Highlights from: The 2007 Prostate Cancer Symposium, February 22–24, 2007; Orlando, FL

Meeting Highlights Highlights from:

The 2007 Prostate Cancer Symposium February 22-24, 2007; Orlando, FL

Prepared by: Manisha Gupta, PhD; Erin Grothey Reviewed by: Tara Gibson, PhD; Oliver Sartor, MD

100

S+P P Median (Weeks) 11.1 9.7

80

FIGURE 2 SPARC: Progression-Free Survival in Intent-to-Treat Patients Who Received Previous Docetaxel Therapy (per IRC) 100

HR, 0.67; P=0.0000003 60 40 Satraplatin/Prednisone

20 Placebo/Prednisone 0

S+P P Median (Weeks) 10.1 9.1

80

Survival (%)

Platinum-based antitumor agents form the mainstay of treatment for a variety of solid tumors.1 The second-generation platinum compounds, such as carboplatin and iproplatin, have shown marginal activity in hormone-refractory prostate cancer (HRPC).2,3 Taxane-based therapies have demonstrated overall survival (OS) in patients with HRPC, but response duration is limited.4,5 As a result, numerous trials are ongoing to identify the agents that will be safe and efficacious in treatment of patients with HRPC. Satraplatin is an orally available, third-generation platinum-based agent demonstrating activity in platinum-resistant tumor models.6,7 In a phase II trial of satraplatin in HRPC, 2 of 20 patients with measurable disease had a partial response (PR) and 10 of 32 evaluable patients showed ≥ 50% decrease in prostate-specific antigen (PSA) response.8 In a randomized phase III trial conducted to evaluate the efficacy of satraplatin/prednisone compared with prednisone alone as first-line therapy, 50 patients who received the combination showed a significant prolongation

FIGURE 1 SPARC: Progression-Free Survival in Intent-to-Treat Patients (per IRC)

Survival (%)

Preliminary Results of a Phase III Randomized Trial of Satraplatin and Prednisone in Patients with Hormone-Refractory Prostate Cancer

10

20

30

40

50

60

70

80

90

40

Placebo/Prednisone 0

in progression-free survival (PFS; 5.2 months vs. 2.5 months; hazard ratio [HR], 0.5; P = 0.023).9 Recently, the results of an international, randomized, phase III trial (Satraplatin and Prednisone Against Refractory Cancer [SPARC]), conducted to assess the efficacy and safety of satraplatin/prednisone compared with prednisone alone as second-line chemotherapy in patients with HRPC were presented by Petrylak and colleagues at the 2007 Prostate Cancer Symposium in Orlando, FL.10 The international, randomized phase III SPARC trial included patients with stage D2 HRPC. After stratification by performance status, pain index, and type of disease progression (PSA only vs. others), eligible patients were randomized 2:1 to receive satraplatin (80 mg/m2 daily for 5 days every 5 weeks) plus prednisone (5 mg twice daily) or placebo /prednisone (5 mg twice daily). The primary endpoints of this trial were PFS and OS, and the secondary endpoint was time to pain progression.

Satraplatin/Prednisone

20

Weeks Abbreviation: IRC = independent review committee

HR, 0.67; P=0.0006

60

10

20

30

40

50

60

70

80

90

Weeks Abbreviation: IRC = independent review committee

Of 950 patients, 635 received satraplatin/prednisone and 315 patients received placebo/prednisone, and no crossover to the satraplatin arm was allowed. Approximately 40% of patients received ≥ 5 cycles of satraplatin. Baseline characteristics were well balanced between the 2 treatment arms, Preliminary analysis of the SPARC trial demonstrated that the PFS was significantly longer in the intent-totreat patient population receiving satraplatin/prednisone compared with those receiving prednisone alone. Patients receiving satraplatin/prednisone demonstrated 33% reduction in the relative risk of disease progression compared with those in the prednisone alone arm (Figure 1; HR, 0.67; 95% confidence interval [CI], 0.57-0.77). Patients in the satraplatin arm who had previously been treated with docetaxel also experienced a longer PFS compared with those in the placebo arm (Figure 2). Overall survival results are pending.

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Meeting Highlights

TABLE 1 SPARC: Grade 3/4 Adverse Events Satraplatin/Prednisone (n = 635)

Placebo/Prednisone (n = 315)

P Value

Neutropenia

13.7%

0.6%

< 0.001

Thrombocytopenia

21.1%

1.3%

< 0.001

Red blood cell transfusion

15.9%

8%

< 0.001

Fatigue

4.9%

2.6%

Not reported

Infectious episodes

4%

1%

0.008

Diarrhea

2.1%

0

0.007

Adverse Event Hematologic Toxicity

Nonhematologic Toxicity

Treatment-related adverse events were moderate in severity and included myelosuppression as the most common adverse event. Other grade 3/4 adverse events in the satraplatin/prednisone and placebo/ prednisone arms included neutropenia (13.7% vs. 0.6%, respectively), thrombocytopenia (21.1% vs. 1.3%), and red blood cell transfusions (15.9% vs. 8%; Table 1).

Clinical Relevance The result of the phase III SPARC trial demonstrated that satrapaltin is a clinically active oral agent with an acceptable safety profile in patients with advanced HRPC. In particular, it was observed that satraplatin significantly prolonged PFS (P < 0.0000003) in patients with HRPC, including patients refractory to previous taxane-based therapy. Myelosuppression was the most common adverse event in patients treated with satraplatin. At this time, OS results for this trial are pending.

TAX327, a Randomized Phase III Trial of Docetaxel/Prednisone in Patients with Metastatic HormoneRefractory Prostate Cancer: Updated Survival Results The Southwest Oncology Group (SWOG) 99-16 and TAX327 trials have demonstrated survival advantages and improved quality of life (QOL) in patients with metastatic HRPC.4,5 The SWOG 99-16 trial demonstrated an improved median OS time of 1.9 months (P = 0.02)

250 • Clinical

and a 50% decrease in PSA levels occurring in 50% of patients (P < 0.001) in the group receiving docetaxel/estramustine.4 The randomized phase III TAX327 trial was conducted to compare the 2 different schedules of docetaxel/prednisone with mitoxantrone/prednisone in patients with metastatic HRPC.5 The results from the TAX327 trial, reported after the protocolspecified occurrence of 557 deaths, demonstrated a prolonged median OS time of 2.4 months and improved QOL in patients receiving docetaxel/prednisone for the treatment of metastatic HRPC.5 The results from these 2 randomized phase III trials led to the approval of docetaxel as standard therapy for the treatment of patients with metastatic HRPC. Recently, an updated analysis of the entire cohort of TAX327 trial was conducted, and the results from this trial were presented by Berthold and colleagues at the 2007 Prostate Cancer Symposium in Orlando, FL.11 TAX327 was conducted from March 2000 through June 2002 and enrolled a total of 1006 men with metastatic HRPC. Patients were randomized to receive docetaxel 75 mg/m2 once every 3 weeks, docetaxel 30 mg/m2 once weekly for 5 of every 6 weeks, or mitoxantrone 12 mg/m2 once every 3 weeks. All patients received prednisone 5 mg orally twice a day. The primary endpoint of this trial was OS, and secondary endpoints were PSA response (≥ 50% decrease), alleviation of pain, and QOL. In this update of TAX327, the investigators analyzed the survival benefits based on the date of death or last follow-up of patients who were alive in August 2003.

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The results of the TAX327 study were initially reported at a median follow-up of 20.8 months for the every-3-week docetaxel/prednisone group and 20.7 months for the once-weekly docetaxel/ prednisone and mitoxantrone groups.5 The HR for death was 0.76 and 0.91 for docetaxel/prednisone and docetaxel/prednisone, respectively, compared with the mitoxantrone group. The combined HR for death in the 2 docetaxel groups was 0.83, and the survival rate for patients receiving every-3-week docetaxel/prednisone was significantly higher (P = 0.009) when compared with the mitoxantrone group. In the subgroup of patients receiving every3-week docetaxel/prednisone, 35% had a pain response compared with 22% on the mitoxantrone arm (P = 0.01), and patients receiving docetaxel demonstrated higher PSA response (45% and 48% in every3-week docetaxel and weekly docetaxel, respectively; P < 0.001) compared with patients receiving mitoxantrone. The improvement in QOL was similar between the 2 docetaxel groups (22% and 23% in every-3-week docetaxel and weekly docetaxel, respectively) compared with the mitaxantrone group (Table 2). The updated analysis of TAX327 reported an additional 283 deaths, for a total of 840 deaths in the study. The median OS was 19.3 months for patients receiving every-3-week docetaxel/ prednisone, 17.8 months for patients receiving weekly docetaxel/prednisone, and 16.3 months for the patients receiving mitoxantrone/prednisone. These updated results were not only statistically significant, but were also consistent with the initial report of TAX327 of improved survival in patients receiving every-3-week docetaxel/prednisone compared with patients receiving mitoxantrone/prednisone. The results for weekly docetaxel treatment were similar to the preliminary analysis, indicating no significant survival benefits in patients with metastatic HRPC. In the updated analysis, median OS was assessed in a variety of subgroups with the following reported as statistically significant: patients aged ≥ 69 years had a median OS of 18.9 months in the

Meeting Highlights

TABLE 2 Efficacy Results of TAX 327* Docetaxel 75 mg/m2 Every 3 Weeks (n = 335)

Docetaxel 30 mg/m2 Weekly (n = 334)

Mitoxantrone 12 mg/m2 (n = 337)

Median Survival

18.9 Months (P = 0.009; HR, 0.76)

17.4 Months (P = 0.36; HR, 0.91)

16.5 Months

Pain Response

35% (n = 153; P = 0.01)

31% (n = 154; P = 0.08)

22% (n = 157)

PSA Response

45% (n = 291; P < 0.001)

48% (n = 282; P < 0.001)

32% (n = 300)

Quality of Life

22% (n = 278; P = 0.009)

23% (n = 270; P = 0.005)

13%

Initial Analysis for TAX 3272

Updated Median Survival Results for TAX 3273 19.3 Months (P = 0.005; HR, 0.79)

17.8 Months (P = 0.1; HR, 0.87)

16.3 Months

) 69 Years

19.5 Months (n = 176; P = 0.071; HR, 0.81)

17.2 Months (n = 158; P = 0.55; HR, 0.93)

16.4 Months (n = 170)

* 69 Years

18.9 Months (n = 159; P = 0.036; HR 0.77)

18.6 Months (n = 176; P = 0.091; HR, 0.82)

15.7 Months (n = 167)

< 115 ng/mL

21.8 Months (n = 124; P = 0.12; HR, 0.83)

21.4 Months (n = 128; P = 0.048; HR, 0.78)

19.2 Months (n = 137 [84%])

* 115 ng/mL

17.5 Months (n = 149; P = 0.008; HR, 0.73)

13.4 Months (n = 141; P = 0.7; HR, 1.05)

12.8 Months (n = 154 [88.5%])

No

23 Months (n = 183; P = 0.009; HR, 0.73)

21.1 Months (n = 183; P = 0.65; HR, 0.95)

19.8 Months (n = 184)

Yes

14.9 Months (n = 152; P = 0.17; HR, 0.85)

15.1 Months (n = 151; P = 0.068; HR, 0.8)

12.8 Months (n = 153)

< 109

18.3 Months (n = 141; P = 0.002; HR, 0.66)

14.3 Months (n = 133; P = 0.075; HR, 0.79)

12.4 Months (n = 134)

* 109

19.7 Months (n = 137; P = 0.48; HR, 0.91)

19.2 Months (n = 137; P = 0.64; HR, 0.94)

20.4 Months (n = 133)

Median Survival Age

Baseline PSA Level

Pain

FACT-P Score

*All statistical analyses is relative to the mitoxantrone arm. Abbreviations: FACT-P = Functional Assessment of Cancer Therapy-Prostate; PSA = prostate-specific antigen

every-3-week docetaxel arm compared with 15.7 months in the mitoxantrone arm (P = 0.036; HR, 0.77); patients with baseline PSA ≥ 115 ng/mL was 17.5 months in the every-3-week docetaxel arm compared with 12.8 months in the mitoxantrone arm (P = 0.008; HR, 0.73); patients with baseline PSA < 115 ng/mL was 21.4 months in the weekly docetaxel arm compared with 19.2 months in the mitoxantrone arm (P = 0.048; HR, 0.78); For patients in the every-3-week docetaxel arm with no pain, the median OS was 23

months versus 19.8 months for mitoxantrone (P = 0.009; HR, 0.73) and median survival for patients who experienced improved QOL with every-3-week with a FACT-P score < 109 was 18.3 months versus 12.4 months with mitoxantrone (P = 0.002; HR, 0.66; Table 2).

Clinical Relevance The updated analyses of the TAX327 trial in patients with metastatic HRPC were consistent with the preliminary results of this randomized phase III trial. The

survival benefit for patients with metastatic HRPC receiving every-3-week docetaxel/ prednisone (19.3 months) was statistically significant compared with mitoxantrone/ prednisone (16.3 months). The updated subgroup analysis also demonstrated an improvement in RRs and QOL, with reduction in pain intensity and decrease in PSA levels for patients treated with docetaxel. Therefore, every-3-week docetaxel/prednisone remains the preferred treatment for patients with metastatic HRPC.

Safety and Efficacy Results of a Phase II Trial of Docetaxel/Capecitabine in Metastatic AndrogenIndependent Prostate Cancer Docetaxel has become the standard of care in patients with metastatic androgen-independent prostate cancer (AIPC) based on the demonstration of a statistically significant survival benefit in 2 phase III randomized trials (SWOG 99-16 and TAX327).4,5 The SWOG 9916 and TAX327 trials demonstrated a significantly improved median OS time of 1.9 months and 2.4 months, respectively, in patients with metastatic AIPC. However, there are currently no available alternate therapies for patients who do not exhibit response to taxane-based chemotherapy; therefore, several clinical trials have been initiated to evaluate the safety and efficacy of novel agents for the treatment of patients with metastatic AIPC. One such novel chemotherapeutic agent, capecitabine, an oral 5-fluorouracil prodrug, has been evaluated in patients with metastatic AIPC, resulting in a median time to progression (TTP) of 12 weeks and a decrease in PSA levels in 12% of patients.12 In a phase II trial evaluating the combination of docetaxel/ capecitabine in patients with metastatic AIPC, 41% had decreased PSA levels ≥ 50% and 54% had a demonstrable clinical benefit.13 Recently, the results of a phase II trial of docetaxel/capecitabine in metastatic AIPC were presented by Vaishampayan and colleagues at the 2007 Prostate Cancer Symposium in Orlando, FL.14

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Meeting Highlights

TABLE 3 Phase II Trial of Docetaxel/ Capecitabine: Safety Docetaxel 36 mg/m2 per Week and Capecitabine 1250 mg/m2 per Day (N = 30)

Grade 3/4 Adverse Events Neutropenia

3

Anemia

3

Diarrhea

2

Fatigue

3

Hand-Foot Syndrome

2

The phase II trial enrolled patients with metastatic AIPC to receive docetaxel 36 mg/m2 per week intravenously (I.V.) on days 1, 8, and 15 and capecitabine 1250 mg/m2 per day on days 5-18 of a 28-day cycle. The primary endpoints of this study were PSA RR and tumor RR by Response Evaluation Criteria in Solid Tumors (RECIST). The secondary endpoints included safety, PFS, TTP, and OS. The eligibility criteria included patients who were previously untreated with chemotherapy for metastatic AIPC and showed progressive disease (PD). Disease progression was measured by increasing levels of PSA (≥ 5 ng/mL) within 1 week apart or by diagnosis of new metastases. Thirty patients

TABLE 4 Phase II Trial of Docetaxel/ Capecitabine: Efficacy Docetaxel 36 mg/m2 per Week Capecitabine 1250 mg/m2 per Day (N = 30)

Efficacy

PSA Response

n = 28, %

PSA decrease * 50%

78.5

PSA decrease > 75%

46

PSA decrease > 90%

32

Measurable Disease

n = 9, %

Partial response

56

Stable disease

33

Progressive disease

11

Median TTP

9.1 Months

Median OS

18.9 Months

252 • Clinical

were accrued for this trial, with a median age of 69 years (range, 47-80 years). All patients were diagnosed with PSA progression (median PSA level, 60.6 ng/mL), and 70% (n = 21) were previously treated for bone pain. A total of 30 patients were evaluable for safety. Grade 3/4 neutropenia occurred in 3 patients, grade 3 anemia in 3 patients, grade 3 diarrhea in 2 patients, and grade 3 hand-foot syndrome in 2 patients, mostly likely because of capecitabine. Overall, docetaxel/capecitabine was well tolerated with no treatment-related deaths reported (Table 3). Of the 28 patients evaluated for overall response, 78.5% demonstrated ≥ 50% decrease in PSA levels, of whom 46% had > 75% PSA decrease and 32% had > 90% PSA decrease (Table 4). The measurable disease was assessed in 9 patients according to RECIST, demonstrating PR in 5 of 9 patients (56%), stable disease in 3 of 9 patients (33%), and PD in 1 patient (11%). The median TTP was 9.1 months and the median OS was 18.9 months.

Clinical Relevance The combination docetaxel/capecitabine was well tolerated in this phase II trial, with no unexpected toxicities reported in patients with metastatic AIPC. Further studies will continue to investigate the addition of other agents to the standard docetaxel regimen in the treatment of metastatic AIPC.15

Early Results of a Phase II Trial of Dual Antiangiogenic Agents in Combination with Docetaxel/Prednisone Advanced AIPC is marked by aggressive cell proliferation and tumor growth no longer suppressed by hormonal ablation. Treatment of AIPC with docetaxel alone is associated with decrease in PSA and reasonable objective RRs (ORRs) in patients with measurable disease.16,17 Two phase II trials have indicated that the addition of antiangiogenic agents to docetaxel improved its efficacy in this patient popula-

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tion. The addition of thalidomide, which interferes with basic fibroblast growth factor–induced angiogenesis, improved PSA decrease ≥ 50% from 37% to 53% and the 18-month survival from 42.9% to 68.2% in a randomized phase II trial design.18,19 In a single-arm phase II trial, 85% of patients with AIPC treated with docetaxel and bevacizumab, which blocks vascular endothelial growth factor–mediated angiogenesis, had ≥ 50% decrease in PSA levels and a 41% ORR in patients with measurable disease.20,21 Based on these previous trials, it was hypothesized that a combination of antiangiogenic agents, which suppress different molecular pathways that promote tumor vascularization, might improve the efficacy of docetaxel in patients with AIPC. At the 2007 Prostate Cancers Symposium, Ning and colleagues presented the results of an open-label phase II study of 60 patients with AIPC with a 2-stage MinMax design to address this question.22 The study was designed to detect a 50% PSA decrease in 80% of patients, with discontinuation if ≥ 22 of the first 33 patients did not experience 50% PSA decrease. Patients were treated with docetaxel 75 mg/m2 plus bevacizumab 15 mg/kg on day 1 every 21 days plus nightly thalidomide 200 mg per day and prednisone 10 mg per day until disease progression or unacceptable toxicity occurred. Enoxaparin 1 mg/kg per day was administered for prevention of thrombosis. The primary objectives of the study were rate and duration of PSA response. Secondary objectives included assessing OS, the relationship between agents’ pharmacokinetic profile and clinical activity or toxicity, the usefulness of dynamic magnetic resonance imaging to monitor progression of soft tissue disease, and the toxicity profile of the combination regimen. Chemotherapy-naive patients were included in the study if they had 2 consecutively increasing PSA levels (≥ 5 ng/mL), measurable disease, and/or 1 new lesion by bone scan, with progressive metastatic AIPC with castrate levels of testosterone. Increasing PSA levels were required for patients treated with previous second-

Meeting Highlights

TABLE 5 Bevacizumab/Thalidomide/ Docetaxel/Prednisone: Efficacy Efficacy Best Response: PSA PSA decrease * 50% PSA decrease>80% Measurable Disease

Percent

TABLE 6 Bevacizumab/Thalidomide/ Docetaxel/Prednisone: Significant Toxicities (n = 39) Toxicity

n = 39 87 72 n = 19

Percent

Febrile Neutropenia

13

Syncope

10

Colonic Perforation or Fistula

5 5

Complete response

5

Grade 3 Bleeding

Partial response

53

Thrombosis (Asymptomatic PEs)

5

42

Grade 2 Epiphora

8

Stable disease

ary hormonal therapy. Adequate hematologic, renal, and hepatic function and an Eastern Cooperative Oncology Group performance status of 0-2 with a life expectancy > 3 months were also required for eligibility. Patients were excluded if they had brain and/or leptomeningeal metastases, persistent high blood pressure (≥ 170/100 mmHg), or current anticoagulation therapy with coumadin, heparin, or heparinoids. A history of arterial thrombotic events within the previous 6 months, uncontrolled angina pectoris, congestive heart failure, transient ischemic attack, or cerebrovascular accident within the past 2 years excluded patients from enrollment. During stage I, 28 of the first 33 patients experienced ≥ 50% PSA decrease. A total of 39 enrolled patients were evaluated after ≥ 2 cycles, with a median of 15 cycles of treatment; PSA levels were recorded after each cycle. Basic patient characteristics included a median Gleason score of 8, median onstudy PSA of 92 ng/mL, median age of 66 years, and median pretreatment PSA doubling time of 1.6 months. Metastatic involvement in bone only was detected in 17 patients, soft tissue only in 4 patients, and both in 18 patients. In the second stage, 87% of enrolled patients experienced a ≥ 50% PSA decrease, which was maintained for a median of 13 cycles. Of particular interest, 72% of treated patients experienced a PSA decrease of > 80% (Table 5). In the 19 patients with measurable disease, 58% had an objective response and 42% had stable disease, which represented disease control in all evaluable patients. This was

Grade 2 Neuropathy

8

Grade 2 Osteonecrosis of the Jaw

15

Abbreviation: PE = pulmonary embolism

accompanied by the disappearance of lesions on multiple bone scans. Bevacizumab/thalidomide/docetaxel/ prednisone was generally well tolerated as first-line therapy for patients with AIPC (Table 6). Major adverse events reported for the study included febrile neutropenia (13%), syncope (10%), and grade 2 osteonecrosis of the jaw (15%).

Clinical Relevance This study was the first to combine bevacizumab and thalidomide (2 antiangiogenic agents functioning through different molecular mechanisms) with docetaxel/prednisone as therapy for patients with AIPC. The combination demonstrated high efficacy and tolerability in this disease setting. A total of 87% of treated patients experienced ≥ 50% decrease in PSA levels, whereas 58% exhibited an objective respsonse. The duration of ≥ 50% PSA decrease was maintained for an average of 13 cycles. This marked a notable

improvement in terms of PSA response in this previously resistant patient population. However, because of the small sample size, more patient accrual is necessary to support the findings of this initial analysis. It remains undetermined whether the considerable PSA decrease and duration will translate to a benefit in OS, and randomized trials are needed to answer this question.

A Phase II Randomized Study of Docetaxel with or Without DMXAA in Patients with Metastatic Hormone-Refractory Prostate Cancer Vascular-disrupting agents (VDAs) selectively disrupt the established tumor blood vasculature, leading to the alteration of blood flow.23 This mechanism differs from antiangiogenic agents, which prevent the formation of new tumor vasculature.24 5,6-dimethylxanthenone-4acetic acid (DMXAA) is a VDA that has demonstrated high potency and activity in various tumor xenografts in mice.25-28 Preclinical studies have demonstrated an enhancement in the antitumor activity of chemotherapeutic agents such as alkylating agents, platinum compounds, and taxanes in combination with DMXAA.29,30 This agent has been evaluated in ovarian and lung cancers in randomized phase II clinical trials.31,32 In non–small-cell lung cancer, the addition of DMXAA to the carboplatin/paclitaxel regimen has demonstrated a survival benefit of 14 months, compared with a median survival

TABLE 7 Phase II Trial of Docetaxel/DMXAA in Patients with Metastatic HRPC: Selected Adverse Events Docetaxel 75 mg/m2 plus DMXAA 1200 mg/m2 (n = 34)

Standard Therapy Docetaxel 75 mg/m2 (n = 40)

Blood and Lymphatic System

3 (9)

5 (13)

Cardiac

4 (12)

1 (3)

Gastrointestinal

3 (9)

3 (8)

General and Administration Site Disorders

2 (6)

3 (8)

Infections and Infestations

1 (3)

3 (8)

Nervous System Disorders

1 (3)

2 (5)

Vascular Disorders

1 (3)

2 (5)

Serious Adverse Events

Values in parentheses are percentages.

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Meeting Highlights

of 8.8 months with carboplatin/paclitaxel.32 Based on these encouraging results, a randomized phase II trial of docetaxel with or without DMXAA was conducted in patients with metastatic HRPC.15 Recently, the preliminary results from this trial were presented by Rosenthal and Pili at the 2007 Prostate Cancer Symposium in Orlando, FL.33 This randomized, multicenter, phase II study was conducted to compare the standard therapy of docetaxel (75 mg/m2) with docetaxel/DMXAA (docetaxel 75 mg/m2 as a 1-hour infusion followed by DMXAA 1200 mg/m2 as a 20-minute infusion). Patients with chemotherapy-naive, progressive HRPC were enrolled in this trial. For safety monitoring, 6 patients in the DMXAA arm received therapy under early discontinuation rules. Treatment was received every 21 days for 10 cycles. Patients with PD receiving standard therapy of docetaxel were allowed to cross over to the DMXAA arm (≤ 6 cycles of DMXAA alone weekly). Progressive disease was defined by RECIST or as ≥ 1 new lesion with an increased PSA level > 5 ng/mL. The objectives of this study were to compare the efficacy of DMXAA/docetaxel with docetaxel alone in patients with metastatic HRPC and to evaluate the safety and tolerability of DMXAA/docetaxel. Thirty-four of 74 patients were randomized to the DMXAA arm, and 40 patients were randomized to the standard docetaxel arm. Patient characteristics were well balanced between the 2 arms. Because of disease progression, 4 patients crossed over to DMXAA alone. Overall, the addition of DMXAA to the standard chemotherapy regimen did not appear to exacerbate serious adverse events in patients with metastatic HRPC. Serious adverse events in the treatment arms were seen in the following categories: blood and lymphatic system (3 patients in the DMXAA arm vs. 5 patients in standard therapy arm), gastrointestinal (3 patients in each arm), general and administration site disorders (2 patients vs. 3 patients, respectively), infections and infestations (1 patient vs. 3 patients), nervous system disorders (1 patient vs. 2

254 • Clinical

patients), and vascular disorders (1 patient vs. 2 patients). Serious cardiac adverse events occurred in 4 patients (12%) receiving DMXAA and in 1 patient (3%) in the standard therapy arm (Table 7). The data available from 64 patients for PSA response (≥ 50% decrease in PSA levels) demonstrated higher RRs in patients receiving DMXAA/docetaxel compared with patients receiving standard therapy (57% vs. 35%, respectively).

Clinical Relevance The results of a randomized phase II trial of docetaxel/DMXAA demonstrated improved efficacy and tolerability in patients with metastatic HRPC. The PSA RRs were higher in the DMXAA/docetaxel arm (57%) compared with the docetaxel alone arm (35%). Thus, the addition of a VDA to a standard taxane-based regimen might significantly enhance clinical benefit in patients with metastatic HRPC. The results for TTP and OS in patients with metastatic HRPC are still pending for this trial. Nevertheless, the combination of DMXAA with standard chemotherapy might demonstrate activity in patients with metastatic HRPC.

References 1. Muggia FM, Fojo T. Platinums: extending their therapeutic spectrum. J Chemother 2004; 4(suppl 16):77-82. 2. Loening SA, Beckley S, Brady MF, et al. Comparison of estramustine phosphate, methotrexate and cis-platinum in patients with advanced, hormone refractory prostate cancer. J Urol 1983; 129:1001-1006. 3. Marshall ME, Wolf MK, Crawford ED, et al. Phase II trial of CHIP for the treatment of advanced, hormonally refractory carcinoma of the prostate. A Southwest Oncology Group study. Am J Clin Oncol 1995; 18:400-402. 4. 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. 5. 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. 6. Choy H. Satraplatin: an orally available platinum analog for the treatment of cancer. Expert Rev Anticancer Ther 2006; 6:973-982. 7. Samimi G, Kishimoto S, Manorek G, et al. Novel mechanisms of platinum drug resistance identified in cells selected for resistance to JM118 the active metabolite of satraplatin. Cancer Chemother Pharmacol 2007; 59:301-312. 8. Latif T, Wood L, Connell C, et al. Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily x 5 in hormone refractory prostate cancer (HRPC). Invest New Drugs 2005; 23:79-84. 9. Sternberg CN, Whelan P, Hetherington J, et al. Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone alone in patients with hormone-

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refractory prostate cancer. Oncology 2005; 68:2-9. 10. Petrylak DP, Sartor O, Witjes F, et al. A phase III, randomized, double-blind trial of satraplatin and prednisone vs placebo and prednisone for patients with hormone refractory prostate cancer (HRPC). Presented at: the 2007 Prostate Cancer Symposium; February 22-24, 2007; Orlando, FL. Abstract #145. 11. Berthold DR, Pond G, De Wit R, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival of the TAX 327 study. Presented at: the 2007 Prostate Cancer Symposium; February 22-24, 2007; Orlando, FL. Abstract #147. 12. Morant R, Bernhard J, Dietrich D, et al. Capecitabine in hormone-resistant metastatic prostatic carcinoma - a phase II trial. Br J Cancer 2004; 90:1312-7. 13. Kolodziej M, Neubauer MA, Rousey SR, et al. Phase II trial of docetaxel/capecitabine in hormone-refractory prostate cancer. Clin Genitourin Cancer 2006; 5:155-61. 14. Vaishampayan UN, Sartucci R, Heilbrun L et al. Phase II trial of docetaxel and capecitabine combination in metastatic androgen independent prostate cancer (AIPC). Presented at: the 2007 Prostate Cancer Symposium; February 22-24, 2007; Orlando, FL. Abstract #239. 15. An Open Label, Randomized, Phase II Study of AS1404 in Combination with Docetaxel in Patients with Hormone Refractory Metastatic Prostate Cancer. Available at: http://clinicaltrials.gov/ct/show/ NCT00119275?order=39. Accessed March 27, 2007. 16. Petrylak DP. Docetaxel (Taxotere) in hormone-refractory prostate cancer. Semin Oncol 2000; 27(2 suppl 3):24-29. 17. Picus J, Schultz M. Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999; 26(5 suppl 17):14-18. 18. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4:314-322. 19. Dahut WL, Gulley JL, Arlen PM, et al. Randomized phase II trial of docetaxel plus thalidomide in androgen-independent prostate cancer. J Clin Oncol 2004; 22:2532-2539. 20. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003; 3:401-410. 21. Picus J, Halabi S, Rini B, et al. The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): initial results of CALGB 90006. Proc Am Soc Clin Oncol 2003; 22:393 (Abstract #1578). 22. Ning Y, Gulley J, Arlen P, et al. Phase II trial of thalidomide, bevacizumab, and docetaxel in patients (pts) with metastatic androgen-independent prostate cancer (AIPC). Presented at: the 2007 Prostate Cancer Symposium; February 22-24, 2007; Orlando, FL. Abstract #228. 23. Siemann DW, Chaplin DJ, Horsman MR. Vasculartargeting therapies for treatment of malignant disease. Cancer 2004; 100:2491-2499. 24. van Heeckeren WJ, Bhakta S, Ortiz J, et al. Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol 2006; 24:1485-1488. 25. Beauregard DA, Pedley RB, Hill SA, et al. Differential sensitivity of two adenocarcinoma xenografts to the anti-vascular drugs combretastatin A4 phosphate and 5,6-dimethylxanthenone-4-acetic acid, assessed using MRI and MRS. NMR Biomed 2002; 15:99-105. 26. Joseph WR, Cao Z, Mountjoy KG, et al. Stimulation of tumors to synthesize tumor necrosis factor-alpha in situ using 5,6-dimethylxanthenone-4-acetic acid: a novel approach to cancer therapy. Cancer Res 1999; 59:633-638. 27. McPhail LD, Chung YL, Madhu B, et al. Tumor dose response to the vascular disrupting agent, 5,6dimethylxanthenone-4-acetic acid, using in vivo magnetic resonance spectroscopy. Clin Cancer Res 2005; 11:3705-3713. 28. Seshadri M, Mazurchuk R, Spernyak JA, et al. Activ-

Meeting Highlights

ity of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid against human head and neck carcinoma xenografts. Neoplasia 2006; 8:534-542. 29. Pruijn FB, van Daalen M, Holford NH, et al. Mechanisms of enhancement of the antitumour activity of melphalan by the tumour-blood-flow inhibitor 5,6dimethylxanthenone-4-acetic acid. Cancer Chemother Pharmacol 1997; 39:541-546. 30. Siim BG, Lee AE, Shalal-Zwain S, et al. Marked potentiation of the antitumour activity of chemo-

therapeutic drugs by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Cancer Chemother Pharmacol 2003; 51:43-52. 31. Gabra H A-SGI. Phase II study of DMXAA combined with carboplatin and paclitaxel in recurrent ovarian cancer. J Clin Oncol 2006; 24(18 suppl):263s (Abstract #5032). 32. Von Pawel J, Reck M, McKeage M, et al. Update on survival in a phase Ib/II study of DMXAA (AS1404) combined with carboplatin and paclitaxel

in non-small cell lung cancer (NSCLC). Presented at: 18th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; Nov 7-10, 2006; Prague, Czech Republic. 33. Rosenthal M, R Pili. Randomized phase II study of docetaxel with or without DMXAA (AS1404) in hormone-refractory metastatic prostate cancer (HRMPC). Presented at: the 2007 Prostate Cancer Symposium; February 22-24, 2007; Orlando, FL. Abstract #219.

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