Phase I/II and pharmacokinetic study of cladribine with 2-h infusion in Japanese patients with relapsed indolent B-cell lymphoma mostly pretreated with rituximab.
ABSTRACT We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2-h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B-cell lymphoma. This was a dose-escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose-limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35-65%), with 11% (2/18) complete response. With a median follow-up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non-hematologic toxicities were mild. In conclusion, cladribine with 2-h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B-cell lymphoma, including those pretreated with rituximab.
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ABSTRACT: Before the contemporary development of rationally designed antineoplastic therapies, cladribine was identified as a lymphocyte-specific agent. Its profound impact on the natural history of hairy cell leukemia, with responses approaching 100% and a median duration of response of nearly a decade after only a single 7-day course, is well known and revolutionized the treatment of hairy cell leukemia. However, cladribine's impressive activity in other lymphoproliferative disorders has been generally underappreciated. Multiple single-arm phase 2 trials have demonstrated cladribine's potency across the full spectrum of lymphoid malignancies. In a limited number of phase 3 trials and cross-study analyses, cladribine compared favorably with fludarabine, another purine nucleoside analog that is more commonly used in the treatment of indolent lymphoid malignancies. Cladribine has been noted to have particular activity among lymphoid disorders with few effective therapies, specifically, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma. Recently approved novel agents may act in synergy with cladribine for these conditions and should be incorporated into future clinical studies.Blood 10/2010; 116(16):2884-96. · 9.78 Impact Factor
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ABSTRACT: Although cladribine has been reported to be an active purine analog against indolent B-cell non-Hodgkin lymphoma (B-NHL), there are few reports of combination use of cladribine and rituximab. This multicenter phase II study evaluated the efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy in relapsed or refractory indolent B-NHL. Twenty patients with the median age of 58.5 yrs (range, 42-72) were enrolled and received R-2-CdA therapy from April 2005 to July 2007. The median number of prior regimens was 2 (range, 1-3), and fifteen patients (75%) were previously treated with rituximab-containing regimens. Disease histology included follicular lymphoma in 16 patients, MALT lymphoma in two patients, nodal marginal B-cell lymphoma in one patient, and lymphoplasmacytic lymphoma in one patient. The overall response rate (ORR) was 90%, with a complete response rate (CRR) of 70%. Estimated median progression-free survival (PFS) time was 22.4 months (95%CI, 10.9-32.6 months) at a median follow-up time of 27 months (range, 12-43). Two-year PFS and 2-yr overall survival (OS) were 52.6% (95%CI, 31.0-73.2%) and 89.5% (95%CI, 66.1-97.3%), respectively. Grade 3 or grade 4 toxicities were neutropenia in 74% and thrombocytopenia in 11%. R-2-CdA therapy was demonstrated to have a high activity with durable PFS and acceptable toxicity in relapsed or refractory indolent B-NHL mostly pretreated with rituximab-containing therapy. Although a large-scale trial is needed for confirmation, R-2-CdA therapy could be a good salvage therapy option in relapsed or refractory indolent B-NHL.European Journal Of Haematology 11/2010; 86(2):117-23. · 2.41 Impact Factor
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ABSTRACT: To evaluate the use and objectives of expansion cohorts in phase I cancer trials and to explore trial characteristics associated with their use. We performed a systematic review of MEDLINE and EMBASE, limiting studies to single-agent phase I trials recruiting adults and published after 2006. Eligibility assessment and data extraction were performed by two reviewers. Data were assessed descriptively, and associations were tested by univariable and multivariable logistic regression. We identified 611 unique phase I cancer trials, of which 149 (24%) included an expansion cohort. The trials were significantly more likely to use an expansion cohort if they were published more recently, were multicenter, or evaluated a noncytotoxic agent. Objectives of the expansion cohort were reported in 74% of trials. In these trials, safety (80%), efficacy (45%), pharmacokinetics (28%), pharmacodynamics (23%), and patient enrichment (14%) were cited as objectives. Among expansion cohorts with safety objectives, the recommended phase II dose was modified in 13% and new toxicities were described in 54% of trials. Among trials aimed at assessing efficacy, only 11% demonstrated antitumor activity assessed by response criteria that was not previously observed during dose escalation. The utilization of expansion cohorts has increased with time. Safety and efficacy are common objectives, but 26% fail to report explicit aims. Expansion cohorts may provide useful supplementary data for phase I trials, particularly with regard to toxicity and definition of recommended dose for phase II studies.Journal of Clinical Oncology 10/2013; · 17.88 Impact Factor
Cancer Sci| July 2009| vol. 100| no. 7| 1344–1350 doi: 10.1111/j.1349-7006.2009.01162.x
© 2009 Japanese Cancer Association
Blackwell Publishing Asia
Phase I/II and pharmacokinetic study of cladribine
with 2-h infusion in Japanese patients with relapsed
indolent B-cell lymphoma mostly pretreated with
Kensei Tobinai,1,13 Takashi Watanabe,1 Kazuki Tanimoto,1,14 Dai Maruyama,1 Masanobu Nakata,2,15 Kuniaki Itoh,2
Yasuo Morishima,3 Michinori Ogura,3,16 Noriko Usui,4,17 Masaharu Kasai,5 Takashi Terauchi,6 Shigeru Nawano,7,18
Masaki Matsusako,8 Yoshihiro Matsuno,9,19 Shigeo Nakamura,10 Shigeo Mori11 and Yasuo Ohashi12
1Hematology and Stem Cell Transplantation Division and 9Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045;
2Division of Oncology and Hematology and 7Diagnostic Radiology Division, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, 277-8577;
3Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681; 4Division of Oncology and
Hematology, Department of Internal Medicine, The Jikei University School of Medicine, 3-19-18 Nishi-Shinbashi, Tokyo, 105-8471; 5Department of Internal
Medicine, Sapporo Hokuyu Hospital, 6-6-5-1 Higashi Sapporo, Shiroishi-ku, Sapporo, 003-0006; 6Screening Technology and Development Division, Research Center
for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045; 8Department of Radiology, St Lukes International Hospital,
9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560; 10Pathology and Clinical Laboratories, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-ku, Nagoya, 466-8560;
11Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8606; 12Department of Biostatistics, School of Public Health,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655; Japan
(Received January 25, 2009/Revised March 7, 2009; March 9, 2009/Accepted March 13, 2009/Online publication April 21, 2009)
We conducted a phase I/II study to investigate the toxicity,
pharmacokinetics, and efficacy profiles of cladribine with 2-h
intravenous infusion for five consecutive days every four weeks in
Japanese patients with relapsed indolent B-cell lymphoma. This was
a dose-escalation study to confirm the safety of the doses which
have been recommended for Caucasian patients (phase I), and to
further evaluate the efficacy and safety (phase II). In the phase I
portion for nine patients, no dose-limiting toxicities were observed
at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No
appreciable accumulation of plasma cladribine concentration was
suggested. We enrolled a total of 20 patients, and an additional
14 patients in the phase II portion at level 2 (0.12 mg/kg/day).
Eighteen patients, including 13 with follicular lymphoma, were
eligible for efficacy evaluation, and 15 (83%) were pretreated with
rituximab. The overall response rate was 50% (9/18; 80%
confidence interval, 35–65%), with 11% (2/18) complete response.
With a median follow-up of 296 days, the estimated median time to
progression for 18 eligible patients was 382 days. The most frequent
adverse events were hematologic toxicities, including grade 4
neutropenia. Non-hematologic toxicities were mild. In conclusion,
cladribine with 2-h intravenous infusion for five consecutive days
every four weeks is effective with acceptable toxicities for Japanese
patients with relapsed indolent B-cell lymphoma, including those
pretreated with rituximab. (Cancer Sci 2009; 100: 1344–1350)
incurable by current treatments. The recent introduction of
anti-CD20 antibody therapies appeared to have improved their
clinical outcomes;(1–5) however, a considerable fraction of patients
are still suffering from relapses.(6) Thus, it is necessary to explore
effective agents with different mechanisms of action for such
Cladribine (2-chlorodeoxyadenosine; 2-CdA) is a chlorinated
purine analog resistant to degradation by adenosine deaminase.
Cladribine is accumulated at a high concentration in its
phosphorylated active form (i.e. 2-chlorodeoxyadenosine tri-
phosphate [2-CdATP]) in lymphocytes with high deoxycytidine
kinase activity. This accumulation of a high concentration of
2-CdATP in lymphocytes inhibits DNA synthesis in dividing
ost patients with indolent B-cell non-Hodgkin lymphoma
(B-NHL), mainly consisting of follicular lymphoma, are
cells by inhibiting the actions of ribonucleotide reductase and
DNA-polymerase α. Meanwhile, in resting cells, 2-CdATP
inhibits the repair of DNA strand breaks, resulting in intracellular
accumulation of such breaks, depletion of ATP and nicotinamide
adenine dinucleotide (NAD), probably due to the activation of
enzyme poly (ADP-ribose) synthetase, and the induction of
apoptosis.(7) Cladribine is thus distinguished from other chemo-
therapeutic agents by its unique characteristics, showing similar
cytotoxic activity towards both dividing and resting cells.
Cladribine has been found to be clinically effective for various
indolent lymphoid malignancies, such as hairy cell leukemia,(8,9)
chronic lymphocytic leukemia (CLL),(10–12) and indolent B-NHL,(13–17)
which are characterized by slow growth.
In Japan, the recommended dose of cladribine was determined
to be 0.09 mg/kg/day with a schedule of 7-day continuous intra-
venous infusion based on phase I and II studies,(18–21) non-
clinical study results showing that the antitumor activity of
cladribine depends on the exposure time,(22) and the preceding
US studies.(8–11,13,14) However, this 7-day continuous infusion
regimen is inconvenient, particularly for outpatients. A more
convenient infusion schedule was therefore required.
In recent reports from western countries, cladribine has been
usually given as a 2-h intravenous infusion alone or in combination
with other medications.(23–31) According to the report of Liliemark
et al. on the pharmacokinetic analysis of cladribine in leukemia
patients, there was no difference in the area under the con-
centration versus time curve (AUC) in tumor cells between
24-h continuous intravenous infusion and intermittent 2-h
13To whom correspondence should be addressed. E-mail: firstname.lastname@example.org
The present addresses of the authors different from those where the work was
carried out are as follows: 14Department of Hematology, Kyushu Medical Center,
1-8-1 Chigyohama, Chuo-ku, Fukuoka, 810-8563; 15Department of Internal Medi-
cine, Sapporo Hokuyu Hospital, 6-6-5-1 Higashi Sapporo, Shiroishi-ku, Sapporo,
003-0006; 16Department of Hematology and Oncology, Nagoya Daini Red Cross
Hospital, 2-9 Myoken-cho, Showa-ku, Nagoya, 466-8650; 17Division of Oncology
and Hematology, Department of Internal Medicine, Jikei University Daisan Hospital,
4-11-1 Izumi-Honcho, Komae-shi, Tokyo, 201-8601; 18Center for Radiological Sciences,
IUHW Mita Hospital, 1-4-3 Mita, Minato-ku, Tokyo, 108-8329; and 19Department
of Pathology, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo,
Tobinai et al.
Cancer Sci| July 2009| vol. 100| no. 7| 1345
© 2009 Japanese Cancer Association
intravenous infusion.(32) In Europe, the current recommended
dose of cladribine is 2-h intravenous infusion at 0.12 mg/kg/day
for five consecutive days.
To assess the toxicity, pharmacokinetics, and efficacy profiles
of new dosages of cladribine in previously treated Japanese
patients with indolent B-NHL, we conducted a phase I/II and
pharmacokinetic study with a schedule of 2-h intravenous
infusions for five consecutive days every four weeks up to a
maximum of six cycles.
Patients and Methods
Patients. Patients with relapsed or refractory indolent B-NHL
who met the following criteria were eligible: histologically
confirmed indolent B-NHL, including CLL/small lymphocytic
lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma,
follicular lymphoma, and marginal zone lymphoma, according
to the WHO Classification;(33) measurable disease (>1.5 cm in
the largest diameter); more than four weeks from the last
chemotherapy or more than three months from rituximab
treatment; expected survival of three months or longer; adequate
bone marrow (absolute neutrophil count ≥1500/μL, platelet
count ≥10.0 × 104/μL, hemoglobin ≥8.0 g/dL), hepatic (bilirubin
level ≤2 times the upper limit of normal [ULN], transaminase
levels ≤2.5 × ULN), renal (creatinine ≤1.5 × ULN), and
pulmonary (PaO2≥ 65 mmHg) functions, and no abnormal
electrocardiogram finding requiring treatment; performance
status of 2 or better on the Eastern Cooperative Oncology Group
scale;(34) age between 20 and 74 years; and written informed
consent. Patients with active infection, active concurrent tumor,
serious complications, or those who had received purine analogs
such as fludarabine, pentostatin, and cladribine were excluded.
This multi-institutional phase I/II study was started after the
approval of the institutional review board at each participating
Drug formulation. JK6251 (cladribine) was supplied by Janssen
Pharmaceutical K.K. (Tokyo, Japan) as a 0.1% (1 mg/mL)
solution of endotoxin-free cladribine in sterile 0.9% sodium
chloride. The desired dosage of cladribine was added to normal
saline in a total volume of 500 mL and infused through
peripheral or central venous access.
Central pathology review. Unstained microscope slides of
lymphoma tissues at initial diagnosis and/or at relapse were
collected from each institution. These specimens were stained
with hematoxylin–eosin. In addition, immunohistochemical
analyses were conducted using monoclonal antibodies (mAb),
including an anti-CD20 mAb (L26), anti-CD3 mAb, anti-CD5
mAb, anti-CD10 mAb, anti-bcl-2 mAb, and anti-cyclin D1
mAb, as described previously.(35) Preparations were microscopically
examined by a central pathological review committee composed
of three hematopathologists (Yo.M., S.Nak., S.M.).
Study design and treatment. This trial was a multi-
institutional phase I/II study. We administered cladribine with a
schedule of 2-h intravenous infusion for five consecutive days
every four weeks up to a maximum of six cycles. This was a
dose-escalation study designed to confirm the safety of the
doses, which have been recommended for Caucasian patients
(phase I portion), and to further evaluate the efficacy and safety
(phase II portion) in Japanese patients. In the phase I portion,
the safety of the doses was evaluated based on the occurrence of
dose-limiting toxicities (DLTs) at the first cycle. The DLTs were
defined as grade 4 hematologic toxicities (thrombocytopenia,
anemia, neutropenia associated with a fever ≥38.0°C) and/or
non-hematologic toxicity of grade 3 or greater, for which a
relation to cladribine could not be ruled out. The study was
started at the initial dosage of 0.09 mg/kg/day (level 1), and
dose escalation was planned up to 0.12 mg/kg/day (level 2),
considering the results of a randomized phase II study of
cladribine and fludarabine that suggested that 5-day, 2-h infusion
of cladribine at 0.14 mg/kg was more toxic.(36) Intrapatient dose
escalation was not allowed.
After confirmation of cladribine tolerability at dose level 2 in
the phase I portion, we enrolled additional patients at this dose
level up to a total of 20 patients to evaluate the efficacy and
safety of cladribine in the phase II portion.
Prophylactic use of sulfamethoxazole/trimethoprim and iso-
niazid was allowed. Broad-spectrum antibiotics were used for
suspected bacterial infections, and granulocyte colony-stimulating
factor (G-CSF) was allowed for grade 4 neutropenia.
Conditions for starting subsequent cladribine treatment
cycles. Before the start of subsequent cladribine treatment cycle,
patients were assessed and should have fulfilled the following
conditions: adequate bone marrow (absolute neutrophil count
≥1500/μL, platelet count ≥10.0 × 104/μL, hemoglobin ≥8.0 g/dL),
hepatic (bilirubin level ≤2 × ULN, transaminase levels ≤2.5 ×
ULN), renal (creatinine level ≤1.5 × ULN), pulmonary (PaO2≥
65 mmHg) functions, and no abnormal electrocardiogram. If
G-CSF or transfusion was given, a seven-day or longer recovery
period was required before assessment. If patients did not meet
the above-described conditions, the cladribine treatment was
delayed by two weeks.
Response and toxicity criteria. Tumor responses were assessed in
each cycle according to the International Workshop Criteria for
NHL.(37) Toxicities were evaluated in all treated patients
according to the National Cancer Institute Common Toxicity
Criteria (NCI-CTC) version 2.0.
Pharmacokinetic analysis. The cladribine concentrations in
plasma and urine were measured in the first treatment cycle of
the phase I portion. Blood samples were obtained predose, at
15 min and 1, 1.5, 2 (end of infusion), 4, 6, 9, 12, and 24 h
postdose on days 1 and 5, and predose on days 3 and 4.
Cladribine concentrations in plasma were determined by liquid
chromatography/tandem mass spectrometry (LC/MS/MS) with
0.1 ng/mL as the lower quantitative limit. The pharmacokinetic
parameters of cladribine were analyzed according to the non-
compartment model, using WinNonlinTM software (Pharsight
Corporation, Mountain View, CA, USA). These parameters were
compared between days 1 and 5 to examine the accumulation
of cladribine, and were compared with data from the
pharmacokinetic study carried out at the Scripps Clinic and
Research Foundation in the USA.(38) Urine samples were
collected predose at an interval of 24 h every day. Cladribine
concentrations in the urine were also determined by LC/MS/MS.
Statistical analysis and sample size. The primary endpoint in the
phase II portion was the overall response rate (ORR) in eligible
patients. In addition to the efficacy evaluation at each participating
institute, an independent review committee consisting of three
radiologists (T.T., S.Naw., M.M.) carried out a central evaluation
using collected computed tomography (CT) films.
This study was designed assuming a threshold ORR of 20%
to detect an expected ORR of 50%. At the 10% level of signifi-
cance (one-tailed; mid-P-value), the required sample size to attain
a statistical power of 90% was 17 patients considering a 15%
possible exclusion rate. The sample size was therefore set at
20 patients. One of the secondary endpoints of the phase II portion
was to estimate the time to progression (TTP), which was
defined as the period from the starting date of cladribine treat-
ment to the date of the assessment of progressive disease (PD).
The Kaplan–Meier method was used to estimate the 50% point
of TTP. The analytical software used was SAS version 8.02.
Patients. Twenty-three patients with relapsed or refractory
indolent B-NHL were enrolled from five institutions in Japan. In
the phase I portion, we enrolled nine patients whose clinical
© 2009 Japanese Cancer Association
characteristics are shown in Table 1. One patient was judged
ineligible after receiving cladribine, because he had not only
B-cell but also T-cell lymphoma. The nine patients received
0.09 mg/kg/day (level 1, n = 3) or 0.12 mg/kg/day (level 2,
n = 6) for five consecutive days every four weeks, for a total of
one to three cycles, and no DLTs were observed at either dose
level. It was suggested that the recommended dose of cladribine
(2-h intravenous infusion at 0.12 mg/kg/day for five consecutive
days) established in Caucasian patients with CLL could be
safety administered to Japanese patients.
We enrolled a total of 20 patients who had been previously
treated with indolent B-NHL including additional 14 patients in
the phase II portion at dose level 2. The patient characteristics
are shown in Table 1. The central pathology review revealed that
most enrolled patients had follicular lymphoma (14/20, 70%).
Most patients were pretreated with rituximab. All 20 enrolled
patients received cladribine treatment. In total 49 cycles of
cladribine treatment were delivered for a median of three cycles
per patient (range 1–6 cycles), including one cycle in five
patients (25%), two cycles in four (20%), three cycles in ten
(50%), and six cycles in one patient (5%). The causes of
completion of the protocol therapy were physicians’ decisions
after confirming objective responses or stable disease (SD) in ten
patients (50%), PD in six (30%), and not reaching the conditions
required for starting subsequent cycles in four (20%).
Two patients (one patient [Case 4] with concurrent T-cell
lymphoma, and the other without measurable disease) were
judged ineligible after receiving cladribine.
Toxicities. The toxicity profiles of the nine patients in the
phase I portion are shown in Table 2. Of the three patients
treated at level 1, grade 3 hematologic toxicities observed were
neutropenia in three patients, CD4-positive lymphocyte decrease
in three, leukopenia in two, and lymphopenia in two patients.
Other hematologic toxicities were of grade 2 or less, and non-
hematologic toxicities were grade 1. Of the six patients treated
at dose level 2, grade 3 or greater hematologic toxicities were
lymphopenia in five, CD4-positive lymphocyte decrease in five,
neutropenia in three, leukopenia in two, and thrombocytopenia
in one patient. Other hematologic and non-hematologic toxicities
were of grade 2 or less.
In the phase II portion, the incidences of hematologic and
non-hematologic toxicities of grade 2 or greater in the
Table 1.Patient characteristics (eligible)
Safety (phase I + phase II)
n = 23
Efficacy (phase II)
n = 18
Disease status, n
Refractory after relapse
Performance status, n
Clinical stage, n
Duration from initial diagnosis, years
Prior therapy, n
Number of regimens
Abbreviations: n, number of patients; ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; MZBCL, marginal zone B-cell
lymphoma; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; Ibritumomab, 90Y-labeled anti-CD20 antibody, ibritumomab tiuxetan;
auto-PBSCT, autologous peripheral blood stem cell transplantation.
Tobinai et al.
Cancer Sci| July 2009| vol. 100| no. 7| 1347
© 2009 Japanese Cancer Association
20 patients are listed in Table 2. Hematologic toxicities, includ-
ing grade 4 neutropenia (7/20, 35%), were the most frequent
toxicities. The time to nadir of neutrophil count was mostly two
weeks after cladribine treatment initiation, and the time to
recovery from nadir of neutrophil count was between one and
two weeks. G-CSF was used in 5 of 49 cycles. There was no
apparent tendency toward cumulative toxicity. Grade 3 non-
hematologic toxicities were observed in two patients (10%).
Febrile neutropenia occurred in one patient; the patient had
prolonged initial hospitalization at the first cycle of cladribine
treatment, but recovered by treatment with antibiotics. The other
patient developed grade 3 herpes zoster at three months after
completion of the third cycle of cladribine treatment, but recovered
by treatment with acyclovir.
Responses. In the phase I portion, of the three patients treated
at level 1, one with follicular lymphoma achieved complete
response (CR). Of the six patients at level 2, one with follicular
lymphoma achieved CR, and another with follicular lymphoma
achieved partial response (PR).
In the phase II portion, therapeutic efficacy was evaluated in
18 eligible patients. ORR in the 18 eligible patients was 50% (9/
18; 80% confidence interval [CI], 35–65%), with 11% (2/18)
CR (Table 3). No association was observed between the response
and the disease status. The onset of induction of a response
occurred within three cycles in all responders. With the median
follow-up period of 296 days, the estimated 50% TTP for all
18 eligible patients was 382 days.
Pharmacokinetics. The pharmacokinetic data of cladribine
are shown in Table 4. The cumulative ratios (day 5/day 1) of
maximum plasma concentration (Cmax) and AUC0–t were 1.1 ± 0.1
and 1.0 ± 0.3 at dose level 1, and 1.1 ± 0.2 and 1.2 ± 0.2 at
dose level 2, respectively. No appreciable accumulations of
plasma cladribine were suggested with five-consecutive-day
These pharmacokinetic parameters were compared with those
in a pharmacokinetic study in the USA using the same treatment
schedule at different doses, after dose-normalization of pharma-
cokinetic parameters at 0.10 mg/kg/day.(38) There was no marked
difference between these two studies, except for two Japanese
patients. The delay in cladribine excretion due to decreased
renal function (creatinine clearance [CLcr]; 55.1, 53.7 mL/min)
might have caused higher values of Cmax and AUC0–t in these
patients. The average cumulative urinary excretion rates for five
days in nine patients were 41.0 ± 3.3% (level 1) and 35.6 ± 7.8%
(level 2). There was a positive correlation (P = 0.0165) between
the cumulative urinary excretion rate and CLcr.
When planning this phase I/II study, we assumed that when dose
level 2 is found to be well tolerated in the phase I portion, this
dose level would be a suitable dose in Japanese patients with
indolent B-NHL for the following reasons: (i) the total dosage
per cycle is nearly the same between the five-day 2-h infusion
of 0.12 mg/kg and the 7-day continuous infusion of 0.09 mg/kg;
(ii) overseas cladribine studies revealed no clear differences
in the therapeutic efficacy and toxicity in indolent B-NHL
patients treated with the two treatment schedules; and (iii)
according to the reports of Liliemark et al.,(32) AUCs of plasma
concentration and intra-tumor cell concentration in patients with
Table 2. Incidence of toxicities of grade 2 or greater (phase I + phase II, n = 23)
Any gradeGrade 2Grade 3 Grade 4
CD4 + lymphocytes decreased
Anemia (hemoglobin decreased)
Infection without neutropenia
Injection site reaction
†A relation to cladribine could not be ruled out.
‡Any infection as the greatest severity.
Abbreviations: n, number; ALT, alanine aminotransferase; AST; aspartate aminotransferase; γ-GTP; gamma-glutamyltransferase;
© 2009 Japanese Cancer Association
CLL after 2-h intravenous infusion suggested that both treatment
schedules brought similar results. On the other hand, when the
daily dose is increased from 0.09 to 0.12 mg/kg, the administration
time is shortened from 24 to 2 h, and Cmax was expected to show
a 10-fold higher value than plasma concentration at steady state
(Css) in 7-day continuous intravenous infusions. Thus, we considered
it necessary to conduct a clinical study to confirm if the
treatment schedule is tolerable in Japanese patients and if the
safety profile is not different from that in the schedule of 7-day
continuous intravenous infusion.
Two patients at dose level 2 who had low creatinine clearance
values showed high values of Cmax and AUC. A significant
positive correlation (P = 0.0165) was observed between the
cumulative urinary excretion rate and creatinine clearance. It
was suggested that patients with impaired renal function showed
delayed cladribine excretion.
According to the protocol, an exploratory study for efficacy
was conducted in 18 eligible patients, including five patients
treated at dose level 2 in the phase I portion. Nine of 18 eligible
patients (50%; 80% CI, 35–65%) showed objective responses.
The results were similar to those in the previous Japanese
phase II study using 7-day continuous intravenous infusion
(0.09 mg/kg/day) (24/41, 59%)(19) and those in clinical studies in
Europe and the USA.(23–27) TTP in 18 eligible patients was esti-
mated to be 382 days, which is considered a favorable result for
single agent therapy for previously treated patients with indolent
B-NHL, compared with the results (median progression-free
survival time of 239 days) in the Japanese phase II study by 7-day
continuous intravenous infusion.(19)
After the introduction of rituximab, most patients with indolent
B-NHL receive rituximab in combination with other anti-
lymphoma agents or in a single agent as initial and salvage
treatments; however, there are very few data on the efficacy of
cladribine for indolent B-NHL pretreated with rituximab. In this
phase I/II study, an ORR of 47% (7/15; 80% CI, 31–63%) and
the median TTP of 382 days were obtained in this population.
Although the results of this study are preliminary because of the
small number of patients and short follow-up duration, it may be
reasonable to consider that 2-h infusion of cladribine for five
consecutive days is a promising treatment option for relapsed or
refractory indolent B-NHL patients, including those pretreated
The most frequent adverse events in the present study were
hematologic toxicities. The time to nadir and the time to recovery
were similar to those in 7-day continuous intravenous infusion,(19)
and no clear accumulative effect was observed with repeated
administrations up to three cycles. Thus, it is suggested to be
feasible to use a schedule of repeated dose administration every
four weeks up to three cycles.
One patient developed grade 3 herpes zoster about 3 months
after the end of cladribine treatment in cycle 3, and recovered
with an antiviral agent. The CD4-positive cell count was low,
Table 3.Therapeutic efficacy of cladribine (phase II portion)
CR CRuPRSDPD ORRmid-P-value (one-tailed) 80% CI
All eligible patients (n = 18)
FL (n = 13)
MZBCL (n = 3)
SLL (n = 1)
MCL (n = 1)
Primary refractory (n = 2)
Relapsed (n = 12)
Refractory after relapse (n = 4)
20763 50% 0.002635–65%
(n = 3)
(n = 15)
(n = 16)
(n = 2)
Number of regimens
(n = 5)
(n = 13)
Abbreviations: n, number of patients; CR, complete response; CRu, CR unconfirmed; PR, partial response; SD, stable disease; PD, progressive
disease; ORR, overall response rate; RR, response rate; CI, confidence interval; FL, follicular lymphoma; MZBCL, marginal zone B-cell lymphoma;
SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma.
Table 4. Pharmacokinetic parameters of nine patients who received cladribine (Mean ± SD)
Dose level DayCmax (ng/mL)AUC0-t (ng h/mL)t1/2 (h) CL (L/h/kg)
Level 1 (n = 3)1
Level 2 (n = 6)
Abbreviations: n, number of patients; AUC0-t, area under the concentration versus time curve; t1/2, elimination half life; CL, total clearance;
Cmax, maximum plasma concentration.
Tobinai et al.
Cancer Sci| July 2009| vol. 100| no. 7| 1349
© 2009 Japanese Cancer Association
53/μL (grade 3) at the end of cycle 3. It has been reported that
the decrease in CD4-positive cells is prolonged with cladribine
treatment, and it is necessary to pay attention to potential oppor-
tunistic infections after cladribine treatment. In a prior Japanese
phase II study for relapsed or refractory indolent B-NHL by 7-day
continuous intravenous infusion (0.09 mg/kg/day), four of the
45 patients developed myelodysplastic syndrome (MDS), whereas
no patients developed MDS in this phase I/II study, partly due to
the shorter follow-up duration.
Several studies have indicated that cladribine, in combina-
tion with other anti-lymphoma agents including rituximab,
mitoxantrone, and etoposide, might be more effective for
indolent B-NHL than single-agent cladribine.(15–17,28–31) To
find more effective combination regimens, further studies
In conclusion, the more convenient administration schedule of
cladribine, 2-h intravenous infusion at 0.12 mg/kg/day for five
consecutive days, revealed no differences in efficacy and safety
profiles compared with the schedule of 7-day continuous intra-
venous infusion at 0.09 mg/kg/day in Japanese patients with
relapsed or refractory indolent B-NHL, and the adverse events
were controllable. Further investigations, including combinations
with other anti-lymphoma agents based on this dose and schedule,
We thank the patients and the investigators, including the physicians,
pharmacists, nurses, clinical research coordinators, and laboratory techni-
cians. We are grateful to Dr T. Nakamura (University of Fukui, Eiheiji,
Fukui, Japan), Dr H. Mizoguchi (Tokyo Women’s Medical University,
Tokyo, Japan), and Dr K. Oshimi (Juntendo University, Tokyo, Japan) for
their critical reviews of the clinical data as members of the Independent
Monitoring Committee. We also acknowledge Dr T. Hotta (Tokai Univer-
sity, Isehara, Japan) for his contribution as a medical advisor, and the
help of Mr T. Takahara, Mr N. Sanada, Mr H. Shibayama, Mr K. Inoue,
and the JK6251 (Cladribine) Study Team (Janssen Pharmaceutical K.K.,
Tokyo, Japan) with data collection and statistical analyses.
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