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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the University of Maryland Greenebaum Cancer
Center, Baltimore, Maryland; University of Rochester Cancer Center,
Rochester, New York; Mayo Clinic, Rochester, Minnesota; Janssen
Research Foundation, Beerse, Belgium and Spring House, PA; National
Cancer Institute, Bethesda, Maryland; and Ortho Clinical Diagnostics,
Rochester, NY; University of Iowa, Iowa City.
R115777 is a nonpeptidomimetic enzyme-specific inhibitor of
farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally
administered R115777 in 35 adults with poor-risk acute leukemias.
Cohorts of patients received R115777 at doses ranging from 100 mg twice
daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by
ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia,
paresthesias, and myelosuppression. R115777 inhibited FT activity at
300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme
of Ras-mediated signaling, was detected in its phosphorylated (activated) form in 8 (36.4%) of 22 pretreatment marrows and became undetectable in 4 of those 8 after one cycle of treatment.
Pharmacokinetics revealed a linear relationship between dose and
maximum plasma concentration or area under the curve over 12 hours at
all dose levels. Weekly marrow samples demonstrated that R115777
accumulated in bone marrow in a dose-dependent fashion, with large
increases in marrow drug levels beginning at 600 mg bid and with
sustained levels throughout drug administration. Clinical responses
occurred in 10 (29%) of the 34 evaluable patients, including 2 complete remissions. Genomic analyses failed to detect
N-ras gene mutations in any of the 35 leukemias. The
results of this first clinical trial of a signal transduction inhibitor
in patients with acute leukemias suggest that inhibitors of FT may have
important clinical antileukemic activity.
(Blood. 2001;97:3361-3369) Adult acute leukemias remain formidable therapeutic
challenge. Only 70% of adults with newly diagnosed acute myelogenous
leukemias (AMLs) achieve complete remission (CR) after cytotoxic
induction chemotherapy. Although these CRs may be prolonged in 35% to
40% of younger adults (age < 60),1-5 the remainder have
a relapse and die. Certain subgroups, including older
adults,3,5,6 patients with AMLs linked to environmental or
occupational exposures (including therapy-induced AMLs), and patients
with previous myelodysplasia (MDS) or other antecedent hematologic
disorders,7,8 have extremely poor outcomes, with CR rates
of 40% or less, CR durations less than 12 months, and cure rates less
than 10% to 15%.3,5,6 The overall outlook for adult
acute lymphoblastic leukemias (ALLs) is similar,9-11 with
a particularly poor prognosis in Philadelphia chromosome
(Ph+) disease.9,12 Thus, new approaches are
needed to improve the outcome for adults with refractory leukemias.
Improved understanding of signal transduction pathways has resulted in
identification of a panoply of potential therapeutic targets.13-16 Among these are the membrane-associated G
proteins encoded by the ras family of proto-oncogenes. Ras
proteins are activated downstream of protein tyrosine kinases (PTKs,
eg, growth factor receptors) and, in turn, trigger a cascade of
phosphorylation events through sequential activation of Raf, MEK-1, and
ERKs (extracellular signal-related kinases). These events are critical
to survival of hematopoietic cells.16-19
The Ras proteins are synthesized as cytosolic precursors that must
attach to the cell membrane to transmit signals. Membrane attachment
depends on the addition of a 15-carbon farnesyl group to Ras, a
reaction that is catalyzed by the enzyme farnesyltransferase (FT).20-22 FT inhibitors (FTIs) were developed on the
premise that FT inhibition would prevent Ras processing and, therefore,
transduction of proliferative signals.22-24 Subsequent
studies, however, have suggested that the cytotoxic actions of FTIs
might also involve other farnesylated polypeptides, including
RhoB25,26 and components of the phosphoinositide 3-OH
kinase (PI3K)/AKT-2 pathway.27
Mutations and abnormal expression of ras genes, especially
N-ras, are detected in roughly 10% to 15% of MDS
(especially those transforming to AML)28,29 and in 15% to
25% of AMLs studied to date.30-33 In addition, the
coupling of Ras proteins to PTKs raises the possibility that PTK-driven
malignancies might be susceptible to FTIs.34,35
R115777, a potent and selective nonpeptidomimetic competitive FT
inhibitor,22 decreases proliferation of T24
H-ras-transfected NIH 3T3 cells as well as
K-ras-transformed CAPAN-2 pancreatic cancer cells and
several human colon cancer lines in vitro.22,36 Phase 1 trials of R115777 in adults with solid tumors37
demonstrated oral bioavailability, with a linear relationship between
dose and maximum plasma concentration (Cmax) or area under
the concentration curve at over 12 hours (AUC0-12h) at
doses up to 500 mg twice daily (bid). Dose-limiting toxicities (DLTs)
on various schedules included reversible myelosuppression, neuropathy,
fatigue, and serum creatinine elevations.36,37
To test the potential molecular, biologic, and clinical effects of
R115777 in adults with refractory and relapsed acute leukemias, we
conducted a phase 1 dose-escalation trial. Results of this trial
provide the first evidence for successful inhibition of FT in
neoplastic cells in vivo as well as promising antileukemic activity.
Patient eligibility and selection
Patients were ineligible if they had a peripheral blast count of
50 000/µL or higher; disseminated intravascular coagulation; active
central nervous system leukemia; prior allogeneic stem cell
transplantation; prior radiation up to more than 25% of bone marrow; concomitant radiotherapy, chemotherapy, or immunotherapy; coexisting medical or psychiatric conditions that could interfere with
study procedures; or known allergy to imidazoles. Pregnant or lactating
women were ineligible. All patients provided written informed consent
according to respective University of Maryland, Baltimore institutional
review board guidelines.
Complete history and physical examination were performed within 3 days
of study entry. Because cataract development was noted in Wistar rats
with prolonged exposure at high doses of R115777,22,28 all
patients underwent visual acuity testing at baseline and at the end of
R115777 administration. The following laboratory parameters were
obtained at 3 days or less before entry: complete blood count with
differential; electrolyte panel, magnesium, calcium, phosphate, blood
urea nitrogen, creatinine, glucose, uric acid, amylase, cholesterol,
total protein and albumin, hepatic transaminases, bilirubin, and
alkaline phosphatase; coagulation profile (prothrombin time, activated
partial thromboplastin time, fibrinogen, fibrin degradation products);
urinalysis; bone marrow aspirate (biopsy when indicated) with
histochemical, cytogenetic and immunophenotypic analysis; chest x-ray;
electrocardiogram; bacterial, fungal, and viral cultures of throat,
stool, and urine; and, for women of childbearing potential, a pregnancy
test. Additional studies (lumbar puncture with cerebrospinal fluid
cytospin, computed tomography scans, gallium scans, multiple gated
acquisition, or echocardiogram) were performed when clinically indicated.
Treatment schema
Definitions of response To assess response to therapy, a bone marrow aspiration was performed weekly during the first 21-day cycle and at the end of each subsequent cycle or at any time that leukemia regrowth was suspected. Hematologic recovery was defined as an absolute neutrophil count (ANC) of at least 500/µL and a transfusion-independent platelet count of 50 000/µL. CR required a normal bone marrow aspirate with absence of identifiable leukemia, ANC of 1000/µL or higher, platelet count of 100 000/µL or higher, and absence of blasts in peripheral blood.38 Clearance of cytogenetic abnormalities was not required for CR, but was noted and described separately. Partial response (PR) was defined as the presence of trilineage hematopoiesis in the marrow with normalization of peripheral counts but with 5% to 25% blasts in the marrow.38 No response (NR) was defined as persistent leukemia in marrow or blood or both without significant decrease from pretreatment levels and without improvement in peripheral counts.The ras gene mutations Bone marrow cells obtained before treatment were analyzed for the presence of N-ras gene mutations using polymerase chain reaction (PCR)-amplified genomic DNA. Primers were designed to amplify 2 DNA fragments of approximately 100 base pairs each, one containing codons 12 and 13 and the other containing codon 61,28 which were screened for mutations using single-strand conformational polymorphism (SSCP) and heteroduplex analysis. Mutations were identified by comparing banding patterns with specimens containing known N-ras mutations or by direct sequencing of the PCR product. Mutations in N-ras codons 12, 13, and 61 were also analyzed by a nested PCR method in which wild-type sequence is digested by restriction enzyme followed by restriction fragment length polymorphism (RFLP) analysis. Samples were also analyzed for K-ras mutations as determined by restriction endonuclease-mediated selective PCR (REMS-PCR)39 and gel analysis.Measures of intracellular FT activity To determine whether leukemic cell FT activity is inhibited in vivo by R115777, we examined serial marrow samples obtained at weekly intervals for R115777-related changes in FT activity.FT enzyme inhibition. 40 Bone marrow cells were isolated by centrifugation in Accuspin-Histopaque tubes, depleted of red blood cells by distilled water lysis, pelleted, and frozen for subsequent analysis. All samples from each individual were run simultaneously. Frozen cell pellets were processed by adding 0.2 mL sonication buffer (20 mM Tris HCl, pH 7.5, plus 1 mM dithiothreitol and 20 µM ZnCl2, supplemented with 1 mM phenylmethylsulfonyl fluoride and Calbiochem Protease Inhibitor Cocktail, San Diego, CA), sonicated for 20 seconds, and centrifuged at 300 000g for 20 minutes in a Beckman microultracentrifuge (Palo Alto, CA). Aliquots of supernate were assayed for protein41 and adjusted to 0.5 mg/mL (10 µg/20 µL). FT activity was measured using a scintillation proximity assay (SPA) kit (Amersham Pharmacia Biotechnology, Piscataway, NJ). In brief, triplicate 20 µL samples were incubated for 60 minutes at 37°C with the lamin B peptide substrate (Biotin-YRASNRSCAIM) and [1-3H(n)]farnesyl-pyrophosphate.40 The resulting farnseylated peptide was recovered using streptavidin-conjugated scintillant-containing beads and quantitated as described by the supplier. Geranylgeranyltransferase (GGT) type 1 assays were performed using an SPA modification that involved incubating biotin-YRASNRSCAIL peptide substrate with [1-3H(n)] geranylgeranylphosphate for 120 minutes at 37°C.40Farnesylation of lamin A and HDJ-2. The intranuclear intermediate filament protein lamin A42 and the chaperone protein HDJ-243 are polypeptides that undergo farnesylation-dependent processing and, therefore, undergo mobility shifts when FT is inhibited.44,45 Thus, serial measurement of farnesylated and unfarnesylated lamin A and HDJ-2 in leukemic bone marrow cells before and during R115777 administration might serve as useful markers of FT inhibition.46,47 To assess the feasibility of this approach, heparinized bone marrow aspirates were cooled to 4°C and shipped by overnight courier to one of the authors (S.H.K.). Bone marrow mononuclear cells were isolated by Ficoll-Hypaque sedimentation and washed with buffer A (RPMI 1640 medium containing 10 mM Hepes, pH 7.4, at 4°C). Aliquots were removed for cell counts and preparation of Wright-stained cytospins for morphologic examination. Cell lysates were then prepared as previously described in detail.46 Aliquots containing total cellular protein from 5 × 105 marrow mononuclear cells were subjected to electrophoresis on sodium dodecyl sulfate (SDS)-polyacrylamide gels containing 8% (vol/vol) acrylamide, transferred to nitrocellulose, and probed48,49 with immunologic agents that react to a polypeptide that is uniquely present in prelamin A,46,50 monoclonal antibody against mature lamin A,51 anti-HDJ-2 or antihistone H1 using techniques previously described in detail.46 Log phase K562 human leukemia cells (American Tissue Culture Collection, Manassas, VA) incubated for 24 hours in RPMI 1640 medium containing 5% fetal bovine serum, 100 U/mL penicillin G, 100 µg/mL streptomycin, 2 mM glutamine, and 0.1% dimethylsulfoxide (DMSO) or the indicated concentration of R115777 (added from a 1000 × stock in DMSO) served as negative and positive controls, respectively. Phosphorylation of signaling intermediates ERK1/ERK2. To assess ERK1/ERK2 phosphorylation, bone marrow aspirates were subjected to Ficoll-Hypaque gradient sedimentation followed by extraction with Tris-buffered salt solution containing nonionic detergent and protease inhibitors. After SDS-polyacrylamide gel electrophoresis, extracts were transferred to Immobilin-P membrane (Millipore, Bedford, MA), probed with anti-ERK1/ERK2 antibody (Upstate Biotechnology, Lake Placid, NY), and visualized by enhanced chemoluminescence (Amersham). Phosphorylated forms were identified by their slowed gel migration. Repeat probing with phosphotyrosine-specific antibody identified the presence or absence of tyrosine phosphorylation. Band intensity was quantitated by phosphorimage analysis using ImageQuant software. Pharmacokinetics Blood samples for pharmacokinetic studies were obtained immediately before administration of R115777 and at 0.5, 1, 2, 3, 5, 8, and 12 hours thereafter on days 1, 8, 15, and 22; immediately prior to the morning dose of R115777 on days 3 through 5; and at 24, 36, 48, and 72 hours after the last dose if dosing was stopped on day 8, 15, or 22. At each time point, 6 mL heparinized blood was transported on ice and centrifuged within 2 hours (1000g for 10 minutes). Separated plasma was immediately frozen on dry ice, stored at 70°C, and
shipped in batches to Janssen Research Foundation (JRF, Beerse,
Belgium), where levels were determined using a validated
high-performance liquid chromatography (HPLC) assay.37
Plasma concentration-time profiles of R115777 were analyzed by standard
noncompartmental methods using the software package WinNonlin
(Pharsight, Mountain View, CA). The following pharmacokinetic
parameters were calculated: maximum plasma concentration (Cmax), time to maximum plasma concentration
(tmax), trough plasma concentration (C0h), and
area under the plasma concentration versus time curve over a 12-hour
dosing interval calculated by trapezoidal summation
(AUC12h). Because the pharmacokinetic profile of R115777 is
biphasic,37 initial (T1/2 dominant) and
terminal half-lives (T1/2 terminal) were estimated by
linear regression of the log-transformed concentration versus time
data. The accumulation ratio was calculated by dividing the
AUC12h determined on day 8 or 15 by that of day 1.
To assess R115777 levels in the target organ, bone marrow aspirates
were obtained concomitantly with morning predose plasma samples on days
1, 8, 15, and 22 (when feasible). Cells were sedimented from
heparinized marrow, frozen at
Patient characteristics A total of 35 patients with leukemia were entered into this phase 1 study of R115777. One patient failed to take drug as instructed and was not evaluable. The remaining 34 patients were evaluable for toxicity or response to R115777. Their demographic and disease characteristics are detailed in Table 1. Median age was 65 (range 24-77), and 67.6% (23 of 34) were men. Twenty-five (74%) had AML (6 newly diagnosed, 9 relapsed, 10 refractory to induction or reinduction therapies). Cytogenetic analyses were evaluable in 21 and abnormal in 12 (57%), with chromosome 7 abnormalities detected in 4. Of 6 patients with ALL, 3 were Ph+; all 3 patients with CML-BC had cytogenetic aberrations (2 complex, 1 Ph ). None of the leukemic marrow
populations from the 35 patients harbored detectable N-ras
mutations despite the reported incidence of N-ras mutations
in AMLs and MDS.28-33
Toxicities As depicted in Table 2, no significant toxicity occurred in patients receiving the first 2 dose levels of R115777. At 600 mg bid, 3 of 8 (37.5%) developed one or more grade 1 to 2 toxicities without DLT. All were older than age 55, and 2 of 3 were older than age 65. One patient developed grade 1 fatigue that began by day 6 and resolved within 2 days of discontinuing the drug on day 21. Two patients developed transient serum creatinine elevations ( 2.7 mg/dL, onset days 8 and 23) that resolved without intervention within 72 hours.
At 900 mg bid, 6 (55%) of 11 patients experienced one or more grade 1 to 2 toxicities without formal DLT. Grade 1 to 2 polydipsia was
detected in 4 (36%) of 11, began by day 3, abated within 5 to 10 days
without specific intervention or drug discontinuation, and was not
accompanied by hypernatremia, serum hyperosmolality, hyperglycemia, or
intravascular collapse. One patient (aged 75) with polydipsia received
concomitant antihypertensive treatment with an angiotensin-converting
enzyme (ACE) inhibitor and developed creatinine elevation (baseline 1.3 mg/dL; peak 2.8 mg/dL) that improved within 2 days of discontinuing
both R115777 and the ACE inhibitor. An additional 3 patients, all over
age 70, developed transient, nonoliguric renal dysfunction of 5 days'
duration or less. In addition, grade 1, nonprogressive fingertip
paresthesias occurred on day 15 in one patient who had previous
vincristine-related neuropathy and during the third cycle in one
patient, who had no previous neuropathy. Although the toxicities
encountered at 900 mg bid were reversible and were not dose limiting by
strict definitions, their occurrences led to temporary ( When the dose of R115777 was increased to 1200 mg bid, 3 of 4 patients experienced grade 2 to 3 central neurotoxicities, including confusion, ataxia, and visual disturbances, that were dose limiting. These toxicities occurred by day 4 and necessitated immediate drug discontinuation. All symptoms resolved completely within 72 hours, but drug was not reinstituted. Thus, these patients did not complete the first course of therapy. Drug-induced myelosuppression was not detected consistently at lower dose levels, but occurred frequently at 600 mg and 900 mg bid. At these dose levels, white blood cell (WBC) count nadir occurred on median day 16 (range, 3-22), with 2 of 8 patients at 600 mg bid and 5 of 8 patients at 900 mg bid reaching WBC nadir of 500/µL or less and an ANC of 100/µL or less. Clinical outcome Table 3 depicts the clinical outcome for the 34 evaluable patients. Measurable responses (CR and PR) occurred at all dose levels where drug administration was adequate for evaluation (100-900 mg bid), without a clear dose-response relationship. Overall response rate was 10 (29%) of 34, with 8 PRs (6 AML, 2 CML-BC) and 2 hematologic CRs (both AML). The response rate in AML was 32% (8 of 25), including 3 (50%) of 6 newly diagnosed, 3 (33%) of 9 relapsed, and 2 of 10 (20%) refractory. Both CRs occurred in patients with relapsed AML. The first (patient 2) entered CR in the course of receiving 3 cycles of R115777 100 mg bid, with the unmaintained CR duration being 7 months. At relapse, he was retreated into second CR with R115777, with the current duration of the second CR being 3+ months. The second (patient 16) entered CR following a 15-day course of R115777 600 mg bid; R115777 was discontinued because of profound neutropenia (ANC 100/µL). He remained in an unmaintained
CR of 3 months' duration and did not undergo retreatment. The 2 patients with refractory AML who responded to R115777 exhibited
deletions of all or part of chromosome 7, a genetic lesion known to be
associated with aberrant ras expression or signaling, as
exemplified by AML associated with defects in the neurofibomatosis
(NF-1) gene.52 Two of the 3 patients with
CML-BC (both Ph+ with complex cytogenetics) achieved PR, as
evidenced by decreasing peripheral WBC counts, normalization of
platelet count, and decreases in peripheral and bone marrow blasts. In
contrast, none of the patients with ALL (including Ph+)
responded and all demonstrated disease progression within 7 to 21 days
of starting R115777.
FT enzyme inhibition The activity of FT was compared in paired marrow samples obtained before treatment on days 1 and 8 from 21 of the 30 evaluable patients who received 100 to 900 mg bid R115777. Samples were obtained immediately prior to the morning dose of R115777 and, therefore, reflected nadir levels of FT inhibition. Relative to pretreatment values, the enzyme was not inhibited consistently in patients receiving 100 mg bid. Beginning at 300 mg bid, however, R115777 suppressed marrow cell FT activity in all patients by a mean of 75% (range 50%-95%) (Figure 1) without clear dose-related increases. There was no apparent relationship between the depth of FT inhibition and clinical response.
Inhibtion of protein farnesylation Data summarized in Figure 2 and Table 4 indicate that R115777 blocked protein farnesylation in marrow cells obtained on days 8 through 21 as detected by accumulation of prelamin A and pre-HDJ-2. This effect was detected consistently in marrow cells obtained from patients treated with 600 mg R115777 bid, but not at lower doses. At 900 mg bid, an unexpected decrease in lamin A following R115777 made interpretation of prelamin A results problematic even though 7 of 10 pretreatment marrows studied expressed lamin A. On the other hand, pre-HDJ-2 appeared or increased in at least 6 (86%) of 7 patients by day 8 of R115777 treatment at this dose level.
Effects on inhibition of ERK activation The ERK kinases are phosphorylated at the end of a signal transduction pathway that starts with activated PTKs or activated Ras and progresses through Raf and MEK-1 kinases.15,16,53 To determine whether this pathway was inhibited by R115777, serial measurements of unphosphorylated and phosphorylated ERK were performed on bone marrow samples from 22 patients, 8 (36.4%) of which displayed constitutive ERK phosphorylation at baseline (Figure 3). Following R115777, phospho-ERK became undetectable in 4 (50%) of the 8 patients in whom activated ERK was detectable in pretreatment samples.
Pharmacokinetics Plasma pharmacokinetics were obtained during the first cycle of R115777 in 32 of the 35 patients entered on study. The data demonstrated a linear relationship between dose and Cmax or AUC12h for all dose levels tested, including 1200 mg bid (Figure 4). R115777 was rapidly absorbed with peak plasma concentrations reached within 2 to 3 hours. Pharmacokinetic parameters are shown in Table 5. The T1/2 associated with the first phase of elimination, as determined on day 1, appeared to be independent of dose and ranged from 1.7 to 4.2 hours. The terminal T1/2 associated with the second phase of elimination, as determined on day 22, varied with the ability to quantify R115777 in plasma and ranged form 14.1 to 61.7 hours, with a median of approximately 20 hours. These data are consistent with a biphasic elimination curve, as described in the previous phase 1 study.37 Steady-state conditions were obtained within 3 days of bid dosing. The accumulation ratio was independent of dose and duration of administration, with an overall mean ratio (± SD) of 1.24 ± 0.69 on day 8 and 1.10 ± 0.83 on day 15, indicating little accumulation of R115777 following a bid dosing schedule.
Oral administration resulted in accumulation of R115777 in bone marrow
cells in a dose-dependent manner. Whereas doses of 100 and 300 mg bid
yielded mean day 8 drug levels of 160 ng/g cell pellet (range, 78-264),
major increases in marrow R115777 levels were noted at 600 mg bid (mean
day 8 level, 1723 ng/g cell pellet; range, 823-3920) and 900 mg bid
(mean, 2942 ng/g cell pellet; range, 2032-3642). Comparison of bone
marrow levels with the plasma Cmin obtained on day 8 for
this subset of patients revealed that marrow levels were 2.5- to
3.5-fold higher than concomitant plasma levels (Cmin) at
all dose levels (Table 6). Serial
measurements indicated that marrow R115777 levels were relatively
steady for all patients at each dose level from week to week
administration (data not shown).
The present phase 1 study represents the first clinical trial of a signal transduction inhibitor in patients with AML and ALL. In this cohort of patients, we found the toxicities of R115777 to be dose related and to consist of reversible renal toxicity, transient myelosuppression, and dose-limiting neurotoxicity. The observed neurotoxicity is consistent with the pivotal role that Ras plays in neuronal development and survival, particularly in response to nerve growth factor,54 where Ras participates through activation of the PI3K/AKT pathway.55 The etiology of the polydipsia, which occurred in the absence of osmotic diuresis (eg, diabetes), defects in pituitary function, or primary metabolic disturbances, is unclear at this time. Transient and reversible renal dysfunction was preceded by polydipsia in patients over 60 years old, but otherwise there was no clear link between the 2 disorders. Renal dysfunction, which has also been noted in previous phase 1 studies of the nonpeptidomimetic FTI SCH6633647 as well as R115777,37 might reflect a role for farnesylated proteins in maintaining normal glomerular and tubular functions. Our studies demonstrate that R115777 accumulates in the bone marrow in a dose-dependent manner, reaches concentrations that equal or exceed Cmax, and remains present at sustained levels throughout the duration of administration. Overall, the pharmacokinetic studies support the notion that the twice-daily administration of R115777 over 7 to 21 days achieves steady-state drug concentrations in both plasma and marrow that are sufficient to inhibit FT activity in target leukemic marrow cells in a dose-dependent fashion. This inhibition was subsequently demonstrated using direct measurements of FT activity as well as assays for accumulation of prelamin A and especially pre-HDJ-2, 2 polypeptides whose processing is FT dependent. The ability to detect processed HDJ-2 in the majority of pretreatment marrow populations and the reproducible increase in unfarnesylated protein (pre-HDJ-2) detected in marrow samples from patients treated with at least 600 mg bid for at least 7 days suggests that this assay provides a consistent marker of functional enzyme inhibition. As such, this assay may be useful in monitoring R115777 therapy to ensure achievement of intracellular FTI levels that, in turn, translate into functional enzyme blockade. In contrast, lamin A was not expressed consistently in these marrow samples (Table 4),48 making assays for prelamin A less informative in these diseases. In this phase 1 study, we were not able to discern a quantitative relationship between FT enzyme inhibition, the accumulation of pre-HDJ-2, and clinical response. Such correlations can be uncovered only with larger numbers of patients receiving a dose of R115777 that has been determined to be effective at least on the basis of intracellular biochemical activities. Phase 2 studies of R115777 in patients with AML receiving a more uniform dose are needed to address this important issue. Multiple downstream targets appear to be affected by FT inhibition. The observation that R115777 results in ERK dephosphorylation raises the possibility that one target in these leukemic marrow cells might be the Ras-Raf-MEK-ERK pathway. Even though ERK phosphorylation was detected in only 36.4% of the leukemic marrow populations obtained prior to R115777, it disappeared in half of the leukemias where it was initially demonstrated. Likewise, the finding that 3 of the 5 patients with AML with chromosome 7 abnormalities, which are associated with aberrant Ras expression,52 responded to R115777 also suggests that R115777 might exert its antileukemic effects, at least in part, by interrupting Ras function. On the other hand, the occurrence of clinical responses in the absence of detectable ras mutations is also noteworthy. Although this result might reflect inhibition of growth factor-driven Ras activation,15,17-19 the possibility that the antileukemic effects of R115777 are partially or completely Ras-independent cannot be ruled out. Recent studies have demonstrated that FTIs interfere with farnesylation and function of other proteins, including RhoB24-26 and possibly other intermediates in cell survival pathways.27 Unfortunately, RhoB is expressed in such limited amounts that it could not be analyzed in the present study.46 Thus, further studies are required to determine which FT substrate(s) is critical to the antileukemic effects of R115777 in the clinical setting. Our results indicate that R115777 produces responses in roughly 30% of patients. The entry criteria were designed to include only patients who were likely to do poorly with traditional cytotoxic chemotherapies. In this small cohort of patients, the effects of R115777 were detected in AML variants and in myeloid CML-BC, but not in ALLs (including Ph+ variants). The observation that responsive patients tended to have a lower percentage of marrow blasts (< 40%) than nonresponders (> 70%) raises the possibility that responsive leukemic clones may be those with some residual capacity to differentiate. Consistent with this possibility, many patients achieved CR or PR without the profound marrow aplasia typically associated with induction chemotherapy. If R115777 is truly able to facilitate some differentiation of blasts, FTIs might find application in disease states such as high-risk MDS, where some capacity for differentiation still persists, or in minimal residual disease states, that is, after cytoreductive induction chemotherapy. Multiple assays of farnesylation demonstrated that FT enzyme activity was reproducibly inhibited at doses of 600 mg bid. At this dose level, clinical responses were detected in 2 (29%) of 7 AMLs, nonhematologic toxicities were acceptable to patients and myelosuppression was transient (< 7 days). At the next higher dose level (900 mg bid), the nonhematologic toxicities were troublesome enough that 3 (27%) of that patient cohort were unable to receive 21 days of treatment. Based on the clinical and molecular data from this phase 1 study, it is reasonable to suggest a dose of 600 mg R115777 bid for phase 1I trials in hematologic malignancies, with possible dose escalation in selected cohorts of younger patients. Based on the promising results presented above, additional trials are needed to address several issues, including optimal duration of dosing to achieve CR or maximal clinical responses, duration of responses, and the effects of combining R115777 with traditional cytotoxic agents.
We wish to thank Chris Bowden for thoughtful advice; Maureen Craig, Kim Altobelli, Patrician Engelen, and Jacqueline Toner for technical expertise and assistance; and Veronica Greenidge for secretarial expertise.
Submitted November 11, 2000; accepted January 30, 2001.
Supported by National Cancer Institute Cooperative Agreement U01 CA69854 (J.E.K.) and by a grant from Janssen Research Foundation (J.R. and J.E.K.). J.L. is a Scholar in Clinical Research of the Leukemia and Lymphoma Society.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Judith E. Karp, University of Maryland Greenebaum Cancer Center, 22 S Greene St, Rm S9D07, Baltimore, MD 21201; e-mail: jkarp{at}umm.edu.
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J. Larghero, N. Gervais, B. Cassinat, J.-D. Rain, M.-H. Schlageter, R. A. Padua, C. Chomienne, and P. Rousselot Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells Blood, May 1, 2005; 105(9): 3743 - 3745. [Abstract] [Full Text] [PDF]
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J. Cortes, S. Faderl, E. Estey, R. Kurzrock, D. Thomas, M. Beran, G. Garcia-Manero, A. Ferrajoli, F. Giles, C. Koller, et al. Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With Acute Leukemias and High-Risk Myelodysplastic Syndromes J. Clin. Oncol., April 20, 2005; 23(12): 2805 - 2812. [Abstract] [Full Text] [PDF]
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J. Tabernero, F. Rojo, I. Marimon, M. Voi, J. Albanell, M. Guix, F. Vazquez, J. Carulla, M. Cooper, J. Andreu, et al. Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors J. Clin. Oncol., April 10, 2005; 23(11): 2521 - 2533. [Abstract] [Full Text] [PDF]
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K. Venkatasubbarao, A. Choudary, and J. W. Freeman Farnesyl Transferase Inhibitor (R115777)-Induced Inhibition of STAT3(Tyr705) Phosphorylation in Human Pancreatic Cancer Cell Lines Require Extracellular Signal-Regulated Kinases Cancer Res., April 1, 2005; 65(7): 2861 - 2871. [Abstract] [Full Text] [PDF]
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P. F. Lebowitz, J. Eng-Wong, B. C. Widemann, F. M. Balis, N. Jayaprakash, C. Chow, G. Clark, S. B. Gantz, D. Venzon, and J. Zujewski A Phase I Trial and Pharmacokinetic Study of Tipifarnib, a Farnesyltransferase Inhibitor, and Tamoxifen in Metastatic Breast Cancer Clin. Cancer Res., February 1, 2005; 11(3): 1247 - 1252. [Abstract] [Full Text] [PDF]
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M. S. Tallman New Strategies for the Treatment of Acute Myeloid Leukemia Including Antibodies and Other Novel Agents Hematology, January 1, 2005; 2005(1): 143 - 150. [Abstract] [Full Text] [PDF]
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T. M. Zimmerman, H. Harlin, O. M. Odenike, S. Berk, E. Sprague, T. Karrison, W. Stock, R. A. Larson, M. J. Ratain, and T. F. Gajewski Dose-Ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients With Relapsed and Refractory Hematologic Malignancies J. Clin. Oncol., December 1, 2004; 22(23): 4816 - 4822. [Abstract] [Full Text] [PDF]
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 J. E. Lancet, J. Gotlib, I. Gojo, E. J. Feldman, L. Morris, A. Thibault, J. L. Liesveld, J. Greer, K. Dugan, M. Raponi, et al. Tipifarnib (ZARNESTRATM in Previously Untreated Poor-Risk AML of the Elderly: Updated Results of a Multicenter Phase 2 Trial. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 874 - 874. [Abstract]
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R. A. Mesa, J. K. Camoriano, S. M. Geyer, S. H. Kaufmann, C. E. Rivera, C. Erlichman, and A. Tefferi A Phase 2 Consortium (P2C) Trial of R115777 (Tipifarnib) in Myelofibrosis with Myeloid Metaplasia. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 1509 - 1509. [Abstract]
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S. L. Moulder, J. J. Mahany, R. Lush, C. Rocha-Lima, M. Langevin, K. J. Ferrante, L. M. Bartkowski, S. M. Kajiji, D. A. Noe, S. Paillet, et al. A Phase I Open Label Study of the Farnesyltransferase Inhibitor CP-609,754 in Patients with Advanced Malignant Tumors Clin. Cancer Res., November 1, 2004; 10(21): 7127 - 7135. [Abstract] [Full Text] [PDF]
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S. Rao, D. Cunningham, A. de Gramont, W. Scheithauer, M. Smakal, Y. Humblet, G. Kourteva, T. Iveson, T. Andre, J. Dostalova, et al. Phase III Double-Blind Placebo-Controlled Study of Farnesyl Transferase Inhibitor R115777 in Patients With Refractory Advanced Colorectal Cancer J. Clin. Oncol., October 1, 2004; 22(19): 3950 - 3957. [Abstract] [Full Text] [PDF]
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J. V. Heymach, D. H. Johnson, F. R. Khuri, H. Safran, L. L. Schlabach, F. Yunus, R. F. DeVore III, P. M. De Porre, H. M. Richards, X. Jia, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer Ann. Onc., August 1, 2004; 15(8): 1187 - 1193. [Abstract] [Full Text] [PDF]
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 H. Mo and C. E. Elson Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention Experimental Biology and Medicine, July 1, 2004; 229(7): 567 - 585. [Abstract] [Full Text] [PDF]
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M. Alsina, R. Fonseca, E. F. Wilson, A. N. Belle, E. Gerbino, T. Price-Troska, R. M. Overton, G. Ahmann, L. M. Bruzek, A. A. Adjei, et al. Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma Blood, May 1, 2004; 103(9): 3271 - 3277. [Abstract] [Full Text] [PDF]
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E. Van Cutsem, H. van de Velde, P. Karasek, H. Oettle, W.L. Vervenne, A. Szawlowski, P. Schoffski, S. Post, C. Verslype, H. Neumann, et al. Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic Cancer J. Clin. Oncol., April 15, 2004; 22(8): 1430 - 1438. [Abstract] [Full Text] [PDF]
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R. Kurzrock, M. Albitar, J. E. Cortes, E. H. Estey, S. H. Faderl, G. Garcia-Manero, D. A. Thomas, F. J. Giles, M. E. Ryback, A. Thibault, et al. Phase II Study of R115777, a Farnesyl Transferase Inhibitor, in Myelodysplastic Syndrome J. Clin. Oncol., April 1, 2004; 22(7): 1287 - 1292. [Abstract] [Full Text] [PDF]
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D. P. Ryan, J. P. Eder Jr., T. Puchlaski, M. V. Seiden, T. J. Lynch, C. S. Fuchs, P. C. Amrein, D. Sonnichsen, J. G. Supko, and J. W. Clark Phase I Clinical Trial of the Farnesyltransferase Inhibitor BMS-214662 Given as a 1-Hour Intravenous Infusion in Patients with Advanced Solid Tumors Clin. Cancer Res., April 1, 2004; 10(7): 2222 - 2230. [Abstract] [Full Text] [PDF]
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R. C. Winterhalder, F. R. Hirsch, G. K. Kotantoulas, W. A. Franklin, and P. A. Bunn Jr Chemoprevention of lung cancer--from biology to clinical reality Ann. Onc., February 1, 2004; 15(2): 185 - 196. [Abstract] [Full Text] [PDF]
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 D. M. Beaupre, E. Cepero, E. A. Obeng, L. H. Boise, and M. G. Lichtenheld R115777 induces Ras-independent apoptosis of myeloma cells via multiple intrinsic pathways Mol. Cancer Ther., February 1, 2004; 3(2): 179 - 186. [Abstract] [Full Text] [PDF]
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R. M. Stone, M. R. O'Donnell, and M. A. Sekeres Acute Myeloid Leukemia Hematology, January 1, 2004; 2004(1): 98 - 117. [Abstract] [Full Text] [PDF]
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R. Kurzrock, H. M. Kantarjian, J. E. Cortes, N. Singhania, D. A. Thomas, E. F. Wilson, J. J. Wright, E. J. Freireich, M. Talpaz, and S. M. Sebti Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting Blood, December 15, 2003; 102(13): 4527 - 4534. [Abstract] [Full Text] [PDF]
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J. E. Lancet and J. E. Karp Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy Blood, December 1, 2003; 102(12): 3880 - 3889. [Abstract] [Full Text] [PDF]
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A.-M. O'Farrell, J. M. Foran, W. Fiedler, H. Serve, R. L. Paquette, M. A. Cooper, H. A. Yuen, S. G. Louie, H. Kim, S. Nicholas, et al. An Innovative Phase I Clinical Study Demonstrates Inhibition of FLT3 Phosphorylation by SU11248 in Acute Myeloid Leukemia Patients Clin. Cancer Res., November 15, 2003; 9(15): 5465 - 5476. [Abstract] [Full Text] [PDF]
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N. Ochiai, R. Uchida, S.-i. Fuchida, A. Okano, M. Okamoto, E. Ashihara, T. Inaba, N. Fujita, H. Matsubara, and C. Shimazaki Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro Blood, November 1, 2003; 102(9): 3349 - 3353. [Abstract] [Full Text] [PDF]
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A. Patnaik, S. G. Eckhardt, E. Izbicka, A. A. Tolcher, L. A. Hammond, C. H. Takimoto, G. Schwartz, H. McCreery, A. Goetz, M. Mori, et al. A Phase I, Pharmacokinetic, and Biological Study of the Farnesyltransferase Inhibitor Tipifarnib in Combination with Gemcitabine in Patients with Advanced Malignancies Clin. Cancer Res., October 15, 2003; 9(13): 4761 - 4771. [Abstract] [Full Text] [PDF]
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C. Selleri, J. P. Maciejewski, N. Montuori, P. Ricci, V. Visconte, B. Serio, L. Luciano, and B. Rotoli Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells Blood, August 15, 2003; 102(4): 1490 - 1498. [Abstract] [Full Text] [PDF]
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 M. Swanson-Mungerson, M. Ikeda, L. Lev, R. Longnecker, and T. Portis Identification of latent membrane protein 2A (LMP2A) specific targets for treatment and eradication of Epstein-Barr virus (EBV)-associated diseases J. Antimicrob. Chemother., August 1, 2003; 52(2): 152 - 154. [Full Text] [PDF]
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A. A. Adjei, G. A. Croghan, C. Erlichman, R. S. Marks, J. M. Reid, J. A. Sloan, H. C. Pitot, S. R. Alberts, R. M. Goldberg, L. J. Hanson, et al. A Phase I Trial of the Farnesyl Protein Transferase Inhibitor R115777 in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer Clin. Cancer Res., July 1, 2003; 9(7): 2520 - 2526. [Abstract] [Full Text] [PDF]
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L. C. Platanias Map kinase signaling pathways and hematologic malignancies Blood, June 15, 2003; 101(12): 4667 - 4679. [Abstract] [Full Text] [PDF]
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E. K. Rowinsky Challenges of Developing Therapeutics That Target Signal Transduction in Patients With Gynecologic and Other Malignancies J. Clin. Oncol., May 15, 2003; 21(90100): 175s - 186. [Abstract] [Full Text] [PDF]
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A. A. Adjei, A. Mauer, L. Bruzek, R. S. Marks, S. Hillman, S. Geyer, L. J. Hanson, J. J. Wright, C. Erlichman, S. H. Kaufmann, et al. Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients With Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., May 1, 2003; 21(9): 1760 - 1766. [Abstract] [Full Text] [PDF]
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S. J. Cohen, L. Ho, S. Ranganathan, J. L. Abbruzzese, R. K. Alpaugh, M. Beard, N. L. Lewis, S. McLaughlin, A. Rogatko, J. J. Perez-Ruixo, et al. Phase II and Pharmacodynamic Study of the Farnesyltransferase Inhibitor R115777 as Initial Therapy in Patients With Metastatic Pancreatic Adenocarcinoma J. Clin. Oncol., April 1, 2003; 21(7): 1301 - 1306. [Abstract] [Full Text] [PDF]
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A. L. Aiyagari, B. R. Taylor, V. Aurora, S. G. Young, and K. M. Shannon Hematologic effects of inactivating the Ras processing enzyme Rce1 Blood, March 15, 2003; 101(6): 2250 - 2252. [Abstract] [Full Text] [PDF]
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B. J. Druker Overcoming Resistance to Imatinib by Combining Targeted Agents Mol. Cancer Ther., March 1, 2003; 2(3): 225 - 226. [Full Text] [PDF]
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J. Cortes, M. Albitar, D. Thomas, F. Giles, R. Kurzrock, A. Thibault, W. Rackoff, C. Koller, S. O'Brien, G. Garcia-Manero, et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies Blood, March 1, 2003; 101(5): 1692 - 1697. [Abstract] [Full Text] [PDF]
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F. Ravandi, M. Talpaz, and Z. Estrov Modulation of Cellular Signaling Pathways: Prospects for Targeted Therapy in Hematological Malignancies Clin. Cancer Res., February 1, 2003; 9(2): 535 - 550. [Abstract] [Full Text] [PDF]
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P. Russo, D. Arzani, S. Trombino, and C. Falugi c-myc Down-Regulation Induces Apoptosis in Human Cancer Cell Lines Exposed to RPR-115135 (C31H29NO4), a Non-Peptidomimetic Farnesyltransferase Inhibitor J. Pharmacol. Exp. Ther., January 1, 2003; 304(1): 37 - 47. [Abstract] [Full Text] [PDF]
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G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho Myelodysplastic Syndrome Hematology, January 1, 2003; 2003(1): 176 - 199. [Abstract] [Full Text] [PDF]
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R. R. Hoover, F.-X. Mahon, J. V. Melo, and G. Q. Daley Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336 Blood, July 18, 2002; 100(3): 1068 - 1071. [Abstract] [Full Text] [PDF]
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R. B. Lobell, D. Liu, C. A. Buser, J. P. Davide, E. DePuy, K. Hamilton, K. S. Koblan, Y. Lee, S. Mosser, S. L. Motzel, et al. Preclinical and Clinical Pharmacodynamic Assessment of L-778,123, a Dual Inhibitor of Farnesyl:Protein Transferase and Geranylgeranyl:Protein Transferase Type-I Mol. Cancer Ther., July 1, 2002; 1(9): 747 - 758. [Abstract] [Full Text] [PDF]
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M. Crul, G. J. de Klerk, M. Swart, L. J. van't Veer, D. de Jong, L. Boerrigter, P. A. Palmer, C. J. Bol, H. Tan, G. C. de Gast, et al. Phase I Clinical and Pharmacologic Study of Chronic Oral Administration of the Farnesyl Protein Transferase Inhibitor R115777 in Advanced Cancer J. Clin. Oncol., June 1, 2002; 20(11): 2726 - 2735. [Abstract] [Full Text] [PDF]
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H. M. Kantarjian Treatment of Myelodysplastic Syndrome: Questions Raised by the Azacitidine Experience J. Clin. Oncol., May 15, 2002; 20(10): 2415 - 2416. [Full Text] [PDF]
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H. M. Kantarjian, J. Cortes, S. O'Brien, F. J. Giles, M. Albitar, M. B. Rios, J. Shan, S. Faderl, G. Garcia-Manero, D. A. Thomas, et al. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase Blood, May 15, 2002; 99(10): 3547 - 3553. [Abstract] [Full Text] [PDF]
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M. O'Dwyer Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias Oncologist, April 1, 2002; 7(90001): 30 - 38. [Abstract] [Full Text] [PDF]
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B. Zhang, G. C. Prendergast, and R. G. Fenton Farnesyltransferase Inhibitors Reverse Ras-mediated Inhibition of Fas Gene Expression Cancer Res., January 1, 2002; 62(2): 450 - 458. [Abstract] [Full Text] [PDF]
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F. J. Giles, A. Keating, A. H. Goldstone, I. Avivi, C. L. Willman, and H. M. Kantarjian Acute Myeloid Leukemia Hematology, January 1, 2002; 2002(1): 73 - 110. [Abstract] [Full Text]
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B. J. Druker, S. G. O'Brien, J. Cortes, and J. Radich Chronic Myelogenous Leukemia Hematology, January 1, 2002; 2002(1): 111 - 135. [Abstract] [Full Text]
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P. L. Greenberg, N. S. Young, and N. Gattermann Myelodysplastic Syndromes Hematology, January 1, 2002; 2002(1): 136 - 161. [Abstract] [Full Text]
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F. R. Appelbaum, J. M. Rowe, J. Radich, and J. E. Dick Acute Myeloid Leukemia Hematology, January 1, 2001; 2001(1): 62 - 86. [Abstract] [Full Text] [PDF]
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R. J. Klasa, A. F. List, and B. D. Cheson Rational Approaches to Design of Therapeutics Targeting Molecular Markers Hematology, January 1, 2001; 2001(1): 443 - 462. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
5 episodes in 24 hours). Drug was
discontinued at any time for other grade 3 or higher nonhematologic
side effects. Using a modified dose-escalation schema, the first 6 patients enrolled received 100 mg bid. Dose escalation could proceed if
no more than one of 3 patients experienced DLT, defined as either grade
3 or higher nonhematologic toxicity or grade 4 bone marrow aplasia with
myelosuppression lasting 40 days or more. Following completion of the
first dose level, cohorts of 4 to 6 patients were treated with the
following doses: 300 mg bid, 600 mg bid, 900 mg bid, and 1200 mg bid.
The occurrence of any DLT in 33% of a patient cohort defined the
maximal tolerated dose (MTD). Once MTD was reached, an expanded cohort
of patients was treated at the dose level below MTD and observed for
DLT. Patients with evidence of response or without disease progression after the first 21 days were eligible to receive up to 3 more 21-day
cycles of R115777, with a 7-day drug-free hiatus between each cycle.
) AUC12h achieved
following oral administration of R115777 at dose levels 100 to 1200 mg
bid. There is a dose-proportional relationship between R115777 dose and
AUC12h for all doses from 100 to 1200 mg bid.