Cancer Therapy: Clinical
`
`Phase I and Pharmacokinetic Study of XRP6258 (RPR 116258A),
`a Novel Taxane, Administered as a 1-Hour Infusion Every
`3 Weeks in Patients with Advanced Solid Tumors
`Alain C. Mita,1Louis J. Denis,1Eric K. Rowinsky,1Johann S. DeBono,1Andrew D. Goetz,1Leonel Ochoa,1
`Bahram Forouzesh,1Muralidhar Beeram,1Amita Patnaik,1Kathleen Molpus,1Dorothe¤ e Semiond,2
`Miche' le Besenval,2 and Anthony W.Tolcher1
`
`Abstract Purpose:To assess the feasibility of administering XRP6258, a new taxane with a low affinity for
`the multidrug resistance1protein, as a1-hour i.v. infusion every 3 weeks.The study also sought to
`determine the maximum tolerated dose and the recommended dose, to describe the pharmacoki-
`netic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity.
`Experimental Design: Twenty-five patients with advanced solid malignancies were treated
`with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m2. Dose escalation
`was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK
`variables were favorable. The maximum tolerated dose was defined as the dose at which at least
`two patients developed a DLTat the first course.
`Results: Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia
`and two others showing prolonged grade 4 neutropenia at the 25 mg/m2 dose level. Nonhema-
`tologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally
`mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination
`profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large
`volume of distribution (mean Vss, 2,034 L/m2). Objective antitumor activity included partial
`responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response,
`and two minor responses.
`Conclusion: The recommended phase II dose of XRP6258 on this schedule is 20 mg/m2. The
`general tolerability and encouraging antitumor activity in taxane-refractory patients warrant
`further evaluations of XRP6258.
`
`The taxanes have emerged as a major class of chemotherapy
`agents over the last 2 decades as shown by their extensive use as
`single agents and in multiagent regimens to treat a wide variety
`of solid malignancies (1, 2). However, one potential limitation
`of the taxanes is their high substrate affinity for the multidrug
`resistance (MDR) proteins, which confer both constitutive and
`acquired resistance (3, 4). For this reason, efforts have been
`made to synthesize new taxanes that are not avid substrates for
`
`Authors’ Affiliations: 1Institute for Drug Development, Cancer Therapy and
`Research Center and University of Texas Health Science Center at San Antonio,
`San Antonio,Texas and 2Sanofi-Aventis, Antony, France
`Received 3/4/08; revised 7/24/08; accepted 9/24/08.
`Grant support: Sanofi-Aventis (Antony, France).
`The costs of publication of this article were defrayed in part by the payment of page
`charges. This article must therefore be hereby marked advertisement in accordance
`with 18 U.S.C. Section 1734 solely to indicate this fact.
`Note: Previously presented at the 37th Annual Meeting of the American Society of
`Clinical Oncology, May 12-15, 2001, San Francisco, California.
`Requests for reprints: Anthony W. Tolcher, South Texas Accelerated Research
`Therapeutics, 4319 Medical Drive Suite 205, San Antonio,TX 78229. Phone: 210-
`593-5255; Fax: 210-615-1121; E-mail: atolcher@start.stoh.com.
`F 2009 American Association for Cancer Research.
`doi:10.1158/1078-0432.CCR-08-0596
`
`MDR proteins to ultimately broaden their antitumor spectra.
`The new taxane XRP6258 was selected for clinical development
`due to its poor affinity for the ATP-dependent drug efflux
`pump, P-glycoprotein 1 (ATP-binding cassette, subfamily B,
`member 1 encoded by the ABCB1 gene and referred to
`hereinafter as P-gp), and its greater penetration of the blood-
`brain barrier compared with docetaxel and paclitaxel (5).
`XRP6258 (formula C45H57NO14) is partially synthesized as a
`single diastereoisomer from 10-deacetyl baccatin III, the major
`taxoid derived from the needles of various Taxus
`natural
`species. XRP6258 promotes the assembly of
`tubulin and
`stabilizes microtubules against cold-induced depolymerization
`in vitro as potently as docetaxel (5).
`The cytotoxicity of XRP6258 was compared with docetaxel in
`several murine and human cell lines (5). In docetaxel-sensitive
`cell lines, including P388 (murine leukemia), HL60 (human
`leukemia) KB (human epidermoid carcinoma), and Calc18
`(human breast carcinoma), XRP6258 showed potent antitumor
`activity comparable with docetaxel, with 50% tumor inhibitory
`concentrations (IC50) ranging from 0.003 to 0.029 Amol/L.
`However, XRP6258 was more potent than docetaxel in a broad
`array of cancer cell lines with acquired resistance to docetaxel
`due to P-gp overexpression, including P388/DOX, P388/TXT,
`P388/VCR, HL60/TAX, Calc18/TXT, and KBV1 (5). Resistance
`
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`MYLAN - EXHIBIT 1012
`
`

`
`Cancer Therapy: Clinical
`
`Translational Relevance
`The selective action of conventional cytotoxic agents
`depends on the relative sensitivity of proliferating tumor
`over critical normal cells to the effects of exposure to these
`drugs. One factor limiting the clinical utility of such com-
`pounds is the innate or acquired drug resistance of the
`tumor. Resistance may be mediated by tumor cell overex-
`pression of efflux pumps, such as theATP-binding cassette,
`subfamily B, member1 (MDR1). Although the development
`of rationally targeted highly specific biological agents
`represents an exciting new approach to anticancer drug
`discovery, it is anticipated that there will be a continuing
`requirement to include broadly active cytotoxic agents in
`treatment strategies. The complementary approach of
`improving on the spectrum of activity or tolerability of such
`cytotoxic compounds therefore remains as an important
`therapeutic objective. The novel taxoid, XRP6258, was
`selected for clinical development based on encouraging
`cytotoxic antitumor activity in cancer cell lines expressing
`a multidrug resistance phenotype. This agent also showed
`effective penetration of the blood-brain barrier. The current
`phase I study was designed primarily to determine the
`maximum tolerated dose and the dose-limiting toxicity
`of XRP6258 given as a 1-hour i.v. infusion. As such, this
`analysis is of direct and immediate clinical relevance.
`
`factor ratios ranged from 1.8 to 10 for XRP6258, whereas
`comparable values were 4.8 to 50.7 for docetaxel. Furthermore,
`XRP6258 showed greater cytotoxicity compared with docetaxel
`in a CaCo-2 human colon adenocarcinoma cell line, which
`exhibits primary resistance to the taxanes, due to MDR (6).
`XRP6258 has also shown a broad spectrum of antitumor
`activity in mice bearing s.c. implanted human xenografts. For
`example, a high complete regression rate was observed in eight
`of nine human tumor cell lines evaluated in human tumor
`xenograft models, with long-term survivors observed in hosts
`bearing HCT116 colon, A549 lung, MIA PaCa-2 pancreatic,
`SR475 squamous cell, and Du-145 prostate cancers (5).
`Prominent antitumor activity was also documented in SF295
`and U251 glioblastoma orthotopic models. XRP6258 retained
`activity against docetaxel-resistant P-gp – expressing B16/TXT
`melanoma xenograft models, but not against Calc18/TXT and
`P388/VCR, which express higher levels of ABCB1 mRNA.
`Interestingly, XRP6258 was found to penetrate the blood-brain
`barrier, which may be due to its low affinity for the P-gp (7),
`and studies in mice have shown that P-gp – mediated transport
`at this barrier can be saturated at circulating concentrations
`of the drug that are likely to be therapeutically useful (8).
`Schedule-dependent antitumor activity and toxicity was sug-
`gested by the results of preclinical studies. Both toxicity and
`antitumor activity profiles seemed optimal on an intermittent
`
`day 1 and 5 dosing schedule compared with daily  5 or split
`
`(three times daily for 5 days) dosing (5).
`The encouraging spectrum of antitumor activity of XRP6258
`in experimental tumor models, particularly its notable activity
`against docetaxel-resistant, P-gp – expressing malignancies,
`served as a rationale to clinical evaluations. The principal
`objectives of this phase I and pharmacokinetic (PK) study of
`
`XRP6258 administered as a 1-hour i.v. infusion every 3 weeks
`in patients with advanced solid malignancies were to (a)
`characterize the toxicities of XRP6258 administered without
`premedication on this schedule, (b) determine the maximum
`tolerated dose (MTD) and the recommended dose for phase II
`studies, (c) characterize the PK profile of the compound and its
`metabolic species, and (d) document preliminary evidence of
`antitumor activity.
`
`Materials and Methods
`
`Eligibility. Patients with histologically documented advanced solid
`malignancies refractory to conventional treatment were candidates for
`this study. Only patients who had received less than two prior
`chemotherapy regimens for metastatic disease and/or radiotherapy
`affecting <25% of their hematopoietic reserve were eligible. Patients
`who had been treated with intensive chemotherapy involving autolo-
`gous stem cell rescue were not eligible. Prior anticancer therapy had
`to be completed at least 28 d before study enrollment (42 d for
`nitrosoureas and mitomycin C). Other eligibility criteria included
`the following: age z18 y; a life expectancy z12 wk; an Eastern
`Cooperative Oncology Group performance status of 0 to 2; recovery
`from the toxic effects of prior treatment to grade V1, except for alopecia;
`adequate organ function, including hematopoietic [absolute neutrophil
`count (ANC) >2.0  109/L; platelets >100  109/L], renal (creatinine
`
`limits,
`<1.5 mg/dL), and hepatic (total bilirubin within normal
`transaminases, and alkaline phosphatase V2.5 times the upper normal
`limits) functions; and a normal neurologic examination. Prior therapy
`with taxanes was permitted. Patients with brain metastasis, coexisting
`medical problems of sufficient severity to limit compliance with the
`study, as well as patients with a prior history of severe hypersensitivity
`to docetaxel or paclitaxel were considered ineligible for this study.
`Routine use of corticosteroids or erythrocyte-stimulating factors as well
`as prophylactic use of colony-stimulating factors were not permitted.
`Pregnant or lactating women were not eligible for this trial. Before
`entering the study, patients gave written informed consent according to
`federal and institutional guidelines.
`Drug administration. XRP6258 was supplied by Sanofi aventis in
`single-dose vials containing 94.4 mg of active product in 2.36 mL of
`polysorbate 80 at the concentration of 40 mg/mL XRP6258. The
`XRP6258 solvent vial contained 7.33 mL of a solution of 95% ethyl
`alcohol/water (13/87, w/w). XRP6258 was administered as 1-h i.v.
`infusion every 3 wk using a polyvinyl chloride – free infusion bag and
`administration set. No prophylactic treatment to prevent hypersensi-
`tivity reaction or emesis was administered during the first course. These
`treatments were provided for subsequent courses, if clinically indicated.
`Corticosteroids were not permitted as prophylactic treatment for nausea
`and/or vomiting.
`Dose escalation. The starting dose was 10 mg/m2, which corre-
`sponds to approximately one tenth of the severe toxic dose (STD10) in
`mice and to the single highest nonseverely toxic dose in dogs, with
`subsequent incremental increase to 15, 20, and 25 mg/m2 dose levels.
`A minimum of three patients was treated at each dose level, and a 2-wk
`interval was required at each dose level from the treatment of the first
`patient until
`treatment of subsequent patients. PK variables were
`monitored during the first course in each patient and dose escalation
`was to be stopped if total area under the concentration versus time
`curve (AUC) for plasma was z10.8 Ag.h/mL (a level that would have
`exposed the patient to concentrations corresponding to severe toxic
`effect level in mice). If one of three patients exhibited a dose-limiting
`toxicity (DLT) during the first course, three more patients were to be
`treated at this dose level and dose escalation was considered only if no
`further DLTs occurred in this group. If two or three of the first three
`treated patients at a dose level experienced DLT during the first course,
`the MTD had been reached and no further escalation was to be
`considered. If none of three patients exhibited a DLT, then dose
`
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`

`
`escalation could be considered without including additional patients.
`DLT was defined as either grade 4 neutropenia lasting longer than 5 d
`or associated with fever (>38.5jC); platelets <25,000/mL; or any grade
`3 to 4 nonhematologic toxicity excluding nausea, vomiting, hypersen-
`sitivity reactions, or alopecia. No intrapatient dose escalation was
`permitted. Due to the anticipated distribution in tissues and lip-
`ophilicity of the drug, the body surface area (BSA) for dose calculation
`was capped at 2.1 m2. Treatment cycles were every 3 wk. Before
`retreatment, patients were required to have recovered from any toxic to
`no more than a grade 1 severity level, and platelets, total bilirubin,
`and creatinine values had to meet initial protocol eligibility require-
`ments. If recovery did not occur within 35 d from the administration of
`XRP6258, the patient was withdrawn from the study. Dose reduction to
`the previous lower dose level was to be made only in the case of DLT.
`The MTD was defined as the dose at which at least two of six patients
`experienced DLT during the first course. The recommended dose for
`phase II studies was defined as one dose level below the MTD. Initially,
`both heavily pretreated (HP) and minimally pretreated (MP) patients
`were to be accrued together at the same dose level. If hematologic DLT
`was consistently and preferentially observed in HP patients, then the
`accrual to the study was to diverge into HP and MP patients to define
`the principal phase I end points, and the MTD was to be defined for
`each group. HP patients were defined as patients who had received
`more than six courses of an alkylating agent (except low-dose cisplatin),
`more than four courses of carboplatin-containing chemotherapy
`regimens, or greater than two courses of nitrosoureas or mitomycin C.
`Pretreatment and follow-up studies. History and physical examina-
`tion (including a detailed neurologic examination) were done before
`study entry and repeated before each course. Pretreatment evaluation
`included complete blood cell count, full chemistry profile, including
`electrolytes, transaminases, alkaline phosphatase, and total bilirubin,
`and electrocardiogram and urine analysis. Thereafter, complete blood
`cell counts were done twice a week, electrocardiogram and urine
`analysis were repeated before each course, and the other laboratory
`screens were repeated weekly. Pretreatment studies also included a
`routine chest radiograph and relevant radiologic studies to evaluate all
`sites of disease and these studies were repeated every other course.
`Toxicities were evaluated according to the National Cancer Institute
`common toxicity criteria version 1.0. Tumor responses were assessed by
`standard WHO response criteria.
`Plasma sampling and assay. To evaluate the PK variables of
`XRP6258, blood samples (3 mL) were collected immediately before
`infusion (time 0), 30 min after the beginning of infusion, 5 min before
`the end of infusion, and then 5, 15, 30, and 60 min and 2, 4, 6, 10, 24,
`and 48 h after completion of infusion in patients treated at 10 and
`15 mg/m2. In the subsequent cohorts, patients were sampled up to
`120 h (at 25 mg/m2) and 240 h (at 20 mg/m2) after infusion. Blood
`specimens were collected in heparinized tubes (lithium heparinate).
`The blood samples were centrifuged within 30 min at 3,000 rpm
`
` 15 min, and the plasma was removed and placed into polypropylene
`tubes, labeled, frozen, and stored at -20jC until analysis. No more than
`1 h was allowed between blood collection and plasma sample freezing
`to avoid degradation of XRP6258.
`Drug concentrations of XRP6258 were measured in plasma using a
`validated liquid chromatography-tandem mass spectrometry method.
`The quantitative determination was done with RPR 109881 as an
`internal standard. The limit of quantitation was 1 Ag/L for a 200 AL
`sample size. The assay accuracy, defined as the percent difference
`between the nominal and the mean measured concentrations of
`quality controls, ranged from 0.01% to 4.6% (n = 67) XRP6258 in
`plasma over the analysis period. The accuracy of the dilution controls
`(1:2 or 1:4) was 1.2% (n = 23). The precision of the assay, established
`by the coefficients of variation (CV) of the quality controls, ranged from
`9.5% to 12% for XRP6258 in plasma over the analysis period.
`PK and pharmacodynamic analyses. The PK analyses were done
`using WinNonlin software, version 2.1 (Scientific Consulting, Inc.).
`Pertinent PK variables were calculated using a three-compartment open
`
`Phase I Pharmacokinetic Study of XRP6258
`
`model with a first-order elimination rate, which best fits the data. A
`weighting factor of 1/yˆ 2 was applied to the concentration data. AUC
`from 0 to infinity (AUC0-1), half-life of the first, second, and third
`t 1/2E2, and t 1/2E3, respectively, where t 1/2E3 was
`phases (t 1/2E1,
`considered the elimination half-life), total body clearance (CL), and
`volume of distribution at steady state (V ss) were determined by
`modeling. The plasma concentration measured 5 min before the end
`of infusion (C max observed) was reported and a noncompartmental
`analysis (trapezoidal method) was also used to estimate the AUC from
`0 to 48 h [AUC(0-48 h)] to compare the exposure over the whole
`dose range. The dose proportionality of the exposure was assessed on
`AUC(0-48 h) data after dose normalization using the Proc GLM
`procedure of SAS (SAS Institute) software version 8.2 followed by a
`test of linearity applied on AUC(0-48 h) against the dose expressed in
`mg/m2. The interpatient and intrapatient variability of AUC(0-48 h) was
`estimated using the Proc MIXED procedure of SAS after normalization
`to the dose and log transformation with patient taken as random effect
`and course of treatment as fixed effect. In addition, as the drug dosing
`is based on BSA, the relationship between the total plasma clearance
`expressed in L/h and the BSA was investigated using a Proc REG
`procedure of SAS software. All test results with P < 0.05 were considered
`statistically significant. The relative reduction in variability was
`calculated according to the formula [CV for CL (L/h) - CV for CL
`
`(L/h/m2)]/[CV for CL (L/h)]  100 and was considered to reach
`
`statistical significance when 15 (9).
`The relationships between the C max and AUC(0-48 h) values and
`hematologic effect were described using the sigmoidal maximal effect
`model (E max), which was fitted to the data by nonlinear least-square
`regression (9). The coefficient of determination (R 2), the SEs for the
`estimated variables, and visual inspection of the fitted plots were used
`to gauge goodness of fit of this pharmacodynamic model.
`
`Table 1. Patient characteristics
`
`Characteristic
`
`Total patients (evaluable)
`Sex: male/female
`Age, median (range), y
`ECOG performance status
`Median
`0
`1
`2
`Race
`Caucasian
`Oriental
`Hispanic
`Previous therapy
`Chemotherapy
`Prior taxane-based therapy
`Radiotherapy
`Immunotherapy
`Hormonal therapy
`Tumor type
`Prostate
`Colon
`Rectum
`Unknown primary
`Other*
`Median number of courses/patient (range)
`
`No. patients
`
`25 (25)
`17/8
`60 (32-80)
`
`1
`12
`12
`1
`
`18 (72%)
`1 (4%)
`6 (24%)
`
`22 (88%)
`8 (32%)
`12 (48%)
`2 (8%)
`8 (32%)
`
`8
`6
`2
`2
`7
`4 (1-9)
`
`Abbreviation: ECOG, Eastern Cooperative Oncology Group.
`*Includes one of each of the following: head and neck squamous
`cell carcinoma, malignant melanoma, non – small cell lung cancer,
`osteosarcoma, pancreatic carcinoma, renal cell carcinoma, and
`urothelial carcinoma.
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`

`
`Cancer Therapy: Clinical
`
`Table 2. Dose-escalation scheme
`
`XRP6258 dose
`level (mg/m2)
`
`New patients at this
`dose level (courses)
`
`Patients reduced to this
`dose level (courses)
`
`Total patients
`(courses)
`
`New patients
`with DLT
`
`3 (10)
`6 (24)
`9 (29)
`7 (19)
`
`0
`1 (1)
`4 (19)
`0 (0)
`
`3 (10)
`7 (25)
`13 (48)
`7 (19)
`
`0
`1
`0
`3
`
`10
`15
`20
`25
`
`Results
`
`General. Between June 1, 1999 and July 12, 2001, 25
`patients were treated with 102 courses of XRP6258 across four
`dose levels. The pertinent demographics of the patients are
`presented in Table 1. The median number of courses
`administered per patient was 4 (range, 1-9). All 25 patients
`(100%) were evaluable for safety and 24 patients (96%) were
`evaluable for efficacy. One patient treated at the 15 mg/m2 dose
`level was found to be ineligible for dose level determination
`due to an elevated alkaline phosphatase value; the patient’s
`toxicities are reported. Twenty-two (88%) patients had previ-
`ously received chemotherapy, with eight patients having
`received prior taxane-based therapy. According to the criteria
`defined in this study, 16 and 9 patients were considered MP
`and HP, respectively. The numbers of patients treated at each
`dose, as well as the number of patients experiencing DLT at
`each dose level, are depicted in Table 2. Dose reduction due to
`hematologic toxicity was done in four patients; one patient
`required two dose reductions. The initiation of eight (8%)
`courses involving four patients were delayed due to unresolved
`nonhematologic toxicities, specifically fatigue and fever in two
`patients, or at the patient’s request (two patients).
`Because drug-related toxicities that exceeded grade 1 were not
`encountered at the first dose level, dose escalation proceeded to
`15 mg/m2. At this dose level, one patient experienced grade 3
`diarrhea during course 1, and the cohort was expanded to a
`total of six patients, with no additional DLT. At the next higher
`dose level, 20 mg/m2, DLT was not observed in the initial three
`patients enrolled. However, three of seven subjects experienced
`DLT, including febrile neutropenia in one MP patient and
`protracted (>5 days) grade 4 neutropenia in two HP patients at
`25 mg/m2. Therefore, the rate of DLT exceeded the predefined
`limits of tolerability at the 25 mg/m2 dose level, and because no
`
`DLT was observed in six additional MP and HP patients treated
`at the previous dose level, 20 mg/m2, it was considered the
`recommended phase II dose for both MP and HP patients.
`Hematologic toxicity. The effects of XRP6258 on ANCs and
`platelets, as well as toxicity grade, as a function of dose level are
`shown in Table 3. Neutropenia was the principal
`toxicity
`encountered with XRP6258. Severe neutropenia was noted only
`at the 25 mg/m2 dose level, with grade 4 events occurring in
`8 of 19 (42%) evaluable courses, including the three afore-
`mentioned DLTs. The median time to ANC nadir was 12 days
`(range, 4-17 days). Because ANC recovery to a grade V1
`occurred in all patients by day 22 (F3 days), treatment delays
`for unresolved hematologic toxicity were not necessary. The
`rate of severe toxicities did not seem greater in HP patients
`compared with MP patients. Neither granulocyte colony-
`stimulating factor (G-CSF) nor granulocyte macrophage colo-
`ny-stimulating factor (GM-CSF) was given as prophylactic
`treatments. Four patients received G-CSF/GM-CSF support
`during a total of five courses following the occurrence of grade
`4 neutropenia (as DLTs in two patients, at cycle 1 and cycles 1
`and 2, and at cycle 5 in two others). Thrombocytopenia
`occurred in only two patients (two courses, one grade 3 in
`course 5 and one grade 1 in course 1). Except for a single
`episode of grade 3 anemic relevant, effects on RBCs were either
`mild or moderate in severity.
`Nonhematologic toxicities. The most common nonhemato-
`logic toxicities are summarized in Table 4. The most common
`nonhematologic toxicities were gastrointestinal
`in nature,
`principally consisting of diarrhea (52% of patients), nausea
`(40% of patients), and vomiting (16% of patients). These
`toxicities were generally grade 1 to 2 in severity, except for a
`single patient who experienced grade 3 diarrhea in the first
`course at 15 mg/m2. The event was short-lived and loperamide
`was administered for symptomatic management. At the 20 and
`
`Table 3. Hematologic toxicity
`
`Dose level
`(mg/m2)
`
`No. evaluable
`courses
`
`No. courses (first course) with toxicity
`
`Median nadir
`ANC (range; ML)*
`
`Grade 1-2 Grade 3 Grade 4 Grade 4 >5 d Grade 3-4 +
`fever
`
`PLTs (/ML)
`25,000-50,000
`
`PLTs (/ML)
`<25,000
`
`Neutropenia
`
`Thrombocytopenia
`
`10
`15
`20
`25
`
`10
`25
`48
`19
`
`4,760 (2,980-7,790)
`2,480 (880-8,500)
`2,280 (260-4,270)
`990 (30-5,090)
`
`0
`9 (3)
`6 (3)
`15 (3)
`
`0
`0
`0 (0)
`4 (1)
`
`0
`0
`0
`8 (3)
`
`0
`0
`0
`2 (2)
`
`0
`0
`0
`1 (1)
`
`0
`0
`0
`1 (0)
`
`0
`0
`0
`0
`
`Abbreviation: PLTs, platelets.
`*Median values (ranges) for first course.
`
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`
`Phase I Pharmacokinetic Study of XRP6258
`
`Table 4. Nonhematologic toxicity occurring at any grade in three or more patients (>10%)
`
`Adverse event,
`no. patients
`(cycles)
`
`Dose level (mg/m2)
`
`10 (3 patients,
`10 cycles)
`
`15 (6 patients,
`25 cycles)
`
`20 (9 patients,
`48 cycles)
`
`25 (7 patients,
`19 cycles)
`
`All (25 patients,
`102 cycles)
`
`Grade
`1-2
`
`Grade
`3
`
`Grade
`1-2
`
`Grade
`3
`
`Grade
`1-2
`
`Grade
`3
`
`Grade
`1-2
`
`Grade
`3
`
`Grade
`1-2
`
`Grade
`3
`
`All
`
`Diarrhea
`Fatigue
`Nausea
`Neuropathy (sensory)
`Vomiting
`Anorexia
`Arthralgia
`Stomatitis/pharyngitis
`
`1 (1)
`1 (5)
`1 (2)
`1 (1)
`1 (1)
`—
`—
`—
`
`—
`—
`—
`—
`—
`—
`—
`—
`
`4 (7)
`1 (4)
`1 (1)
`1 (6)
`—
`—
`0
`1 (1)
`
`1 (1)
`—
`—
`—
`—
`—
`—
`—
`
`4 (13)
`3 (15)
`3 (13)
`3 (8)
`2 (8)
`—
`2 (3)
`1 (3)
`
`—
`—
`—
`—
`—
`—
`—
`—
`
`4 (7)
`4 (5)
`5 (3)
`4 (4)
`1 (1)
`4 (6)
`1 (1)
`1 (1)
`
`—
`—
`—
`—
`—
`—
`—
`—
`
`13 (28) 1 (1) 14 = 56% (29 = 28%)
`9 (29) —
`9 = 36% (29 = 28%)
`10 (19) — 10 = 40% (19 = 19%)
`9 (19) —
`9 = 36% (19 = 19%)
`4 (10) —
`4 = 16% (10 = 10%)
`4 (6)
`—
`4 = 16% (6 = 6%)
`3 (4)
`—
`3 = 12% (4 = 4%)
`3 (5)
`—
`3 = 12% (5 = 5%)
`
`25 mg/m2 dose levels, grade 1 to 2 fatigue and grade 1
`neurosensory symptoms were common. Neurosensory mani-
`festations consisted principally of acral paresthesia and
`diminished deep tendon reflexes and discrimination of
`vibratory sensation. Cumulative neurotoxicity was not apparent
`in nine patients who received more than three courses at the
`two higher dose levels. Two patients experienced grade 1
`hypersensitivity reactions, characterized by flushing, dizziness,
`and chest tightness, which did not reoccur on retreatment in
`the absence of premedication. Alopecia was noted in two
`patients treated at 25 mg/m2, one each experiencing grade 1
`and 2. Neither onychodystrophy nor fluid retention was
`observed.
`Anticancer activity. Evidence of anticancer activity due to
`XRP6258 was noted in two patients. An 80-year-old male with
`prostate cancer metastatic to liver and bones whose disease had
`progressed through surgical castration, bicalutamide, diethyl
`stilbestrol, and mitoxantrone and prednisone experienced a
`reduction in prostate-specific antigen from 62 to 21 ng/mL,
`decreased disease-related bone pain, and reduction in his target
`lesion, a lymph node metastasis, which qualified as confirmed
`partial response after four courses at the 15 mg/m2 dose level.
`The patient declined further treatment after his sixth course,
`at which time his response persisted. A 50-year-old male with
`hormone- and docetaxel-refractory prostate cancer metastatic to
`bone and iliac lymph nodes also experienced a partial response
`after treatment with XRP6258 at the 25 mg/m2 dose level of
`XRP6258. His prostate-specific antigen decreased from 415 to
`44 ng/mL, and his measurable disease showed a confirmed
`partial response. Progressive disease was noted after eight
`courses. In addition, a patient with transitional cell carcinoma
`of the bladder experienced an unconfirmed partial response,
`and minor responses (tumor size reduction not meeting criteria
`for partial response) were observed in one patient each with
`osteosarcoma and prostate cancer. Twelve (48%) patients had
`stable disease as their best response for greater than 4 months.
`PK and pharmacodynamic evaluation. Blood sampling for
`PK studies was done in 25 patients, and C max and AUC(0-48 h)
`values were estimated in 23 evaluable subjects. Compartmental
`PK modeling was done in 23 patients, with 9 and 2 patients
`having PK data from two and three consecutive courses,
`respectively. A scatter plot of individual AUC(0-48 h) data as a
`function of XRP6258 dose is shown in Fig. 1A. The relationship
`
`between XRP6258 dose and AUC0-48 h and C max was
`proportional. The decrease in plasma concentrations of
`XRP6258 was best described by a triphasic model. Plasma
`concentration data and superimposed model fit for a typical
`individual are depicted in Fig. 1B. Pertinent PK variables, as
`determined by this model, as a function of dose level are listed
`in Table 5. The PK behavior in plasma was characterized by a
`rapid initial phase with a t 1/2E1 averaging 2.6 F 1.4 minutes,
`followed by an intermediate phase with a mean t 1/2E2 of
`1.3 F 0.6 hours, and a prolonged terminal phase (mean t 1/2E3,
`77.3 F 45.5 hours). V ss values for XRP6258 were very large
`(mean, 2,034 F 1,495 L/m2), and CL rates were high, averaging
`53.5 F 20.3 L/h (27.3 F 9.7 L/h/m2), which represented 61%
`of hepatic blood flow (87 L/h; ref. 10). The interpatient
`variability was moderate and estimated at 40.7% of AUC(0-48 h)
`(95% confidence interval, 28.9-69.8). The intrapatient varia-
`bility for AUC(0-48 h) was also relatively low (27.3%; 95%
`confidence interval, 20.6-40.6%) in 18 patients with at least
`two courses evaluable for PK. Based on CVs, the total variability
`in CL values expressed in L/h/m2 was also moderate (CV, 35%),
`whereas the variability of terminal half-life and V ss values was
`higher (CV, 59% and 74%, respectively). CL, expressed in L/h,
`did not relate well to BSA (R 2 = 0.303; P = 0.0065). However,
`after correction for the BSA of each individual patient (11), the
`total variability in the CL of XRP6258 was slightly lower (35.4%
`versus 38.8%). Indeed, the value for relative reduction in PK
`variability was 8.8%.
`An analysis of PK data from individuals in whom plasma
`sampling was done during multiple courses showed no
`apparent changes in CL or AUC(0-48 h) with repetitive treatment.
`Relationships between PK variables reflecting XRP6258
`exposure, such as AUC(0-48 h) and C max values, from course 1
`and the percent decrements in ANCs were assessed, and scatter
`plots depicting percentage decrements in ANC as functions of
`both AUC(0-48 h) and C max are depicted in Fig. 1C. Although
`decrements in the ANC seem to loosely relate to these variables,
`neither linear nor nonlinear models could be derived to
`adequately fit these relationships.
`
`Discussion
`
`Primary and acquired tumor resistance limits the effective-
`ness and spectrum of activity of the taxanes in preclinical and
`
`www.aacrjournals.org
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`727
`Clin Cancer Res 2009;15(2) January 15, 2009
`
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`Research.
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`

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`Cancer Therapy: Clinical
`
`clinical studies. The synthesis of new taxoids, such as XRP6258,
`which are poor substrates for P-gp and evade MDR, may be one
`means to increase both the magnitude and spectrum of activity
`of this class of agents, as well as enable penetration of these
`agents into tissues and membranes, such as the central nervous
`system, in which P-gp pumps may serve as barriers.
`Neutropenia was the principal DLT of XRP6258 observed in
`this study. Although neutropenia was common at the higher
`dose levels, the duration of severe neutropenia was typically
`brief and rarely associated with fever. At the recommended dose
`level, 20 mg/m2, grade 4 neutropenia was observed in only 4%
`of courses, which compares favorably to other taxanes. Similar
`to other taxanes, anemia and thrombocytopenia were rarely
`observed, even in HP patients. Gastrointestinal
`toxicities,
`particularly nausea, vomiting, and diarrhea, were mild to
`moderate even in the absence of routine prophylaxis and were
`generally manageable with standard therapies. Diarrhea was
`observed commonly with XRP6258, with 1