Anda di halaman 1dari 9

Cancer Chemother Pharmacol (2013) 72:7583

DOI 10.1007/s00280-013-2170-5

ORIGINAL ARTICLE

Phase I study of weekly kahalalide F as prolonged infusion


in patients with advanced solid tumors
R. Salazar H. Cortes-Funes E. Casado B. Pardo A. Lopez-Martn
C. Cuadra J. Tabernero C. Coronado M. Garca A. Soto Matos-Pita

B. Miguel-Lillo M. Cullell-Young J. L. Iglesias Dios L. Paz-Ares

Received: 14 January 2013 / Accepted: 17 April 2013 / Published online: 5 May 2013
Springer-Verlag Berlin Heidelberg 2013

Abstract paresthesia, pruritus, nausea, vomiting, and rash were the


Purpose Kahalalide F (KF) is a dehydroaminobutyric most common KF-related adverse events. No major devi-
acid-containing peptide from marine origin with activity ations from linearity were detected in the pharmacokinetic
against several human malignant cell lines. This dose- (PK) profiles of both schedules, which showed a narrow
escalating phase I clinical trial evaluated the maximum distribution and short body residence. Prolonged disease
tolerated dose (MTD), and the recommended dose for stabilization (C3 months) occurred in eight patients: two
further phase II studies (RD) of weekly KF given as a with the 3-h schedule and six with the 24-h schedule.
prolonged (3- to 24-h) intravenous (i.v.) infusion. Conclusions Administration of KF as prolonged weekly
Methods Eligible patients with advanced solid tumors infusion appears feasible, with 3-h and 24-h infusion times
and adequate performance status, hematologic, renal, and having an acceptable safety profile.
hepatic function were recruited into this study.
Results A total of 106 patients were treated with KF at Keywords Kahalalide  Advanced solid tumors  Marine
four different weekly schedules: 3-h (n = 40), 24-h compounds  Phase I clinical trials
(n = 59), and two transitional schedules [6-h (n = 4) and
12-h (n = 3)]. For the 3-h weekly schedule, the MTD was
1,200 lg/m2 and the RD was 1,000 lg/m2. For the 24-h Introduction
weekly schedule, the MTD was reached (6,650 lg/m2), but
the RD could not be confirmed. Asymptomatic and Kahalalide F (KF) is a dehydroaminobutyric acid-con-
reversible grade 3/4 transaminase increase was the most taining peptide isolated from the herbivorous marine mol-
common dose-limiting toxicity in both schedules. Fatigue, lusk Elysia rufescens [13]. KF was active against several
human malignant cell lines both in vitro and in vivo [4, 5].
Several mechanisms of action have been proposed for the
R. Salazar (&)  B. Pardo  C. Cuadra  M. Garca antitumor activity of KF, such as alterations in the lyso-
Instituto Catalan de Oncologa, Ctra. Gran Va, 08907 s/n. somal membrane, inhibition of the erbB2 tyrosine kinase
LHospitalet de Llobregat, Barcelona, Spain
activity, inhibition of transforming growth factor-a (TGF-
e-mail: ramonsalazar@iconcologia.net
a) gene expression, cell cycle block in the G0G1 stage,
H. Cortes-Funes  A. Lopez-Martn  C. Coronado  L. Paz-Ares and blockage of epidermal growth factor (EGF) receptors
Hospital Universitario Doce de Octubre, Madrid, Spain [69]. In addition, KF induces non-p53-mediated apoptosis
without causing damage to DNA, and a selective cytotoxic
E. Casado  J. Tabernero
Hospital Vall dHebron, University Hospital, Universitat effect on neu? cells overexpressing Her2 without inhibit-
Autonoma de Barcelona, Barcelona, Spain ing autophosphorylation or MEK kinase activity [5].
Previous phase I trials established transient and
A. Soto Matos-Pita  B. Miguel-Lillo  M. Cullell-Young 
asymptomatic transaminases increases starting soon after
J. L. Iglesias Dios
Pharma Mar, S.A. Sociedad Unipersonal, Colmenar Viejo, the first administration as the main dose-limiting toxicity
Madrid, Spain (DLT) associated with single-agent KF when given to adult

123
76 Cancer Chemother Pharmacol (2013) 72:7583

cancer patients as a 1-h intravenous (i.v.) infusion weekly liver disease, grade C2 peripheral or sensory neuropathy,
(qw) or for five consecutive days in 21-day cycles or another nonmalignant disease considered incompatible
(dx5q3w) [10, 11]. A relatively low median volume of with the protocol; or a history of myocardial infarction,
distribution (5.5 l) and a short median half-life (0.52 h) uncontrolled angor pectoris or arrhythmia requiring medi-
were found with the 1-h infusion [11]. The fact that the cation, or hypersensitivity to any drug formulated in
recommended dose per infusion was very similar in both Cremophor.
schedules (560 lg/m2 in the dx5q3w schedule and 650 lg/
m2 in the qw schedule) suggests that transaminases Study treatment and dose escalation
increases found at the maximum tolerated dose (MTD) in
previous phase I trials might be dependent on the maxi- Kahalalide F was supplied by PharmaMar as a sterile
mum KF concentration in plasma (Cmax). Hence, longer lyophilized product. Vials with two different KF strengths
infusion times could help to reduce the incidence of this (50 or 150 lg) were reconstituted by adding 1.5 ml (50-lg
DLT and to achieve a longer KF exposure. The current vials) or 3 ml (150-lg vials) of reconstitution solution
dose-escalating phase I clinical trial had the aim of iden- [Cremophor/Ethanol/Water at 15/15/70 % (v/v/v)]. The
tifying a suitable schedule and recommended dose for resulting solution was further diluted in normal saline
phase II trials (RD) of weekly KF administered i.v. at solution (0.9 % NaCl for injection) before i.v. adminis-
infusion times longer than 1 h in patients with advanced tration. In addition, patients treated with KF at infusion
solid tumors. The safety, pharmacokinetics (PK), and times shorter than 24 h were premedicated with H1-
antitumor activity of these KF schedules were also receptor and H2-receptor antagonists at 30 min before each
evaluated. KF infusion. Further premedication with dexamethasone
20 mg i.v. or equivalent was to be given if hypersensitivity
reactions were experienced. Secondary prophylactic an-
Materials and methods tiemetics, red blood cell transfusions and/or erythropoietin
were allowed.
This clinical trial was conducted at three centers in Spain The starting dose was 530 lg/m2 given as a 3-h weekly
according to the good clinical practice requirements and infusion; this was lower than the RD of 650 lg/m2 estab-
the declaration of Helsinki. The protocol was approved by lished previously for KF given as a weekly 1-h infusion [11].
the Clinical Research Ethics Committee of each center. A Each KF infusion was considered one cycle. Dose escalation
signed written informed consent was obtained for each is summarized in Table 1. Escalating doses of KF were
patient before any study procedure was done. administered i.v. weekly in two parallel arms. In one arm,
infusion length was first increased from 3 to 24 h while
Eligibility criteria maintaining dose at 530 lg/m2 (two transitional schedules of
6-h and 12-h were included), and once reached the 24-h
The study enrolled adult patients diagnosed with advanced schedule, dose was increased while keeping the infusion
malignant solid tumors for which no effective conventional length. In the other arm, dose was escalated while main-
therapy existed; recovered from any toxicity derived from taining an infusion length of 3 h. Patients were allocated to
the previous treatments; Eastern Cooperative Oncology either arm according to slot availability. The study followed
Group performance status (ECOG PS) B2; life expectancy a standard phase I dose-escalation design with cohorts of 36
[3 months, and adequate organ function [neutrophil patients treated at each dose level. The RD was defined as the
count [ 1.0 9 109/l, platelet count [100 9 109/l, hemo- highest dose level at which less than 2 of 6 patients experi-
globin [9 g/dl; aspartate aminotransferase (AST) and ala- enced DLTs during the first 2 weeks of treatment. Once the
nine aminotransferase (ALT)\2.5 9 upper limit of normal RD had been established, this cohort had to be expanded to
(ULN); bilirubin \1.5 9 ULN; creatinine clearance between 12 and 24 patients to obtain preliminary information
[40 ml/min]. on the antitumor activity of the KF schedule.
Patients were excluded if they had received prior ther- Dose-limiting toxicities occurring during the first
apy with KF, any investigational product within 30 days 2 weeks of treatment were defined as any of the following:
prior to inclusion or any antitumor therapy within 4 weeks absolute neutrophil count \500/mm3 for [5 days or with
prior to inclusion (6 weeks in case of mitomycin C, ni- fever (C38.5 C); platelet count \25,000/mm3; any other
trosoureas, or temozolamide); if they had evidence of grade 3/4 non-hematological adverse event (AE) suspected
cerebral involvement; were pregnant or lactating women, to be related to study drug(s) (except for nausea/vomiting
or men and women not using effective contraceptive without prophylaxis and/or treatment, grade 3 transaminase
methods; had active bacterial infection, known human increase for \7 days, grade 3 gamma-glutamyltransferase
immunodeficiency virus (HIV) infection, known chronic (GGT) increase, and hypersensitivity reactions); and any

123
Cancer Chemother Pharmacol (2013) 72:7583 77

Table 1 Dose escalation, distribution of patients, treatment cycles, and dose-limiting toxicities over the dose levels studied
Dose KF dose KF infusion No. of cycles No. of patients with Description of DLTs
level (lg/m2) length (hours) administered DLTs/no. of patients treated

Starting dose
1 530 3 38 0/3
Escalation from 3- to 24-h infusion
2 530 6 25 0/4
3 530 12 26 0/3
4 530 24 19 0/3
5 650 24 18 0/4
6 800 24 24 0/3
7 1,000 24 22 0/3
8 1,200 24 17 0/3
9 1,400 24 15 0/3
10 1,700 24 37 0/4
11 2,000 24 56 0/3
12 2,200 24 49 0/4
13 2,650 24 15 0/3
14 3,200 24 19 0/3
15 3,850 24 19 0/4
16 4,620 24 35 1/7 Grade 3 transaminase increase for C7 days.
17 5,540 24 16 0/3
18 6,650 (MTD) 24 34 3a/9 Grade 3 transaminase increase for C7 days.Grade 4
transaminase increase.Dose delay [2 weeks.b
Escalation at 3-h infusion
2 650 3 24 0/3
3 800 3 34 0/4
4 1,000 (RD) 3 121 During dose escalation: 1/6 Grade 4 transaminase increase.
During cohort expansion: 1/14 Grade 4 transaminase increase.
5 1,200 (MTD) 3 32 2c/6 Grade 4 transaminase increase.
6 1,400 3 25 2/4 Grade 4 transaminase increase.
The values in bold show how many patients had DLTs at each dose level
DLT dose-limiting toxicity, KF kahalalide F, MTD maximum tolerated dose, RD recommended dose
a
One of these DLTs was not found at the time of escalation
b
This dose delay lasted 3 weeks: The first 2 weeks of delay were due to KF-related grade 2 ALT/AST increase, while the third week of delay
was requested by the patient due to holidays
c
One of these DLTs was not reported as such during dose escalation, but was found after patient accrual had already started at the next cohort

delays in the administration of a subsequent dose of KF interrupted until the DLTs had resolved and was to be
exceeding 2 weeks due to AEs suspected to be drug- resumed at the next lowest dose level upon fulfillment of
related. the criteria for re-treatment. Patients were withdrawn from
Patients continued receiving treatment as long as they the study if they required more than 2 dose reductions, and
did not experience disease progression or unacceptable there was no objective evidence of clinical benefit.
toxicity, and they recovered from any previous toxicity; Patients were evaluable for toxicity if they had received
that is, patients had to fulfill the same laboratory require- at least one KF infusion and for efficacy if they had
ments for inclusion into the study. Otherwise, treatment received at least one KF infusion and had evaluable lesions
was delayed until recovery. If no recovery occurred within as per the Response Evaluation Criteria In Solid Tumors
2 weeks, the patients were withdrawn from the study (RECIST, v.1.0) [12]. All toxicities were graded following
except in case of obvious clinical benefit. If any DLTs the National Cancer Institute Common Toxicity Criteria
appeared during the first 2 weeks, treatment was to be (NCI-CTC, v. 2.0). Clinical and/or radiological

123
78 Cancer Chemother Pharmacol (2013) 72:7583

assessments of the tumor according to the RECIST were Table 2 Baseline characteristics of the patients (n = 108)
done every 8 weeks. Total

Pharmacokinetic analyses Gender


Male 72 (67 %)
Blood samples (5 ml) for PK evaluation were collected at Female 36 (33 %)
predefined times at the first and second KF infusions, Median age (range) 60.0 (2786)
which varied depending on the length of infusion, from ECOG performance status
before infusion onset to up to 24 h after its end. Blood 0 60 (56 %)
samples were taken from the contralateral arm to the site of 1 44 (41 %)
KF administration. The samples were centrifuged at 2 4 (4 %)
2,5009g for 15 min to obtain the plasma fraction, which Primary tumor
was then stored at -20 C. Plasma concentrations of KF Colorectal adenocarcinoma 28 (26 %)
were determined using a validated high performance liquid Melanoma 19 (18 %)
chromatography system coupled with electrospray ioniza- Lung carcinoma 15 (14 %)
tion tandem mass spectrometry (HPLCMS/MS) method. Pancreas adenocarcinoma 6 (6 %)
The lower limit of quantification (LLOQ) was 1 ng/ml [13, Othera 40 (37 %)
14]. Complete concentrationtime profiles of KF were Previous anticancer therapy
analyzed by standard non-compartmental methods. Chemotherapy 106 (98 %)
Surgery 87 (81 %)
Radiotherapy 45 (42 %)
Results Otherb 19 (18 %)
ECOG Eastern Cooperative Oncology Group
Patient characteristics a
Prostate adenocarcinoma (n = 5), gastric adenocarcinoma, bladder
carcinoma, ovary adenocarcinoma, adenocarcinoma of unknown
A total of 108 patients were enrolled, and 106 of them were origin (n = 4 each), cholangiocarcinoma, breast carcinoma, oral
treated with KF (Table 2). Most patients (n = 104, 96 %) cavity squamous carcinoma (n = 3 each), renal carcinoma, leiomy-
had ECOG PS score 0 or 1 at baseline. The most frequent osarcoma (n = 2 each), hepatocarcinoma, pelvis squamous carci-
noma, penis carcinoma, testicle carcinoma, choriocarcinoma, and
tumor types were colorectal cancer (n = 28, 26 %), mel-
liposarcoma (n = 1 each)
anoma (n = 19, 18 %), NSCLC (n = 15, 14 %), and b
Biological therapy (n = 10), hormone therapy (n = 8) and gene
pancreatic cancer (n = 6, 6 %). All patients had metastatic therapy (n = 1)
(n = 93, 86 %) or locally advanced disease (n = 15,
14 %) at baseline. Most of them (n = 106, 98 %) had Dose-limiting toxicities, maximum tolerated dose,
previously received chemotherapy (median of 3 lines; and recommended dose
range 08). In addition, 87 patients (81 %) had undergone
surgery, 45 (42 %) had been given radiotherapy, and 19 All DLTs found during the 3-h infusion escalation were
(18 %) had received other anticancer therapies. asymptomatic and reversible grade 4 transaminase increa-
ses (Table 1). The first one occurred in one patient treated
Treatment at 1,000 lg/m2. No more DLTs were found upon expan-
sion of the cohort to 6 patients, and dose escalation was
A total of 720 cycles were administered at 23 different dose resumed. None of the first 3 patients treated at 1,200 lg/m2
levels, each cycle lasting 1 week: 274 cycles at 6 dose had DLTs, and hence, dose was again escalated. DLTs
levels as 3-h infusion (including 38 cycles at the starting occurred in 2 of 4 patients treated at 1,400 lg/m2. As a
dose of 530 lg/m2), 25 cycles at one dose level as 6-h result, further dose escalation was discontinued, and the
infusion (transitional schedule), 26 cycles at one dose level 1,200 lg/m2 cohort was expanded. However, 2 out of 6
as 12-h infusion (transitional schedule), and 395 cycles at patients treated at this dose level had DLTs, and therefore,
15 dose levels as 24-h infusion (Table 1). The median 1,200 lg/m2 was considered the MTD for the 3-h schedule.
number of cycles administered per patient was 6.5 (range Consequently, 14 additional patients (for a total of 20)
126 cycles) for the 3-h schedule, 8.0 (range 18 cycles) were evaluated at the immediately lowest dose level
for the 6-h schedule, and 6.0 (range 218 and 133) for the (1,000 lg/m2), and one DLT was found. This dose level
12-h and 24-h schedules, respectively. was established as the RD for the 3-h weekly schedule.

123
Cancer Chemother Pharmacol (2013) 72:7583 79

No DLTs occurred in the first 15 dose levels during transient and reversible, lasting for a median of 6 days
escalation from 3 to 12 h, but at the 24-h infusion (113 days) with the 3-h schedule and 6.5 days (18 days)
(Table 1), one of the first 3 patients treated at 4,620 lg/m2 with the 24-h schedule. The incidence of grade 3/4 GGT
had a DLT (grade 3 transaminase increase for C7 days) increase was similar in the two schedules (25 % of patients
and the cohort was expanded. No further patients had in the 3-h schedule and 27 % of patients in the 24-h
DLTs, and hence, dose escalation was resumed. DLTs schedule). Of note, the 4 cases of grade 4 GGT increase
(grade 3 transaminase increase for C7 days, grade 4 found in both schedules occurred in patients who already
transaminase increase, and dose delay [2 weeks) occurred had grade 3/4 GGT increase at baseline (n = 2) or were
in 3 of 9 patients treated at 6,650 lg/m2 as 24-h infusion; showing evidence for clinical progression of hepatocarci-
one of these DLTs was not detected at the time of esca- noma (n = 1) or pancreatic cancer (n = 1). A total of 4
lation. Hence, the dose level of 6,650 lg/m2 was estab- patients had grade 3/4 total bilirubin increase: one grade 4
lished as the MTD for the 24-h schedule. No RD could be episode with the 3-h schedule and three grade 3 episodes
confirmed for this schedule because the number of patients with the 24-h schedule. All episodes were concomitant
who were treated at the dose level immediately below the with grade 3/4 increases in plasma levels of transaminases,
MTD (i.e., 5,540 lg/m2) was too low (3 instead of the 6 AP and/or GGT levels, and occurred in patients with
required by the study protocol, as the study was stopped cholangiocarcinoma (n = 2) or with other tumor types that
following the sponsors decision to search for a synthetic had metastatized to the liver (n = 2). Other severe bio-
KF analogue). All patients with DLTs in this escalation chemical abnormalities (grade 3 AP increase) were less
arm recovered from these toxicities. common and had no effects on treatment.

Toxicity profile
Efficacy
All 106 treated patients were evaluable for safety. Most
A total of 93 patients at all dose levels were evaluable for
treatment-related AEs found with all KF infusion lengths
response. Ten patients had stable disease (SD) as best
were mild or moderate, with paresthesia, fatigue, pruritus,
response: 3 treated with the 3-h schedule (2 at the RD of
rash, nausea, and vomiting as the most common (Table 3).
1,000 lg/m2 and one at 1,400 lg/m2) and 7 treated with
Of note, the incidence of most of these AEs decreased
the 24-h schedule (at doses ranging from 800 to 6,650 lg/
when the infusion length increased from 3 to 24 h. Severe
m2) (Table 4). Of note, 8 of these disease stabilizations
treatment-related AEs were grade 3 only and occurred in 2
were achieved in patients who had been treated with at
patients: hypersensitivity in one patient treated at 800 lg/
least 2 prior chemotherapy lines. In 8 patients, disease
m2 as 3-h infusion and fatigue in one patient treated at
stabilization lasted for C3 months. Their tumor types
530 lg/m2 as 12-h infusion. Two patients treated with the
comprised NSCLC and colorectal cancer (n = 1 each) with
3-h schedule discontinued due to drug-related events: one
the 3-h schedule, and NSCLC (n = 2), colorectal cancer,
due to grade 2 rash and one due to grade 3 hypersensitivity;
hepatocarcinoma, bladder cancer, and cholangiocarcinoma
the latter occurred prior to the implementation of the pre-
(n = 1 each) with the 24-h schedule.
medication with H1 and H2 receptor antagonists for all
patients receiving KF at infusion times shorter than 24 h.
No discontinuations due to drug-related AEs occurred at Pharmacokinetics
the other schedules. In addition, no dose delays or reduc-
tions at any schedule were due to related AEs. PK data were available from 103 patients in Cycle 1 and 93
Regardless of causality, grade 3/4 hematological or patients in Cycle 2. No clear trend was found in the dif-
biochemical abnormalities only occurred in patients treated ferences between the PK parameters after the first and
with the 3-h or 24-h schedules (Table 3). No hematological second KF infusions. No major deviations from linearity
abnormalities reached grade 4, while grade 3 lymphopenia were detected when the area under the curve (AUC) and
was found in 13 % of patients in the 3-h schedule and 11 % Cmax values of the 3- and 24-h schedules were analyzed
of patients in the 24-h schedule, and grade 3 anemia was independently (Table 5). At the RD of 1,000 lg/m2 given
found in 5 % of patients in the 24-h schedule. Grade 3/4 as 3-h infusion, the mean AUC was 159.6 h*ng/ml and the
transaminase increases were more common in the 3-h mean Cmax was 56.3 ng/ml after the first administration of
schedule than in the 24-h schedule: 38 % versus 15 % KF. At the MTD of 6,650 lg/m2 given as 24-h infusion,
(ALT increase) and 35 % versus 11 % (AST increase). the mean AUC was 2,404.2 h*ng/ml and the mean Cmax
Most of these episodes occurred in patients treated at the was 162.4 ng/ml.
highest dose levels (C1,000 lg/m2 for the 3-h infusion or The half-life (t), total body clearance (CL), and vol-
C4,620 lg/m2 for the 24-h infusion). They were also ume of distribution at steady state (Vss) showed moderate

123
80 Cancer Chemother Pharmacol (2013) 72:7583

Table 3 Treatment-related adverse events and laboratory abnormalities at all dose levels with the 3-h and 24-h schedules (at least 10 % of
patients)
KF infusion length
3-h (n = 40) 24-h (n = 59)
NCI-CTC grade NCI-CTC grade
12 3 4 12 3 4

Treatment-related adverse eventsa


Fatigue 8 (20 %) 7 (12 %)
Nausea 6 (15 %) 4 (7 %)
Paresthesia 9 (23 %) 6 (10 %)
Pruritus 12 (29 %) 9 (15 %)
Rash 4 (10 %) 2 (3 %)
Vomiting 5 (13 %) 2 (3 %)
Hematological abnormalitiesb
Anemia 29 (73 %) 39 (66 %) 3 (5 %)
Leukopenia 9 (23 %) 5 (9 %)
Lymphopenia 22 (55 %) 5 (13 %) 24 (41 %) 6 (11 %)
Neutropenia 5 (13 %) 2 (3 %)
Thrombocytopenia 10 (25 %) 13 (22 %)
Biochemical abnormalitiesb
ALT increase 13 (33 %) 11 (28 %) 4 (10 %) 32 (54 %) 7 (12 %) 2 (3 %)
AP increase 23 (58 %) 1 (3 %) 34 (58 %) 5 (9 %)
AST increase 16 (40 %) 8 (20 %) 6 (15 %) 41 (70 %) 5 (9 %) 1 (2 %)
Bilirubin increase 8 (20 %) 1 (3 %) 11 (19 %) 3 (5 %)
Creatinine increase 12 (30 %) 13 (22 %)
GGT increase 22 (55 %) 8 (20 %) 2 (5 %) 25 (42 %) 14 (24 %) 2 (3 %)
Data shown are number (%) of patients
KF Kahalalide F, NCI-CTC National Cancer Institute Common Toxicity Criteria
a
Includes adverse events with an unknown relationship with the treatment, according to the investigator
b
Regardless of relationship with the treatment

inter- and intrapatient variability in the 3-h infusion sche- 3-h infusion and 6,650 lg/m2 for 24-h infusion) were
dule, whereas variability in the 24-h infusion was moderate greater than the MTD of 800 lg/m2 established for weekly
for CL and high or very high for both t and Vss. Of note, a KF when given as a 1-h infusion [11]. A dose of 1,000 lg/
significant correlation was found between Cmax values, and m2 was established as the RD for phase II trials with the
the peak ALT value was measured after administration of 3-h schedule; no recommended dose could be confirmed
the first KF infusion; no such correlation was found for the 24-h schedule. The majority of the DLTs found with
between AUC and peak ALT values. the 3-h and the 24-h schedules consisted of grade 3/4
transient transaminase increases, which was in accordance
with the findings of previous phase I trials with single-
Discussion agent KF [10, 11].
Both the 3-h and the 24-h schedules were generally well
This phase I clinical trial evaluated the administration of tolerated and associated with manageable, predictable, and
weekly i.v. KF at infusion times longer than 1 h in patients reversible toxicities. Most treatment-related AEs in these
with advanced solid tumors. Two dose escalations were schedules were mild or moderate, and the only one to reach
conducted in parallel: one increased the KF dose while grade 3 severity was one episode of hypersensitivity that
maintaining the infusion time at 3 h, while the other one occurred prior to the implementation of specific guidelines
first increased the infusion time from 3 to 24 h, and then for the management of these cases. Regardless of causality,
increased the KF dose at an infusion time of 24 h. The severe hematological abnormalities were grade 3 lympho-
MTDs established for these escalations (1,200 lg/m2 for penia, which occurred at a similar frequency in both

123
Cancer Chemother Pharmacol (2013) 72:7583 81

Table 4 Characteristics of patients with evidence of antitumor activity


Dose level Gender Age PS Tumor type Prior CT Last Best overall TTP OS
(lg/m2) (years) lines cycle response (mo) (mo)

3-h schedule
1,000 Female 65 1 Ovary adenocarcinoma 3 6 SD 1.61 1.81a
Male 72 1 Lung carcinoma 4 12 SD 3.22 4.73
1,400 Male 59 1 Colorectal adenocarcinoma 4 16 SD 3.45 9.86
24-h schedule
800 Male 51 0 Lung carcinoma 3 14 SD 3.48 4.60
1,700 Female 39 1 Colorectal adenocarcinoma 2 16 SD 3.91 4.11a
2,000 Male 74 0 Lung carcinoma 2 32 SD 8.78 18.73
Male 59 Hepatocarcinoma 16 SD 3.52 3.68a
2,200 Male 59 0 Bladder carcinoma 3 33 SD 9.63 9.63a
4,620 Male 61 0 Cholangiocarcinoma 1 10 SD 3.48 3.68a
6,650 Female 47 1 Ovary adenocarcinoma 5 6 SD 1.87 1.87a
CT chemotherapy, OS overall survival, PS performance status, SD stable disease, TTP time to progression
a
These patients were still alive at the end of study follow-up

Table 5 Mean area under the curve (AUC) and maximum plasma concentration (Cmax) values by dose level after the first treatment infusion,
grouped by infusion length
Dose level Infusion length in hours
(lg/m2)
3h 6h 12 h 24 h
n AUC Cmax n AUC Cmax n AUC Cmax n AUC Cmax
(h*ng/ml) (ng/ml) (h*ng/ml) (ng/ml) (h*ng/ml) (ng/ml) (h*ng/ml) (ng/ml)

530 3 89.1 (7.2) 32.3 (2.6) 4 120.3 (74.5) 14.8 (5.3) 3 71.5 (7.4) 7.3 (0.6) 2 143.1 (84.7) 7.7 (0.2)
650 3 106.1 (60.1) 37.7 (19.9) 3 135.6 (54.7) 11.5 (7.4)
800 4 127.9 (21.0) 46.5 (6.4) 3 107.2 (23.2) 5.4 (0.8)
1,000 20 159.6 (44.7) 56.3 (15.9) 3 184.8 (86.6) 8.6 (2.7)
1,200 6 191.3 (66.0) 66.9 (17.9) 3 157.6 (21.1) 11.0 (5.4)
1,400 4 193.7 (72.8) 65.3 (19.0) 3 219.4 (49.5) 11.5 (3.6)
1,700 3 200.9 (66.1) 11.4 (3.7)
2,000 3 324.1 (27.0) 23.5 (12.5)
2,200 3 207.7 (3.8) 10.5 (1.2)
2,650 3 446.4 (76.0) 25.5 (2.1)
3,200 3 580.8 (165.3) 30.3 (2.5)
3,850 4 604.8 (201.8) 34.2 (7.4)
4,620 7 698.7 (129.7) 39.2 (13.6)
5,540 3 1,038.9 (632.6) 51.7 (34.2)
6,650 8 2,404.2 (2,792.5) 162.4 (256.9)
Values are expressed as mean (SDev)
One patient received an incorrect drug dose and has not been included in this table
AUC area under the curve, Cmax maximum plasma concentration, SDev standard deviation

schedules, and anemia, which involved only 5 % of treated liver dysfunction were reported. Transitory, non-clinically
patients in the 24-h schedule. Among the biochemical relevant transaminases increases were also found as a
abnormalities, all grade 3/4 transaminase increases found common laboratory abnormality in a phase II trial evalu-
in either schedule were related to treatment but were ating the 1-h weekly KF schedule at the RD of 650 lg/m2
transient and asymptomatic. No cases of treatment-related in patients with advanced malignant melanoma [15]. These

123
82 Cancer Chemother Pharmacol (2013) 72:7583

abnormalities were more common with the 3-h schedule and colon cancer. Clinical trials are currently ongoing with
compared to the 24-h schedule, but while they caused most the synthetic KF analogue PM02734.
treatment-related dose delays and reductions in either
schedule, only 2 patients treated with the 24-h schedule Conflict of interest Josep Tabernero has participated in advisory
boards of Pharma Mar, and his institution has received research
were withdrawn because of them. funding from Pharma Mar to conduct clinical trials. Cinthya Coro-
Overall, the PK profiles of weekly KF given as 3-h or nado, Arturo Soto Matos-Pita, Bernardo Miguel-Lillo, Martin Cullell-
24-h infusions agree with those reported for the other Young, and Jorge Luis Iglesias Dios are currently PharmaMar
single-agent KF schedules tested to date [10, 11]. All employees. All other authors declare no conflicts of interest.
profiles are characterized by linear kinetics for AUC val-
ues, a narrow volume of distribution and a short terminal
half-life. Inter- and intrapatient variability of clearance was References
moderate in the 3-h and 24-h schedules. The AUC values
found in the present study for weekly KF at 8001,200 lg/ 1. Hamann MT, Scheuer PJ (1993) Kahalalide F: a bioactive dep-
sipeptide from the sacoglossan mollusk Elysia rufescens and the
m2 given as 3-h and 24-h infusions were lower than those green alga Bryopsis sp. J Am Chem Soc 115:58255826
found in a previous phase I study for these same dose levels 2. Hamann MT, Otto CS, Scheuer PJ, Dunbar DC (1996) Kahala-
given as 1-h infusions [11]. This might be due to the lides: bioactive peptides from a marine mollusk elysia rufescens
interference of Cremophor, a nonionic surfactant used as and its algal diet bryopsis sp. (1). J Org Chem 61:65946600
3. Lopez-Macia A, Jimenez JC, Royo M, Giralt E, Albericio F
formulation vehicle of KF that is known to induce the (2001) Synthesis and structure determination of kahalalide F
formation of micellae that sequester drugs, thereby (1,2). J Am Chem Soc 123:1139811401
decreasing their free fraction and causing kinetic pseudo- 4. Hanauske AR, Hanauske U, Von Hoff DD (1985) The human
nonlinearity. This could also explain the higher Vss value tumor clonogenic assay in cancer research and therapy. Curr
Probl Cancer 9:166
found in this phase I study at longer infusion times. 5. Suarez Y, Gonzalez L, Cuadrado A, Berciano M, Lafarga M,
The short half-life and narrow distribution observed in Munoz A (2003) Kahalalide F, a new marine-derived compound,
the PK profiles of single-agent KF schedules suggest that induces oncosis in human prostate and breast cancer cells. Mol
the compound has limited extravascular tissue binding and Cancer Ther 2:863872
6. Garcia-Rocha M, Bonay P, Avila J (1996) The antitumoral
is rapidly eliminated from the system. Although the exact compound Kahalalide F acts on cell lysosomes. Cancer Lett
metabolism of KF has not been completely elucidated yet, 99:4350
renal elimination is not an extensive route of elimination 7. Janmaat ML, Rodriguez JA, Jimeno J, Kruyt FA, Giaccone G
(\2 % of recovery in 24-h urine). In addition, experiments (2005) Kahalalide F induces necrosis-like cell death that involves
depletion of ErbB3 and inhibition of Akt signaling. Mol Phar-
with human liver microsomes have not been conclusive, as macol 68:502510
no biotransformation has been observed. There probably is 8. Wosikowski K, Schuurhuis D, Johnson K, Paull KD, Myers TG,
some minor chemical degradation to the product kahalalide Weinstein JN, Bates SE (1997) Identification of epidermal
G, observed in incubations with buffered solutions, growth factor receptor and c-erbB2 pathway inhibitors by cor-
relation with gene expression patterns. J Natl Cancer Inst
although kahalalide G could not be distinguished in pooled 89:15051515
human plasma due to endogenous interference [16, 17]. 9. Faircloth G, Cuevas C (2006) Kahalalide F and ES285: potent
Prolonged disease stabilizations occurred in 8 heavily anticancer agents from marine molluscs. Prog Mol Subcell Biol
pretreated patients with NSCLC (n = 3), colorectal cancer 43:363379
10. Rademaker-Lakhai JM, Horenblas S, Meinhardt W, Stokvis E, de
(n = 2), hepatocarcinoma, bladder cancer, and cholangio- Reijke TM, Jimeno JM, Lopez-Lazaro L, Lopez Martin JA,
carcinoma (n = 1 each). Three of these tumor types (lung Beijnen JH, Schellens JH (2005) Phase I clinical and pharmaco-
cancer, hepatocarcinoma, and colon cancer) have already kinetic study of kahalalide F in patients with advanced androgen
been shown to be sensitive to KF by in vitro studies [5, 18] refractory prostate cancer. Clin Cancer Res 11:18541862
11. Pardo B, Paz-Ares L, Tabernero J, Ciruelos E, Garcia M, Salazar
or in a previous phase I trial [11]. R, Lopez A, Blanco M, Nieto A, Jimeno J, Izquierdo MA, Trigo
In conclusion, this study shows that administration of JM (2008) Phase I clinical and pharmacokinetic study of kaha-
weekly KF at prolonged infusion times is feasible, with 3-h lalide F administered weekly as a 1-hour infusion to patients with
and 24-h infusion times showing tolerable safety profiles. advanced solid tumors. Clin Cancer Res 14:11161123
12. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS,
The DLTs found for both schedules consist of asymp- Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT,
tomatic, reversible, and transient transaminase increases. A Christian MC, Gwyther SG (2000) New guidelines to evaluate the
dose of 1,000 lg/m2 was established as the RD for further response to treatment in solid tumors. European organization for
development with the 3-h schedule; no such dose could be research and treatment of cancer, National Cancer Institute of the
United States, National Cancer Institute of Canada. J Natl Cancer
confirmed for the 24-h infusion schedule. Tumor types that Inst 92:205216
may be adequate for future exploratory studies with the 13. Stokvis E, Rosing H, Lopez-Lazaro L, Rodriguez I, Jimeno JM,
weekly 3-h schedule comprise non-small cell lung cancer Supko JG, Schellens JH, Beijnen JH (2002) Quantitative analysis

123
Cancer Chemother Pharmacol (2013) 72:7583 83

of the novel depsipeptide anticancer drug Kahalalide F in human 16. Gao J, Hamann MT (2011) Chemistry and biology of kahalalides.
plasma by high-performance liquid chromatography under basic Chem Rev 111:32083235. doi:10.1021/cr100187n
conditions coupled to electrospray ionization tandem mass 17. Provencio M, Izquierdo A, Vinolas N, Paz-Ares L, Feliu J,
spectrometry. J Mass Spectrom 37:9921000 Constenla M, De las Heras B, Erustes M, Izquierdo MA, Rossell
14. Stokvis E, Rosing H, Lopez-Lazaro L, Schellens JH, Beijnen JH R (2006) Phase II clinical trial of Kahalalide F (KF) as a second
(2004) Switching from an analogous to a stable isotopically line therapy in patients (pts) with advanced non-small cell lung
labeled internal standard for the LC-MS/MS quantitation of the cancer (NSCLC). Ann Oncol 17:Abstract #755P
novel anticancer drug Kahalalide F significantly improves assay 18. Jimeno J, Lopez-Martin JA, Ruiz-Casado A, Izquierdo MA,
performance. Biomed Chromatogr 18:400402 Scheuer PJ, Rinehart K (2004) Progress in the clinical develop-
15. Martin-Algarra S, Espinosa E, Rubio J, Lopez Lopez JJ, Manzano ment of new marine-derived anticancer compounds. Anticancer
JL, Carrion LA, Plazaola A, Tanovic A, Paz-Ares L (2009) Phase Drugs 15:321329
II study of weekly Kahalalide F in patients with advanced
malignant melanoma. Eur J Cancer 45:732735

123