Phase I/II Study of Bortezomib Plus Docetaxel in Patients With

Cancer Therapy: Clinical

Phase I/II Study of Bortezomib Plus Docetaxel in Patients with Advanced Androgen-Independent Prostate Cancer Robert Dreicer,1Daniel Petrylak,2 David Agus,3 Iain Webb,4 and Bruce Roth5

Abstract Purpose: To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer. Experimental Design: Two bortezomib doses (1.3 and 1.6 mg/m2/dose) in combination with four docetaxel doses (25-40 mg/m2/dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in SolidTumors guidelines. Results: Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (z50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for z4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines,11% achieved a partial response, and an additional 67% had stable disease.The degree of proteasome inhibition was similar to that reported with single-agent bortezomib.Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred. Conclusions: The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m2 bortezomib plus 40 mg/m2 docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.

Recent therapeutic advances have, to some extent, modulated in patients treated with docetaxel-based therapies remains in the nihilism historically associated with the management of the range of 18 to 19 months. patients with advanced prostate cancer. Standard first-line Various strategies have been investigated in an attempt to treatment of metastatic androgen-independent prostate cancer augment the therapeutic yield of docetaxel-based therapies. (AIPC)now includes docetaxel, based on findings from two One approach involves combining docetaxel with novel agents prospective, randomized phase III trials (SWOG 9916 and TAX that target specific pathways associated with AIPC, including 327). These trials showed that patients treated with docetaxel- the activation of androgen receptors independently of ligands, based chemotherapy had significantly improved survival activation of the transcription factor nuclear factor-nB, and compared with patients receiving mitoxantrone and prednisone activation of growth-signaling pathways, such as phosphatidy- (1, 2). Despite this important clinical advance, median survival linositol-3¶-kinase/Akt (3). Of note, constitutive activation of nuclear factor-nB may be associated with phosphatidylinositol- 3¶-kinase/Akt activation, leading to protection from apoptosis and more aggressive behavior of prostate tumors (4, 5). Blockade of nuclear factor-nB in prostate tumors inhibits Authors’ Affiliations: 1Cleveland Clinic Foundation, Cleveland, Ohio, 2Columbia Presbyterian Medical Center, NewYork, NewYork, 3Cedars-Sinai Medical Center, angiogenesis, cancer cell invasion and metastasis (3), and Prostate Cancer Center, Los Angeles, California, 4Millenium Pharmaceuticals, increases sensitivity to apoptosis induced by tumor necrosis Cambridge, Massachusetts, and 5Vanderbilt-Ingram Cancer Center, Nashville, factor a (6). In addition, in BCL-2–overexpressing tumors such Tennessee as prostate cancer, targeting transcriptional activation may be a Received 8/17/06; revised 11/8/06; accepted 11/21/06. more effective strategy for inducing apoptosis than inhibiting Grant support: Millennium Pharmaceuticals, Inc., and Sanofi-Aventis. The costs of publication of this article were defrayed in part by the payment of page signal transduction pathways (7). charges. This article must therefore be hereby marked advertisement in accordance Bortezomib (velcade/PS-341; Millennium Pharmaceuticals, with 18 U.S.C. Section 1734 solely to indicate this fact. Inc., Cambridge, MA, and Johnson & Johnson Pharmaceuticals, Requests for reprints: Robert Dreicer, Department of Solid Tumor Oncology Research and Development, L.L.C., Raritan, NJ)is a novel Cleveland Clinic, 9500 Euclid Avenue R35, Cleveland, OH 44195. Phone: 216- 445-4623; Fax: 216-445-2360; E-mail: [email protected]. dipeptide boronic acid. It is the first clinically studied reversible F 2007 American Association for Cancer Research. inhibitor of the 26S proteasome, the degradative enzyme doi:10.1158/1078-0432.CCR-06-2046 involved in the catabolic pathway for many intracellular

Clin Cancer Res 2007;13(4) February 15, 2007 1208 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2007 American Association for Cancer Research. Bortezomib Plus Docetaxel in Advanced AIPC regulatory proteins including inhibitor of nuclear factor-nB bisphosphonates were not allowed to begin bisphosphonates therapy. (InBa), p53, p21, and p27 (8–10). Based on the results of two Patients with greater than grade 2 peripheral neuropathy, myocardial phase II trials (11, 12)and a randomized phase III trial versus infarction within 6 months of enrollment, or uncontrolled arrhythmias dexamethasone (13), bortezomib has been approved for the or heart failure were excluded from enrollment. Men of reproductive potential had to agree to use an effective contraceptive method. All treatment of patients with multiple myeloma who have patients were informed of the investigational nature of the study and received at least one prior therapy. signed written informed consent in accordance with institutional and In preclinical studies, single-agent bortezomib at concen- federal guidelines. The protocol was approved annually by the trations of 7 to 500 nmol/L induced growth arrest and institutional review board for each treating institution. apoptosis in vitro and in vivo against androgen-dependent Baseline radiographic and laboratory assessments. Acomputed (LNCaP)and androgen-independent (PC-3 and DU145) tomography scan of the abdomen and pelvis and a bone scan were prostate cancer cell lines (14–17). The maximally tolerated required at baseline. Radiologic assessment for measurable disease was dose of bortezomib in vivo was 1 mg/kg. Phase I dose escalation done within 28 days before enrollment. Other baseline laboratory has been guided by biochemical assays of proteasome activity assessments included an electrocardiogram, serum testosterone, com- to achieve target inhibition of 70% to 80% (18). plete blood count (differential and platelets), clinical chemistries, Inhibition of proteasome activity increases sensitivity to urinalysis, C-reactive protein (CRP), IL-6, and two PSA measurements taken at least 1 week apart. chemotherapy and radiotherapy (19–25). In vitro and in vivo Efficacy was assessed throughout the study by measuring PSA, tumor studies of prostate cancer and other solid tumors suggest that response, Karnofsky performance status, CRP, IL-6, and bone resorp- bortezomib activity is enhanced when given with docetaxel tion markers. PSA levels were measured on (or within 7 days of): day 1 (26–29). Docetaxel stabilizes the h-subunit of tubulin resulting of cycle 1, day 1 of subsequent odd-numbered cycles, and at the end-of- in cell cycle arrest at M phase and apoptosis. Sequencing these study visit if it had been >1 week since the previous assessment. PSA drugs is therefore an important consideration as proteasome response was defined as a z50% decrease from baseline PSA (35), as inhibition with bortezomib arrests cell cycle in G1 and G2, determined by two separate measurements at least 4 to 6 weeks apart. whereas docetaxel is most effective in M phase (27, 28). Various Every 4 to 6 weeks during treatment, target and nontarget lesions were human cancer cell lines and xenograft models provide measured and overall disease response (confirmed complete response conflicting evidence of the ability of bortezomib to antago- or partial response, or stable disease)was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST; ref. 36). nize/sensitize taxane-induced apoptosis (26, 30). At the time Responses were confirmed 4 to 6 weeks after the first complete this clinical trial was written, preliminary preclinical evidence response or partial response. Blood samples were obtained from all supported the taxane-bortezomib sequence used in this study. patients before and 1 h after bortezomib administration during the first In phase I and II trials, bortezomib administered alone two cycles for pharmacodynamic analysis of 20S proteasome inhibi- showed minimal antitumor activity in AIPC (31, 32). However, tion. Adverse events, serious adverse events, and all concomitant medi- as a component of combination regimens, bortezomib shows cations, procedures, and supportive therapies were also documented potential (33). Initial results from a multicenter phase II trial throughout the study. Laboratory abnormalities considered by the suggest encouraging antitumor activity and tolerability with investigator to be clinically significant were reported as adverse events. weekly docetaxel/bortezomib combination therapy in meta- Study design and dose escalation schedule. This open-label, phase I/ static AIPC (34). II, dose escalation study was carried out at four centers in the United The primary objectives of the present study were to establish States. During each 21-day treatment cycle, eligible patients received two docetaxel infusions (days 1 and 8)with 8 mg of dexamethasone the dose-limiting toxicity (DLT)and maximum tolerated dose given orally the evening prior, the morning of, and the evening after (MTD)of docetaxel in combination with bortezomib admin- docetaxel infusion, and two bortezomib injections (days 2 and 9, at istered weekly for 2 out of 3 weeks in patients with AIPC, and to least 24 h after docetaxel administration)followed by a 12-day rest evaluate the effect of the combination on prostate-specific period. antigen (PSA)levels. Secondary objectives included the Two bortezomib dose levels were investigated: low dose (1.3 mg/m2/ assessment of objective response, additional selected variables dose)and high dose (1.6 mg/m 2/dose). Docetaxel dose levels were 25, of clinical benefit, bone resorption markers, and proteasome 30, 35, and 40 mg/m2/dose with low-dose bortezomib (dose levels 1-4, 2 inhibition (20S assay)following docetaxel/bortezomib combi- respectively)and 35 and 40 mg/m /dose with high-dose bortezomib nation therapy, and investigation of the relationship between (dose levels 5 and 6, respectively). These doses were selected based on interleukin 6 (IL-6)and PSA levels in patients with AIPC. experience with weekly docetaxel in refractory malignancies (37, 38) and phase I clinical experience of bortezomib in AIPC (32). Initially, three patients were treated at dose level 1. If no DLTs occurred during the first cycle, recruitment continued at the next dose Materials and Methods level. If one patient experienced a DLT, the dose level was expanded to include six patients. Dose escalation continued if none of the additional Eligibility criteria. Eligible patients were required to have patho- three patients experienced a DLT. If two or three of the first three patients logic evidence of prostate adenocarcinoma, with documented meta- experienced a DLT, no additional patients were treated at that dose and static disease, having progressed on androgen deprivation therapy 30 patients were subsequently treated at the previous dose level (the following antiandrogen withdrawal if applicable. Progression was low MTD). If the MTD was not identified at the first three dose levels, defined by one or more of the following: progressive soft tissue or an additional 30 patients were enrolled to dose level 4. After the first bone metastasis or progressive PSA levels (z5 ng/mL), as shown by two 10 patients in the expanded cohort had completed one cycle of therapy, separate measurements taken at least 1 week apart and confirmed by a enrollment began at dose level 5 and dose escalation continued as larger third or fourth measurement. Patients had to have a Karnofsky appropriate. An additional 30 patients were enrolled to the dose level performance status z60% and be maintained on testosterone-suppress- identified as the high MTD in the same manner as the low MTD. ing therapy. Identification of the MTD was based on the occurrence of DLTs Patients may have received prior chemotherapy. Patients on during the first cycle only. The following hematologic adverse events, bisphosphonates therapy were eligible, whereas those not receiving graded using National Cancer Institute Common Toxicity Criteria

www.aacrjournals.org 12 0 9 Clin Cancer Res 2007;13(4) February 15, 2007 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2007 American Association for Cancer Research. Cancer Therapy: Clinical version 2.0 guidelines, were defined as DLTs if considered by the had undergone sufficient safety assessments to determine occurrence of investigator to be related to study drug: grade 3 or 4 thrombocytopenia, DLTs); (c)PSA response evaluation population (patients who received febrile neutropenia, grade 4 neutropenia without fever for z7 days, or at least one dose of combination study drug, had baseline PSA levels z5 grade 4 anemia. Any grade 3 or 4 nonhematologic adverse event ng/mL, and had at least one post-baseline assessment). Subsets of considered by the investigator to be related to study drug, except for patients based on prior chemotherapy were used when analyzing bone-derived alkaline phosphatase elevations and inadequately treated changes in PSA levels and tumor response to evaluate the combination nausea, vomiting, or diarrhea was defined as a DLT. in taxane-pretreated patients. A full treatment course consisted of eight treatment cycles (24 Efficacy analyses were carried out using the PSA response evaluation weeks). Intrapatient dose escalation was not allowed. For each study population and included change in PSA level, as well as the change drug, a maximum of two dose reductions (total dose reduction of 50%) from baseline levels in tumor lesion size. In addition, change from was recommended. Patients responding to treatment could continue baseline levels of CRP, IL-6, and bone resorption markers, and the therapy for up to 16 cycles at the investigator’s discretion. Patients relationship between IL-6 and PSA levels were evaluated. Descriptive experiencing progressive disease or unacceptable toxicity were with- statistics were used for all efficacy analyses. drawn from the study. Assessment of IL-6, CRP, and bone resorption markers. The proin- flammatory molecules CRP and IL-6 have been shown to be associated Results with PSA and metastatic disease in prostate cancer (32, 39, 40). To further assess the relationship between these markers of chronic Patient demographics. Between January 2002 and December inflammation and prostate cancer, blood samples for CRP and IL-6 2004, 83 patients with measurable or evaluable advanced and/ assessment were collected during screening, before study drug or metastatic AIPC were enrolled, all of whom received at least administration on days 1 and 8 of cycles 1, 2, 4, 6, and 8, and at the one dose of docetaxel/bortezomib combination therapy. end-of-therapy and end-of-study visits. Demographic and baseline characteristics are summarized in n It has been hypothesized that inhibition of nuclear factor- Bmay Table 1. The majority of patients (n = 59, 71%)had previously lead to a reduction in bone resorption (or turnover). Therefore, the rate received radiation therapy, 77 patients (93%)had undergone of bone turnover was assessed in this study by measurement of selected biochemical markers of resorbed bone collagen—N-telopeptide, surgery for prostate cancer. Approximately half of the patients deoxypyridinoline, bone-specific alkaline phosphatase, and osteocalcin. (52%)had previously received chemotherapy (Table 1). Urine samples for the assessment of N-telopeptide/creatinine ratio and Exposure to study drug. Of the 83 patients enrolled, 21 deoxypyridinoline/creatinine ratio and blood samples for the assess- (25%)completed eight cycles of treatment. The most common ment of serum bone-specific alkaline phosphatase and osteocalcin were reason for early discontinuation was progressive disease (37 of collected before study drug administration on day 1 of cycles 1, 2, and 62 patients, 60%). Compliance was high throughout the study: 4, and at the end-of-study visit. only 5% to 11% of patients had a missed or delayed dose Statistical analysis. The sample size in the expanded dose level(s) during cycles 1 to 8. The mean number of cycles administered was 30 additional patients, based on the aim of determining whether was 4.8, median 4.0 (range, 0-15), with 100%, 99%, 69%, the PSA response rate was at least 35%, as indicated by the lower bound 63%, 48%, 41%, 34%, and 31% of patients being treated in of a two-sided 90% confidence interval. Three analysis populations were used: (a)safety population (all cycles 1-8, respectively. Median duration of treatment was 11.4 patients who had received any amount of docetaxel and/or bortezo- weeks (range, 0-43 weeks). mib); (b)MTD evaluable population (all patients who received Evaluation of MTD. No DLTs occurred at the first four dose bortezomib and docetaxel in the MTD phase of the study and who levels. Therefore, an additional 30 patients were enrolled at

Table 1. Patient demographics and baseline characteristics

Bortezomib/docetaxel dose (mg/m2/dose) Low-dose group 1.3, High-dose group 1.6, All doses, subtotal (n =42) subtotal (n =41) total (N = 83) Median age, range (y) 68.5 (52-83) 69 (48-82) 69 (48-83) Race, n (%) Black 2 (5) 4 (10) 6 (7) White 37 (88) 34 (83) 71 (86) Hispanic 2 (5) 0 2 (2) Other 1 (2) 3 (7) 4 (5) Karnofsky performance status, n (%) V60 2 (5) 0 2 (2) 70 4 (10) 8 (20) 12 (14) 80 17 (40) 14 (34) 31 (37) 90 19 (45) 19 (46) 38 (46) Median (range) 80 (60-90) 80 (70-100) 80 (70-100) Median PSA level, ng/mL (range) 209.85 (1.8-3,233.0) 98.60 (0.1-974.0) 117.50 (0.1-3,233.0) Prior lines of chemotherapy, n (%) 0 14 (33) 26 (63) 40 (48) 1 16 (38) 5 (12) 21 (25) >1 12 (29) 10 (24) 22 (27) Prior taxane therapy, n (%) 16 (38) 12 (29) 28 (34)

*Safety population, N = 83.

Clin Cancer Res 2007;13(4) February 15, 2007 1210 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2007 American Association for Cancer Research. Bortezomib Plus Docetaxel in Advanced AIPC the 1.3/40 mg/m2 dose level, and no DLTs were seen. In the 1.6/ 9% partial response, 64% stable disease, 27% progressive 35 mg/m2 dose level, one patient experienced grade 3 angina disease)and taxane-pretreated patients ( n = 14; 7% partial pectoris, and an additional patient was enrolled into this group. response, 64% stable disease, 29% progressive disease). A At the 1.6/40 mg/m2 dose level, none of the first three patients greater response among patients who had previously received experienced a DLT. However, as a result of safety concerns noted nontaxane chemotherapy was observed (n = 9; 22% partial in one of the patients receiving this dose (grade 3 nausea, response, 78% stable disease, 0% progressive disease), although vomiting, and diarrhea, which the investigator considered to be the small patient numbers involved make meaningful compar- related to study drug but which had not been adequately treated ison difficult. with antiemetics), an additional three patients were enrolled at Of the 14 patients achieving a PSA response, 7 were also this dose level, none of whom experienced a DLT. Consequent- evaluable for tumor response. PSA response was associated with ly, 31 additional patients were enrolled. No DLTs occurred in partial response in three patients (two patients in the 1.3/40 this expanded cohort. As no DLTs were observed in the dose mg/m2 and one in the 1.6/40 mg/m2 group)and stable disease escalation phase for either of the bortezomib dose levels, the in four patients (two patients in the 1.3/40 mg/m2 group, two low MTD and high MTD were not established. in the 1.6/40 mg/m2 group). Two other patients achieved a Efficacy. PSA response (50% decline from baseline)was partial response according to RECIST without a PSA response. observed in 19 (28%)of 67 evaluable patients (90% confidence No significant changes from baseline in CRP and IL-6 levels interval, 19-39). The response was maintained for at least 4 were observed (data not shown). weeks in 14 patients (21%). PSA response rates are summarized Pharmacodynamics. The percentage of inhibition of protea- in Table 2. Subpopulation analyses showed that PSA response some activity is depicted in Fig. 1 (n = 52). The degree of was higher in chemotherapy-naBve patients [13 of 34, 38%; 5 of inhibition observed with the docetaxel and bortezomib comb- 12 (42%)receiving 1.3 mg/m 2 of bortezomib, 8 of 22 (36%) ination was similar to that seen in previous studies after the receiving 1.6 mg/m2 of bortezomib] than in patients who had administration of bortezomib alone (32, 39–43). In patients previously received chemotherapy [6 of 33, 18%; 5 of 23 (22%) in the different dose cohorts, mean percentage inhibition of receiving 1.3 mg/m2 of bortezomib, 1 of 10 (10%)receiving 1.6 proteasome activity 1 h postdose on day 2 (cycle 1)ranged mg/m2 of bortezomib], and higher in taxane-naBve patients [4 of from 61.9% to 73.6%, and on day 9 (cycle 1)immediately prior 12, 33%; 4 of 10 (40%)receiving 1.3 mg/m 2 of bortezomib, 0 of to dosing, ranged from 14.4% to 22.5%. 2 receiving 1.6 mg/m2 of bortezomib] than in taxane-pretreated Safety. All 83 patients experienced at least one adverse event, patients [2 of 21, 10%; 1 of 13 (8%)receiving 1.3 mg/m 2 of most commonly fatigue, diarrhea, flushing, and nausea (Table 3). bortezomib, 1 of 8 (13%)receiving 1.6 mg/m 2 of bortezomib]. Eighty-one patients (98%)experienced at least one adverse event Among the 45 patients evaluable for tumor response considered by the investigator to be at least possibly related to according to RECIST, five (11%)achieved a partial response bortezomib and/or docetaxel. Fatigue (70%)was the most (three receiving the 1.3/40 mg/m2 dose and two receiving the common drug-related adverse event. Drug-related diarrhea and 1.6/40 mg/m2 dose). Partial response was confirmed in three nausea occurred in 60% and 55% of patients, respectively. Grade of these patients (7%; two receiving 1.3/40 mg/m2 and one 3 or 4 adverse events occurred in 47 patients (57%)and were receiving 1.6/40 mg/m2). An additional 30 (67%) patients had considered drug-related in 28 patients (34%). The most common stable disease (Table 2). Subpopulation analyses according to grade 3 or 4 adverse events are listed in Table 4. Drug-related prior chemotherapy and taxane exposure revealed similar grade 3 or 4 adverse events were more common in the high-dose response rates between chemotherapy-naBve patients (n = 22; than the low-dose group (39% versus 29%, respectively). The

Table 2. Summary of changes in PSA from baseline and of best tumor response by bortezomib dose level

Bortezomib dose (mg/m2/dose) Low-dose group 1.3, High-dose group 1.6, All doses, total subtotal subtotal Change in PSA, n (%) n =35 n =32 n =67 50% PSA decline from baseline 10 (29) 9 (28) 19 (28) 90% confidence interval of PSA response rate [16-44] [16-44] [19-39] Best response, n (%)* n =25 n =20 n =45 Complete response 0 0 0 Partial response 3 (12) 2 (10) 5 (11) Stable disease 18 (72) 12 (60) 30 (67) Progressive disease 4 (16) 6 (30) 10 (22) Total responders (complete response + partial response) 3 (12) 2 (10) 5 (11) 90% confidence interval for response rate [3-28] [2-28] [4-22] Best confirmed response, n (%)c Total responders (complete response + partial response) 2 (8) 1 (5) 3 (7) 90% confidence interval for response rate [1-23] [0-22] [2-16]

NOTE: PSA response evaluation population, N = 67 and RECIST population, N = 45. *Derived according to RECIST standards. cResponse must be observed at two consecutive assessments.

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acute myocardial infarction and dyspnea, anemia, and hypogly- cemia. Overall, 11 patients (13%)discontinued the study drug early because of an adverse event. There was no apparent trend in terms of adverse events from any particular system organ class more frequently leading to early discontinuation. In total, 31% of patients experienced at least one treatment- emergent serious adverse event. Gastrointestinal hemorrhage, urinary retention, and anemia each occurred in three patients; acute myocardial infarction, hematuria, and infection were each reported in two patients. The incidence of serious adverse events was similar in low-dose and high-dose groups (27% versus 30%, respectively). During the study, two deaths were reported, both at dose level 6. One patient died from sepsis 26 days after his last dose of study drug; a secondary complication of a cholecystectomy. The other patient died from disease progression 29 days after his last dose. Dose reductions were necessary in only eight patients (two in cycle 2, four in cycle 4, one in cycle 5, and one in cycle 8). Only two of these patients were treated at the lower bortezomib dose. The proportion of patients in the low-dose group requiring a dose to be missed, held, or delayed in any cycle was 2% to 14% in cycles 1 to 8. In the high-dose group, 5% to 12% of patients in cycles 1 to 6, and none during cycles 7 and 8, required doses Fig. 1. Percentage of inhibition of 20S proteasome activity relative to baseline. to be missed, held, or delayed. Safety population (n =52).

Discussion most common drug-related grade 3 or 4 adverse events were diarrhea (7%)and fatigue (6%).Five patients experienced drug- The recent demonstration of a survival benefit, albeit a related grade 4 adverse events: anemia and duodenal ulcer, acute modest one, resulting from docetaxel-based therapy has myocardial infarction and increased cardiac troponin I levels, established a new baseline for the management of patients

Table 3. Most common adverse events*

Adverse event Bortezomib dose (mg/m2/dose) Low-dose group 1.3, High-dose group 1.6, All doses, subtotal (n =42) subtotal (n =41) total (N = 83) n (%) n (%) n (%) Fatigue 31 (74) 34 (83) 65 (78) Diarrhea NOS 27 (64) 29 (71) 56 (67) Flushing 26 (62) 24 (59) 50 (60) Nausea 21 (50) 26 (63) 47 (57) Edema lower limb 21 (50) 18 (44) 39 (47) Dysgeusia 18 (43) 20 (49) 38 (46) Lacrimation increased 20 (48) 16 (39) 36 (43) Constipation 19 (45) 16 (39) 35 (42) Vomiting NOS 12 (29) 18 (44) 30 (36) Insomnia 18 (43) 11 (27) 29 (35) Nail disorder NOS 18 (43) 10 (24) 28 (34) Appetite decreased NOS 18 (43) 8 (20) 26 (31) Dizziness (excluding vertigo) 12 (29) 13 (32) 25 (30) Musculoskeletal pain 11 (26) 14 (34) 25 (30) Anemia NOS 14 (33) 10 (24) 24 (29) Weakness 10 (24) 13 (32) 23 (28) Alopecia 10 (24) 11 (27) 21 (25) Anorexia 7 (17) 12 (29) 19 (23) Hyperglycemia 6 (14) 13 (32) 19 (23) Paresthesia 12 (29) 7 (17) 19 (23) Cough 10 (24) 8 (20) 18 (22) Dyspnea NOS 12 (29) 6 (15) 18 (22) Dyspepsia 11 (26) 6 (15) 17 (20)

Abbreviation: NOS, not otherwise specified. *>20%; N = 83.

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Table 4. Most common grade 3 or 4 adverse events*

Bortezomib dose (mg/m2/dose) Low-dose group 1.3, High-dose group 1.6, All doses, subtotal (n =42) subtotal (n =41) total (N = 83) n (%) n (%) n (%) Hyperglycemia NOS 4 (10) 8 (20) 12 (14) Anemia NOS 4 (10) 4 (10) 8 (10) Diarrhea NOS 3 (7) 4 (10) 7 (8) Hematuria 3 (7) 3 (7) 6 (7) Fatigue 1 (2) 4 (10) 5 (6) Musculoskeletal pain 3 (7) 2 (5) 5 (6) Dyspnea NOS 1 (2) 3 (7) 4 (5) Peripheral sensory neuropathy 0 4 (10) 4 (5) Weakness 1 (2) 3 (7) 4 (5)

Abbreviation: NOS, not otherwise specified. *>5% overall or in either bortezomib dose group; N = 83.

with advanced androgen-resistant metastatic prostate cancer. asthenia, and fatigue. No cases of febrile neutropenia or Many questions, such as the optimal timing of initiation of neuropathy were reported; these have previously been reported therapy and its duration, remain. What is clear, however, is the with docetaxel plus bortezomib in patients with anthracycline- need to build upon this therapeutic advance as essentially all pretreated breast cancer (46)and in patients with solid tumors these patients will ultimately progress and die of disease. (45). Neutropenic fever, neutropenia, cardiovascular events, Bortezomib is the first clinically studied reversible inhibitor diarrhea, and nausea were characteristic of docetaxel-based of the 26S proteasome with has shown activity in multiple therapy in recent randomized trials in AIPC (1, 2, 47), yet none myeloma. Although bortezomib showed minimal single-agent of these side effects were sufficiently severe to be classified as a activity in advanced prostate cancer, preclinical and early DLT with bortezomib/docetaxel therapy in the present study. clinical experience provided a rationale to further explore the This observation may be explained by the dosing schedule of activity of the combination of bortezomib and docetaxel. The docetaxel (up to 40 mg/m2 twice every 21 days compared results of this phase I/II dose escalation study show that with 60-75 mg/m2 every 21 days). Adverse events were more bortezomib/docetaxel combination therapy is feasible in common with high-dose than low-dose bortezomib. This trend patients with AIPC, whether or not they have previously was most pronounced for vomiting, hyperglycemia, and grade received chemotherapy. The combination is well tolerated and 3/4 fatigue. However, none of these events was considered dose- active, as shown by the response rate according to reduction in limiting with 1.6 mg/m2 of bortezomib. PSA levels and RECIST. The bortezomib/docetaxel combination therapy showed anti- No DLTs occurred at any dose level, despite dose escalation tumor activity in the range of what would be anticipated with to 1.6 mg/m2 of bortezomib plus 40 mg/m2 of docetaxel, and docetaxel alone. PSA levels declined by z50% in 28% of evaluable therefore, the MTD of this regimen was not determined. In the patients. The proportion of patients achieving a z50% decrease phase I dose escalation study of single-agent bortezomib in PSA levels was similar in the high- and low-dose groups (28% reported by Papandreou et al., diarrhea and hypotension were versus 29%, respectively). Among patients evaluable for tumor dose-limiting and the MTD was determined as 1.6 mg/m2 (32). response according to RECIST, 78% achieved partial response or However, a weekly dosing regimen was used, with bortezomib stable disease as best response and 7% had confirmed partial administered for 4 weeks followed by a 1-week rest period. response. Of note, only patients receiving the highest docetaxel Aghajanian et al. determined a MTD of 1.56 mg/m2 when dose (40 mg/m2/dose)achieved a clinical response. single-agent bortezomib was administered twice weekly for 2 The results of this trial are generally consistent with data from weeks followed by a 1-week rest period in patients with heavily other phase I/II studies evaluating bortezomib alone or in combi- pretreated advanced solid tumors (44). The study included four nation with docetaxel (32, 34), showing antitumor activity and patients with prostate cancer. DLTs were diarrhea and painful tolerability. The activity of the combination in patients whose sensory neuropathy, each in two patients at grade 3 intensity. disease had progressed with prior taxane-based therapy was of No hematologic DLTs were observed. Likewise, Dy et al. interest. Although activity in terms of PSA response was lower identified an MTD of 1.5 mg/m2 with single-agent bortezomib in taxane-pretreated than taxane-naBve patients (10% versus twice weekly for 2 out of every 3 weeks in their study in patients 33%, respectively), tumor responses based on RECIST were with advanced cancer (43). similar in these two subgroups (7% versus 9%, respectively). In This schedule of bortezomib plus docetaxel combination the >5 years since this trial was initiated and first presented in therapy was well tolerated, as shown by the lack of DLTs. Fatigue, abstract form, substantial experience has accumulated, showing diarrhea, flushing, and nausea were the most common adverse that selected taxane-responsive patients may achieve clinically events, reflecting previous experience of bortezomib alone or in meaningful benefit with retreatment after a drug holiday (48). combination with docetaxel (12, 13, 32, 34, 45). The most In conclusion, bortezomib/docetaxel showed antitumor common grade 3 or 4 drug-related adverse events were diarrhea, activity in patients with AIPC and was well tolerated. No DLTs

www.aacrjournals.org 12 13 Clin Cancer Res 2007;13(4) February 15, 2007 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2007 American Association for Cancer Research. Cancer Therapy: Clinical occurred in our trial, and therefore, we were unable to This phase II combination study was one of the first trials determine the MTD. However, the highest dosing regimen combining docetaxel with a then novel small molecule, and in evaluated was feasible and tolerable. The relatively small the 6 years since its design, many similar trials with a range of proportion of patients with evaluable disease makes it difficult agents have been conducted with similar problems in to draw firm conclusions about the efficacy of the combination, interpretation, i.e., is there a meaningful benefit to the addition and therefore, further investigations are warranted to determine of a novel agent to an active cytotoxic agent? Although ongoing and optimize the efficacy of docetaxel and bortezomib trials of bortezomib, in combination with other agents such as combination treatment in prostate cancer. The relatively mitoxantrone (33), may help to establish how a proteasome modest PSA response rates may be ascribed to the somewhat inhibitor could be integrated into treatment strategies, the suboptimal doses of docetaxel used (25 and 30 mg/m2/dose)in ultimate utility of the bortezomib/docetaxel combination in the subset of patients treated. advanced prostate cancer remains undefined.

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