`
`
`
`Cancer Therapy: Clinical
`
`Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib
`
`with Weekly Paclitaxel in Patients with Solid Tumors
`
`Neal E. Ready.1 Alan Lipton.2 Yali Zhu.3 Paul Statkevich,3 Emily Frank,3
`Dolores Curtis,3 and Ronald M. Bukowski4
`
`Abstract
`
`Purpose: To establish the maximum tolerated dose of the farnesyltransferase Inhibitor lonafarnib
`(Sarasar. Schering-Plough Corp., Kenilworth. NJ) in combination with weekly paclitaxel in patients
`with solid tumors.Tolerability. phannacokinetics. safety, and dose-limitingtoxicity were characterized.
`Experimental Design: Patients were enrolled from January 2000 to May 2001. Lonafarnib was
`administered continuously orally twice daily at doses of100,125, and 150 mg in combination with
`paclitaxel at closes 0140, 60, or 80 mg/m2 i.v. over1 h weekly in 28-day cycles in a phase I design.
`Plasma samples for determinations of lonafarnib and paclitaxel concentrations were collected at
`selected time points.
`Results: Twenty-seven patients were enrolled. The maximum tolerated dose (the dose level bew
`low where dose-limiting toxicity occurred and the recommended phase II dose) was lonafarnib
`125 mg/m2 twice daily and paclitaxel 80 mg/m2 weekly. Dose-limiting toxicity was neutropenia
`with or without fever, which occurred in two of three patients treated at the lonafarnib 150 mg
`twice daily dose level. Diarrhea was a common side effect of lonafarnib but usually was mild to
`moderate in severity and could be controlled with standard medication without lonafarnib dose
`adjustment. Other reported adverse events included nausea, vomiting, fatigue, and taste changes.
`These adverse events were neither more frequent nor more severe than would be expected with
`paclitaxel alone. There were no apparent pharmacokinetic interactions between weekly paclitaxel
`and continuous twice-daily lonafarnib.
`ConclusionszThe recommended dose of lonafarnib for phase II trials is 125 mg orally twice daily
`when combined with weekly paclitaxel 80 mg/m2. The dose-limiting toxicity was neutropenia.
`
`Prenylation is a posttranslational process through which
`proteins are modified by the addition of a 15»carbon famesyl
`or a 20»carbon geranylgeranyl group (1) Several hundred
`proteins including potentially oncogenic proteins require
`posttranslatjonal modification through prenylation to become
`functional. in the case of Ras for instance, prenylation increases
`the hydrophobicity of the protein and allows it to associate
`with the plasma membrane where it
`interacts with other
`molecules involved in cell signaling. Famesyl protein transfer-
`ase, geranylgeranyltransferase I, and geranylgeranyltransferase
`
`Authors' Affiliations: 'Rhode Island Hospital, Brown University. Providence.
`Rhode Island; 2Milton S. Hershey Medical Center. Pennsylvania State University.
`Hershey, Pennsylvania; ascherlng—Plough Research Institute, Kenllworth, New
`Jersey; and ‘Claveland Clinic Cancer Center, Cleveland. Ohio
`Received 5/23/06; revised 10f3f06; accepted 11/7/05.
`Grant support: Schering—Plough Research Institute as part of the clinical
`development program for lonafarnib.
`The costs of publication of this article were defrayed In part by the payment of page
`charges. This article must therelore be hereby marked advertisement in accordance
`with 18 U.S.C. Section 1734 solely to indicate this fact.
`Conflict of interest: N.E. Ready has received honorana (less than $10,000) and
`research funding from Bristol-Myers Squibb. Y. Zhu. R Statkewch. E. Frank. and
`D. Curtis are employees of Schering— Plough Research Institute
`Requests for reprints: Neal E. Ready. Division of Medical Oncology. Duke
`University Medical Center. 25178 Morris Building, Durham, NC 27710. Phone.
`919-684-5195: Fax: 919-684-5163. E—mail: ready001@mc.duka edu.
`02007 Amerlcan Assocration for Cancer Research.
`doi:10.1158/1078-0432.CCR-06-1262
`
`II are the only three known prenyltransferases. inhibition of the
`critical prenyltransferase protein modification step has become
`a strategy in translational cancer research.
`Lonafarnib (SCH 66336; Sarasar, Schering-Plough Corp.,
`Kenilwonh, N1) is an oral, nonpeptide, tricyciic, specific inhibitor
`of famesyl protein transferase. Lonafarnib was initially evaluated
`in clinical trials for cancers that frequently have Ra: mutations
`because such mutations leading to constitutively activated Ras
`protein are found in many human cancers (2); the first step in
`postsynthesis processing of Ra: gene products is catalyzed by
`famesyi protein transferase (3); experiments have shown that
`inhibition of famesylation by famesyl
`transferase inhibitors
`prevents membrane localization and the activity of the Ras
`protein (3); and lonafarnib inhibits famesyl protein transferase
`activity in vitro and blocks processing of H-Ras protein in whole
`cells (4). However, Ionafamib has shown activity against cell lines
`with mutated K-Ras or wild-type Ras (5). Phase II and III trials
`evaluating Ionafamib and other famesyl transferase inhibitors
`as single agents or with chemotherapy have shown little activity
`in tumors that frequently contain mutated Ras. Ras protein can
`be processed to an active form by geranylgeranyltransferases
`as an alternative pathway to famesyl protein transferase. and
`famesyl protein transferase inhibition is relatively ineffective
`at blocking the geranylgeranyltransferase process (6).
`There has been evidence for efficacy of lonafarnib and other
`famesyl
`transferase inhibitors in breast cancer and acute
`myelogenous leukemia, malignancies that rarely have mutated
`Ras
`(7, B).
`It
`is now thought
`that proteins that
`require
`
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`
`576
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`www.aacrjournals.org
`
`esearc .
`Downloaded from clincancerres.aacrjoumals.org (an August 4. 2017. © 2007 American Association for Cancer
`
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`Genentech Exhibit 2033
`
`

`

`Combination Lanafarnib and Paclitaxe/ for Solid Tumors
`
`targets for
`prenylation other than Ras are the relevant
`lonafamib and other famesyl
`transferase inhibitors that do
`not
`inhibit the geranylgeranyltransferases (9). Some of the
`other possible target proteins that require famesylation for
`activation include the two centromen'c proteins, CENP—E and
`CENP—F, which are preferentially expressed in mitotic cells
`and are direct substrates for famesyl
`transferase inhibitors
`(10). The relevant
`target proteins of famesyl
`transferase
`inhibitors in breast cancer and acute myelogenous leukemia
`are not known.
`
`Lonafamib has been shown to have a synergistic effect with
`paclitaxel
`in some human cell
`lines in vitro and enhances
`paclitaxel activity in vivo (11, 12). There is evidence that the
`combination of paclitaxel and lonafamib is synergistic through
`enhancement of tubulin acetylation (13). A phase I trial of
`paclitaxel dosed every 3 weeks in combination with continuous
`twice-daily oral lonafamib established a maximum tolerated
`dose of paclitaxel 175 mg/m2 and lonafamib 100 mg twice
`daily (14). Diarrhea was the most important grade 3 or 4
`toxicity that was increased with the addition of lonafamib to
`paclitaxel. There was no apparent effect of paclitaxel on
`lonafamib pharmacokinetics or of lonafamib on paclitaxel
`pharmacokinetics. Three patients who had received previous
`taxane therapy had a durable partial response to the combina-
`tion of paclitaxel and lonafamib.
`tolerated and
`Paclitaxel dosed at weekly intervals is well
`provides dose-dense therapy. Weekly paclitaxel
`therapy has
`shown increased efficacy compared with paclitaxel every 3
`weeks in some breast cancer
`trials (15, 16) and famesyl
`transferase inhibitors have shown single-agent activity against
`metastatic breast cancer. The primary objective of this trial was
`to establish the maximum tolerated dose of weekly paclitaxel
`at a dose up to 80 mg/mz/wk with continuous lonafamib
`twice daily in 28—day cycles for patients with solid tumors.
`Secondary objectives were to characterize the tolerability,
`safety, and dose-limiting toxicities of the combination. The
`pharmacokinetics of paclitaxel and lonafamib were also
`assessed during coadministration of weekly paclitaxel and
`twice daily lonafamib.
`
`Patients and Methods
`
`This was a three-center phase I trial conducted through Schering-
`Plough Research institute (Kenilworth, NJ). Patients were enrolled from
`lanuary 2000 to May 2001. The primary end point of the study was to
`determine the maximum tolerated dose of continuously dosed, twice-
`daily lonafamib when combined with paclitaxel up to 80 mg/m2,
`administered weekly. Eligible patients were adults with previously
`treated or untreated solid tumors for which no curative treatment was
`available. All patients signed a written informed consent approved by
`the institutional Review Board at the medical center where they received
`therapy.
`Eligibility criteria included age >18 years. Kamofsky performance
`status of at least 50%, histologically confirmed cancer, measurable or
`evaluable disease, absolute neutrophil count 21.8 X 109/1. platelet
`count 2100 X 10"/L, hemoglobin 210 g/dL, serum creatinine 51.5
`times upper limits of normal, transaminase $1.5 times upper limits
`of normal, total bilirubin 51.5 mg/dL, and albumin 23.0 g/dL. A
`history of malabsorption syndrome or surgery that might
`impair
`absorption of lonafamib was not allowed. Women of childbearing
`potential were required to have a negative urine or serum pregnancy
`test. Men and women with reproductive potential must have been
`using an effective method of contraception. Patients with any of the
`
`following were excluded: more than two previous chemotherapy
`regimens, active comorbid medical probiems. grade 22 nausea, grade
`21 vomiting, prior cancer therapy within 4 weeks. mitomycin or
`nitrosurea within the previous 6 weeks. previous radiation to 225%
`bone marrow, pregnant or nursing status, active central nervous
`system metastases, prior bone marrow or stem cell transplant, known
`HIV positivity, known hypersensitivity to cremaphor, and QTr >440
`ms at baseline. Patients who were taking medications that might alter
`the metabolism of lonafamib by the CYP3A4 hepatic enzyme system,
`such as systemic corticosteroids (except as pretreatment for paclitaxel
`administration), antiseizure drugs. azoles, rifampin, isoniazid, estro-
`gens, macrolides. or cyclosporin, were exduded from the trial.
`Screening criteria were reviewed with the study monitor to confirm
`eligibility, and subjects were assigned to the appropriate dose level
`based on their enrollment sequence.
`Lonafamib capsules were administered orally, twice daily with food
`as 50-, 75-, and 100-mg formulations with paclitaxel administered i.v.
`over 1 h at 40, 60, or 80 mg/m2 weekly in 28-day cycles. Dose levels for
`lonafamib and paclitaxel are shown in Table 1. The first cohort of
`patients was treated at dose level 2. During cycle 1. paclitaxel was given
`on day 1 and lonafamib begun on day 3. During subsequent cycles
`of therapy.
`lonafamib and paclitaxel were both started on day 1.
`Premedications for paclitaxel included dexamethasone, diphenhydra-
`mine, antiemetics, and cimetidine or ranitidine. Although chronic
`corticosteroid administration was an exclusion criteria due to potential
`effects on CYP3A4 activity. transient (one-time) dosing of dexameth-
`asone as required here should not alter CYP3A4 activity (17). Therapy
`for diarrhea was recommended at
`the discretion of the treating
`physician on the onset of grade 1
`toxicity per standard practice.
`Colony-stimulating factors including erythropoietin and granulocyte
`colony-stimulating factor could not be used to prevent myelotoxicity;
`however, patients who developed febrile neutropenia could receive
`granulocyte colony-stimulating factor in accordance with standard
`medical care. Prophylactic antibiotics were prohibited. Radiation,
`biological therapy, other chemotherapy, or any other anticancer therapy
`was prohibited during the study.
`Cohorts of three subjects each were assigned sequentially to increasing
`doses of lonafamib and paclitaxel, beginning with lonafamib 100 mg bid
`and paclitaxel 60 mg/mz/wk (dose level 2). Enrollment of a new cohort
`of three patients or expansion of an ongoing dose-level cohort did not
`occur until three subjects had completed one cycle (28 days) of therapy
`and the results of day 29 laboratory tests were evaluated. Maximum
`tolerated dose and dose-limiting toxicity (for the purposes of dose
`escalation) were defined from the safety profile during the first 28-day
`cycle for each dose level. When dose-limiting toxicity occurred during
`the first cycle in one subject, a maximum of three additional subjects
`could be treated at that level (for a total of six subjects). The dose-limiting
`toxicity dose level was defined as the dose level at which a minimum of
`two subjects experienced dose-limiting toxicity.
`Dose-limiting toxicity was defined as any of the following: absolute
`neutrophil count SOOIuL for 7 days or longer; absolute neutrophil
`
`Table 1. Dose escalation protocol for lonafamib
`and paclitaxel
`
`Dose level
`
`Lonafarnib dose
`(mg twice daily)
`100
`100
`125
`150
`
`Paclitaxel dose
`("19/ mzlwk)
`60
`80
`80
`80
`
`Patients
`(H)
`
`7
`7
`10
`3
`
`
`
`NOTE: Lonafarnib was administered on days 3 to 28 in cycle 1 and
`on days 1 to 28 in all subsequent cycles. Paclitaxe! was
`administered weekly during each cycie.
`
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`Research.
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`

`

`Cancer Therapy: Clinical
`
`Table 2. Patient demographics
`
`Subjects (n)
`Age (v)
`Median
`Range
`Gender, n (%)
`Male
`Female
`Karnofsky performance status, n (%)
`70-<90
`90-100
`Histology (n)
`Non—small cell lung cancer
`Colon
`Renal
`Pancreatic
`Melanoma
`Adrenal
`Hepatobiiiary
`Unknown
`Prostate
`Sarcoma
`Prior treatment, n (%)
`Chemotherapy
`Taxane
`Surgery
`Radiation
`
`13 (4s)
`
`27
`
`58
`27-74
`
`19 (70)
`8 (30)
`
`5 (19)
`22 (81)
`
`HHNNNMUMUILH
`
`24 (89)
`5 (22)
`25 (93)
`
`cycle 1 and day 1 of cycle 2. Thus, the pharmacokinetics of paclitaxel was
`assessed once without (cycle 1 day l) and twice with (cycle 1 day 15 and
`cycle 2 day 1)
`lonafamib administration. Plasma was separated by
`centrifugation (4°C, 3,000 rpm for 15 min), divided into two aliquots,
`and stored frozen at —70°C until shipped to the analytic facility.
`Plasma lonafamib concentrations were determined using validated
`liquid chromatography with tandem mass spectrometry method (done
`at Taylor Technology, Princeton, NI). The lower limit of quantitation
`was 5.00 ng/mL and the linear range was 5.00 to 2,500 ng/mL. Plasma
`paclitaxel concentrations were determined using a validated high-
`performance liquid chromatography method with a lower limit of
`quantitation of 10.0 ng/mL and a linear range of 10.0 to 2,500 ng/mL.
`The assay precision (percent coefficient of variation) and accuracy
`(percent bias) were <11% and <10%, respectively, for lonafamib and
`<9% and <6%, respectively, for paclitaxel. Noninterference from the
`respective administered drug was shown and validated for both the
`lonafamib and paclitaxel methods.
`individual plasma lonafamib and paclitaxel concentrations were
`used for phannacokinetic analysis using model-independent methods.
`The maximum plasma concentration (Gum) and time of maximum
`plasma concentration (me) were the observed values. The terminal
`phase rate constant (K) was calculated as the negative of the slope of the
`log-linear terminal portion of the plasma concentration-versus-time
`curve using linear regression. The terminal phase half-life (t1 ,2) was
`calculated as 0.693/K. The area under the plasma concentration-versus-
`time curve from time 0 to the final quantifiable sample [AUij] and
`from time 0 to 12 h [AUCwu ml was calculated using the linear
`trapezoidal method. For paclitaxel, area under the plasma concentra-
`tion-time curve from time 0 to infinity [AUCm] was determined as
`follows: AUCU) = AUCM + Cmm / K, where Cam is the estimated
`concentration determined from linear regression at
`time tr. Total
`body clearance (CL/F) for lonafamib following multiple-dose oral
`administration was calculated by the following equation: CL/F = dose /
`AUCmu h). Total body clearance of paclitaxel following weekly i.v.
`infusion was calculated as follows: CL = dose / AUG“).
`Paclitaxel AUC values from patients who had samples collected on
`all three sampling days were pooled across all dose levels. An ANOVA
`model to extract effects due to dose, subject with dose, and day was
`applied on the log-transformed AUC data. The effect due to day was
`used to determine the effect of lonafamib (i.e., cycle 1 day 15 and cycle
`2 day 1 versus cycle 1 day 1) and sampling day (i.e., cycle 2 day 1 versus
`cycle 1 day 15) on paclitaxel pharmacokinetics.
`Inhibition of HDl-2 farnesylation. HDl-2, a substrate of famesyl
`protein transferase, was used as a marker of farnesyl protein transferase
`inhibition (16). When farnesylation is inhibited, llDl-2 undergoes a
`mobility shift on SDS-PACE, such that the unfamesylated protein
`displays lower electrophoretic mobility. Levels of prenylated and
`unprenylated HDl-Z were evaluated in peripheral blood mononuclear
`cell samples by immunoblot analysis and densitometric quantification.
`Biological assays for the inhibition of HDI-2 farnesylation were done at
`Schering-Plough Research Institute.
`Tumor response. Subjects were clinically evaluated for tumor
`response after the first cycle and every 28 days thereafter. Radiographic
`assessments were done every 8 weeks or more frequently if clinically
`indicated. Responses were to be confirmed 4 weeks after
`initial
`observations and criteria for determining partial or complete response
`had to be present for at least 4 weeks. Throughout the study. all lesions
`were measured by the same method, either similar radiographic study
`or physical examination, for consistent comparisons.
`
`Results
`
`Twenty-seven subjects were enrolled in this trial and 26
`subjects received study medication (Table 1). Patient demo—
`graphics are reported in Table 2. A total of 87 cycles of
`combination therapy were administered with a median of
`
`count SOO/uL with fever (238.3‘C); platelets <25,000/j1L (grade 4);
`grade 4 anemia (hemoglobin <6.5 g/dL); grade 3 to 4 nausea/vomiting
`while receiving an optimal antiemetic regimen for prophylaxis and
`management (i.e., consisting of a 5-HT3 antagonist on an optimal dose
`schedule), grade 3 diarrhea while receiving an optimal antidiarrheal
`regimen, or any other treatment-related grade 3 nonhematologic
`toxicity; grade 22 neuropathy; dose modifications resulting in the
`subject's receiving <80% of the intended cumulative dose of paclitaxel;
`or treatment delay for toxicity lasting longer than 2 weeks. The
`maximum tolerated dose was defined as the dose level at which none of
`six or one of six subjects experienced dose-limiting toxicity during the
`first cycle when at least two subjects experienced dose-limiting toxicity
`at the next higher dose level.
`Dose modification. Dosing was modified based on observed toxicity
`on the day of each planned dose of weekly paclitaxel. Lonafamib was
`dosed without modification and paclitaxel was reduced by 50% for
`granulocytes <1 ,500/uL or platelets <100,000/uL. Lonafamib was dosed
`without modification and paclitaxel was omitted for platelets <75,000/
`uL or granulocytes <500/j1L for 27 days or with fever. A full paclitaxel
`dose was resumed following recovery. For platelet counts <50,000/uL,
`both paclitaxel and lonafamib were omitted and continued at one
`lower dose level after recovery (Table 1). Paclitaxel dose was decreased
`by 50% for grade 2 neuropathy. Paclitaxel was omitted for grade 3 or
`4 neuropathy and resumed at 50% the initial dose when neuropathy
`decreased to grade 52.
`Lonafamib was decreased by one dose level (Table 1) for grade 23
`nausea or vomiting despite optimal antiemetic therapy on days when
`paclitaxel was not administered. Lonafamib was decreased by one dose
`level for grade 3 diarrhea that was unresponsive to standard therapy.
`if the QTc interval increased to >500 ms and was >130% of baseline
`QT“ lonafamib was held and resumed at one dose level lower after the
`QTc normalized.
`Phannacokinetic methods. Blood samples (3 mL) for determination
`of plasma lonafamib concentrations were collected before (0 h) and at
`1, 2, 4, 6, 8, and 12 h after the morning dose on day 15 of cycle 1. Blood
`samples (5 mL) for determination of plasma paclitaxel concentrations
`were collected before (0 h) and at 0.5 h, 1 h, 1 h 5 min, and 1.5, 2, 4,6,8,
`12, and 24 h after the beginning ofthe i.v. infusion on days 1 and 15 of
`
`Clin Cancer Res 2007;13(2) January 15, 2007
`
`578
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`Researc .
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`

`Combination Lonafamib and Pac/itaxel for Solid Tumors
`
`three cycles. Seven subjects were treated in both dose levels 1
`and 2, whereas 10 were treated at the maximum tolerated
`dose (Table 1). One subject was discontinued and replaced in
`each of dose levels 1 and 2 for protocol ineligibility and one
`subject
`in each of those dose levels had a dose-limiting
`toxicity, requiring treatment of an additional three subjects at
`each dose.
`
`Among all dose level cohorts, 93% of subjects reported
`at least one treatment—related adverse reaction of any grade
`and 44% of subjects reported at least'one grade 3/4 event
`(Table 3). The most common treatment-related adverse events
`of any grade were gastrointestinal and constitutional; diar-
`rhea, nausea, and vomiting occurring in 22 of 27 (81%), 18
`of 27 (67%), and 16 (59%) of subjects,
`respectively, and
`fatigue and anoratia occurring in 19 of 27 (70%) and 13 of
`27 (48%) of subjects,
`respectively. The most common
`treatment—related grade 3/4 events were fatigue and vomiting,
`each occurring in 3 (11%) subjects, and anemia, neutropenia,
`anorexia, nausea, diarrhea, and dehydration, each occurring
`in 2 (7%) subjects. There was no dose relationship noted
`(Table 4B).
`Gastrointestinal and constitutional symptoms were the most
`common nonhematologic toxicities reported, occurring in 25 of
`27 (93%) and 24 of 27 (89%) of subjects, respectively. The most
`frequently reported nonhematologic adverse events overall were
`diarrhea (81%; grade 3/4, 7%), nausea (78%; grade 3f4, 7%),
`fatigue (70%; grade 3/4, 11%), vomiting (59%; grade 3/4,
`11%), and dyspnea (56%; Table 3). No treatment—emergent
`hematologic adverse events were reported at rates of 225%.
`Nausea and neuropathy, which are adverse events associated
`with paclitaxel (17), as well as insomnia, rhinitis. and taste
`perversion, seemed to be potentially dose related, occurring
`more frequently in the 80—mg paclitaxel dosing groups
`
`(Table 3). At levels below the non-dose-limiting toxicity dose,
`the majority of adverse events were mild to moderate in severity.
`Among all dose level cohorts, 46% (12 of 26) of treated
`subjects with baseline grade 0 to 2 hematologic laboratory data
`developed at least one treatment-emergent grade 3,:‘4 hemato-
`logic toxicity, 30% within the first treatment cycle. Approxi-
`mately 25% of subjects developed grade 3f4 neutropenia or
`leukopenia, 8% developed grade 3J4 thrombocytopenia, and
`15% developed grade 3/4 anemia (Table 4A). The majority of
`these events were clinically asymptomatic and required no
`intervention. Hematologic toxicities observed with lonafamib
`plus paclitaxel combination therapy were consistent with those
`that have been observed with paclitaxel,
`including weekly
`administration (12, 18). However, hematologic toxicity,
`particularly neutropenia, became dose—limiting at the highest
`dose level of the combination.
`
`Grade 1 or 2 diarrhea was frequently associated with
`lonafamib therapy but usually responded to standard antidiar-
`rheal
`therapy; 22 subjects received short-tenn therapy with
`loperamide and 2 required additional therapy with diphenox-
`ylate. Lonafamib did not seem to increase the frequency or
`severity of the most common toxicities expected for weekly
`paclitaxel such as nausea, vomiting, fatigue, asthenia, periph-
`eral neuropathy, and taste changes (Table 3).
`There were no reductions in lonafamib dose due to adverse
`
`events. The paclitaxel dose was reduced from 80 to 40 mg/m2/
`wk due to adverse events in three subjects:
`
`' 01/008 during cycle 4 for neuropathy
`' 01/026 during cycle 3 and cycle 4 for neuropathy
`' 04/009 during cycle 1 for gastrointestinal symptoms.
`
`Six subjects discontinued the study due to adverse events,
`which included severe anorexia.
`fatigue, and vomiting.
`
`Table 3. Summary of most frequent (>25%) treatment-emergent adverse events by dose level
`
`Lonafamib dose (mg twice daily) 100
`Paclitaxel dose (mg/mzlwk)
`60
`No. patients
`7
`
`100
`80
`7
`
`125
`80
`10
`
`150
`80
`3
`
`27
`
`Adverse event rate"
`
`Any
`severity
`
`Grade 3/4 Any
`severity
`
`Grade 3M Any
`
`Grade 3/4 Any
`severity
`
`Grade 3/4 Any
`severity
`
`Grade 3/4
`
`2 (7)
`2(7)
`3 (11)
`3 (11)
`2(7)
`
`0 2
`
`(7)
`2(7)
`
`ALa)UV
`
`22(31)
`21(78)
`19(70)
`16(59)
`15(56)
`14(52)
`13(48)
`10(37)
`860)
`8B0)
`860)
`8(30)
`8(30)
`8(30)
`8(30)
`8(30)
`7(26)
`7(26)
`
`2 (67)
`2 (67)
`2 (67)
`1 (33)
`1 (33)
`
`o 2
`
`(67)
`1 (33)
`
`o 1
`
`oo 1
`
`o 1
`
`severity
`OOOOOOOOOOHOOOHOOOAAHHbAvv
`00000H0000HH000H00 AuU0
`
`(33)
`
`(33)
`
`(33)
`1 (33)
`1 (33)
`0
`
`(10)
`
`(10)
`
`0 1
`
`o 1
`
`o 1
`
`00000000000
`
`(10)
`2 (20)
`
`6 (86)
`6 (86)
`4 (S7)
`2 (29)
`3 (43)
`3 (43)
`2 (29)
`3 (43)
`1 (14)
`1 (14)
`1 (14)
`3 (43)
`1 (14)
`2 (29)
`3 (43)
`2 (29)
`2 (29)
`2 (29)
`
`7 (70)
`8 (80)
`8 (80)
`8 (80)
`6 (60)
`5 (50)
`5 (50)
`4 (40)
`3 (30)
`3 (30)
`4 (40)
`3 (30)
`4 (40)
`S (50)
`3 (30)
`4 (40)
`3 (30)
`4 (40)
`
`2 (29)
`1 (14)
`
`o 2
`
`(29)
`1 (14)
`
`0000000000000
`
`Diarrhea
`Nausea
`Fatigue
`Vomiting
`Dyspnea
`Alopecia
`Anorexia
`Neuropathy
`Abdominal pain
`Coughing
`Epistaxis
`Dyspepsia
`Fever
`Constipation
`Insomnia
`Rhinitis
`Taste perversion
`Arthraigia
`
`7 (100)
`5 (71)
`5 (71)
`s (71)
`5 (71)
`6 (86)
`4 (57)
`2 (29)
`4 (s7)
`3 (43)
`3 (43)
`2 (29)
`2 (29)
`1 (14)
`1 (14)
`1 (14)
`1 (14)
`1 (14)
`
`* Values expressed as n We).
`
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`
`579
`
`Clin Cancer Res 2007;13(2) January 15, 2007
`
`Downloaded from clincancerres.aacrjoumals.org on August 4, 2017. © 2007 American Association for Cancer
`Research.
`
`

`

`Cancer Therapy:- glinical
`
`Table 4. Summary of treatment-related, treatment-emergent adverse events during the treatment period
`
`(A) Hematologic laboratory parameters that changed from grade 0-2 to grade 3 or 4 abnormalities by dose
`
`26
`4 (15.4)
`7 (26.9)
`6 (23.1)
`2 (7.7)
`
`27
`
`150
`80
`
`30
`
`1 (33.3)
`1 (33.3)
`o
`
`100
`80
`7
`1 (14.3)
`2 (28.6)
`1 (14.3)
`0
`
`125
`80
`7
`2 (22.2)
`3 (33.3)
`4 (44.4)
`1 (11.1)
`
`Lonafarnib dose (mg/twice daily) 100
`60
`Paclitaxel dose (mg/mz/wk)
`7
`No. patients (n)
`1 (14.3)
`Hemoglobin
`WBC
`1 (14.3)
`0
`Neutrophils
`Platelets
`1 (14.3)
`
`(B) Treatment-related, treatment-emergent, adverse events
`
`by descending frequency
`
`Lonafarnib dose (mg/twice daily) 100
`Paclitaxel dose (mg/mZ/wk)
`60
`No. patients (n)
`7
`
`100
`80
`7
`
`125
`80
`10
`
`Adverse event rate*
`
`Any
`severity
`
`Grade
`3/4
`
`Any
`severity
`
`Grade
`3/4
`
`Any
`severity
`
`Grade
`3/4
`
`Grade
`Grade
`Any
`Any
`
`severity severity
`3/4
`3/4
`
`0 4
`
`(57)
`2 (29)
`
`o 2
`
`(29)
`4 (57)
`
`o 2
`
`(29)
`2 (29)
`
`Hematologic
`Neutropenia
`Anemia
`Nonhematologlc
`Diarrhea
`Vomiting
`Dehydration
`Heart block
`Nausea
`Anorexia
`Cellulitis
`Edema (legs)
`Fatigue
`Herpes zoster
`Neuropathy
`Rash
`
`o
`0
`
`7 (100)
`s (71)
`3 (43)
`1 (14)
`5 (71)
`4 (47)
`0
`1 (14)
`5 (71)
`o
`2 (29)
`o
`
`* Values expressed as n (%).
`
`1 (4)
`
`2 (67)
`
`2 (7)
`2 (7)
`
`22 (81)
`16 (59)
`5 (19)
`1 (4)
`18 (67)
`13 (48)
`1 (4)
`5 (19)
`19 (70)
`1 (4)
`8 (30)
`4 (15)
`
`2 (7)
`2 (7)
`
`2 (7)
`3 (11)
`2 (7)
`1 (4)
`2 (7)
`2 (7)
`1 (4)
`1 (4)
`3 (11)
`1 (4)
`1 (4)
`
`2 (67)
`0
`
`2 (67)
`1 (33)
`1 (33)
`0
`2 (67)
`2 (67)
`1 (33)
`2 (67)
`2 (67)
`
`oo
`
`2 (67)
`
`0
`1 (10)
`
`0
`1 (10)
`
`7 (70)
`8 (80)
`
`0o
`
`7 (70)
`5 (50)
`
`oo
`
`8 (80)
`1 (10)
`4 (40)
`o
`
`o
`1 (14)
`
`O
`H A HAv
`
`OOOOOOOO
`
`o
`1 (14)
`
`6 (86)
`2 (29)
`1 (14)
`
`Life-threatening heart block and neutropenia also led to
`discontinuation. Two patients died during the study or within
`30 days of study completion, both of disease progression.
`Dose-limiting toxicity. The dose-limiting toxicity dose level
`was defined as the dose level at which at least two subjects
`experienced dose-limiting toxicity during the first treatment
`cycle. Four subjects etperienced dose-limiting toxicities: one
`subject at dose level 2 with grade 4 heart block, one subject at
`dose level 3 with neutropenia, and two subjects at dose level 5
`(one subject with grade 4 neutropenia and a second subject
`
`with febrile neutropenia). Neutropenia that occurred in two of
`three subjects, one in association with febrile neutropenia, was
`experienced at the dose-limiting toxicity dose level of paclitaxel
`80 mg/mZ/wk and lonafamib 150 mg twice daily continuously
`(dose level 4, Table 1). Therefore, the maximum tolerated dose
`was lonafamib 125 mg twice daily given continuously with
`paclitaxel 80 mg/mz/wk.
`Tumor response. One subject with malignant melanoma
`experienced a partial response at cycle 2, which was maintained
`until cycle 5, when progressive disease was noted. This subject
`
`Table 5. Mean (CV) pharmacokinetic parameters
`paclitaxel
`
`of lonafamib when administered in combination with
`
`AUC(0.12 h)! ngh/mL
`7,535 (93)
`7,672 (71)
`13,022 (32)
`
`CL/F, mL/min
`
`382 (74)
`307 (59)
`172 (30)
`203 (65)
`
`tf, h
`
`12 (0)
`12 (0)
`12 (0)
`12 (0)
`
`Predose, ng/mL
`
`434 (100)
`494 (78)
`726 (38)
`1,723 (110)
`
`cmax, ng/mL
`929 (77)
`919 (61)
`1,400 (30)
`2,685 (NA)
`
`Tmax. h ‘
`4 (0—6)
`4 (2-12)
`4 (2-6)
`5 (4-6)
`
`n
`
`647 3
`
`Dose’
`100 + 60
`100 + 80
`125 + 80
`150 + 80
`
`19,729 (91)
`
`Abbreviation: NA, not appropriate (sample size = 2).
`‘Lonafarnib dose (mg) twice daily + paclitaxel dose (mg/m2) weekly.
`'Median value (range).
`
`Clin Cancer Res 2007;13(2) January 15, 2007
`
`580
`
`www.aacrjournals.org
`
`Downloaded from clincancerres.aacn'oumals.org on August 4, 2017. © 2007 American Association for Cancer
`Research.
`
`

`

`Combination Lonafarnib and Pac/itaxel for Solid Tumors
`
`following administration of paclitaxel alone and in combina-
`tion with either 100, 125, or 150 mg of lonafamib encompassed
`the same range across pharmacokinetic evaluation days. These
`results suggest that multiple doses of lonafamib had no effect on
`the pharmacokinetics of paclitaxel.
`There was no statistically significant difference (P = 0.559) in
`the AUCm values between cycle 1 day 15 and cycle 2 day 1
`based on log-transformed data (Table 7). The point estimate
`was 90% when comparing cycle 2 day 1 to cycle 1 day 15. The
`95% confidence interval for the point estimate was 66% to
`123%, which suggests that sampling day had no effect on the
`pharmacokinetics of paclitaxel following once-weekly paclitaxel
`administration in combination with lonafamib.
`
`Plasma paclitaxel concentrations decreased rapidly after
`cessation of the l'h infusion. This was followed by a prolonged
`terminal phase. Mean half-life (t, li2) values ranged from 6 to 17
`h and mean clearance ranged from 53 to 425 ij‘minfml
`(Table 8). There were no apparent differences in the mean 11.12
`or clearance values among cycle 1 day 1, cycle 1 day 15, and
`cycle 2 day 1 at each dose level.
`HDl-2 famesylation. The prenylation status of HDI-2 for
`baseline (pretreatment) and posttreatment peripheral blood
`mononuclear cell samples were available for 10 patients.
`Compared with pretreatment samples,
`increased levels of
`unprenylated HDI—2 were detected in posttreatment samples
`from 6 of the 10 patients.
`In one of these patients,
`the
`maximum fraction of unprenylated HDI-2 was only 8.5%. The
`fraction of unprenylated HDI-Z in posttreatment samples from
`the other five patients ranged from 10.7% to 18.4%. These
`results are similar to those reported from posttreatment
`peripheral blood mononuclear cell samples in clinical studies
`with other famesyl transferase inhibitors (20—22). Four of the
`10 patients had no detectable increase in unprenylated HDI-2
`in peripheral blood mononuclear cells following treatment
`with lonafamib. However, two of these patients had detectable
`levels of unprenylated HDl-2 (20.6% and 16%, respectively) in
`pretreatment samples.
`The reason for the relatively high frequency of baseline
`unprenylated HDI—Z in this study is not known. Patients in
`whom an increase in posttreatment unprenylated HDI-2 was
`observed were exposed to predose lonafamib concentrations
`ranging from 204 to 1,310 ng/mL. However, given the small
`
`Table 6. Comparisons of mean (CV)
`pharmacokinetic parameters of lonafamib following
`multiple-dose administration of 100 mg lonafamib
`alone in previous phase I studies (12, 19) or in
`combination with pac