- Email: [email protected]
Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer
original article
Annals of Oncology 20: 1264–1269, 2009 doi:10.1093/annonc/mdn784 Published online 17 March 2009
Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer C. N. Sternberg1*, H. Dumez2, H. Van Poppel3, I. Skoneczna4, A. Sella5, G. Daugaard6, T. Gil7, J. Graham8, P. Carpentier9, F. Calabro1, L. Collette10 & D. Lacombe10 for the EORTC Genitourinary Tract Cancer Group 1
Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy; Departments of 2Oncology and 3Urology, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; 4Chemotherapy Unit, Department of Urology, Maria Sklodowska–Curie Memorial Cancer Centre, Warsaw, Poland; 5Department of Oncology, Assaf Harofeh Medical Center, Zerifin, Israel; 6Department of Oncology, Rigshospitalet, Copenhagen, Denmark; 7Department of Chemotherapy, Institut Jules Bordet, Brussels, Belgium; 8Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK; 9Department of Urology, Onze Lieve Vrouw Ziekenhuis, Aalst, Belgium and 10EORTC Headquarters, Brussels, Belgium
Received 11 September 2008; revised 3 December 2008; accepted 15 December 2008
original article
Background: This randomized, phase II study assessed the activity of oblimersen sodium, a Bcl-2 antisense oligonucleotide, administered before docetaxel (Taxotere) to patients with castration-resistant prostate cancer. Patients and methods: Chemotherapy-naive patients with prostate-specific antigen (PSA) progression and testosterone £0.5 ng/ml received docetaxel 75 mg/m2 on day 1 or oblimersen 7 mg/kg/day continuous i.v. infusion on days 1–7 with docetaxel 75 mg/m2 on day 5 every 3 weeks for £12 cycles. Primary end points were confirmed PSA response (Bubley criteria) and major toxic events. Results: Confirmed PSA response was observed in 46% and 37% of 57 and 54 patients treated with docetaxel and docetaxel–oblimersen, respectively. Partial response (RECIST) was achieved in 18% and 24%, respectively. Oblimersen added to docetaxel was associated with an increase in the incidence of grade ‡3 fatigue, mucositis, and thrombocytopenia. Major toxic events were reported in 22.8% and 40.7% of patients with docetaxel and docetaxel– oblimersen, respectively. Conclusions: The primary end points of the study were not met: a rate of confirmed PSA response >30% and a major toxic event rate <45% were not observed with docetaxel–oblimersen. Key words: chemotherapy, castration-resistant prostate cancer, docetaxel, oblimersen sodium, phase II clinical trial, targeted therapy
introduction Prostate cancer is the second most common cancer in men worldwide. It is a heterogeneous disease group including patient cohorts with differing expected survival times. The term ‘hormone-refractory prostate cancer’ is often used interchangeably with other terms to describe relapse after hormonal ablation therapy, such as androgen-independent prostate cancer and castration-resistant prostate cancer (CRPC). Two large landmark randomized phase III studies (TAX 327 and SWOG 9916) have demonstrated a survival benefit and *Correspondence to: Dr C. N. Sternberg, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Nuovi Padiglioni, 4th Floor, Circonvallazione Gianicolense 87, 00152 Rome, Italy. Tel: +39 06 58704356; Fax: +39 06 6630771; E-mail: [email protected]
pain palliation with docetaxel-based chemotherapy for patients with metastatic CRPC [1, 2], setting a new standard of care for this disease [3]. These data have recently been updated [4]. However, new therapeutic modalities are clearly required for patients receiving androgen deprivation therapy who have disease progression and to improve upon the advances that have been achieved with chemotherapy. Adding to docetaxelbased chemotherapy is one possible avenue in which progress could be achieved. Bcl-2 overexpression, which is observed in a high percentage of patients with CRPC, impedes apoptosis and has a critical role in the transition from androgen-dependent to androgenindependent tumor growth [5]. This protein contributes to resistance to docetaxel [6, 7]. The current phase II study was initiated in an effort to enhance the efficacy of docetaxel in CRPC by combining the agent with oblimersen, a fully
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
phosphorothioated antisense oligonucleotide that selectively down-regulates Bcl-2 protein expression. Previous phase I and II trials of oblimersen as a chemosensitizing agent before docetaxel therapy have yielded promising results [8–10]. In this phase II randomized multinational study, the biologic antitumor activity [based on confirmed prostate-specific antigen (PSA) response] and safety of docetaxel plus oblimersen were evaluated among CRPC patients. A docetaxelalone treatment group was included in the study design for validation. This trial is registered with ClinicalTrials.gov with number NCT00085228.
patients and methods patient selection criteria Eligible patients were to have histologically proven prostate adenocarcinoma and evidence of PSA progression under prior hormonal treatment with luteinizing hormone–releasing hormone (LH–RH) analogues or orchiectomy and antiandrogens. Baseline PSA progression was documented by a sequence of two increased PSA levels over a reference value taken ‡1 week before the first increase [11]. PSA measurements were to be obtained ‡6 weeks after withdrawal from antiandrogen therapy. Because of the difficulty of interpreting PSA changes at lower values, a PSA level of ‡5 ng/ml was required £1 week before randomization. Additional selection criteria were as follows: age ‡18 years; World Health Organization performance status of two or less; castrate testosterone level of £0.5 ng/ml; adequate hematologic, liver, and renal function; and adequate coagulation parameters. Patients were excluded if they had clinical evidence of brain metastases; painful or destructive bone metastases for which radiation therapy, bisphosphonates, or bone-seeking radionuclides were required; daily intake of high-dose opioid analgesics; prior treatment with chemotherapy, boneseeking radionuclides, or radiotherapy involving >25% of marrowproducing area (although prior use of estramustine or bisphosphonates was allowed); or hormonal manipulation with PC-SPES £6 weeks before study entry. Also excluded were patients with known contraindication for any of the study drugs. All patients provided written informed consent according to the International Conference on Harmonisation/Good Clinical Practice and national regulations. The protocol was reviewed and approved by the Ethics Committee in each institution and was conducted in accordance with the Declaration of Helsinki.
treatment Patients were centrally randomized at the European Organisation for Research and Treatment of Cancer (EORTC) Headquarters using a minimization technique [12] stratifying for institution, presence of metastatic (M1) measurable disease according to RECIST [13], prior use of estramustine, and prior use of bisphosphonates. Protocol treatment was to be initiated £15 days after randomization. In arm A, docetaxel (Taxotere) 75 mg/m2 was given as an i.v. infusion (plus standard premedication with dexamethasone or equivalent) over 60 min on day 1 of each cycle. In arm B, oblimersen 7 mg/kg/day was given by continuous i.v. infusion on days 1–7 and docetaxel 75 mg/m2 was administered as in arm A on day 5 of each cycle, consistent with the regimen of Tolcher et al. In particular, oblimersen administration preceded docetaxel administration by 5 days to achieve down-regulation of Bcl-2 and was continued for 2 days after docetaxel administration to allow adequate coexposure of the two study agents [10]. Oblimersen was administered through a central venous catheter or peripherally inserted central catheter via an ambulatory infusion pump. Treatment was to continue every 3 weeks for £12 cycles, unless the
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following withdrawal criteria were met: PSA progression [11], objective clinical progression (RECIST) [13], excessive toxicity, or patient refusal to continue therapy. The oblimersen dose was not to be adjusted. For patients with treatment-related hematologic or specific non-hematologic toxic effects (i.e. nausea with vomiting, skin changes, or liver function abnormalities), protocol therapy was to be delayed for £2 weeks. Upon recovery, docetaxel dose was to be lowered by 1 dose level at the start of the subsequent cycle. A maximum of 2 dose reductions (from 75 to 60 mg/m2 and from 60 to 45 mg/m2) was allowed. With other non-hematologic toxic effects, protocol therapy was to be delayed, but docetaxel dose was not to be reduced. No cycle was to be initiated unless absolute neutrophil count (ANC) was ‡1500 cells/mm3, platelet count was ‡100 000 cells/mm3, aspartate aminotransferase and alanine aminotransferase returned to £1.5· upper limit of normal (ULN), bilirubin returned to £ULN, skin toxicity resolved to grade £1, and all other toxic effects resolved to grade £2. All non-orchiectomized patients were required to continue therapy with LH–RH agonist. Growth factor support was allowed for recovery of white blood cell count in grade 4 leukopenia or neutropenia or grade 3 or 4 neutropenia with infection. Diuretic treatment was recommended, along with potassium supplementation, as appropriate, to manage docetaxelinduced edema at its early stages. Other ancillary therapy and supportive care were to be administered, as indicated.
evaluations Baseline evaluations included medical history, physical examination, performance status, laboratory tests, electrocardiography, and scans. Hematologic tests were carried out £2 days before treatment start, weekly during therapy, and every 8 weeks until objective progression during follow-up. At the end of each cycle and every 8 weeks during follow-up until objective progression, assessments were to include physical examination, performance status, serum chemistry, adverse events (scored by International Common Toxicity Criteria version 3.0, http:// ctep.info.nih.gov/reporting/ctc.html), and serum PSA (with repeated measures ‡4 weeks after the first observation of response or progression). Every three cycles and every 16 weeks during follow-up until objective progression, chest X-rays were to be carried out in all patients and bone scan and computed tomography or magnetic resonance imaging were to be carried out, as appropriate, among those patients who had measurable disease at baseline or who were presenting with signs/symptoms suggestive of metastases. After progression, patients were to be followed for survival until death or lost to follow-up.
statistical methods and end points The trial was designed according to the one-stage Bryant and Day design [14] with two coprimary end points: confirmed PSA response [11] and the rate of major toxic events. Confirmed PSA response [11] was defined as a 50% decrease of PSA level from baseline that persisted for ‡4 weeks (as determined by two consecutive measurements). A major toxic event was defined as any of (i) grade 4 (Common Toxicity Criteria version 3.0) hematologic and non-hematologic toxicity, except asymptomatic grade 4 neutropenia (ANC < 500/mm3) lasting <7 days; (ii) grade 3 febrile neutropenia for >5 days or any grade 4 febrile neutropenia; (iii) grade 3 or 4 sepsis; (iv) grade 3 or 4 bleeding associated with grade >2 thrombocytopenia (<50 000/mm3); (v) grade 3 or 4 renal toxicity (serum creatinine level >3· ULN or need for dialysis); (vi) discontinuation of protocol therapy due to unacceptable toxicity; or (vii) death at least possibly due to toxicity. The sample size was determined to ensure 90% power of rejecting the null hypothesis that, within the docetaxel–oblimersen group, either the PSA response rate was £30% or the major toxic event rate was ‡45% at the onesided 10% significance level, under the alternative that the PSA response
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Table 1. Baseline characteristics
Table 2. Protocol and concomitant therapy Docetaxel (N = 57)
Age, years, n (%) <65 65–69 70–74 ‡75 Median Range Associated chronic disease, n (%) Yes Unknown WHO performance status, n (%) 0 1 2 Presence of metastases, n (%) Yes Measurable lesions at entry Sum of longest diameter in target lesionsa, mm Median Range Type of progression, n (%) PSA only PSA + bone lesions PSA + visceral lesions PSA + bone + visceral lesions Prior estramustine therapy, n (%) Yes Prior bisphosphonate therapy, n (%) Yes Daily low-dose opioid intake, n (%) Yes Confirmed PSA level, ng/ml Median Range Pretreatment LDH, n (%) £ULN >ULN Unknown
Docetaxel– oblimersen (N = 54)
19 (33) 11 (19) 15 (26) 12 (21) 69 43–82
29 (54) 12 (22) 6 (11) 7 (13) 64 54–84
25 (44) 1 (2)
29 (54) 0 (0)
34 (60) 22 (39) 1 (2)
32 (59) 20 (37) 2 (4)
54 (95) 28 (52)
50 (93) 21 (42)
56 10–235
175 2–155
3 21 9 24
(5) (37) (16) (42)
4 22 6 22
(7) (41) (11) (41)
13 (23)
14 (26)
18 (32)
13 (24)
2 (4)
6 (11)
86 7–2766
99 10–2469
39 (68) 17 (30) 1 (2)
38 (70) 13 (24) 3 (6)
Number of cycles Median Range Docetaxel treatment duration, days Median Range Oblimersen treatment duration, days Median Range Docetaxel relative dose intensity, % Median Range Oblimersen relative dose intensity, % Median Range Patients with one or more treatment cycle delayed ‡4 days, n (%) Number of cycles with delays ‡4 days per patient Median Range Number of patients with at least one docetaxel schedule modification, n (%) Number of patients with docetaxel dose reduction, n (%), mg/m2 To 60 To 45 Number of patients with oblimersen schedule modificationb, n (%) Number of patients with concomitant therapy, n (%) Antiemetics Growth factors Continued with LH–RH analoguesa
Docetaxel (N = 57)
Docetaxel– oblimersen (N = 54)
8 1213
6 1212
167 20–286
133 202287
N/A
134 202288
98 67–107
N/A
93 68–107
21 (37)
97 12–112 25 (46)
1 1–3 6 (11)
2 1–4 11 (20)
12 (21) 6 (11) N/A
15 (28) 5 (9) 10 (19)
35 (61) 9 (16) 51 (90)
39 (72) 14 (26) 47 (87)
a
Data were based on 28 and 21 patients in respective treatment groups who had measurable lesions at study entry. WHO, World Health Organization; PSA, prostate-specific antigen; LDH, baseline lactate dehydrogenase; ULN, upper limit of normal.
A total of 51 and 47 patients in respective treatment groups were receiving treatment with LH–RH analogues at baseline. b Oblimersen infusion was interrupted £12 h in all 10 patients, mostly because of technical reasons. LH–RH, luteinizing hormone–releasing hormone.
rate was ‡50% and the toxicity rate was £25%. According to this design, the study required that 51 patients in each treatment group be included in the per-protocol population of eligible patients who started the allocated treatment. A treatment arm was declared sufficiently active and safe if the 80% exact confidence interval (CI) around the PSA response rate excluded
30% and that around the major toxic event rate excluded 45%. Exact 95% CIs are also presented. PSA progression was defined according to the 1999 Bubley recommendations [11] Time to progression (TTP) was counted from the day of randomization to the day of PSA progression, objective progression, or death due to progression and is presented in Kaplan–Meier curves [15].
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a
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Figure 1. Waterfall plot of maximum prostate-specific antigen (PSA) reduction from baseline.
Figure 2. Time to progression.
results patient characteristics A total of 115 patients (57 in the docetaxel and 58 in the docetaxel–oblimersen group) were enrolled from April 2004 to January 2006 at 15 centers. Four patients in the docetaxel– oblimersen group did not initiate protocol therapy (two were ineligible and two had early progression).
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At baseline, >90% of patients in each group had bone and/or visceral metastases (Table 1). Median Gleason score at diagnosis was 8 (range 5210) in both groups. Several differences in baseline characteristics were observed between treatment groups (Table 1). In the docetaxel–oblimersen group versus the docetaxel group, patients were younger (54% versus 33%, respectively, <65 years of age) and had a greater extent of measurable disease, greater PSA elevation, increased daily
doi:10.1093/annonc/mdn784 | 1267
original article opioid intake, and more associated chronic diseases (particularly hypertension or other cardiovascular disease).
treatment Protocol therapy was generally administered as specified by protocol (Table 2). Patients in the docetaxel group received a median of eight cycles and those in the docetaxel–oblimersen group received a median of six cycles. The median relative dose intensity of docetaxel was 98% in the docetaxel group (range 67%– 107%) and 93% in the combination treatment group (range 68%– 107%). The relative dose intensity of oblimersen was 97% (range 12%–112%). Docetaxel dose reductions were attributed to toxicity (particularly neutropenia in both groups) among 18 (32%) and 20 (37%) patients in corresponding groups. efficacy Confirmed PSA response was observed in 26 (46%) patients in the docetaxel group (80% CI 36.5% to 55.0% and 95% CI 32.4% to 59.3%) and 20 (37%) in the docetaxel–oblimersen group (80% CI 28.2% to 46.7% and 95% CI 24.3% to 51.3%). The true PSA response rate of 30% could thus not be rejected by the results in the docetaxel–oblimersen group. A waterfall plot of the maximum decline in PSA is displayed in Figure 1 as recommended in the Prostate Cancer Clinical Trials Working Group 2 [16]. In those patients with measurable disease according to RECIST [13], a partial objective response was achieved in 5 of 28 (18%) patients in the docetaxel group and 5 of 21 (24%) patients in the docetaxel–oblimersen group. Stable disease was evident in 13 (46%) and nine (43%) patients, respectively. TTP defined according to the Bubley criteria [11] is presented in Figure 2. When the updated criteria of PSA progression were applied [16], the results were essentially similar, with medians of 6.3 and 4.2 months without and with oblimersen, respectively. safety One death in each group was attributed to toxicity: multiorgan failure from typhlitis and septic shock in the docetaxel group and Klebsiella pneumonia in the docetaxel–oblimersen group. Protocol therapy was discontinued early for eight (14%) and 12 (22%) patients in the corresponding groups due to toxicity. No pattern in either group was discernible with respect to adverse events associated with discontinuation. Grade ‡3 adverse events during protocol therapy were generally balanced between treatment groups. The docetaxel– oblimersen treatment was associated with an increase in the incidence of grade ‡3 fatigue, mucositis, and decreases in platelet count; docetaxel alone was associated with an increase in the incidence of grade 3 elevations in alkaline phosphatase (Table 3). Major toxic events were reported for 13 patients (22.8%) in the docetaxel group (80% CI 15.7% to 31.5% and 95% CI 12.7% to 35.8%) and 22 patients (40.7%) in the docetaxel– oblimersen group (80% CI 31.6% to 50.4% and 95% CI 27.6% to 55.0%). The results thus fail to show that the true major toxic event rate is <45% with docetaxel–oblimersen.
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Table 3. Grade ‡3 non-hematologic and hematologic adverse events during protocol therapy in ‡5% of patients in either treatment group
Fatigue Fever Diarrhea Mucositis Febrile neutropenia Infection Thrombosis Leukopenia Neutropenia Thrombocytopenia Alkaline phosphatase increased Hypocalcemia
Docetaxel (N = 57), n (%)
Docetaxel–oblimersen (N = 54), n (%)
1 0 3 1 8 9 0 33 48 0 7
7 3 5 5 7 9 3 32 43 6 2
(2) (0) (5) (2) (14) (16) (0) (58) (84) (0) (12)
5 (9)
(13) (6) (9) (9) (13) (17) (6) (59) (79) (11) (4)
7 (13)
Adverse events and laboratory values were assessed using the International Common Toxicity Criteria (version 3.0) scoring system.
discussion This is the first randomized phase II trial to evaluate the concept of lowering Bcl-2 before docetaxel therapy in CRPC. Baseline prognostic variables in this study suggest a population with advanced disease. Although grade ‡3 adverse events during protocol therapy were generally balanced between treatment groups, the overall safety profile of the combination treatment was worse than that of docetaxel alone. Based on the relatively small cohorts, docetaxel–oblimersen treatment was associated with an increased incidence of fatigue, mucositis, and hematological toxicity; docetaxel alone was associated with an increased incidence of grade 3 elevations in alkaline phosphatase. Major toxic events as defined by the protocol were reported for 40.7% of patients treated with the combination and 22.8% treated with docetaxel alone, reflecting the increased myelosuppression of the combination. We did not achieve a rate of confirmed PSA response >30% in our study, despite the fact that overexpression of Bcl-2 protein has been documented in CRPC [9]. As apoptotic failure may result from molecular mechanisms other than Bcl-2 overexpression, patients with CRPC most likely to benefit from the addition of oblimersen to chemotherapy will be those in whom chemoresistance is due to overexpression of this protein [9]. How such patients can be identified in the clinical setting has yet to be determined. Consistent with the literature, this study highlights the importance of identifying a target population of patients who may benefit from antisense therapy with oblimersen. In a randomized phase III study of advanced melanoma, patients with normal baseline lactate dehydrogenase (LDH) (£1.1· ULN) achieved maximum benefit from combination therapy with dacarbazine and oblimersen; this treatment effect was not observed in patients with elevated baseline LDH [17]. This randomized phase II study was designed to evaluate whether Bcl-2 antisense therapy could improve upon the results
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achievable with docetaxel alone in CRPC. That the benefit of this therapy in patients with advanced disease was not shown supports that further study of this combination treatment in a population so generally defined as in our study is not warranted. Further study in patients with CRPC and less advanced disease should be considered.
funding Genta Incorporated and Sanofi-Aventis (formerly Aventis Pharmaceuticals).
acknowledgements Oblimersen and docetaxel were supplied by Genta Incorporated (Berkeley Heights, NJ) and Sanofi-Aventis (Bridgewater, NJ), respectively. We are grateful to the patients who participated in the trial, investigators and institutions listed below and the EORTC Headquarter staff who supported the trial (Christine de Balincourt, project manager, Steven Deleu, data manager, and Je´roˆme Rapion for support with the statistical analysis). Centers and investigators not listed as coauthors and who contributed to the study include: Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium (A. T. Van Oosterom); Academisch Medisch Centrum, Amsterdam, The Netherlands (Th. M. de Reijke); Kaiser Franz Joseph Hospital, Vienna, Austria (M. De Santis); Universiteit Gent, Gent, Belgium (A. Verbaeys); Centre Hospitalier Re´gional de Grenoble—La Tronche, Grenoble, France (F. Ringeisen); Hospital General Vall’ d’Hebron, Barcelona, Spain (J. Bellmunt, now at Hospital del Mar, Barcelona); Klinikum Kassel, Kassel, Germany (P. Albers); and Hospital do Desterro, Lisboa, Portugal (F. Calais-da-Silva).
references 1. Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513–1520. 2. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–1512.
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original article 3. Calabro` F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007; 51(1): 17–26. 4. Berthold DR, Pond GR, Soban F et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008; 26(2): 242–245. 5. Gleave ME, Miayake H, Goldie J et al. Targeting bcl-2 gene to delay androgenindependent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology 1999; 54: 36–46. 6. Goodin S, Rao KV, DiPaola RS. State-of-the-art treatment of metastatic hormone-refractory prostate cancer. Mayo Clinic hematology/oncology reviews: part II. Oncologist 2002; 7: 360–370. 7. Pienta KJ, Smith DC. Advances in prostate cancer chemotherapy: a new era begins. CA Cancer J Clin 2005; 55: 300–318. 8. Tolcher AW. Preliminary phase I results of G3139 (bcl-2 antisense oligonucleotide) therapy in combination with docetaxel in hormone-refractory prostate cancer. Semin Oncol 2001; 28 (4 Suppl 15): 67–70. 9. Tolcher AW, Kuhn J, Schwartz G et al. A phase I pharmacokinetic and biological correlative study of oblimersen sodium (Genasense, G3139), an antisense oligonucleotide to the Bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 2004; 10: 5048–5057. 10. Tolcher AW, Chi K, Kuhn J et al. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormonerefractory prostate cancer. Clin Cancer Res 2005; 11: 3854–3861. 11. Bubley GJ, Carducci M, Dawson N et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17(11): 3461–3467; with erratum in J Clin Oncol 2000; 18(13): 2644. 12. Freedman JS, White SJ. On the use of Pocock and Simon’s method for balancing treatment numbers over prognostic factors in the controlled clinical trial. Biometrics 1976; 32: 691–694. 13. Therasse P, Arbuck SG, Eisenhauer E et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3): 205–216. 14. Bryant J, Day R. Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics 1995; 51: 1372–1383. 15. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 16. Scher HI, Halabi S, Tanock I et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Party. J Clin Oncol 2008; 7: 1148–1159. 17. Bedikian AY, Millward M, Pehamberger H et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma. J Clin Oncol 2006; 24: 4738–4745.
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Annals of Oncology 20: 1264–1269, 2009 doi:10.1093/annonc/mdn784 Published online 17 March 2009
Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer C. N. Sternberg1*, H. Dumez2, H. Van Poppel3, I. Skoneczna4, A. Sella5, G. Daugaard6, T. Gil7, J. Graham8, P. Carpentier9, F. Calabro1, L. Collette10 & D. Lacombe10 for the EORTC Genitourinary Tract Cancer Group 1
Department of Medical Oncology, San Camillo and Forlanini Hospitals, Rome, Italy; Departments of 2Oncology and 3Urology, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium; 4Chemotherapy Unit, Department of Urology, Maria Sklodowska–Curie Memorial Cancer Centre, Warsaw, Poland; 5Department of Oncology, Assaf Harofeh Medical Center, Zerifin, Israel; 6Department of Oncology, Rigshospitalet, Copenhagen, Denmark; 7Department of Chemotherapy, Institut Jules Bordet, Brussels, Belgium; 8Beatson West of Scotland Cancer Centre, Gartnavel General Hospital, Glasgow, UK; 9Department of Urology, Onze Lieve Vrouw Ziekenhuis, Aalst, Belgium and 10EORTC Headquarters, Brussels, Belgium
Received 11 September 2008; revised 3 December 2008; accepted 15 December 2008
original article
Background: This randomized, phase II study assessed the activity of oblimersen sodium, a Bcl-2 antisense oligonucleotide, administered before docetaxel (Taxotere) to patients with castration-resistant prostate cancer. Patients and methods: Chemotherapy-naive patients with prostate-specific antigen (PSA) progression and testosterone £0.5 ng/ml received docetaxel 75 mg/m2 on day 1 or oblimersen 7 mg/kg/day continuous i.v. infusion on days 1–7 with docetaxel 75 mg/m2 on day 5 every 3 weeks for £12 cycles. Primary end points were confirmed PSA response (Bubley criteria) and major toxic events. Results: Confirmed PSA response was observed in 46% and 37% of 57 and 54 patients treated with docetaxel and docetaxel–oblimersen, respectively. Partial response (RECIST) was achieved in 18% and 24%, respectively. Oblimersen added to docetaxel was associated with an increase in the incidence of grade ‡3 fatigue, mucositis, and thrombocytopenia. Major toxic events were reported in 22.8% and 40.7% of patients with docetaxel and docetaxel– oblimersen, respectively. Conclusions: The primary end points of the study were not met: a rate of confirmed PSA response >30% and a major toxic event rate <45% were not observed with docetaxel–oblimersen. Key words: chemotherapy, castration-resistant prostate cancer, docetaxel, oblimersen sodium, phase II clinical trial, targeted therapy
introduction Prostate cancer is the second most common cancer in men worldwide. It is a heterogeneous disease group including patient cohorts with differing expected survival times. The term ‘hormone-refractory prostate cancer’ is often used interchangeably with other terms to describe relapse after hormonal ablation therapy, such as androgen-independent prostate cancer and castration-resistant prostate cancer (CRPC). Two large landmark randomized phase III studies (TAX 327 and SWOG 9916) have demonstrated a survival benefit and *Correspondence to: Dr C. N. Sternberg, Department of Medical Oncology, San Camillo and Forlanini Hospitals, Nuovi Padiglioni, 4th Floor, Circonvallazione Gianicolense 87, 00152 Rome, Italy. Tel: +39 06 58704356; Fax: +39 06 6630771; E-mail: [email protected]
pain palliation with docetaxel-based chemotherapy for patients with metastatic CRPC [1, 2], setting a new standard of care for this disease [3]. These data have recently been updated [4]. However, new therapeutic modalities are clearly required for patients receiving androgen deprivation therapy who have disease progression and to improve upon the advances that have been achieved with chemotherapy. Adding to docetaxelbased chemotherapy is one possible avenue in which progress could be achieved. Bcl-2 overexpression, which is observed in a high percentage of patients with CRPC, impedes apoptosis and has a critical role in the transition from androgen-dependent to androgenindependent tumor growth [5]. This protein contributes to resistance to docetaxel [6, 7]. The current phase II study was initiated in an effort to enhance the efficacy of docetaxel in CRPC by combining the agent with oblimersen, a fully
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
phosphorothioated antisense oligonucleotide that selectively down-regulates Bcl-2 protein expression. Previous phase I and II trials of oblimersen as a chemosensitizing agent before docetaxel therapy have yielded promising results [8–10]. In this phase II randomized multinational study, the biologic antitumor activity [based on confirmed prostate-specific antigen (PSA) response] and safety of docetaxel plus oblimersen were evaluated among CRPC patients. A docetaxelalone treatment group was included in the study design for validation. This trial is registered with ClinicalTrials.gov with number NCT00085228.
patients and methods patient selection criteria Eligible patients were to have histologically proven prostate adenocarcinoma and evidence of PSA progression under prior hormonal treatment with luteinizing hormone–releasing hormone (LH–RH) analogues or orchiectomy and antiandrogens. Baseline PSA progression was documented by a sequence of two increased PSA levels over a reference value taken ‡1 week before the first increase [11]. PSA measurements were to be obtained ‡6 weeks after withdrawal from antiandrogen therapy. Because of the difficulty of interpreting PSA changes at lower values, a PSA level of ‡5 ng/ml was required £1 week before randomization. Additional selection criteria were as follows: age ‡18 years; World Health Organization performance status of two or less; castrate testosterone level of £0.5 ng/ml; adequate hematologic, liver, and renal function; and adequate coagulation parameters. Patients were excluded if they had clinical evidence of brain metastases; painful or destructive bone metastases for which radiation therapy, bisphosphonates, or bone-seeking radionuclides were required; daily intake of high-dose opioid analgesics; prior treatment with chemotherapy, boneseeking radionuclides, or radiotherapy involving >25% of marrowproducing area (although prior use of estramustine or bisphosphonates was allowed); or hormonal manipulation with PC-SPES £6 weeks before study entry. Also excluded were patients with known contraindication for any of the study drugs. All patients provided written informed consent according to the International Conference on Harmonisation/Good Clinical Practice and national regulations. The protocol was reviewed and approved by the Ethics Committee in each institution and was conducted in accordance with the Declaration of Helsinki.
treatment Patients were centrally randomized at the European Organisation for Research and Treatment of Cancer (EORTC) Headquarters using a minimization technique [12] stratifying for institution, presence of metastatic (M1) measurable disease according to RECIST [13], prior use of estramustine, and prior use of bisphosphonates. Protocol treatment was to be initiated £15 days after randomization. In arm A, docetaxel (Taxotere) 75 mg/m2 was given as an i.v. infusion (plus standard premedication with dexamethasone or equivalent) over 60 min on day 1 of each cycle. In arm B, oblimersen 7 mg/kg/day was given by continuous i.v. infusion on days 1–7 and docetaxel 75 mg/m2 was administered as in arm A on day 5 of each cycle, consistent with the regimen of Tolcher et al. In particular, oblimersen administration preceded docetaxel administration by 5 days to achieve down-regulation of Bcl-2 and was continued for 2 days after docetaxel administration to allow adequate coexposure of the two study agents [10]. Oblimersen was administered through a central venous catheter or peripherally inserted central catheter via an ambulatory infusion pump. Treatment was to continue every 3 weeks for £12 cycles, unless the
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following withdrawal criteria were met: PSA progression [11], objective clinical progression (RECIST) [13], excessive toxicity, or patient refusal to continue therapy. The oblimersen dose was not to be adjusted. For patients with treatment-related hematologic or specific non-hematologic toxic effects (i.e. nausea with vomiting, skin changes, or liver function abnormalities), protocol therapy was to be delayed for £2 weeks. Upon recovery, docetaxel dose was to be lowered by 1 dose level at the start of the subsequent cycle. A maximum of 2 dose reductions (from 75 to 60 mg/m2 and from 60 to 45 mg/m2) was allowed. With other non-hematologic toxic effects, protocol therapy was to be delayed, but docetaxel dose was not to be reduced. No cycle was to be initiated unless absolute neutrophil count (ANC) was ‡1500 cells/mm3, platelet count was ‡100 000 cells/mm3, aspartate aminotransferase and alanine aminotransferase returned to £1.5· upper limit of normal (ULN), bilirubin returned to £ULN, skin toxicity resolved to grade £1, and all other toxic effects resolved to grade £2. All non-orchiectomized patients were required to continue therapy with LH–RH agonist. Growth factor support was allowed for recovery of white blood cell count in grade 4 leukopenia or neutropenia or grade 3 or 4 neutropenia with infection. Diuretic treatment was recommended, along with potassium supplementation, as appropriate, to manage docetaxelinduced edema at its early stages. Other ancillary therapy and supportive care were to be administered, as indicated.
evaluations Baseline evaluations included medical history, physical examination, performance status, laboratory tests, electrocardiography, and scans. Hematologic tests were carried out £2 days before treatment start, weekly during therapy, and every 8 weeks until objective progression during follow-up. At the end of each cycle and every 8 weeks during follow-up until objective progression, assessments were to include physical examination, performance status, serum chemistry, adverse events (scored by International Common Toxicity Criteria version 3.0, http:// ctep.info.nih.gov/reporting/ctc.html), and serum PSA (with repeated measures ‡4 weeks after the first observation of response or progression). Every three cycles and every 16 weeks during follow-up until objective progression, chest X-rays were to be carried out in all patients and bone scan and computed tomography or magnetic resonance imaging were to be carried out, as appropriate, among those patients who had measurable disease at baseline or who were presenting with signs/symptoms suggestive of metastases. After progression, patients were to be followed for survival until death or lost to follow-up.
statistical methods and end points The trial was designed according to the one-stage Bryant and Day design [14] with two coprimary end points: confirmed PSA response [11] and the rate of major toxic events. Confirmed PSA response [11] was defined as a 50% decrease of PSA level from baseline that persisted for ‡4 weeks (as determined by two consecutive measurements). A major toxic event was defined as any of (i) grade 4 (Common Toxicity Criteria version 3.0) hematologic and non-hematologic toxicity, except asymptomatic grade 4 neutropenia (ANC < 500/mm3) lasting <7 days; (ii) grade 3 febrile neutropenia for >5 days or any grade 4 febrile neutropenia; (iii) grade 3 or 4 sepsis; (iv) grade 3 or 4 bleeding associated with grade >2 thrombocytopenia (<50 000/mm3); (v) grade 3 or 4 renal toxicity (serum creatinine level >3· ULN or need for dialysis); (vi) discontinuation of protocol therapy due to unacceptable toxicity; or (vii) death at least possibly due to toxicity. The sample size was determined to ensure 90% power of rejecting the null hypothesis that, within the docetaxel–oblimersen group, either the PSA response rate was £30% or the major toxic event rate was ‡45% at the onesided 10% significance level, under the alternative that the PSA response
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Table 1. Baseline characteristics
Table 2. Protocol and concomitant therapy Docetaxel (N = 57)
Age, years, n (%) <65 65–69 70–74 ‡75 Median Range Associated chronic disease, n (%) Yes Unknown WHO performance status, n (%) 0 1 2 Presence of metastases, n (%) Yes Measurable lesions at entry Sum of longest diameter in target lesionsa, mm Median Range Type of progression, n (%) PSA only PSA + bone lesions PSA + visceral lesions PSA + bone + visceral lesions Prior estramustine therapy, n (%) Yes Prior bisphosphonate therapy, n (%) Yes Daily low-dose opioid intake, n (%) Yes Confirmed PSA level, ng/ml Median Range Pretreatment LDH, n (%) £ULN >ULN Unknown
Docetaxel– oblimersen (N = 54)
19 (33) 11 (19) 15 (26) 12 (21) 69 43–82
29 (54) 12 (22) 6 (11) 7 (13) 64 54–84
25 (44) 1 (2)
29 (54) 0 (0)
34 (60) 22 (39) 1 (2)
32 (59) 20 (37) 2 (4)
54 (95) 28 (52)
50 (93) 21 (42)
56 10–235
175 2–155
3 21 9 24
(5) (37) (16) (42)
4 22 6 22
(7) (41) (11) (41)
13 (23)
14 (26)
18 (32)
13 (24)
2 (4)
6 (11)
86 7–2766
99 10–2469
39 (68) 17 (30) 1 (2)
38 (70) 13 (24) 3 (6)
Number of cycles Median Range Docetaxel treatment duration, days Median Range Oblimersen treatment duration, days Median Range Docetaxel relative dose intensity, % Median Range Oblimersen relative dose intensity, % Median Range Patients with one or more treatment cycle delayed ‡4 days, n (%) Number of cycles with delays ‡4 days per patient Median Range Number of patients with at least one docetaxel schedule modification, n (%) Number of patients with docetaxel dose reduction, n (%), mg/m2 To 60 To 45 Number of patients with oblimersen schedule modificationb, n (%) Number of patients with concomitant therapy, n (%) Antiemetics Growth factors Continued with LH–RH analoguesa
Docetaxel (N = 57)
Docetaxel– oblimersen (N = 54)
8 1213
6 1212
167 20–286
133 202287
N/A
134 202288
98 67–107
N/A
93 68–107
21 (37)
97 12–112 25 (46)
1 1–3 6 (11)
2 1–4 11 (20)
12 (21) 6 (11) N/A
15 (28) 5 (9) 10 (19)
35 (61) 9 (16) 51 (90)
39 (72) 14 (26) 47 (87)
a
Data were based on 28 and 21 patients in respective treatment groups who had measurable lesions at study entry. WHO, World Health Organization; PSA, prostate-specific antigen; LDH, baseline lactate dehydrogenase; ULN, upper limit of normal.
A total of 51 and 47 patients in respective treatment groups were receiving treatment with LH–RH analogues at baseline. b Oblimersen infusion was interrupted £12 h in all 10 patients, mostly because of technical reasons. LH–RH, luteinizing hormone–releasing hormone.
rate was ‡50% and the toxicity rate was £25%. According to this design, the study required that 51 patients in each treatment group be included in the per-protocol population of eligible patients who started the allocated treatment. A treatment arm was declared sufficiently active and safe if the 80% exact confidence interval (CI) around the PSA response rate excluded
30% and that around the major toxic event rate excluded 45%. Exact 95% CIs are also presented. PSA progression was defined according to the 1999 Bubley recommendations [11] Time to progression (TTP) was counted from the day of randomization to the day of PSA progression, objective progression, or death due to progression and is presented in Kaplan–Meier curves [15].
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a
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Figure 1. Waterfall plot of maximum prostate-specific antigen (PSA) reduction from baseline.
Figure 2. Time to progression.
results patient characteristics A total of 115 patients (57 in the docetaxel and 58 in the docetaxel–oblimersen group) were enrolled from April 2004 to January 2006 at 15 centers. Four patients in the docetaxel– oblimersen group did not initiate protocol therapy (two were ineligible and two had early progression).
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At baseline, >90% of patients in each group had bone and/or visceral metastases (Table 1). Median Gleason score at diagnosis was 8 (range 5210) in both groups. Several differences in baseline characteristics were observed between treatment groups (Table 1). In the docetaxel–oblimersen group versus the docetaxel group, patients were younger (54% versus 33%, respectively, <65 years of age) and had a greater extent of measurable disease, greater PSA elevation, increased daily
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original article opioid intake, and more associated chronic diseases (particularly hypertension or other cardiovascular disease).
treatment Protocol therapy was generally administered as specified by protocol (Table 2). Patients in the docetaxel group received a median of eight cycles and those in the docetaxel–oblimersen group received a median of six cycles. The median relative dose intensity of docetaxel was 98% in the docetaxel group (range 67%– 107%) and 93% in the combination treatment group (range 68%– 107%). The relative dose intensity of oblimersen was 97% (range 12%–112%). Docetaxel dose reductions were attributed to toxicity (particularly neutropenia in both groups) among 18 (32%) and 20 (37%) patients in corresponding groups. efficacy Confirmed PSA response was observed in 26 (46%) patients in the docetaxel group (80% CI 36.5% to 55.0% and 95% CI 32.4% to 59.3%) and 20 (37%) in the docetaxel–oblimersen group (80% CI 28.2% to 46.7% and 95% CI 24.3% to 51.3%). The true PSA response rate of 30% could thus not be rejected by the results in the docetaxel–oblimersen group. A waterfall plot of the maximum decline in PSA is displayed in Figure 1 as recommended in the Prostate Cancer Clinical Trials Working Group 2 [16]. In those patients with measurable disease according to RECIST [13], a partial objective response was achieved in 5 of 28 (18%) patients in the docetaxel group and 5 of 21 (24%) patients in the docetaxel–oblimersen group. Stable disease was evident in 13 (46%) and nine (43%) patients, respectively. TTP defined according to the Bubley criteria [11] is presented in Figure 2. When the updated criteria of PSA progression were applied [16], the results were essentially similar, with medians of 6.3 and 4.2 months without and with oblimersen, respectively. safety One death in each group was attributed to toxicity: multiorgan failure from typhlitis and septic shock in the docetaxel group and Klebsiella pneumonia in the docetaxel–oblimersen group. Protocol therapy was discontinued early for eight (14%) and 12 (22%) patients in the corresponding groups due to toxicity. No pattern in either group was discernible with respect to adverse events associated with discontinuation. Grade ‡3 adverse events during protocol therapy were generally balanced between treatment groups. The docetaxel– oblimersen treatment was associated with an increase in the incidence of grade ‡3 fatigue, mucositis, and decreases in platelet count; docetaxel alone was associated with an increase in the incidence of grade 3 elevations in alkaline phosphatase (Table 3). Major toxic events were reported for 13 patients (22.8%) in the docetaxel group (80% CI 15.7% to 31.5% and 95% CI 12.7% to 35.8%) and 22 patients (40.7%) in the docetaxel– oblimersen group (80% CI 31.6% to 50.4% and 95% CI 27.6% to 55.0%). The results thus fail to show that the true major toxic event rate is <45% with docetaxel–oblimersen.
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Table 3. Grade ‡3 non-hematologic and hematologic adverse events during protocol therapy in ‡5% of patients in either treatment group
Fatigue Fever Diarrhea Mucositis Febrile neutropenia Infection Thrombosis Leukopenia Neutropenia Thrombocytopenia Alkaline phosphatase increased Hypocalcemia
Docetaxel (N = 57), n (%)
Docetaxel–oblimersen (N = 54), n (%)
1 0 3 1 8 9 0 33 48 0 7
7 3 5 5 7 9 3 32 43 6 2
(2) (0) (5) (2) (14) (16) (0) (58) (84) (0) (12)
5 (9)
(13) (6) (9) (9) (13) (17) (6) (59) (79) (11) (4)
7 (13)
Adverse events and laboratory values were assessed using the International Common Toxicity Criteria (version 3.0) scoring system.
discussion This is the first randomized phase II trial to evaluate the concept of lowering Bcl-2 before docetaxel therapy in CRPC. Baseline prognostic variables in this study suggest a population with advanced disease. Although grade ‡3 adverse events during protocol therapy were generally balanced between treatment groups, the overall safety profile of the combination treatment was worse than that of docetaxel alone. Based on the relatively small cohorts, docetaxel–oblimersen treatment was associated with an increased incidence of fatigue, mucositis, and hematological toxicity; docetaxel alone was associated with an increased incidence of grade 3 elevations in alkaline phosphatase. Major toxic events as defined by the protocol were reported for 40.7% of patients treated with the combination and 22.8% treated with docetaxel alone, reflecting the increased myelosuppression of the combination. We did not achieve a rate of confirmed PSA response >30% in our study, despite the fact that overexpression of Bcl-2 protein has been documented in CRPC [9]. As apoptotic failure may result from molecular mechanisms other than Bcl-2 overexpression, patients with CRPC most likely to benefit from the addition of oblimersen to chemotherapy will be those in whom chemoresistance is due to overexpression of this protein [9]. How such patients can be identified in the clinical setting has yet to be determined. Consistent with the literature, this study highlights the importance of identifying a target population of patients who may benefit from antisense therapy with oblimersen. In a randomized phase III study of advanced melanoma, patients with normal baseline lactate dehydrogenase (LDH) (£1.1· ULN) achieved maximum benefit from combination therapy with dacarbazine and oblimersen; this treatment effect was not observed in patients with elevated baseline LDH [17]. This randomized phase II study was designed to evaluate whether Bcl-2 antisense therapy could improve upon the results
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achievable with docetaxel alone in CRPC. That the benefit of this therapy in patients with advanced disease was not shown supports that further study of this combination treatment in a population so generally defined as in our study is not warranted. Further study in patients with CRPC and less advanced disease should be considered.
funding Genta Incorporated and Sanofi-Aventis (formerly Aventis Pharmaceuticals).
acknowledgements Oblimersen and docetaxel were supplied by Genta Incorporated (Berkeley Heights, NJ) and Sanofi-Aventis (Bridgewater, NJ), respectively. We are grateful to the patients who participated in the trial, investigators and institutions listed below and the EORTC Headquarter staff who supported the trial (Christine de Balincourt, project manager, Steven Deleu, data manager, and Je´roˆme Rapion for support with the statistical analysis). Centers and investigators not listed as coauthors and who contributed to the study include: Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium (A. T. Van Oosterom); Academisch Medisch Centrum, Amsterdam, The Netherlands (Th. M. de Reijke); Kaiser Franz Joseph Hospital, Vienna, Austria (M. De Santis); Universiteit Gent, Gent, Belgium (A. Verbaeys); Centre Hospitalier Re´gional de Grenoble—La Tronche, Grenoble, France (F. Ringeisen); Hospital General Vall’ d’Hebron, Barcelona, Spain (J. Bellmunt, now at Hospital del Mar, Barcelona); Klinikum Kassel, Kassel, Germany (P. Albers); and Hospital do Desterro, Lisboa, Portugal (F. Calais-da-Silva).
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original article 3. Calabro` F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007; 51(1): 17–26. 4. Berthold DR, Pond GR, Soban F et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008; 26(2): 242–245. 5. Gleave ME, Miayake H, Goldie J et al. Targeting bcl-2 gene to delay androgenindependent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology 1999; 54: 36–46. 6. Goodin S, Rao KV, DiPaola RS. State-of-the-art treatment of metastatic hormone-refractory prostate cancer. Mayo Clinic hematology/oncology reviews: part II. Oncologist 2002; 7: 360–370. 7. Pienta KJ, Smith DC. Advances in prostate cancer chemotherapy: a new era begins. CA Cancer J Clin 2005; 55: 300–318. 8. Tolcher AW. Preliminary phase I results of G3139 (bcl-2 antisense oligonucleotide) therapy in combination with docetaxel in hormone-refractory prostate cancer. Semin Oncol 2001; 28 (4 Suppl 15): 67–70. 9. Tolcher AW, Kuhn J, Schwartz G et al. A phase I pharmacokinetic and biological correlative study of oblimersen sodium (Genasense, G3139), an antisense oligonucleotide to the Bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 2004; 10: 5048–5057. 10. Tolcher AW, Chi K, Kuhn J et al. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormonerefractory prostate cancer. Clin Cancer Res 2005; 11: 3854–3861. 11. Bubley GJ, Carducci M, Dawson N et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17(11): 3461–3467; with erratum in J Clin Oncol 2000; 18(13): 2644. 12. Freedman JS, White SJ. On the use of Pocock and Simon’s method for balancing treatment numbers over prognostic factors in the controlled clinical trial. Biometrics 1976; 32: 691–694. 13. Therasse P, Arbuck SG, Eisenhauer E et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92(3): 205–216. 14. Bryant J, Day R. Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics 1995; 51: 1372–1383. 15. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481. 16. Scher HI, Halabi S, Tanock I et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Party. J Clin Oncol 2008; 7: 1148–1159. 17. Bedikian AY, Millward M, Pehamberger H et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma. J Clin Oncol 2006; 24: 4738–4745.
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