Cancer Therapy: Clinical

Phase I Trial of Bortezomib in Combination with Docetaxel in Patients with Advanced Solid Tumors Wells A. Messersmith,1Sharyn D. Baker,1Lance Lassiter,1Rana A. Sullivan,1Kimberly Dinh,1VirnaI.Almuete,1 John J. Wright,2 Ross C. Donehower,1Michael A. Carducci,1and Deborah K. Armstrong1

Abstract Purpose: Bortezomib (PS-341), a first-in-class proteasome inhibitor, is metabolized by deboro- nation involving cytochrome P4503A (CYP3A), which also metabolizes docetaxel. Preclinical studies have shown synergy between bortezomib and taxanes. We conducted a phase I study combining bortezomib and docetaxel in refractory solid tumor patients. Experimental Design: Patients received escalating doses of weekly docetaxel (days 1and 8) and twice weekly bortezomib (days 2, 5, 9, and12) in 3-week cycles.Two subjects were enrolled at each dose level, with cohort expansion to six for dose-limiting toxicity (DLT). Dose levels 1, 2, and 3 consisted of docetaxel/bortezomib 25/0.8, 25/1.0, and 30/1.0 mg/m2, respectively. CYP3A activity and docetaxel pharmacokinetic studies were conducted, and proteasome inhibi- tion was assessed. Results: Fourteen patients received a total of 34 cycles of treatment. Dose level 2 was expanded for DLT that occurred in two of six patients consisting of febrile neutropenia in one patient and grade 3 thrombocytopenia in one patient. One patient received two cycles at dose level 3 with dose reduction to dose level 2, where grade 3 thrombocytopenia occurred at cycle 3. Both episodes of grade 3 thrombocytopenia were transient (<7 days). Dose level 1was then expanded tosix patients where noDLTs occurred. CYP3A activity and docetaxel clearance did notchange between weeks1and 5. Conclusions: The maximum tolerated dose was docetaxel 25 mg/m2 (days 1and 8) with borte- zomib 0.8 mg/m2 (days 2, 5, 9, and 12) given every 21days. Bortezomib treatment did not alter CYP3A activity and docetaxel clearance.

Bortezomib (Velcade, formerly PS-341) is a first-in-class cancer (6). Both weekly and once every 3 weeks (3-weekly) reversible inhibitor of the 26S proteasome, which degrades schedules have been explored, with schedule-dependent proteins involved in cell cycle regulation and cell signaling (1). toxicities observed despite similar pharmacokinetics (7). Bortezomib is approved by the Food and Drug Administration Docetaxel has been shown to function in part by phosphory- for the treatment of multiple myeloma (2). Several phase I trials lation of bcl-2, thereby suppressing the normal antiapoptotic of bortezomib in solid tumor patients have been completed, function of this protein (8). Interestingly, proteasome inhib- with the primary dose-limiting toxicities (DLT) being diarrhea, itors have also been shown to overcome bcl-2-mediated fatigue, and sensory neurotoxicity (3–5). Because proteasome protection from apoptosis (9). Thus, there is potential for inhibition may alter the sensitivity of cancer cells to therapeutic significant antitumor activity with the combined use of doce- agents, there is interest in combining bortezomib with cytotoxic taxel and bortezomib, and this has been shown in preclinical chemotherapy. studies (10). Significantly, the administration of docetaxel Docetaxel is a semisynthetic taxane with wide activity in a before bortezomib has been found to produce greater tumor number of solid tumors, including breast, lung, and prostate cell kill than the reverse order (11). Docetaxel undergoes extensive metabolism by cytochrome P450 (CYP) 3A4 and 3A5, and the predominant route of 1 Authors’ Affiliations: Sidney Kimmel Comprehensive Cancer Center at Johns elimination of parent drug and metabolites is via biliary Hopkins, Baltimore, Maryland and 2Cancer Therapeutics Evaluation Program, National Cancer Institute, Bethesda, Maryland excretion (12, 13). Docetaxel metabolites show substantially Received 9/5/05; revised 10/31/05; accepted 11/30/05. reduced cytotoxic activity compared with the parent drug, Grant support: Grant U01CA70095 and research grant GIA 19075 from Sanofi- making biotransformation by CYP3A a major route of inacti- Aventis (Bridgewater, NJ) for correlative studies. vation (14). Substantial intrapatient variability in docetaxel 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 pharmacokinetics has been seen, and decreased docetaxel with 18 U.S.C. Section 1734 solely to indicate this fact. clearance (hence high plasma concentrations) has been Requests for reprints: Wells Messersmith, Sidney Kimmel Comprehensive associated with increased frequency of grade 4 neutropenia Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, and febrile neutropenia in a population pharmacokinetic- CRB 1M88, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-502-6873; Fax: 410-614-9006; E-mail: [email protected]. pharmacodynamic analysis (15). The primary route of metab- F 2006 American Association for Cancer Research. olism for bortezomib is deboronation by several CYP enzymes, doi:10.1158/1078-0432.CCR-05-1942 including CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2

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(16). Because bortezomib binds the proteasome via the boronic acid moiety, deboronation is the principal route of bortezomib detoxification (17). Bortezomib also may affect the intracellular concentration of multiple CYP isoenzymes by inhibiting their degradation after induction (18, 19). Thus, the potential for a significant interaction between bortezomib and docetaxel exists. The primary objective of this phase I study was to determine the DLT and maximum tolerated dose of bortezo- mib administered twice weekly combined with weekly docetaxel in patients with advanced solid malignancies. Secondary objectives included the following: (a) to assess the pharmacokinetics of docetaxel administered alone and in Fig. 1. Schema of dosing and correlative studies. Each cycle lasted 3 weeks and b consisted of docetaxel administered on days1and 8, and bortezomib given on days combination with bortezomib, ( ) to determine the effects of 2, 5, 9, and 12 (both i.v.). Bortezomib was held the first week (days 2 and 5 during the combination on CYP3A4 activity using the erythromycin cycle 1only) so that docetaxel pharmacokinetic studies could be done during breath test, and (c) to explore the pharmacodynamic effects monotherapy. Serial sampling for docetaxel was subsequently repeated during week 5 during combination therapy. Erythromycin breath tests for CYP3A phenotyping of bortezomib combined with docetaxel using the 20S studies were done before study drug administration and during week 5.The 20S proteasome inhibition assay on peripheral blood mononu- proteasome assay was done during the first dose of bortezomib. *, docetaxel clear cells. pharmacokinetic studies; +, 20S proteasome inhibition assay; d, day; ERMBT, erythromycin breath test; Wk, week.

Patients and Methods commercially from Sanofi-Aventis (formerly Aventis) and administered Eligibility. Patients with histologically confirmed advanced solid i.v. as a 1-hour infusion. Study subjects were premedicated with malignancies without conventional treatment options were eligible for dexamethasone before docetaxel, either 8 mg i.v. 30 minutes before the trial. Inclusion criteria included age z18 years; Eastern Cooper- treatment or 8 mg orally twice daily the day before, day of, and day after ative Oncology Groupperformance status of 0, 1, or 2 (Karnofsky docetaxel treatment. Antiemetics were added as a premedication for performance status z 50%); life expectancy >12 weeks; at least 4 subjects who experienced nausea. weeks elapsed since prior chemotherapy or radiation therapy [6 weeks Both study drugs were not administered on scheduled days if DLT if the regimen included 1,3-bis(2-chloroethyl)-1-nitrosourea or mito- occurred (see below). Docetaxel alone was also held for neutropenia mycin C, without receiving >3 cycles of mitomycin C total]; at least 6 (ANC < 1,500/mm3 on day 1, or 1,000/mm3 on day 8, of any cycle) months elapsed since previous weekly docetaxel treatment; adequate or grade 2 neuropathy. Missed doses were not substituted. Treatment organ function [leukocytes z3,000/AL, hemoglobin z8mg/dL, delays >2 weeks were considered as a DLT. Dose reductions were absolute neutrophil count z1,500/AL, platelets z100,000/AL, total implemented for subjects who experienced DLT. Treatment was bilirubin within normal institutional limits (WNL), creatinine WNL or continued until unacceptable toxicity, disease progression, or with- creatinine clearance z60 mL/min/1.73 m2 for patients with creatinine drawal of consent. levels above institutional normal]. Patients were excluded if they had Toxicity assessment. Toxicity was assessed weekly using the National known brain metastases, hypersensitivity to taxanes or corticosteroids, Cancer Institute Common Toxicity Criteria version 2. DLT was defined intolerance of corticosteroids, peripheral neuropathy >grade 1 as dose delays > 2 weeks or treatment-related grade 3 thrombocytopenia (Common Toxicity Criteria version 2), pregnancy, HIV infection, or (platelet count < 50,000/mm3), grade 4 neutropenia lasting z7 days, within 14 days of study drug administration total bilirubin above febrile neutropenia (>38.5jC), grade 4 anemia (hemoglobin < 6.5 g/ institutional normal limits, alanine aminotransferase/aspartate ami- dL), or any grade z3 nonhematologic toxicity occurring during cycle 1 notransferase >1.5 upper limit of normal, alkaline phosphatase > 2.5 or 2 except inadequately treated nausea, vomiting, or diarrhea. If the upper limit of normal (unless shown to be bone-derived whereas delivered dose of docetaxel was <75% planned in the first two cycles, or alanine aminotransferase/aspartate aminotransferase < 1.5 Â upper similarly <80% of planned bortezomib during cycles 1 and 2, it was limit of normal). considered a DLT. The maximum tolerated dose (recommended dose The clinical protocol was approved by the Johns Hopkins Institu- for phase II testing) was considered to be the dose level where none or tional Review Board and all subjects provided written informed consent one of six subjects experienced DLT. before study drug administration. Pretreatment and follow-up studies. Baseline evaluations were Drug dosage and administration. Both bortezomib and docetaxel conducted within 1 week of study entry and included medical history were dosed i.v. by body surface area. Bortezomib was administered (including performance status), concurrent medications, vital signs, on days 2, 5, 9, and 12, and docetaxel was given on days 1 and 8, of physical exam, complete blood count with differential, serum chemistry a 21-day cycle (Fig. 1). Dose levels, outlined in Table 1, were as (sodium, potassium, chloride, bicarbonate, urea nitrogen, creatinine, follows: dose level 1, 0.8 mg/m2 bortezomib and 25 mg/m2 of glucose, albumin, alkaline phosphatase, total bilirubin, alanine docetaxel; dose level 2, 1.0/25; and dose level 3, 1.0/30. There was no aminotransferase, aspartate aminotransferase, lactate dehydrogenase, intrapatient dose escalation. Two patients were enrolled at each dose phosphorus, and total protein), and electrocardiography. Radiologic level, with cohort expansion to six subjects when a DLT was seen. For evaluations were done within 4 weeks of study entry. Vital signs were docetaxel pharmacokinetic studies during a monotherapy period, recorded on each treatment day and complete blood counts, serum bortezomib administration was held during week 1 (days 2 and 5) of chemistries, and adverse event evaluations were done weekly. Physical cycle 1. exams were repeated once per cycle. Response of measurable lesions Bortezomib was supplied by the National Cancer Institute Cancer was done every 2 cycles (6 weeks) using Response Evaluation Criteria in Therapy Evaluation Program in conjunction with Millenium Pharma- Solid Tumors (20). A 30-day off-study follow-upevaluation of toxicities ceuticals. Each vial contained 3.5 mg bortezomib and 35 mg mannitol and blood tests was done. as a sterile, lyophilized powder and was reconstituted with normal Drug assay and pharmacokinetic analysis. Docetaxel pharmacoki- saline to a final concentration of 1 mg/mL bortezomib. Each dose was netic studies were done at week 1 (during docetaxel monotherapy in given as a rapid i.v. bolus over 3 to 5 seconds. Docetaxel was purchased which bortezomib was held) and week 5 (during combination

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Ta b l e 1. Dose escalation scheme and incidence of DLT

Dose level Bortezomib dose (mg/m2) Docetaxel dose (mg/m2)No.patientsNo.cyclesDLT(no.) 1 0.8 25 7* 21 0 21.0 256142 31.0 3013c 0

*One patient not evaluable for toxicity. cPatient reduced todoselevel 2 after one cycle. treatment with bortezomib). Serial sampling of venous blood was done proteasome inhibition assays were collected at the first dose of at the following time points: immediately pretreatment, 30 minutes bortezomib (cycle 1, day 9) immediately pretreatment, and posttreat- into the infusion, at 59 minutes (just before the end of the docetaxel ment at 1, 24, and 48. Assays were done by Millenium Pharmaceuticals infusion), and postinfusion at 10 minutes, 30 minutes, 1 hour, 3 hours, (Cambridge, MA) using a published spectrofluorometric method (24). 7.5 hours, and the morning of days 2 (24 hours), 3 (48 hours), and 8. Statistical considerations. All study subjects who received at least one Docetaxel concentrations in plasma were quantitated in the Sidney dose of study drugs are included in the toxicity and efficacy analysis. Kimmel Comprehensive Cancer Center at Johns Hopkins Analytical For pharmacokinetic analysis, variables are presented as mean values Pharmacology Core Laboratory (Baltimore, MD) using a validated F SD, and for all tests the a priori cutoff for statistical significance was analytic assay consisting of high-performance liquid chromatography taken at P < 0.05. Differences between pharmacokinetic variables and with mass spectrometric detection (liquid chromatography/tandem CYP3A activity were compared by a two-sided paired Student’s t test. mass spectrometry) as previously described (7). Plasma docetaxel Statistical calculations were done with the software package JMP version concentrations were quantitated over a range of 0.50 to 100 nmol/L. 3.2.6 (SAS Institute, Cary, NC). The accuracy and precision of quality control samples was <15%. Samples with docetaxel concentrations >100 nmol/L were diluted with Results analyte-free human plasma before extraction and quantitation. Individual docetaxel pharmacokinetic variables were estimated by Fourteen patients were enrolled and pretreatment character- model-dependent methods as implemented in Adapt II, release 4 istics are summarized in Table 2. A variety of solid tumor types (Biomedical Simulations Resource, Los Angeles, CA). Data were fit with were enrolled, with the most frequent being non–small cell either a two- or three-compartment model by use of weighted least squares as the estimation procedure and inverse variance of the output error (linear) as the weighting option. Maximum plasma concentrations Ta b l e 2 . Patient characteristics (Cmax) values were obtained from the model-estimated plasma concentration at the end of the docetaxel infusion. Calculated n secondary pharmacokinetic variables included half-life during the Characteristic No. patients ( =14) T terminal phase of the disposition curve ( 1/2,kz) and systemic clearance. Sex The area under the plasma concentration-time curve was calculated as Male 10 dose divided by systemic clearance. Female 4 Assessment of CYP3A4 activity. CYP3A4 activity was assessed using Age, y the erythromycin breath test as previously described (21). The test was administered immediately pretreatment on day 1 of cycle 1 and on day Median 65 12 of cycle 2. The erythromycin breath test is based on detection of Range 40-76 14 C-labeled CO2 after N-demethylation of erythromycin by hepatic ECOG performance status CYP3A4. The erythromycin breath test dose, consisting of 0.04 mg 03 [14C-N-methyl]erythromycin (containing 3 ACi of radioactivity), and 111 collection balloons were obtained from Metabolic Solutions (Nashua, Diagnosis NH). The dose was dissolved in 4.5 mL of 5% dextrose solution and Lung (non-small cell) 4 administered as an i.v. injection over 1 minute. Postinjection breath Bladder 2 samples were collected in balloons at 5, 10, 15, 20, 25, 30, and 40 Prostate 2 minutes. Samples were shipped to Metabolic Solutions for measure- Colon 1 ment of breath carbon dioxide. The data were reported as the flux of 14 Pancreas 1 CO2 and expressed as a percentage of dose exhaled per minute at each 2 Anal 1 collection time point assuming a CO2 output of 5 mmol/min/m body surface area (22). The conventional erythromycin breath test variable, Bile duct 1 percentage 14C metabolized per hour (% 14C exhaled/h), was calculated Renal cell 1 using the equation y = À65.988x2 + 54.645x + 0.0377, where x is the Oropharynx 1 14 value for % C exhaled/min at the 20-minute time point (23). Prior treatment Although it was not strictly forbidden in the protocol, subjects were Chemotherapy 11 strongly discouraged from using food supplements or herbal prepara- z2 Chemotherapy regimens 8 tions. Radiotherapy 7 20S proteasome assay. Preclinical studies have shown that although Hormonal therapy 2 bortezomib has a short plasma half-life measured in minutes, a dose- dependent decrease in peripheral blood mononuclear cell proteasome activity is seen 1 hour after drug administration and returns to baseline Abbreviations: ECOG, Eastern Cooperative Oncology Group. in 24 to 48 hours. Whole blood samples for determination of 20S

Clin Cancer Res 2006;12(4) February 15, 2006 1272 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. Phase I Trial of Docetaxel/Bortezomib lung cancer (n = 4), bladder (n = 2), and prostate cancer to docetaxel, also occurred. No other grade 4 adverse events (n = 2). In all, 38 three-week cycles of bortezomib/docetaxel were encountered. were administered. The median number of cycles was 2 (range, Of the toxicities encountered, cytopenias were the only side 0.67-8). One patient did not complete cycle 1 due to rapid effects that seemed to be dose dependent, albeit a limited disease progression. Thirteen patients completed at least two number of subjects were treated at each dose level. At dose level cycles. The third dose level was explored in only one patient 3, one of one patient had grade 3 thrombocytopenia; at dose due to a late-occurring DLT at the second dose level, at which level 2, five of six patients had some type of grade 2 to 3 time the second dose level was further explored. cytopenia; and at dose level 1, none of seven patients had grade DLT and maximum tolerated dose. DLT was observed in two 2 to 3 cytopenias (Table 3). There were no unexpected toxicities. patients at dose level 2 of 1.0 mg/m2 bortezomib and 25 mg/ Pharmacokinetic analysis. All patients were evaluated for m2 docetaxel (grade 3 thrombocytopenia and febrile neutro- docetaxel pharmacokinetics during week 1, where docetaxel penia each in one patient). No other treatment-related grade 4 was administered alone, and week 5, when docetaxel and toxicities occurred. One patient at dose level 3 of 1.0 mg/m2 bortezomib were administered together. One patient withdrew bortezomib and 30 mg/m2 docetaxel experienced grade 3 early from the study due to disease progression before week 5. thrombocytopenia during cycle 3. The maximum tolerated dose Docetaxel pharmacokinetic variables for weeks 1 and 5 are and recommended phase II dose at this schedule is 0.8 mg/m2 summarized in Table 4. Mean (SD) values for docetaxel bortezomib and 25 mg/m2 docetaxel. clearance were similar during weeks 1 and 5 [26 (12) L/h versus Toxicity. The adverse events are summarized in Table 3. 24 (13) L/h, respectively; P = 0.28]. No significant differences The most common adverse events were cytopenias, especially were observed for other docetaxel pharmacokinetic variables thrombocytopenia and anemia, as well as fatigue. Thrombo- listed in Table 4 between week 1 and week 5, indicating a lack cytopenia was delayed (both grade 3 events occurred during of effect of bortezomib administration on docetaxel pharma- cycle 2, week 3) and short-lived (lasting <7 days), and no cokinetics. bleeding episodes occurred. One episode of febrile neutro- CYP3A4 activity. Mean (SD) values for the erythromycin penia was seen without documented infection or sequelae. breath test variable %14C exhaled/h during weeks 1 and 5 were Infusion reactions and lower extremity edema, likely related similar [2.13% (0.83%) versus 2.16% (0.76%), respectively;

Ta b l e 3 . Treatment-related side effects per dose level after multiple administrations

No. patients Dose level 1: bortezomib 0.8 mg/m2, Dose level 2: bortezomib 1.0 mg/m2, Dose level 3, bortezomib 1.0 mg/m2, docetaxel 25 mg/m2 (n =7) docetaxel 25 mg/m2 (n =6) docetaxel 30 mg/m2 (n =1)

Side effect (grade) 1 2 3 1 2 3 1 2 3 Thrombocytopenia 1 0 0 0 1 1 0 0 1 Febrile neutropenia 0 0 0 0 0 1 0 0 0 Neutropenia000000100 Anemia100131000 Fatigue310011010 Dyspnea101001000 Infusion reaction 0 1 0 1 0 0 0 0 0 Flushing 000100000 Peripheral edema 1 1 0 1 1 0 0 0 0 Arthralgia 0 0 0 1 0 0 0 0 0 Nausea 1 0 0 0 1 0 0 0 0 Vomiting 100000000 Diarrhea 000001000 ElevatedALT/AST210000000 Eccymoses 0 0 0 0 0 0 1 0 0 Thrombosis 000010000 Headache 100000000 Backpain 110000000 Neuropathy 200100000 Tearing 000000100 Dizziness 000100000 Alopecia 1 0 0 0 0 0 0 0 0

NOTE: Toxicities are graded per the National Cancer Institute Common Toxicity Criteria version 2 criteria. Toxicities are worst-grade, treatment-related (‘‘possible,’’ ‘‘probable,’’or ‘‘definite’’relationship to study drugs), and occurring during any cycle. No treatment-related grade 4 toxicity occurred. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

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Ta b l e 4 . Pharmacokinetic variables for docetaxel during week 1 (monotherapy) and week 5 (combination therapy with bortezomib)

Cmax*(Mg/mL) AUClast*(Mg/mL-h) Clearance (L/h) Vss (L/h) t1/2 g (h) Week 1 (n = 14) 1.4 (0.6) 2.3 (1.0) 26 (12) 426 (251) 43 (21) Week 5 (n =13) 1.5 (0.8) 2.7 (1.3) 24 (13) 606 (527) 55 (38)

NOTE: All values are mean (SD).

Abbreviations: AUClast, area under the concentration-time curve; t1/2 c , terminal half-life; Vss, steady-state volume of distribution. 2 2 *Cmax and area under the concentration-time curve were normalized to a dose of 25 mg/m for one patient who received 30 mg/m .

P = 0.67]. The average CYP3A activity as assessed by obtained in this trial (3). In a more recent study with pharma- erythromycin breath test was not altered by the administration codynamic end points using a days 1 and 4 schedule every 2 of bortezomib in combination with docetaxel. weeks, the recommended dose was 3.0 mg (equivalent to 1.75 Proteasome inhibition assay. Eleven subjects had evaluable mg/m2) because reversible inhibition of proteosome activity best results for the proteasome inhibition assay at all time points. fit a total dose (mg) per fraction rather than mg/m2 (5). These In all cases, maximal inhibition was seen at 1 hour, with data were not available, however, before completion of our study. progressive decreases at 24 and 48 hours, which is consistent Bortezomib and docetaxel are known to have overlapping with previous studies. No significant difference was seen toxicities when given as single agents. For bortezomib, throm- between patients treated at dose level 1 (n = 6, 0.8 mg/m2), bocytopenia (29%) was the most common grade z3adverse where the mean (SD) inhibition was 46.8% (7.8%) and dose event in the SUMMIT and CREST multiple myeloma trials, level 2 (n = 4, 1.0 mg/m2), where it was 44.0% (9.4%). There followed by neutropenia (15%), fatigue (11%), and peripheral was no difference in inhibition between the patients with stable neuropathy (11%; ref. 2). In the phase I monotherapy studies in disease (n = 3) and progressive disease (n = 7; data not shown). solid tumor patients, the DLTs of bortezomib were diarrhea, Response. No objective responses were seen in this patient fatigue, and sensory neuropathy, and hematologic toxicities were population. Four subjects (two non–small cell lung, one generally not dose limiting (3–5). The side effect profile of bladder, one prostate) had stable disease after four cycles. One docetaxel depends in part on the schedule and patient character- patient with non–small cell lung had stable disease for eight istics. Weekly docetaxel is associated with less frequent neutro- cycles of treatment. penia (4-14%) compared with 3-weekly schedules (27, 28). Thrombocytopenia following administration of docetaxel is Discussion relatively infrequent with both 3-weekly (1-4%) and weekly (0%) schedules. Thus, the thrombocytopenia seen in this study This phase I trial of twice-weekly bortezomib and weekly at these low doses was greater than expected despite the potential docetaxel establishes the recommended dose at 0.8 mg/m2 for overlap. Of note, due to safety concerns, the criterion for (days 2, 5, 9, and 12) and 25 mg/m2 (days 1 and 8), dose-limiting thrombocytopenia (grade 3) in this trial was more respectively, every 21 days. The DLTs were thrombocytopenia conservative than other studies with bortezomib, where grade 4 and febrile neutropenia. Other common side effects were was selected as a DLT. A more liberal DLT definition likely would anemia and fatigue. Although the number of patients was have allowed the exploration of higher dose levels. limited, a pharmacokinetic interaction between these agents One explanation for the grade 3 thrombocytopenia may have was not seen with regard to docetaxel metabolism, and CYP3A been the heavy pretreatment of the individual patients who phenotyping studies did not show a significant difference in experienced it. Both patients had prostate cancer and had enzyme activity before and after combination treatment. previously received wide-field radiation therapy in addition to Proteasome inhibition studies reflecting the activity of borte- multiple cytotoxic chemotherapy regimens. The patient who zomib showed profiles that are consistent with previously experienced febrile neutropenia also had received multiple reported results from bortezomib monotherapy studies (3–5). cycles of conventional chemotherapy before enrollment. When given on a weekly schedule, docetaxel monotherapy is However, in the phase I trial of single-agent bortezomib where typically administered at a dose of 30 mg/m2, and the Food and twice-weekly doses upto 1.56 mg/m 2 were explored with only Drug Administration–approved dosing of bortezomib mono- 2 of 12 subjects experiencing grade 3 hemotologic toxicity, therapyis1.3mg/m2 twice weekly (days 1, 4, 8, and 11 of a 24 (50%) of 48 patients had received definitive or palliative 21-day cycle; refs. 2, 25). Therefore, the recommended dose radiotherapy and all subjects had received prior chemotherapy based on this study includes a 17% dose reduction of docetaxel (median = 4, range 1-16). The short-lived (<7 days) length of and a 38% dose reduction of bortezomib when given in combi- grade 3 thrombocytopenia seen in this trial and lack of clinical nation compared with monotherapy. Particularly for bortezo- sequelae indicate that this side effect may be tolerable for future mib, the decreased dose may be clinically significant given that studies of this combination, and perhaps more permissible slightly higher response rates were seen at 1.3 mg/m2 compared variables of tolerable thrombocytopenia could be incorporated. with 1.0 mg/m2 in a phase II trial in multiple myeloma (26). In Sensory neuropathy (any grade) is seen in 20% to 30% of addition, the recommended phase II dose in patients with solid patients receiving docetaxel therapy in 3 weekly and weekly tumors receiving single-agent bortezomib in a twice-weekly schedules. Given that neuropathy is one of the DLTs typically schedule was 1.56 mg/m2, which is nearly double the dose seen with bortezomib, the potential for overlap in our trial was

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significant. The lack of neurotoxicity may be due to the relatively 8, 9, and 12), followed by 1 week off. Study subjects informally low doses that were explored. In most trials of bortezomib, reported that this was an inconvenient schedule. A phase I/II neuropathy was not reported at doses <1.2 mg/m2, and dose- study of docetaxel/bortezomib in prostate cancer patients using limiting neuropathy was reported at doses >1.5 (3, 5). a weekly schedule for each agent (docetaxel days 1 and 8 and Neuropathy from taxanes tends to be cumulative, which in bortezomib days 2 and 9) has been reported without DLTs at addition to the low dose may partially explain the low incidence docetaxel 40 mg/m2 and bortezomib 1.3 mg/m2 (29). Four of of neuropathy seen in this trial because the majority of the 12 patients has a z50% decline in prostate-specific antigen patients received only two cycles (6 weeks) of study drugs. values in that study, and grade 3/4 thrombocytopenia was not The results of this trial indicate that weekly docetaxel and reported despite the fact that six subjects had received prior twice-weekly bortezomib can be safely combined, albeit at radiotherapy. The effects on efficacy of dropping one of the slightly reduced doses compared with each agent alone. No weekly doses of bortezomib are unknown. Further evaluation interaction was detected in an analysis of docetaxel pharmaco- of this combination is warranted, although perhaps with an kinetics, and no change in CYP3A4 activity was detected using altered schedule of weekly bortezomib, an exclusion criterion the erythromycin breath test. The somewhat low proteasome for heavily pretreated patients, and/or permissible transient inhibition seen at these doses was as anticipated. Clinical thrombocytopenia. Due to the inconvenience of the schedule activity was modest in this pretreated population. in this study, combined with promising clinical activity seen The tested schedule in this study required that patients early trials of once-weekly combination regimens, further receive treatment three times per week for 2 weeks (days 1, 2, 5, exploration of this schedule was not done.

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