Phase 1 Study of Lonafarnib (SCH 66336)and Imatinib Mesylate in Patients With ChronicMyeloid Leukemia Who Have Failed PriorSingle-Agent Therapy With Imatinib

Jorge Cortes, MD1

Elias Jabbour, MD1

George Q. Daley, MD2

Susan O’Brien, MD1

Srdan Verstovsek, MD1

Alessandra Ferrajoli, MD1

Charles Koller, MD1

Yali Zhu, MD3

Paul Statkevich, MD3

Hagop Kantarjian, MD1

1 Department of Leukemia, The University ofTexas M. D. Anderson Cancer Center, Houston,Texas.

2 Division of Pediatric Hematology/Oncology, Chil-dren’s Hospital Boston and Dana Farber CancerInstitute, Boston, Massachusetts.

3 Schering-Plough Research Institute, Kenilworth,New Jersey.

BACKGROUND. Lonafarnib is an orally bioavailable nonpetidomimetic farnesyl

transferase inhibitor with significant activity against BCR-ABL-positive cell lines

and primary human chronic myeloid leukemia (CML) cells. Lonafarnib can in-

hibit the proliferation of imatinib-resistant cells and increases imatinib-induced

apoptosis in vitro in cells from imatinib-resistant patients.

METHODS. The authors conducted a phase 1 study of lonafarnib in combination

with imatinib in patients with CML who failed imatinib therapy. The starting

dose level for patients with chronic phase (CP) disease was imatinib, 400 mg/

day,plus lonafarnib at a dose of 100 mg twice daily. The starting dose levels

for accelerated phase (AP) and blast phase (BP) disease were 600 mg/day and

100 mg twice daily, respectively.

RESULTS. A total of 23 patients were treated (9 with CP, 11 with AP, and 3 with

BP) for a median of 25 weeks (range, 4–102 weeks). Of those with CP disease,

2 patients had grade 3 (according to the National Cancer Institute Common Toxic-

ity Criteria [version 2.0]) dose-limiting toxicities (DLTs) at the 400 1 125-mg

dose, including diarrhea (2 patients), vomiting (1 patient), and fatigue (1 patient).

In patients with AP/BP disease, DLTs were observed at the 600 1 125-mg dose

and was comprised of diarrhea (1 patient) and hypokalemia (1 patient). Eight

patients (35%) responded; 3 with CP disease achieved a complete hematologic

response (CHR) (2 patients) and a complete cytogenetic response (1 patient).

Three patients with AP disease responded (2 CHR, 1 partial cytogenetic

response), and 2 patients with BP disease demonstrated hematologic improve-

ment. Pharmacokinetics data suggest no apparent increase in exposure or

changes in the pharmacokinetics of either lonafarnib or imatinib when they are

coadministered.

CONCLUSIONS. The results of the current study indicate that the combination of

lonafarnib and imatinib is well tolerated and the maximum tolerated dose of

lonafarnib is 100 mg twice daily when combined with imatinib at a dose of either

400 mg or 600 mg daily. Cancer 2007;110:1295–302. � 2007 American Cancer

Society.

KEYWORDS: lonafarnib, imatinib, chronic myeloid leukemia, phase 1 study, farne-syl transferase inhibitor.

C hronic myelogenous leukemia (CML) is characterized by a

balanced translocation involving the Abelson oncogene (ABL)

from chromosome 9q34 and the breakpoint cluster region (BCR) on

chromosome 22q11.2, t(9;22)(q34;q11.2), known as the Philadelphia

chromosome (Ph). This translocation generates the BCR-ABL fusion

Dr. Cortes and Dr. Kantarjian received researchgrants from Novartis and Schering-Plough. Dr.Daley received a research grant from Schering-Plough.

Research sponsored in part by a sponsoredresearch agreement from the Schering-PloughResearch Institute (G.D.) and a research grantfrom the Leukemia and Lymphoma Society(J.C.).

Drs. Zhu and Statkevich are employees ofSchering-Plough.

Address for reprints: Jorge Cortes, MD, Depart-ment of Leukemia, The University of Texas M. D.Anderson Cancer Center, 1515 Holcombe Blvd.,Box 428, Houston, TX 77030; Fax: (713) 794-4297; E-mail: jcortes@mdanderson.org

Received March 14, 2007; revision received May15, 2007; accepted May 16, 2007.

ª 2007 American Cancer SocietyDOI 10.1002/cncr.22901Published online 10 July 2007 in Wiley InterScience (www.interscience.wiley.com).

1295

oncogene, which translates into a Bcr-Abl oncopro-

tein with increased tyrosine kinase activity.1,2 Imati-

nib is standard therapy for patients with CML,2

inducing durable responses,3–6 particularly among

those who achieved a major molecular response.7,8

However, a subset of patients eventually develop re-

sistance, particularly those treated in the advanced

stages of disease.9,10 Thus, there is a need to investi-

gate novel agents to overcome and potentially pre-

vent resistance to imatinib.

Ras is one of the downstream pathways activated

through Bcr-Abl tyrosine kinase activity. Suppression

of Ras function leads to the inhibition of cellular

growth in Bcr-Abl-positive cells, suggesting that Ras

inhibition could be a therapeutic target in CML.11–13

Ras activation requires a post-translational modifica-

tion that allows attachment to the inner leaflet of the

plasma membrane. This process requires a prenyla-

tion process that is mediated by at least 2 known

enzymes, farnesyl transferase (FTase) and geranyl-ge-

ranyl transferase (GGTase).14,15 Inhibition of these

enzymes was sought as a means of inhibiting Ras,

leading to the development of Ftase inhibitors (FTIs).

Although FTIs indeed inhibit FTase, their antineo-

plastic effect is mediated only partially, if at all,

through Ras inhibition. Other proteins that require

farnesylation, such as RhoB, the centromeric proteins

CENP-E and CENP-F, and Rab may be more relevant

for their mechanism of action.16–19

Lonafarnib (SCH66336) is a nonpeptidomimetic

FTI that induces the dose-dependent inhibition of

colony formation and proliferation of Bcr-Abl-trans-

formed BaF3 cells and cells from CML patients.20,21

In Bcr-Abl leukemic mouse models, treatment with

lonafarnib resulted in prolonged survival.21,22 Lona-

farnib also inhibits the proliferation of imatinib-re-

sistant Bcr-Abl-positive cell lines and colony

formation of cells from imatinib-resistant CML

patients, and sensitizes imatinib-resistant cells to

imatinib-induced apoptosis.23 Furthermore, lonafar-

nib may reduce the resistance of primitive quiescent

CML stem cells to imatinib.24

By itself, lonafarnib has minimal clinical activity

among patients with imatinib failure.25 However,

based on the in vitro synergy of imatinib and lonafar-

nib, we conducted a phase 1 study to determine the

maximum tolerated dose (MTD) and dose-limiting

toxicities (DLTs) of this combination for patients with

CML in chronic phase (CP), accelerated phase (AP),

or blast phase (BP) who failed prior imatinib therapy.

MATERIALS AND METHODSPatients age �16 years with Ph-positive CML in CP,

AP, or BP were treated. The eligibility criteria for

patients in CP were failure to achieve or loss of

a complete hematologic response (CHR) after

3 months of imatinib therapy, minimal cytogenetic

response after 6 months of imatinib therapy, or

major cytogenetic response after 12 months of imati-

nib therapy. AP and BP were defined as previously

reported.26 Other eligibility criteria included: 1)

ECOG performance status < 2, 2) bilirubin < 2.0 mg/

dL, and 3) creatinine < 2 mg/mL. Patients with a

QTc > 500 milliseconds or class III and IV New York

Heart Association heart disease were excluded. All

patients provided informed consent approved by the

Institutional Review Board.

Treatment ScheduleFor patients with CP disease, the starting dose was

imatinib, 400 mg orally daily, and lonafarnib, 100 mg

orally twice daily. For patients with disease in

advanced stages, the starting dose was imatinib, 600

mg orally every day, and lonafarnib, 100 mg orally

twice daily. Dose escalation of lonafarnib in subse-

quent cohorts of patients was performed by 25-mg,

twice-daily dose increments, up to a maximum

planned dose of 250 mg twice daily. This dose escala-

tion was performed according to a classic ‘‘3 1 3’’

phase 1 design. There was no dose escalation of ima-

tinib. Patients who developed grade �3 nonhemato-

logic toxicity had their treatment interrupted until

toxicity resolved to grade < 1. Therapy was then

reinstituted with 1 dose level reduction. Therapy also

could be interrupted in patients with CP disease for

grade 4 neutropenia (absolute neutrophil count

[ANC] < 0.5 3 109/L) or a platelet count < 40 3 109/L

until counts recovered above these values. Therapy

was then reinitiated at the same dose level if recov-

ered within 2 weeks, or with a dose reduction by 1

dose level if recovered after 2 weeks. For patients

with AP disease, therapy was continued below this

platelet threshold if thrombocytopenia was disease

related. For patients in BP, there were no dose modi-

fications for hematologic toxicity during the first

month. For patients with AP and BP disease who

achieved a CHR, the dose modification schema for

myelosuppression described in CP was used there-

after. Dose adjustment was done for 1 of the drugs

only if the toxicity was clearly attributable to it. The

administration of hydroxyurea was allowed in any

disease stage for the first 3 months of therapy only.

The use of anagrelide was allowed at any time. Intra-

patient dose escalation was allowed for patient who

demonstrated no grade �3 toxicity after 4 weeks of

therapy if not in CHR, or if no improvement in cyto-

genetic response by 1 category provided there was

no persistent grade > 2 toxicity.

1296 CANCER September 15, 2007 / Volume 110 / Number 6

Toxicities were evaluated using the revised Na-

tional Cancer Institute Common Toxicity Criteria

(version 2.0). DLT was defined as any grade �3 non-

hematologic adverse event occurring during the first

cycle of therapy. Nausea and vomiting were consid-

ered DLTs only if they were not responsive to antie-

metic therapy and diarrhea only if uncontrolled for

48 hours despite adequate antidiarrheal therapy. A

hematologic DLT was defined as an ANC < 1 3 109/

L or platelet count < 50 3 109/L lasting for �6 weeks

with a hypocellular bone marrow and no bone mar-

row blasts. Anemia was not considered to be a hema-

tologic DLT.

Pretreatment and Follow-up StudiesPretreatment evaluation included history and physi-

cal examination; complete blood count (CBC) and

differential, blood chemistry, and coagulation studies;

bone marrow aspiration with cytogenetics; and elec-

trocardiogram (EKG). During the study, CBC and dif-

ferential were performed weekly for the first 2 weeks,

and every 2 to 4 weeks thereafter. Blood chemistry

was performed weekly for the first 2 weeks, and then

every 4 to 6 weeks. Bone marrow aspiration and cy-

togenetics were performed every 3 months for the

first year, and every 6 to 12 months thereafter. EKG

was performed monthly. Response was defined as

previously reported.27

PharmacokineticsBlood samples for the determination of plasma lona-

farnib concentrations were collected on Day 15 at 0,

1, 2, 4, 6, 8, and 12 hours. Blood samples for the

determination of plasma imatinib concentrations

were collected on Days 7 and 15 at the same times.

Blood samples were analyzed by liquid chromatogra-

phy with the tandem mass spectrometric detection

method. The lower limit of quantification was 5.00

ng/mL and 20.0 ng/mL, respectively, for lonafarnib

and imatinib. Plasma was separated by centrifuga-

tion, divided into 2 aliquots, and stored frozen until

analysis. The analysis for lonafarnib was performed

at Taylor Technology (Princeton, NJ) and at MDS

Pharma Service, Inc. (St. Laurent, Quebec, Canada)

for imatinib.

Individual plasma lonafarnib and imatinib con-

centrations were used for pharmacokinetics analysis

using model-independent methods.28 The maximum

plasma concentration (Cmax) and time of maximum

plasma concentration (Tmax) were the observed

values. The area under the plasma concentration-time

curve (AUC) during each dosing interval (s) was calcu-

lated using the linear trapezoidal method. The termi-

nal phase rate constant (K) could not be calculated in

this study for both lonafarnib and imatinib due to

insufficient numbers of time points in the terminal

phase. At steady-state, the apparent total body clear-

ance was calculated as Cl/F 5 Dose/AUC(s), in which

s is 12 hours and 24 hours, respectively, for lonafarnib

and imatinib.

Statistical AnalysisA minimum of 3 patients were entered at each dose

level. If no DLT was observed in 3 patients treated at

a given dose level after the last patient treated had

been observed for a minimum of 3 weeks, dose esca-

lation was indicated in the next cohort of patients.

If a DLT occurred in 1 of 3 patients, 3 additional

patients were to be entered at the same dose level. If

grade 3 or 4 toxicity developed in 2 of 3 or 6 patients,

the dose was considered to exceed the MTD. There-

fore, the MTD was defined as the dose resulting in a

DLT in �1 of 6 patients. Once the MTD was defined,

additional patients were treated at this dose to define

the toxicity profile more precisely.

RESULTSPatient CharacteristicsBetween November 2002 and July 2004, 23 patients

were treated (Table 1). Prior therapy included imati-

nib (23 patients); interferon-based therapy (16

patients); and other agents such homoharringtonine,

decitabine, and clofarabine (7 patients). Four

patients had received imatinib as their first therapy

for CML. The median time from diagnosis was 51

TABLE 1Patient Characteristics (N 5 23)

Characteristics No. (%) Median Range

Age, y 55 26–79

CML phase

CP 9 (39)

AP 11 (48)

BP 3 (13)

Clonal evolution 8 (35)

Prior therapy

Imatinib 23 (100)

Interferon 16 (70)

Other 7 (30)

Time from diagnosis, mo 51 10–187

Time receiving imatinib, mo 23 4–45

Percentage of Ph1 metaphases 100 35–100

Leukocyte count, 3 109/L 9.7 1.5–56

Platelet count, 3 109/L 235 17–820

Hemoglobin level, g/dL 10.4 7.5–14.4

CML indicates chronic myeloid leukemia; CP, chronic phase; AP, accelerated phase; BP, blast phase;

Ph1, Philadelphia chromosome–positive.

Lonafarnib and Imatinib Combination in CML/Cortes et al. 1297

months and patients had received imatinib for a me-

dian of 23 months. At the time the combination

treatment was initiated, 10 patients were still receiv-

ing imatinib at a median dose of 800 mg (range,

400–800 mg), and 8 were being treated with other

agents, including hydroxyurea (7 patients) and ana-

grelide (1 patient). Eight of the 14 patients in AP or

BP (62%) had clonal evolution. ABL sequencing was

performed in 21 patients at the start of this trial and

mutations were found in 11 patients (52%). The most

frequent mutations were G250E (3 patients) and

Y253H (2 patients).

Toxicity and Dose EscalationAll 23 patients were assessable for toxicity (Table 2).

The most common adverse events were diarrhea in

13 patients (5 of whom had CP disease), and nausea

in 7 patients (1 of whom had CP disease).

For patients in CP, the initial 3 patients received

lonafarnib at a dose of 100 mg twice daily and imati-

nib at a dose of 400 mg/day. The median time on

therapy was 8 months (range, 2–18 months). No

patients experienced a DLT. One patient required a

dose escalation of imatinib to 600 mg due to a lack

of optimal response. Three patients received lonafar-

nib at a dose of 125 mg twice daily and imatinib at a

dose of 400 mg/day. The median time on therapy

was 3 months. Grade 3 diarrhea was observed in all

3 patients and was considered to be a DLT in 2 of

them. One patient had intermittent short-term grade

3 diarrhea, nausea, and vomiting resulting in grade 3

fatigue. These events occurred 6 weeks after the

initiation of therapy and resulted in drug interrup-

tion and reduction of lonafarnib to 100 mg twice

daily. The patient was managed with supportive

measures, did not respond, and was removed from

the study after 3 months. The second patient devel-

oped grade 3 recurrent diarrhea 2 days after the

initiation of treatment. Therapy was withheld repeti-

tively and resumed after the diarrhea resolved. Due

to the recurrence of diarrhea, lonafarnib was reduced

to a dose of 100 mg twice daily. However, the patient

developed disease progression and was removed

from the study 1 month later. Thus, the MTD for

lonafarnib was 100 mg twice daily and was 400 mg/

day for imatinib. Therefore, this cohort was

expanded and 3 additional patients were treated for

a median of 12 months (range, 2–24 months). None

of these patients developed a DLT.

For patients in advanced stages of disease, the 3

initial patients received lonafarnib at a dose of 100

mg twice daily and imatinib at a dose of 600 mg/day.

The median time on therapy was 2 months (range,

1–4 months). There was no DLT reported. The next

3 patients were treated with lonafarnib at a dose

of 125 mg twice daily and imatinib at a dose of

600 mg/day for a median of 2 months (range,

1–3 months). One patient in BP developed grade 3

TABLE 2Adverse Events During Therapy With Lonafarnib and Imatinib

Adverse event

Chronic phase Accelerated phase/Blast phase

Dose level 0 Dose level 11 Dose level 0 Dose level 11

No. Any Grade* �3 Any Grade �3 No. Any Grade �3 Any Grade �3

Diarrhea 5 3 1 2 2 8 4 1 4 1

Nausea 1 0 0 1 1 6 3 0 3 1

Vomiting 1 0 0 1 1 4 1 0 3 1

Neutropenia 1 1 1 0 0 3 1 1 2 2

Thrombocytopenia 0 0 0 0 0 2 0 0 2 2

Fatigue 2 1 0 1 1 2 2 2 0 0

Hypokalemia 0 0 0 0 0 2 1 1 1 1

Herpes infection 0 0 0 0 0 1 1 1 0 0

Anorexia 0 0 0 0 0 1 1 1 0 0

Abscess 0 0 0 0 0 1 0 0 1 0

Somnolence 0 0 0 0 0 1 0 0 1 0

Arthralgia 0 0 0 0 0 1 1 0 0 0

Dehydration 1 1 1 0 0 0 0 0 0 0

Palpitation 1 1 1 0 0 0 0 0 0 0

Pruritus 1 1 1 0 0 0 0 0 0 0

Fungal infection 1 1 1 0 0 0 0 0 0 0

* Grading was performed according to the National Cancer Institute Common Toxicity Criteria (version 2.0).

1298 CANCER September 15, 2007 / Volume 110 / Number 6

diarrhea 3 days after the start of treatment. The treat-

ment was withheld for 3 days and the patient was

treated symptomatically. Lonafarnib was resumed at

a dose of 100 mg twice daily once diarrhea resolved.

The treatment was withdrawn after 1 month due to

lack of response. This constituted a DLT and the

cohort was expanded with 3 additional patients trea-

ted for a median of 9 months (range, 4–16 months).

One patient in BP experienced grade 3 hypokalemia

4 weeks after the initiation of therapy. The potassium

was replaced and treatment was withheld for 7 days

and then resumed with dose reduction. The patient

had a second prolonged episode of hypokalemia,

necessitating treatment interruption that resulted in

disease progression. Thus, lonafarnib at a dose of

100 mg twice daily and imatinib at a dose of 600

mg/day was considered the MTD. Five additional

patients were treated at this dose for a median of

7 months (range, 1–20 months), 3 of whom devel-

oped grade 3 toxicity consisting of fatigue, hypokale-

mia, and diarrhea, respectively, which occurred after

2 cycles, 4 cycles, and 4 cycles, respectively.

PharmacokineticsBlood samples for the evaluation of lonafarnib phar-

macokinetics were collected on Day 15 for all

patients. There was no apparent increase in plasma

lonafarnib concentrations when a dose of 100 mg of

lonafarnib was coadministered with 400 mg and 600

mg of imatinib (Figs. 1a and 1b). The mean plasma

concentrations and AUC values of lonafarnib

appeared to be lower when 100 mg and 125 mg of

lonafarnib were coadministered with 600 mg of ima-

tinib compared with 400 mg.

Blood samples for the evaluation of imatinib

pharmacokinetics were collected on Days 7 and 15.

Plasma imatinib concentrations were similar

between Days 7 and 15, indicating steady-state was

attained. There were no apparent increases in expo-

sure to imatinib when coadministered with lonafarnib.

The AUC values of imatinib when coadministered

with 100 mg to 125 mg of lonafarnib were found to

be similar to those reported in a previous study in

which imatinib was administered alone.29 An increase

in the dose of lonafarnib from 100 mg to 125 mg was

found to have no effect on the pharmacokinetics of

imatinib (Figs. 2a and 2b).

ResponsePatient response is shown in Table 3. Eight patients

(35%) had evidence of antileukemia activity. Three of

9 patients (33%) in CP responded. Two of 6 patients

not in CHR at the initiation of therapy achieved a

CHR that lasted for 7 months and �13 months,

respectively. The later patient was withdrawn from

the study because of a lack of cytogenetic response

and received another tyrosine kinase inhibitor. One

patient, who started the study in CHR and had lost a

prior cytogenetic response, achieved a complete

cytogenetic response that lasted 12 months. None of

the patients who responded had mutations at the

initiation of therapy.

Five of 14 patients (36%) with advanced stage

disease responded. Two patients with AP disease

achieved CHRs that lasted 2 months and 19 months,

respectively, and another patient with a CHR but

with clonal evolution at the initiation of treatment

achieved a partial cytogenetic response but discon-

tinued therapy because of persistent grade 2 diar-

FIGURE 1. (a) Mean plasma lonafarnib concentration versus time profileson Day 15 of Cycle 1 after the oral administration of lonafarnib given twice

daily in combination with imatinib given once daily in patients with chronic

myelogenous leukemia. (b) Individual lonafarnib area under the plasma con-

centration-time curve (AUC) values on Day 15 of Cycle 1 after the oral

administration of lonafarnib given twice daily in combination with imatinib

given once daily in patients with chronic myelogenous leukemia. L indicates

lonafarnib; IM, imatinib.

Lonafarnib and Imatinib Combination in CML/Cortes et al. 1299

rhea. Two patients in BP achieved, respectively, a

partial hematologic response and a hematologic

improvement that were transient and were lost after

1 month and 2 months, respectively. The 3 respond-

ing patients with AP disease had mutations (Y253H,

F359V, and E292V, respectively) of the kinase domain.

DISCUSSIONThe purpose of the current study was to define the

MTD for the combination of lonafarnib and imatinib

for patients with CML. This combination is of inter-

est because of the nonoverlapping mechanisms of

action of the combination that could induce a

sequential blockade of activated pathways in CML.30

As single agents, FTIs have modest activity in

patients who fail therapy with imatinib.25,31 Lonafar-

nib, given continuously at a dose of 200 mg twice

daily, induced transient responses in 2 of 13 patients

(15%) who failed prior therapy with imatinib.25 In

vitro studies have suggested that the combination of

FTI and imatinib may be synergistic.23 Furthermore,

some studies have suggested that early progenitors

are quiescent and insensitive to imatinib32 and dasa-

tinib.33 Lonafarnib24 and another FTI, BMS-214662,34

have been reported to significantly reduce the resist-

ance of these progenitors to imatinib24,34 and dasati-

nib.34 All of this data suggested this combination

could be potentially beneficial in patients with CML.

Consistent with the established toxicities of sin-

gle-agent lonafarnib,32 gastrointestinal toxicities were

found to be the most significant, with diarrhea being

the DLT. This could frequently be controlled with

proper management, but in 3 patients it led to the

permanent discontinuation of therapy. Although ima-

tinib can also cause diarrhea in approximately 30%

of patients,4,6 these DLTs were most likely due to

lonafarnib because these patients had not experi-

enced diarrhea while receiving imatinib. Grade 3/4

myelosuppression was uncommon and transient.

The MTD of lonafarnib was lower than the dose

recommended as a single agent (200 mg twice

daily35) but was similar to other combination trials

in solid tumors in which the MTD was 100 mg twice

daily.36 In other lonafarnib studies,25,37 diarrhea has

responded to treatment interruptions, and it is possi-

ble that an intermittent schedule in which lonafarnib

is administered for a few weeks and a rest period

given between cycles might be better tolerated.

TABLE 3Response to the Combination of Lonafarnib and Imatinib in CMLPatients After Imatinib Failure

CP not inCHR N 5 6

CP inCHR N 5 3

AP/BPN 5 14

Hematologic response

PHR/HI 2

Duration (range), mo 1–2

CHR 2 2

Duration (range), mo 7–13 2–19

Cytogentic response

CGCR 1

CGPR 1

Duration (range), mo 12 9

CML indicates chronic myeloid leukemia; CP, chronic phase; CHR, complete hematologic response;

AP, accelerated phase; BP, blast phase; PHR, partial hematologic response; HI, hematologic improve-

ment; CGCR, complete cytogenetic response; CCPR, partial cytogenetic response.

FIGURE 2. (a) Mean plasma imatinib concentration versus time profiles onDays 7 and 15 of Cycle 1 after the oral administration of imatinib given

once daily in combination with lonafarnib given twice daily in patients with

chronic myelogenous leukemia. (b) Individual imatinib area under the plasma

concentration-time curve (AUC) values on Days 7 and 15 of Cycle 1 after the

oral administration of imatinib given once daily in combination with lonafar-

nib given twice daily in patients with chronic myelogenous leukemia. IM indi-

cates imatinib; L, lonafarnib.

1300 CANCER September 15, 2007 / Volume 110 / Number 6

Pharmacokinetic analysis indicated that the con-

comitant administration of these agents did not result

in increased exposure to either agent. The AUCs of

both drugs were in the active range and similar to

those observed when each drug is used alone.29 It is

interesting to note that the mean plasma concentra-

tions and AUC values of lonafarnib were lower when

doses of 100 mg and 125 mg were coadministered

with 600 mg of imatinib compared with patients who

received 400 mg. The small number of patients pre-

cludes firm conclusions, but 1 possible explanation

may be an increase in the volume of distribution at

the higher dose of imatinib,4,6 although none of the

patients treated in the current study developed grade

3 edema. Imatinib is not an inducer of CYP 3A4.29

Thus, the decreased plasma concentrations of lonafar-

nib when it is coadministered with the higher dose of

imatinib are unlikely to be due to the induction of

CYP 3A4 that metabolizes lonafarnib.

Responses occurred in 8 patients (35%). The ma-

jority of responses were hematologic but 2 patients

achieved a cytogenetic response. Three responding

patients (all with AP disease) had Abl kinase muta-

tions. The clinical efficacy of this combination

remains modest and inferior to the new TKIs such as

nilotinib38 and dasatinib.39 Allogeneic stem cell

transplantation was also reported to be an important

salvage option for patients who develop resistance to

imatinib, including those with mutations in the Bcr-

Abl kinase domain.40 New TKIs have demonstrated

significant preclinical activity in cells carrying the

majority of abl-kinase mutants (except T315I),41,42

which has translated into significant clinical activity

in patients with CML after imatinib failure. In fact,

11 of the 23 patients reported in the current study

received new TKIs after failure with the combination

of imatinib and lonafarnib; 5 of them achieved he-

matologic or cytogenetic responses. Nevertheless,

single-agent therapy may be unable to eliminate all

leukemia cells43 and may lead to the eventual devel-

opment of resistance. Indeed, new mutations can be

induced in vitro after exposure to dasatinib or niloti-

nib under appropriate experimental conditions.44,45

These mutations already have been identified in

patients failing dasatinib.46 It is conceivable that

multiagent therapy may be needed to completely

eradicate the disease. In this regard, it is interesting

that the earliest leukemic progenitors have been

reported to be insensitive to the available TKI,32,34

and FTI may reduce the resistance of these progeni-

tors to TKI.24,34 Therefore, further exploration of

these combinations, perhaps with the new TKI, and

using them in an earlier setting to prevent the devel-

opment of resistance might be attractive.

We conclude that lonafarnib given at a dose of

100 mg twice daily in combination with imatinib can

be administered safely in patients with CML. This

combination has nonoverlaping mechanisms of action

that result in clinical activity in some patients with

imatinib-resistant disease. With the development of

novel, more potent TKIs, the combination of FTIs and

these new agents deserves further investigation.

REFERENCES1. Faderl S, Talpaz M, Estrov Z, O’Brien S, Kurzrock R, Kantar-

jian HM. The biology of chronic myeloid leukemia. N Engl

Med. 1999;341:164–172.

2. Goldman JM, Melo JV. Chronic myeloid leukemia-advances

in biology and new approaches to treatment. N Engl J Med.

2003;349:1451–1464.

3. Kantarjian HM, Cortes JE, O’Brien S, et al. Long-term survival

benefit and improved complete cytogenetic and molecular

response rates with imatinib mesylate in Philadelphia chro-

mosome-positive chronic-phase chronic myeloid leukemia

after failure of interferon-alpha. Blood. 2004;104:1979–1988.

4. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic

and cytogenetic responses to imatinib mesylate in chronic

myelogenous leukemia. N Engl Med. 2002;346:645–652.

5. Kantarjian H, Talpaz M, O’Brien S, et al. High-dose imati-

nib mesylate therapy in newly diagnosed Philadelphia

chromosome-positive chronic phase chronic myeloid leu-

kemia. Blood. 2004;103:2873–2878.

6. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared

with interferon and low-dose cytarabine for newly diag-

nosed chronic-phase chronic myeloid leukemia. N Engl J

Med. 2003;348:994–1004.

7. Hughes TP, Kaeda J, Branford S, et al. Frequency of major

molecular responses to imatinib or interferon alfa plus

cytarabine in newly diagnosed chronic myeloid leukemia.

N Engl J Med. 2003;349:1423–1432.

8. Cortes J, Talpaz M, O’Brien S, et al. Molecular responses in

patients with chronic myelogenous leukemia in chronic

phase treated with imatinib mesylate. Clin Cancer Res.

2005;11:3425–3432.

9. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A,

Rostagno R, Scapozza L. Molecular mechanisms of resist-

ance to imatinib in Philadelphia-hromosome-positive leu-

kaemias. Lancet Oncol. 2003;4:75–85.

10. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chro-

mosomal mechanisms of resistance to imatinib (STI571)

therapy. Leukemia. 2002;16:2190–2196.

11. Mandanas RA, Leibowitz DS, Gharehbaghi K, et al. Role of

p21 RAS in p210 bcr-abl transformation of murine myeloid

cells. Blood. 1993;82:1838–1847.

12. Puil L, Liu J, Gish G, et al. Bcr-Abl oncoproteins bind

directly to activators of the Ras signalling pathway. EMBO

J. 1994;13:764–773.

13. Sawyers CL, McLaughlin J, Witte ON. Genetic requirement

for Ras in the transformation of fibroblasts and hematopoi-

etic cells by the Bcr-Abl oncogene. J Exp Med. 1995;181:

307–313.

14. Gelb MH. Protein prenylation, et cetera: signal transduc-

tion in two dimensions. Science. 1997;275:1750–1751.

15. Khosravi-Far R, Cox AD, Kato K, Der CJ. Protein prenyla-

tion: key to ras function and cancer intervention? Cell

Growth Differ. 1992;3:461–469.

Lonafarnib and Imatinib Combination in CML/Cortes et al. 1301

16. Ashar HR, James L, Gray K, et al. Farnesyl transferase inhi-

bitors block the farnesylation of CENP-E and CENP-F and

alter the association of CENP-E with the microtubules.

J Biol Chem. 2000;275:30451–30457.

17. Beaupre DM, Kurzrock R. RAS and leukemia: from basic

mechanisms to gene-directed therapy. J Clin Oncol. 1999;

17:1071–1079.

18. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyl-

transferase: a strategic target for anticancer therapeutic de-

velopment. J Clin Oncol. 1999;17:3631–3652.

19. Lackner MR, Kindt RM, Carroll PM, et al. Chemical genet-

ics identifies Rab geranylgeranyl transferase as an apopto-

tic target of farnesyl transferase inhibitors. Cancer Cell.

2005;7:325–336.

20. Liu M, Bryant MS, Chen J, et al. Antitumor activity of SCH

66336, an orally bioavailable tricyclic inhibitor of farnesyl

protein transferase, in human tumor xenograft models and

wap-ras transgenic mice. Cancer Res. 1998;58:4947–4956.

21. Peters DG, Hoover RR, Gerlach MJ, et al. Activity of the far-

nesyl protein transferase inhibitor SCH66336 against BCR/

ABL-induced murine leukemia and primary cells from

patients with chronic myeloid leukemia. Blood. 2001;97:

1404–1412.

22. Reichert A, Heisterkamp N, Daley GQ, Groffen J. Treatment

of Bcr/Abl-positive acute lymphoblastic leukemia in P190

transgenic mice with the farnesyl transferase inhibitor

SCH66336. Blood. 2001;97:1399–1403.

23. Hoover RR, Mahon F-X, Melo JV, Daley GQ. Overcoming

STI571 resistance with the farnesyl transferase inhibitor

SCH66336. Blood. 2002;100:1068–1071.

24. Jorgensen HG, Allan EK, Graham SM, et al. Lonafarnib

reduces the resistance of primitive quiescent CML cells to

imatinib mesylate in vitro. Leukemia. 2005;19:1184–1191.

25. Borthakur G, Kantarjian H, Daley G, et al. Pilot study of

lonafarnib, a farnesyl transferase inhibitor, in patients with

chronic myeloid leukemia in the chronic or accelerated

phase that is resistant or refractory to imatinib therapy.

Cancer. 2006;106:346–352.

26. Kantarjian HM, Keating MJ, Smith TL, Talpaz M, McCredie

KB. Proposal for a simple synthesis prognostic staging sys-

tem in chronic myelogenous leukemia. Am J Med. 1990;

88:1–8.

27. Kantarjian HM, Smith T, O’Brien S, et al. Prolonged sur-

vival in chronic myelogenous leukemia after cytogenetic

response to interferon- therapy. Ann Intern Med. 1995;122:

254–261.

28. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York:

Dekker; 1982.

29. Peng B, Hayes M, Resta D, et al. Pharmacokinetics and

pharmacodynamics of imatinib in a phase I trial with

chronic myeloid leukemia patients. J Clin Oncol. 2004;22:

935–942.

30. Jabbour E, Kantarjian H, Cortes J. Clinical activity of farne-

syl transferase inhibitors in hematologic malignancies: pos-

sible mechanisms of action. Leuk Lymphoma. 2004;45:

2187–2195.

31. Cortes J, Garcia-Manero G, O’Brien S, et al. Phase I study

of Imatinib and Tipifarnib (Zarnestra, R115777) in patients

with chronic myeloid leukemia in chronic phase refractory

to imatinib. Blood. 2003;102:909a. Abstract 3383.

32. Graham SM, Jorgensen HG, Allan E, et al. Primitive, quies-

cent, Philadelphia-positive stem cells from patients with

chronic myeloid leukemia are insensitive to STI571 in vitro.

Blood. 2002;99:319–325.

33. Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-

354825) targets an earlier progenitor population than ima-

tinib in primary CML but does not eliminate the quiescent

fraction. Blood. 2006;107:4532–4539.

34. Copland M, Hamilton A, Allan EK, Brunton V, Holyoake TL.

BMS-214662 targets quiescent chronic myeloid leukaemia

stem cells and enhances the activity of both imatinib and

dasatinib (BMS-354825). Blood. 2005;106:204a. Abstract

693.

35. Adjei AA, Erlichman C, Davis JN, et al. A Phase I trial of

the farnesyl transferase inhibitor SCH66336: evidence for

biological and clinical activity. Cancer Res. 2000;60:1871–

1877.

36. Khuri FR, Glisson BS, Kim ES, et al. Phase I study of the

farnesyltransferase inhibitor lonafarnib with paclitaxel in

solid tumors. Clin Cancer Res. 2004;10:2968–2976.

37. Feldman EJ, Cortes J, Holyoake TL, et al. Continuous oral

Lonafarnib (SarasarTM) for the treatment of patients with

myelodysplastic syndrome. Blood. 2003;102:421a. Abstract

1531.

38. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imati-

nib-resistant CML and Philadelphia chromosome-positive

ALL. N Engl J Med. 2006;354:2542–2551.

39. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imati-

nib-resistant Philadelphia chromosome-positive leukemias.

N Engl J Med. 2006;354:2531–2541.

40. Jabbour E, Cortes J, Kantarjian H, et al. Allogeneic stem

cell transplantation for patients with chronic myeloid leu-

kemia and acute lymphocytic leukemia after Bcr-Abl kinase

mutation-related imatinib failure. Blood. 2006;108:1421–

1423.

41. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity

of Bcr-Abl inhibitors AMN107 and BMS-354825 against

clinically relevant imatinib-resistant Abl kinase domain

mutants. Cancer Res. 2005;65:4500–4505.

42. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL.

Overriding imatinib resistance with a novel ABL kinase in-

hibitor. Science. 2004;305:399–401.

43. Wong S, McLaughlin J, Cheng D, Zhang C, Shokat KM,

Witte ON. Sole BCR-ABL inhibition is insufficient to elimi-

nate all myeloproliferative disorder cell populations. Proc

Natl Acad Sci USA. 2004;101:17456–17461.

44. Burgess MR, Skaggs BJ, Shah NP, Lee FY, Sawyers CL. Com-

parative analysis of two clinically active BCR-ABL kinase

inhibitors reveals the role of conformation-specific binding

in resistance. Proc Natl Acad Sci USA. 2005;102:3395–3400.

45. Bradeen HA, Eide CA, O’Hare T, et al. Comparison of ima-

tinib, dasatinib (BMS-354825), and nilotinib (AMN107)

in an n-ethyl-n-nitrosourea (ENU) -based mutagenesis

screen: high efficacy of drug combinations. Blood. 2006;108:

2332–2338.

46. Shah NP, Nicoll JM, Branford S, et al. Molecular analysis of

dasatinib resistance mechanisms in CML patients identifies

novel BCR-ABL mutations predicted to retain sensitivity to

imatinib: rationale for combination tyrosine kinase inhibi-

tor therapy. Blood. 2005;106:318a. Abstract 1093.

1302 CANCER September 15, 2007 / Volume 110 / Number 6