in the palms was a characteristic side effect of kahalalide F. However, there was no indication of worsening with subsequent cycles and did not indicate dose reductions or delays.
Other treatment-related adverse events (e.g., fatigue or nausea) were mild or moderate. Other potential drug-related toxic effects suggested by preclinical studies, such as nephrotoxicity or neurotoxicity, had little relevance as they were found in few patients and never reached grade 3/4 severity. The incidence of other toxicities such as alopecia, mucositis, vomiting, and myocardiotoxicity was negligible.
Overall, the toxicity profile of kahalalide F given as once-weekly 1-h infusions was similar to that reported in a previous phase I trial with kahalalide F given as a 1-h infusion daily for 5 days in cycles of 3 weeks. The recommended dose of kahalalide F 560 µg/m2 was also characterized by transient and noncumulative grade 3/4 transaminase elevation, negligible hematologic toxicity, and generally mild-moderate adverse events (the most common being nausea, fatigue, vomiting, and hypersensitivity reactions; ref. 12). The absence of hematologic toxicity and cumulative toxic effects suggests that kahalalide F may be suitable for combination trials with other anticancer agents.
The pharmacokinetic profile of kahalalide F given as a once-weekly 1-h i.v. infusion overall agrees with that reported for the other kahalalide F schedule tested to date (12). Both infusion schedules were characterized by linear kinetics for Cmax and AUC values (at doses up to the recommended dose for phase II studies), a narrow volume of distribution (5.55 liters at the recommended dose with the once-weekly schedule versus 7.16 liters at the recommended dose with the daily schedule), and a short terminal half-life (0.52 h versus 0.47 h, respectively). In both kahalalide F schedules, clearance and volume of distribution increased with body size and were best predicted with body surface area and height, respectively, although height might be a surrogate for lean body mass. A close correlation was suggested between exposure to kahalalide F and the risk of severe grade 3/4 increases in transaminase levels at higher dose levels; however, no evidence of biotransformation has been found to date (16), and therefore, the changes in liver function found at higher kahalalide F levels may not be explained by the presence of metabolites. The apparent lack of biotransformation also suggests that drug-drug interactions derived from interferences with cytochrome P450–mediated metabolism are unlikely.
Of the eight patients who experienced clinical benefit after receiving kahalalide F given once weekly as 1-h infusions, five had tumor types previously shown to be sensitive to kahalalide F by in vitro studies (6, 17): these included two patients with forms of non–small cell lung (squamous cell carcinoma or adenocarcinoma), one with adenocarcinoma of cervix, one with infiltrating ductal breast carcinoma, and one with malignant melanoma. In addition, two patients with pancreatic cancer and hepatocellular carcinoma also showed evidence of clinical benefit.
In conclusion, this study confirms acute and reversible grade 3/4 transaminase increases as the main DLT associated with weekly kahalalide F 1-h infusions, and shows kahalalide F 650 µg/m2 as a safe dose for future phase II studies evaluating this schedule in the treatment of solid tumors. Additionally, evidence suggests that kahalalide F may be active against more tumor types than was originally thought based on preclinical studies. The combination of both low toxicity and early evidence for clinical benefit in pretreated patients supports that kahalalide F may have a favorable therapeutic index and, therefore, deserves further clinical testing either as single agent or in combination.
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Acknowledgments |
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Footnotes |
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Note: M.A. Izquierdo is currently an employee of PharmaMar.
Received 9/18/07; revised 11/14/07; accepted 11/18/07.
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