A Phase II Study of Estramustine, Docetaxel, and Exisulind in Patients with Hormone- Refractory Prostate Cancer: Results of Cancer and Leukemia Group B Trial 90004

Original Contribution

A Phase II Study of Estramustine, Docetaxel, and Exisulind in Patients with HormoneRefractory Prostate Cancer: Results of Cancer and Leukemia Group B Trial 90004 Nancy A. Dawson,1 Susan Halabi,2,3 San-San Ou,2 David D. Biggs,4 Anne Kessinger,5 Nicholas Vogelzang,6 Gerald H. Clamon,7 David M. Nanus,8 W. Kevin Kelly,9 Eric J. Small10; For Cancer and Leukemia Group B 1Georgetown University Medical Center, Washington, DC 2Cancer and Leukemia Group B Statistical Center, Durham, NC 3Department of Biostatistics and Bioinformatics, Duke

University Medical Center, Durham, NC 4Christiana Care Health Services, Inc. CCOP, Wilmington, DE 5University of Nebraska Medical Center, Omaha, NE 6Nevada Cancer Institute, Las Vegas 7University of Iowa Hospitals, Iowa City 8Weill Cornell Medical School, New York, NY 9Department of Medical Oncology, Yale University,

New Haven, CT 10Department of Medicine, University of California at

San Francisco

Clinical Genitourinary Cancer, Vol. 6, No. 2, 110-116, 2008 Keywords: Deep vein thrombosis, Progressionfree survival, Prostate-specific antigen, Selective apoptotic antineoplastic drug DOI: 10.3816/CGC.2008.n.017 Submitted: Oct 29, 2007; Revised: Jan 25, 2008; Accepted: Feb 22, 2008 Address for correspondence: Nancy A. Dawson, MD Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Rd NW, Washington, DC 20007-2113 Fax: 202-444-9429; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.

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Genitourinary Cancer

Abstract Purpose: Docetaxel/estramustine is a known active regimen in hormonerefractory prostate cancer (HRPC). A phase II study was conducted to assess the safety and efficacy of docetaxel/estramustine combined with exisulind, an apoptotic antineoplastic drug. Patients and Methods: Eighty men with chemotherapy-naive HRPC were enrolled in a multicenter, cooperative group study. The treatment regimen consisted of oral estramustine (280 mg 3 times daily for 5 days), docetaxel 70 mg/m2, oral exisulind (250 mg twice daily), oral dexamethasone (8 mg twice daily for 3 days), and oral warfarin (2 mg daily). Results: Seventy-five eligible patients were treated with a median of 6 cycles of therapy. Fortyseven patients (62.7%; 95% CI, 50.7%-73.6%) had a ≥ 50% decline in prostate-specific antigen levels. Forty-six patients had measurable disease with 6 partial responses (13%; 95% CI, 4.9%-26.3%). The main grade 3/4 toxicities were neutrophils (79%), fatigue (15%), and thrombosis/embolism (10%). The median time to first progression was 5.1 months (95% CI, 4.4-6.3 months) and the median survival time was 17.8 months (95% CI, 14.7-20.1 months). Conclusion: The combination of estramustine/docetaxel/exisulind was associated with significant thomboembolic toxicity despite prophylactic warfarin. The contribution of exisulind to toxicity is uncertain. Prostate-specific antigen decline, response rates, and progression-free and overall survival are similar to those reported with docetaxel/estramustine.

Introduction Prostate cancer is the second leading cause of cancer death in men in the United States.1 Although most advanced cancers initially are responsive to androgen ablation, eventually virtually all of these tumors become hormone refractory.2 Historically, prostate cancer has been considered chemotherapy resistant.3,4 However, in the past few years taxanes have emerged as an active class of drugs. In 2004, docetaxel/prednisone was FDA approved as the first regimen to prolong survival in men with hormone-refractory prostate cancer (HRPC). Compared with mitoxantrone/prednisone, docetaxel-based regimens provide a median overall survival (OS) prolongation of 2.5 months.5 Estamustine is a conjugate of nitrogen mustard and estradiol which, like docetaxel, has a mechanism of action based on microtubule inhibition.6 However, rather than stabilizing microtules, estramustine binds to microtubule-associated proteins. Preclinical studies in prostate cancer cell lines demonstrated synergistic activity for the combination of estramustine and taxanes and led to a series of phase I/II trials of estramustine/taxane–based combinations,7-12 including the first multicenter trial of docetaxel/estramustine conducted by the CALGB (Cancer and Leukemia Group B).10

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In CALGB 9780, estramustine/docetaxel/low-dose hydrocortisone was assessed. Hydrocortisone was added in anticipation of the eventual need to compare this regimen with the previously approved mitoxantrone/steroid regimen.13,14 A prostate-specific antigen (PSA) decline of ≥ 50% was observed in 68%, and 50% had an objective response in measurable disease.10 Similar results were demonstrated in the subsequent study of estramustine/docetaxel/ carboplatin (CALGB 99813).11 The preliminary results of a third trial of estramustine/docetaxel/bevacizumab (CALGB 90006) were the basis of the current randomized phase III trial of docetaxel/prednisone versus docetaxel/prednisone/bevacizumab.12 Exisulind is a selective apoptotic antineoplastic drug (SAAND) which exhibits its effects through degradation of cyclic guanosine monophosphate phosphodiesterase.15 Exisulind has been shown to induce growth inhibition in prostate cancer cell lines and in prostate cancer mouse models.16,17 This effect appears to be in part mediated by the inhibition of androgen receptor signaling.18 Further preclinical data have demonstrated synergistic or additive antitumor effects when SAANDs are combined with chemotherapy.19 In a doubleblind, placebo-controlled trial of 96 men with PSA-only recurrent cancer after radical prostatectomy, compared with placebo, exisulind significantly suppressed the increase in PSA levels in all patients (P = .017).20 In men at high risk for metastases, exisulind lengthened PSA doubling time (2.12-month increase) compared with those on placebo (3.37-month decrease; P = .048). Median change in PSA levels and median PSA doubling time were analyzed nonparametrically with the Wilcoxon rank sum test. Based on these preliminary observations, the CALGB evaluated the efficacy and toxicity of adding exisulind to the docetaxel/estramustine doublet.

Patients and Methods Eligibility Patients had histologically documented adenocarcinoma of the prostate with progressive systemic disease despite castrate levels of testosterone because of androgen deprivation therapy. Patients required either measurable disease defined according to the Response Evaluation Criteria in Solid Tumors (RECIST)21 with any PSA level or nonmeasurable disease with a PSA level of ≥ 5 ng/mL. Patients must have had evidence of progressive disease (PD) after the most recent change in therapy, defined according to the Prostate-Specific Antigen Working Group criteria.22 Patients could not have received previous chemotherapy. More than 4 weeks must have elapsed since any previous systemic therapy for their cancer, any previous major surgery or radiation therapy (RT), > 6 weeks since discontinuation of bicalutamide or nilutamide and > 8 weeks for any radiopharmaceutical treatment. Patients must have been willing to remain off chronic nonsteroidal antiinflammatory drugs, salicylates, or sulindac for the duration of the study with the exception of low-dose aspirin. Bisphosphonate therapy must have been initiated ≥ 4 weeks before initiating protocol therapy. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 was required and patients were ineligible if they had experienced myocardial infarction, congestive heart failure, change in anginal pattern, deep vein thrombosis (DVT), or pulmonary embolus within 1 year. Patients could not have a known hypersensitivity to sulindac or a clinically significant peripheral neuropathy. Baseline laboratory

values required for entry included a granulocyte count ≥ 1500/μL, a platelet count ≥ 100,000/μL, a serum creatinine level ≤ 1.5 × the upper limit of normal (ULN), an aspartate aminotransaminase level ≤ 1.5 × ULN, an alanine aminotransaminase ≤ 1.5 × ULN, a bilirubin ≤ 1 × ULN, a PSA ≥ 5 ng/mL if nonmeasurable disease and serum testosterone level of ≤ 50 ng/dL for patients who have not had a bilateral orchiectomy. The study was approved by the individual review boards of each participating institution. Signed written informed consent was obtained from all patients.

Treatment Plan Primary testicular androgen suppression with a luteinizing hormone-releasing hormone analogue was continued in all patients who had not undergone bilateral orchiectomy. Each cycle lasted 21 days. Patients received estramustine 280 mg taken orally 3 times daily (840 mg per day) on days 1-5. Estramustine was taken on an empty stomach, 1 hour before or 2 hours after meals. Docetaxel 70 mg/m2 was administered intravenously (I.V.) over 1 hour on day 2. Patients were treated with dexamethasone 8 mg orally twice daily on the day before, the day of, and the day after docetaxel. Exisulind was administered orally at a dose of 250 mg (two 125-mg capsules) twice daily at approximately the same time each day. Warfarin 2 mg daily was required in all patients for prophylaxis against thrombosis. No target international normalized ratio (INR) was required. However, if the INR was prolonged, further management of the warfarin was at the discretion of the treating physician. Treatment was continued until disease progression or unacceptable toxicity. Protocol therapy could be discontinued if a complete response (CR) was achieved. These patients could restart protocol therapy after subsequent progression. For patients who discontinued protocol treatment, all further therapy was dispensed at the discretion of the treating physician. A monthly conference call was held to monitor toxicity and included the study chair, committee chair, statistician, data coordinator, CALGB executive officer, and protocol editor.

Evaluation of Response The level of PSA was measured before each chemotherapy cycle. The reference PSA was measured within 2 weeks before starting treatment. A PSA decline was defined as a decrease in PSA value by ≥ 50% for 2 successive evaluations ≥ 4 weeks apart. Beginning of PSA decline was measured from the date of the first 50% decline in PSA and ended at the date of first PSA ≥ 50% above nadir. In addition, a minimum PSA increase of 5 ng/mL or a return to pretreatment PSA value, confirmation by a second PSA ≥ 2 weeks apart was required. In patients whose PSA did not decrease by ≥ 50%, progression was defined as an increase in PSA by 25% above either the pretreatment level or the nadir PSA level, whichever is lowest and an increase in PSA by a minimum of 5 ng/mL again with a confirmatory PSA level ≥ 2 weeks apart. Radiologic response was evaluated every 3 cycles. Complete and partial responses (PRs) and PD for measurable disease were determined according to the RECIST criteria. With a documented measurable response, confirmatory computed tomography scans were obtained ≥ 4 weeks later. For nonmeasurable disease, CR was defined as complete resolution of all osseous lesions and all nontarget lesions as evaluated by scans. Progressive disease for nonmeasur-

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Estramustine, Docetaxel, and Exisulind in Prostate Cancer

Table 1 Baseline Characteristics for Eligible Patients Enrolled

Figure 1 Kaplan-Meier Plot of Overall Survival

on CALGB 90004

Age, Years (Range)* Years Since Initial

Diagnosis*

Body Mass Index*

100

N = 75 68.9 (63.1-76.8) 4.4 (2.2-8) 27.5 (23.6-31.8)

Gleason Score of Tumor (N = 71) 5

5 (7)

6

6 (8.5)

7

18 (25.4)

8

19 (26.8)

9

19 (26.8)

10

4 (5.6)

Overall Survival (%)

Characteristic

60

40

20

0

6

12

18

24

30

36

42

2

1

48

Time (Months) Number of Patients at Risk

Ethnicity

75

White

58 (77.3)

Black

15 (20)

Other

2 ( 2.7)

Visceral

19 (25.3)

Bone

63 (84)

Soft tissue

9 (12)

Lymph node

40 (53.3)

Other

4 (5.3)

Any

75 (100) 46 (61.3)

Nonmeasurable disease

29 (38.7)

ECOG Performance Status 0

33 (44)

1

38 (50.7)

2

4 (5.3)

Laboratory Values* PSA, ng/mL

157 (70.8-361)

Hemoglobin, g/dL

12 (11.3-13.1)

Creatinine, mg/dL

1 (0.8-1.2)

Alkaline phosphatase, U/L (N = 72)

111 (86-195)

Testosterone, ng/dL (N = 72)

20 (11.2-27.5)

Previous Therapy† Prostatectomy

34 (45.3)

Radiation

44 (58.7)

Orchiectomy (N = 74)

11 (14.9)

Hormonal therapy (N = 74)

73 (98.6)

Values in parentheses are percentages unless otherwise indicated. *Median (interquartile range). †Patients may have had > 1 previous therapy.

Genitourinary Cancer

52

35

20

10

Statistical Design and Data Analysis

Disease Measurability Measurable disease

68

able disease was defined as PSA progression or the appearance of ≥ 2 new lesions on bone scan not felt to be consistent with a tumor flare or the appearance of new metastatic lesions outside of bone or unequivocal progression of nontarget lesions or the need for RT. If there was discordance between the PSA level and other manifestations of systemic disease (eg, normalization or decrease in PSA level and worsening of the bone scan or measurable disease), the patient was considered to have PD.

Site of Disease

112 • Clinical

80

The primary endpoints of this study were time to objective progression and response rates (RRs; objective and PSA). Objective progression-free survival (PFS) was defined as the interval between treatment initiation and the date of objective progression or death, whichever occurred first. Sample size computation was based on the primary endpoint, time to objective progression. The null hypothesis is that the median time to objective progression is ≤ 11 months, and the alternative hypothesis is the median time to objective progression is ≥ 16 months (45% increase) in patients treated with estramustine/docetaxel/bevacizumab. The normal approximation to the exact exponential test was used for sample size computation and the following assumptions were made: type I error rate, 0.05; power = 89% (type II error rate, 11%); accrual rate of 4 patients per month over a 18-month accrual period; a 24-month follow-up period; and the time to objective progression follows an exponential distribution. Under the alternative hypothesis, 55 progression events were expected at the end of the trial. Toxicity was an important secondary endpoint with a hypothesized null hypothesis that the acceptable toxicity probability was ≤ 0.8 versus the alternative hypothesis that acceptable toxicity probability was ≥ 0.9. Interim analysis to assess toxicity without suspension of accrual was performed using a 3-stage design after 15 patients, 35 patients, and 72 patients were enrolled on the trial and underwent 1 cycle of treatment. The decision rules for continuation of accrual and having an open trial required ≥ 11 of 15 patients, ≥ 27 of 35 patients, and

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Nancy A. Dawson et al ≥ 62 of 72 patients did not experience unacceptable Table 2A Summary of Adverse Events (N = 75) toxicity. This design has a type I error rate of 0.1 and a type II error rate of 0.11. Grade of Adverse Event Toxicity, n (%) Unacceptable toxicity was defined as either 1-2 3-Severe 4-LT 5-Lethal death or grade 4 febrile neutropenia or any serious Hematologic Adverse Event grade 3/4 toxicity, excluding nausea, vomiting, alopecia, or hypersensitivity. For the purpose of Hemoglobin 65 (86.7) 6 (8) 1 (1.3) 0 this study, a “serious” toxicity was defined as carNeutrophils/granulocytes 7 (9.3) 17 (22.7) 42 (56) 0 (ANC/AGC) diac, thrombosis/embolism, central nervous system hemorrhage/bleeding, and febrile neutropenia. If Platelets 20 (26.7) 0 0 0 at any time during the study, the observed proporNonhematologic Adverse Event tion of unacceptable toxicity as defined previously Allergic reaction/hypersensitivity 4 (5.3) 1 (1.3) 0 0 exceeded 15% by ≥ 1 standard error, accrual was to Supraventricular and nodal arrhythmia 2 (2.7) 1 (1.3) 0 0 be immediately suspended to the trial. Cardiac ischemia/infarction 0 0 0 1 (1.3) Other endpoints considered were PFS, PSA PFS, Supraventricular arrhythmias OS, duration of objective response, and duration of 1 (1.3) 1 (1.3) 1 (1.3) 0 PSA decline. Progression-free survival was defined as Cardiovascular (general other) 0 1 (1.3) 0 1 (1.3) the interval between treatment initiation and the date Hypotension 13 (17.3) 2 (2.7) 0 0 of disease progression (bone, PFS, and soft tissue) Fatigue (asthenia, lethargy, malaise) 45 (60) 11 (14.7) 0 0 or death, whichever occurred first. Prostate-specific Fever (in the absence of neutropenia) 6 (8) 0 0 0 antigen PFS was defined as time to first biochemical Hair loss/alopecia (scalp or body) 45 (60) 0 0 0 progression using the PSA consensus criteria or death, whichever occurred first. Overall survival was defined Abbreviations: AGC = absolute granulocyte count; ANC = absolute neutophil count; as interval between treatment initiation and the date LT = life-threatening of death. Duration of response was defined as the date of the first CR or PR to the date that the patient had disease progresResponse to Therapy sion. Duration of PSA response was interval between date from the The median number of cycles of treatment was 6 (inter-quartile first 50% decline in PSA to the date when the patient met the criteria range, 3-10 cycles). Forty-seven of 75 patients (62.7%; 95% CI, for disease progression. The 95% confidence interval for the objective 50.7%-73.6%) had a ≥ 50% posttherapy PSA decline. The median RR was computed based on the binomial distribution. Overall survival, time to posttherapy PSA decline of ≥ 50% was 4.2 months (95% objective PFS, PSA PFS, and PFS distributions were estimated using CI, 3.5-5.9 months). Of the 46 patients with measurable disease, 6 the Kaplan-Meier product-limit method.23 (13%; 95% CI, 4.9%-26.3%) achieved a PR. The median duration of As part of the quality assurance program of the CALGB, members response was 19 months (95% CI, 12.6-24.7 months). of the Audit Committee visit all participating institutions at least once every 3 years to review source documents. The auditors verify comClinical Outcomes: Progression-Free Survival and pliance with federal regulations and protocol requirements, includOverall Survival ing those pertaining to eligibility, treatment, adverse events, tumor The median time to any progression (PSA, bone progression, response, and outcome in a sample of protocols at each institution. measurable disease progression, or death) was 5.1 months (95% Such onsite review of medical records was performed for a subgroup CI, 4.4-6.3 months). The time to first PSA progression or death of 39 of the 80 patients (48.8%) under this study. Patient registration was 6.9 months (95% CI, 5.5-8.1 months). Time to objective and data collection were managed by the CALGB Statistical Center. PFS, measured in the 46 patients with measurable disease, was Data quality was ensured by careful review of data by CALGB Sta13.1 months (95% CI, 9.6-18.9 months). Fifty-eight of 63 patients tistical Center staff and by the study chairperson. Statistical analyses (92%) died of prostate cancer since registration. The median folwere performed by CALGB statisticians. low-up time for the surviving patients was 28.8 months (95% CI, 24-32 months). The median survival time was 17.8 months (95% Results CI, 14.7-20.1 months; Figure 1). Between December 2002 and January 2004, 80 patients were enrolled in this multiinstitutional study. Five patients were subseToxicity quently found to be ineligible: no pre-study testosterone level (n = 2), Toxicity data are available for all 75 patients (Table 2). Two patestosterone > 50 ng/dL (n = 1), DVT < 1 month before enrollment tients died during treatment. One patient had a myocardial infarction (n = 1), and no demonstrable metastatic disease (n = 1). All eligible felt to be secondary to preexisting cardiac disease and 1 patient had patients were assessable for response and toxicity. Baseline charactera sudden cardiac arrest on day 12 of treatment. The most common istics are presented in Table 1. The median age was 68.9 years (intergrade 3/4 toxicities were neutrophils (78.7%), fatigue (14.7%), infecquartile range, 63.1-76.8 years). Ninety-five percent of men had an tion (12%), thrombosis/embolism (10.6%), nausea (9.3%), vomiting ECOG PS of 0/1. The majority of patients had bone metastases and (9.3%), hyperglycemia (9.3%), hyponatremia (8%), and pain (8%). 61.3% had measurable disease. Four patients (5.3%) had febrile neutropenia. Three patients had

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Estramustine, Docetaxel, and Exisulind in Prostate Cancer Discussion

Table 2B Summary of Adverse Events (N = 75)

Improving the treatment of HRPC has presented a particularly difficult challenge for inToxicity, n (%) vestigators focusing on this disease. For decades, 1-2 3-Severe 4-LT 5-Lethal chemotherapy was labeled as ineffective. Although Nonhematologic Adverse Events the combination mitoxantrone/prednisone was Nail changes 21 (28) 1 (1.3) 0 0 FDA approved based on superior palliation of bone pain compared with prednisone alone, it Wound (infectious) 1 (1.3) 1 (1.3) 0 0 did not prolong survival duration.13 Compared Anorexia 29 (38.7) 3 (4) 0 0 with mitoxantrone/prednisone, both docetaxel/ Constipation 16 (21.3) 1 (1.3) 0 0 prednisone and docetaxel/estramustine improved Dehydration 11 (14.7) 3 (4) 0 0 survival, establishing the new standard of care Diarrhea (patients without colostomy) 25 (33.3) 2 (2.7) 0 0 against which new treatments and combinations Heartburn/dyspepsia 8 (10.7) 1 (1.3) 0 0 should be compared.13,24 One common strategy used in clinical trials has been the addition of a Mucositis/stomatitis 12 (16) 1 (1.3) 0 0 third agent in the phase II setting with the anNausea 46 (61.3) 7 (9.3) 0 0 ticipation that promising and well-tolerated triplet Taste disturbance 12 (16) 0 0 0 therapies would lead to randomized phase III trials Vomiting 20 (26.7) 7 (9.3) 0 0 to determine effect on survival. Selecting the best Epistaxis 5 (6.7) 0 0 0 third drugs to assess survival outcomes has been Hematuria one aspect of the challenge. Based on preclinical 3 (4) 1 (1.3) 0 0 and clinical data in prostate cancer, exisulind was Bilirubin 14 (18.7) 0 0 0 deemed an appropriate candidate drug to add to Febrile neutropenia 0 4 (5.3) 0 0 the docetaxel/estramustine doublet. Infection 0 9 (12) 0 0 In a phase I trial of exisulind in patients with Infection without neutropenia 10 (13.3) 4 (5.3) 0 0 familial adenomatous polyposis, dose-limiting Alanine aminotransaminase 20 (26.7) 4 (5.3) 0 0 toxicity was reversible hepatic transaminitis with Aspartate aminotransaminase additional common grade 1/2 toxicities being 21 (28) 4 (5.3) 0 0 headache, nausea, vomiting, dyspepsia, diarrhea, Hypocalcemia 27 (36) 3 (4) 1 (1.3) 0 and abdominal pain.25 The maximum tolerated Creatinine 10 (13.3) 0 0 0 dose in patients with subtotal colectomies was Hyperglycemia 46 (61.3) 6 (8) 1 (1.3) 0 300 mg twice daily. Based on preclinical activity, Hypophosphatemia 0 3 (4) 1 (1.3) 0 exisulind (250 mg twice daily) was then assessed Muscle weakness 3 (4) 3 (4) 0 0 in a randomized, placebo-controlled trial of men with recurrent prostate cancer after prostatectomy, Confusion 4 (5.3) 0 1 (1.3) 0 with no evidence of metastases.20 Exisulind sigDizziness 10 (13.3) 0 0 0 nificantly suppressed the rise in PSA in all patients, Mood alteration 6 (8) 3 (4) 0 0 which was most pronounced in men at high risk Neuropathy (sensory) 27 (36) 4 (5.3) 0 0 for metastases (P = .0003). Somnolence 1 (1.3) 0 1 (1.3) 0 Again in preclinical models, exisulind was comTearing 6 (8) 0 0 0 bined with taxanes and demonstrated synergistic effects in lung cancer cell and animal models.19 Dyspnea 13 (17.3) 0 1 (1.3) 0 Phase I dose escalation and pharmacokinetic studCough 9 (12) 1 (1.3) 0 0 ies of docetaxel/exisulind in advanced solid tumors, Pleural effusion (nonmalignant) 2 (2.7) 2 (2.7) 0 0 demonstrated mild to moderate adverse events Thrombosis/thrombus/embolism 0 4 (5.3) 4 (5.3) 0 with exisulind (150-250 mg twice daily) and docetaxel (30-36 mg/m2 I.V. on days 1, 8, and 15 Abbreviation: LT = life-threatening of a 28-day cycle).26 In a small, phase I/II dose-escalation study of exisulind and docetaxel in patients with HRPC, the recommended phase II dose was determined to be supraventricular arrhythmias (1 patient had atrial flutter, 1 patient exisulind 250 mg twice daily and docetaxel 60 mg/m2 with escalation had atrial fibrillation, and in 1 patient, the arrhythmia was not further to 75 mg/m2 after cycle 1 was tolerated.27 A dose of 70 mg/m2 was characterized). Overall, 81% of patients had grade 3/4 hematologic selected for this trial. toxicity, and 73% had grade 3-5 nonhematologic toxicity. The reaAlthough preclinical and clinical data in prostate cancer demsons for treatment cessation were disease progression or death during onstrated that exisulind was promising in prostate cancer and that treatment (n = 39; 52%), adverse events (n = 18; 24%), refusal of combination with docetaxel was both synergistic and well tolerated, further treatment, or physician choice (n = 18; 24%).

Grade of Adverse Event

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Nancy A. Dawson et al the results from this study showed no obvious benefit for this triplet regimen over the docetaxel/estramustine combination. Subsequent published results from the phase I/II dose escalation study and a subsequent phase II trial of docetaxel/exisulind suggested that at least this doublet was no better than docetaxel alone.27,28 In the former study, final analysis showed that only 4 of 17 evaluable patients (23.5%; 95% CI, 10%-47%) treated at the recommended phase II dose demonstrated a > 50% decline in PSA level.27 In the phase II trial of exisulind 250 mg orally given twice daily and weekly docetaxel at a dose of 35 mg/m2 for 4 weeks followed by 2 weeks of rest, only 3 of 14 patients (21.4%) had a 50% decline in PSA that lasted ≥ 4 weeks.28 Unfortunately, even agents with evidence of drug activity in > 33% of preclinical models have at best a 50% chance of consistently positive phase II clinical trial outcome.29 While the relative contribution to toxicity of each of the components of the tested triplet cannot be ascertained, the toxicity demonstrated in this trial supports the abandonment of the estramustine/ docetaxel combination. The 10% rate of thrombosis/pulmonary embolism, attributed to the estramustine is unacceptably high, because of the similar survival benefit attributed to docetaxel and prednisone, where this complication was not reported in the recently completed large phase III trial.5 It does not appear that the exisulind increased the incidence of thrombosis because other reported trials building on the docetaxel/estramustine backbone had similar rates of thrombosis. In both CALGB trials 9780 and 99813, a 7% incidence of grade 3/4 thrombosis was reported.10,11 The use of prophylactic warfarin was intended to mitigate this complication. However, in a large randomized trial of docetaxel/estramustine versus mitoxantrone/prednisone, the incidence of thrombosis or embolism was not reduced when prophylactic anticoagulation was added midstudy.24

Conclusion In summary, in the current study of docetaxel/estramustine/exisulind, clinical outcomes are similar to what have been reported with the docetaxel/estramustine combination alone and for docetaxel/ prednisone. The significant thrombotic complications and significant neutropenia support not only the abandonment of this regimen, but also the docetaxel/estramustine combination favoring the use of a docetaxel/prednisone backbone for future clinical trials in HRPC. This experience also points out the importance of conducting carefully designed phase II trials before embarking on larger and costly phase III trials.

Acknowledgements The research for CALGB 90004 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, chairman) and to the CALGB Statistical Center (Stephen George, PhD, CA33601). The content of this paper is solely the responsibility of the authors, and does not necessarily represent the official views of the National Cancer Institute. The research for CALGB 90004 was also partly supported by OSI Pharmaceuticals, Inc (previously Cell Pathways, Inc.) and sanofi-aventis. The following institutions participated in the study: Cancer and Leukemia Group B Statistical Office, Durham, NC (Stephen George, PhD, supported by Grant CA33601); Christiana Care

Health Services, Inc. (Stephen S. Grubbs, MD, supported by Grant CA45418); Covenant Health System- Covenant Clinic; Dana-Farber Cancer Institute, Boston, MA (Eric P. Winer, MD, supported by Grant CA32291); Dartmouth Medical School-North Cotton Cancer Center, Lebanon, NH (Marc S. Ernstoff, MD, supported by Grant CA04326) Georgetown University Medical Center, Lombardi Cancer Center, Washington, DC (Minetta C. Liu, MD, supported by Grant CA77597); Hematology Oncology Associates of Central New York, Syracuse, NY (Jeffrey Kirshner, MD, supported by Grant CA45389); Kansas City Community Clinical Oncology Program, Kansas City, MO (Rakesh Gaur, MD); Memorial Sloan-Kettering Cancer Center, New York, NY (Clifford A. Hudis, MD, supported by Grant CA04457); Nevada Cancer Research Foundation (John A. Ellerton, MD, supported by Grant CA35421); North Shore University Hospital, Manhasset, NY (Daniel R. Budman, MD, supported by Grant CA35279); Southeast Cancer Control Consortium, Inc, WinstonSalem, NC (James N. Atkins, MD, supported by Grant CA45808); The Ohio State University Medical Center, Columbus, OH (Clara D. Bloomfield, MD, supported by Grant CA77658); University of California at San Diego, San Diego, CA (Joanne E. Mortimer, MD, supported by Grant CA11789); University of California at San Francisco, San Francisco, CA (Alan P. Venook, MD, supported by Grant CA60138); University of Chicago, Chicago, IL (Gini Fleming, MD, supported by Grant CA41287); University of Illinois at Chicago, Chicago, IL (Lawrence E. Feldman, MD, supported by Grant CA74811) University of Iowa, Iowa City, IA (Gerald H. Clamon, MD, supported by Grant CA47642); University of Maryland Cancer Center, Baltimore, MD (Martin J. Edelman, MD, supported by Grant CA31983); University of Minnesota, Minneapolis, MN (Bruce A. Peterson, MD, supported by Grant CA16450); University of Nebraska Medical Center (Anne Kessinger, MD, supported by Grant CA77298); University of North Carolina at Chapel Hill, Chapel Hill, NC (Thomas C. Shea, MD, supported by Grant CA47559); University of Vermont, Burlington, VT (Hyman B. Muss, MD, supported by Grant CA77406); Washington University School of Medicine, St. Louis, MO (Nancy L. Bartlett, MD, supported by Grant CA77440); Weill Medical College of Cornell University, New York, NY (John Leonard, MD, supported by Grant CA07968); Western Pennsylvania Hospital, Pittsburgh, PA (Richard K. Shadduck, MD).

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