Progressive Castrate Metastatic Prostate Cancer Research Articles

Phase I study of docetaxel (Tax) and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC)

5001 Background: Tax prolongs survival in patients (pts) with CMPC. Early clinical data suggest that Tax combined with bone seeking radiopharmaceuticals may improve survival relative to chemotherapy alone. 153Sm-lexidronam (Sm) (Quadramet, Cytogen Corp.) is a radiopharmaceutical with a 46.3 hour T1/2 and a favorable toxicity profile. Methods: Pts with progressive CMPC are treated in cohorts of 3–6. Prior treatment with taxanes is permissible. Cohorts are defined by dose escalations of: Tax 65, 70, 75, 75, 75 mg/m2 and Sm 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle is 6 weeks, except cohort 6, which explores a q9 week cycle for Sm. Tax is given day 1 and 22 and Sm day -1 to 1 of each cycle. DLT is defined as cycle 1 ≥ grade 3 non-hematologic toxicity, grade 3 neutropenia that lasts for >29 days, or grade 3–4 anemia or thrombocytopenia of ≥ 5 days. Pts with an ANC of grade 0–1 or platelet count (PLT) of >100,000/mm3 at the end of cycle 1 may receive additional cycles. Pts are treated until progression or toxicity. Results: 28 pts have received 81 cycles (mean 2.9, range 1–6/pt) in 6 cohorts to date. 6 pts were treated in cohorts 2, 5, and 6. As anticipated, toxicities have primarily been hematologic (Table 1). Six pts came off study for prolonged thrombocytopenia; to date, 3 have not recovered. 1 pt in cohort 6 experienced a DLT (neutropenic fever). Mean baseline PSA was 262 ng/ml with 13/28 (46%) pts achieving ≥ 50% decline in PSA. Conclusions: Coadministration of Tax and Sm has been well tolerated even with full doses of both drugs; repetitive dosing is feasible. MTD has not been reached; repetitive full doses of each drug are being tested in an expansion of Cohort 6 (12 patients) to explore the optimal dose and schedule in preparation for phase II. Support: Cytogen, Inc., NIH CA102544 Cycle 1** (n=28 pts; 28 cycles) All Cycles** (n=28 pts; 81 cycles) Median nadir ANC [K/mcl] 0.5 (0.1 - 1.7) 0.3 (0.1 - 1.3) Avg # of occurrences of ANC ≥ grade 3 per cycle 1.8 (49 occurrences/ 28 cycles) 1.9 (152 occurrences/ 81 cycles) Median days to ANC recovery* of pts with nadir ANC ≥ grade 3 7 days (3 - 15) 7 days (4 - 15) # pts who did not recover ANC to allow recycling 0/28 pts 0/28 pts Median nadir PLT [K/mcl] 118 (51 - 183) 80 (8 - 172) Avg # of occurrences of PLT ≥ grade 2 per cycle 0.1 (3 occurrences/ 28 cycles) 0.8 (64 occurrences/ 81 cycles) Median days to PLT recovery of patients whose PLT dropped below 100 K/mcL * 7 days (2 - 44) 9 days (2 - 126) Number of patients whose PLT did not drop below 100 K/mcL 19/28 pts 10/28 pts # pts who did not recover PLTS to allow recycling 0/28 6/28 * Counts sufficient to allow pts to recycle without dose reduction; ** Each cycle consists of 2 or 3 chemotherapy doses depending on the cohort Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cytogen, sanofi-aventis

Circulating tumor cells in patients with castration-resistant metastatic prostate cancer

5076 Background: Blood-based assays are urgently needed to provide molecular information on the specific targets expressed in tumor cells to optimize treatment selection. Antibody-capture technologies have been applied to isolate circulating tumor cells (CTC) from small volumes of peripheral blood from patients with progressive castrate metastatic prostate cancer. It has been demonstrated previously that CTC isolated from these patients represent authentic prostate cancer cells. Methods: CTC, positive for EpCAM (epithelial cellular adhesion molecule) and nuclear DAPI, and CD45 negative, were isolated from 120 patients with clinical castrate metastatic disease. All patients had rising PSA levels and were on stable treatment regimens at the time of CTC sampling. We tested the association between CTC counts and PSA levels, and the extent of disease to bone, and soft tissue metastasis by Wilcoxon rank sum. Fluorescence in situ hybridization was performed for AR and ERBB2 genes by an adapted method in CTC. Results: The average age in this patient cohort was 69 years, and median PSA at the time when CTC were drawn was 111 ng/mL (range 0.86–12147 ng/mL). The patterns of metastatic spread included disease in soft tissue only in 12 patients (10%), in bone and soft tissue in 67 (56%), and in bone only in 41 patients (34%). CTC counts ranged from 0 to 1958 cells per 7.5 mL of blood. A large number of patients (54, 45%) had 10 or more circulating tumor cells, while only 33 patients (27.5%) had 1 or less CTC per sample of blood. Significantly higher numbers of CTC were detected in patients with bone metastasis compared to those without bone metastasis (11 vs. 2.5, p<0.01). In patients with marked amplification of AR locus (five patients), tetraploidy was noted in the majority of cases (four cases). Two patients without AR amplification showed apparent tetraploidy, while no analyzed samples (nine) had amplification of ERBB2. Conclusions: The analysis of cancer-related gene alterations in CTC is feasible in a hospital-based laboratory. Further gene expression studies focused on the patients with higher numbers of CTC in correlation with clinical outcomes, as well as the investigation of CTC gene expression during specific treatments are under way. No significant financial relationships to disclose.

Phase I study of docetaxel and 153Sm repetitively administered for castrate metastatic prostate cancer (CMPC)

5152 Background: Docetaxel (Tax) prolongs survival in patients (pts) with CMPC. Early clinical data suggest that Tax combined with bone seeking radiopharmaceuticals may improve survival relative to chemotherapy alone. 153Sm-lexidronam (Sam) (Quadramet, Cytogen Inc.) is a radiopharmaceutical with a short T1/2 and a favorable toxicity profile. Methods: Pts with progressive CMPC are treated in cohorts of 3–6. Prior treatment with taxanes is permissible. Cohorts are defined by dose escalations of: Tax 65, 70, 75, 75, 75 mg/m2 and Sam 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle is 6 weeks. Tax is given day 1 and 22 and Sam day -1 to 1 of each cycle. DLT is defined as cycle 1 = grade 3 non-hematologic toxicity, grade 3 neutropenia that lasts for >29 days, or grade 3- 4 anemia or thrombocytopenia of = 5 days. Pts with an ANC of grade 0–1 or platelet count (PLT) of >100,000/mm3 at the end of cycle 1 may receive additional cycles. Pts are treated until progression or toxicity. Results: 18 pts have been treated in 5 cohorts of 3 pts to date. 6 pts were treated in cohort 2. Two pts have not yet received enough treatment to be evaluable. DLT has not yet been reached. The mean number of cycles/pt is 3 (range 1–6). As anticipated, toxicities have primarily been hematologic (see table ). Two pts came off study for hematologic toxicity; one in cohort 2 had grade 3 PLT after 5 cycles and has not recovered at >175 days and 1 pt (cohort 2) failed to recover PLT in the allotted time frame during cycle 4 prohibiting further treatment. No other pts required treatment delays for hematologic toxicity. Mean baseline PSA was 294.6ng/ml with 7/16 (44%) pts achieving = 50% decline in PSA. Conclusions: Coadministration of Tax and Sam has been well tolerated. Repetitive dosing is feasible. Standard approved doses of each drug are being tested in the present (and final) cohort. DLT has not yet been reached. Accrual continues, to refine the optimal dose and schedule in preparation for phase II. Support: Cytogen, Inc., NIH CA102544 [Table: see text] No significant financial relationships to disclose.

Second-Line Chemotherapy for Prostate Cancer: Patient Characteristics and Survival

PurposeFirst-line chemotherapy with docetaxel in patients with progressive castrate metastatic prostate cancer has been shown to improve overall survival compared with mitoxantrone-based therapies. The use and outcomes of chemotherapy after first-line antimicrotubule-based therapy have not been well described. Patients and MethodsPatients with progressive castrate metastatic prostate cancer enrolled on an antimicrotubule-based protocol for treatment were followed to determine their baseline characteristics and outcomes with second- or third-line systemic therapy. ResultsOf 108 patients treated with antimicrotubulebased therapy, 81% received second-line therapy, and 40% received third-line therapies. Corresponding prostate-specific antigen (PSA) decreases ≥ 50% were observed in 72%, 15%, and 22% of patients. Median survival times from the start of first-, second-, and third-line therapy were 21 months (95% confidence interval [CI], 18-25 months), 13 months (95% CI, 10-15 months) and 12 months (95% CI, 9-19 months). Significant prognostic indicators for survival in the second-line setting include pretreatment PSA level, alkaline phosphatase level, and performance status. Patients not fit to receive second-line therapy were more symptomatic with first-line therapy, as illustrated by a greater need for narcotic therapy (67% vs. 15%) and palliative radiation therapy after first-line therapy (57% vs. 10%) in lieu of second-line systemic therapy. ConclusionEighty percent of patients received second-line chemotherapy, with a median survival of 12 months from the start of second-line treatment. Although only 40% received third-line chemotherapy, median survival was similar to that of patients in the second-line setting. Our data show that patients who initiate chemotherapy with symptoms are more likely to require palliative radiation therapy rather than chemotherapy as second-line therapy. A sequential or continuous administration of therapy may optimize the care of this subset of symptomatic patients.

Multi-institutional randomized phase II trial of the epothilone B analog ixabepilone (BMS-247550) with or without estramustine phosphate in patients with progressive castrate metastatic prostate cancer: Galsky, MD, Small EJ, Oh WK, Chen I, Smith DC, Colevas AD, Martone L, Curley T, Delacruz A, Scher HI, Kelly WK, Memorial Sloan-Kettering Cancer Center, New York, NY

Purpose To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. Patients and Methods Patients were randomly assigned to receive ixabepilone (35 mg/m2) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. Results Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of ≥50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. Conclusion Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Outcomes with second-line chemotherapy in castrate metastatic prostate cancer

4659 Background: Docetaxel is the standard 1st-line chemotherapy for patients (pts) with progressive castrate metastatic prostate cancer (CMPC). We describe the outcomes of patients following first-line therapy in the contemporary era. Methods: The outcomes of 108 pts treated with a microtubule-targeting chemotherapy as 1st-line were evaluated for response to 2nd and 3rd line cytotoxic treatments. The subsequent treatments included a docetaxel/paclitaxel, mitoxantrone, doxorubicin, cyclophosphamide or investigational agents. Parameters evaluated were: the proportion who received a subsequent treatment, and the Karnofsky Performance Status (KPS), LDH, Alk, Hb, Alb, and PSA at the start of the therapy. Post-therapy PSA levels were also recorded. Survival estimates were performed using the Kaplan-Meier method. Results: Of the entire cohort, 83% (90 of 108) received 2nd and 40% (44 of 108) received 3rd line therapy. The median survival for 1st line treatment was 21 months (95% CI, 18–25), for 2nd line 13 months (95% CI, 10–15), and 12 months (95% CI, 9–19) for 3rd line therapy. Baseline characteristics showed similar Hgb, Alb, and LDH between those receiving 1st, 2nd and 3rd line treatment, with a trend to higher Alk and PSA values. The proportion showing post-therapy PSA declines were .72, .15 and .24. Conclusions: In this cohort, a significant proportion of pts with CMPC who receive 1st-line therapy go on to receive 2nd and 3rd line chemotherapy. Most baseline characteristics do not change and survival remains notable. The results have implications in the design of trials for 2nd and 3rd line chemotherapy. Support: Prostate Cancer Foundation Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

Multi-Institutional Randomized Phase II Trial of the Epothilone B Analog Ixabepilone (BMS-247550) With or Without Estramustine Phosphate in Patients With Progressive Castrate Metastatic Prostate Cancer

To evaluate the antitumor activity and safety of the epothilone B analog, ixabepilone, with or without estramustine phosphate (EMP), in chemotherapy-naive patients with progressive castrate metastatic prostate cancer. Patients were randomly assigned to receive ixabepilone (35 mg/m(2)) by intravenous infusion every 3 weeks with or without EMP 280 mg orally three times daily on days 1 to 5. Between December 2001 and October 2003, 92 patients were enrolled and randomly assigned to treatment with ixabepilone alone (45 patients) or in combination with EMP (47 patients). Grades 3 and 4 toxicities experienced by more than 5% of patients included neutropenia (22%), fatigue (9%), and neuropathy (13%) on the ixabepilone arm, and neutropenia (29%), febrile neutropenia (9%), fatigue (9%), neuropathy (7%), and thrombosis (6%) on the ixabepilone + EMP arm. Post-treatment declines in prostate-specific antigen of > or = 50% were achieved in 21 of 44 patients (48%; 95% CI, 33% to 64%) on the ixabepilone arm, and 31 of 45 patients (69%; 95% CI, 55% to 82%) on the ixabepilone + EMP arm. In patients with measurable disease, partial responses were observed in eight of 25 patients (32%; 95% CI, 14% to 50%) on the ixabepilone arm, and 11 of 23 (48%; 95% CI, 27% to 68%) on the ixabepilone + EMP arm. Time to prostate-specific antigen progression was 4.4 months (95% CI, 3.1 to 6.9 months) on the ixabepilone-alone arm and 5.2 months (95% CI, 4.5 to 6.8 months) on the combination arm. Ixabepilone, with or without estramustine phosphate, is well tolerated and has antitumor activity in patients with castrate metastatic prostate cancer.

Multi-institutional trial of the epothilone B analogue BMS-247550 with or without estramustine phosphate (EMP) in patients with progressive castrate-metastatic prostate cancer (PCMPC): Updated results

4509 Background: BMS-247550 is a semi-synthetic analogue of epothilone B with preclinical activity in taxane-resistant cell lines. We have previously shown that BMS-247550 + EMP could be safely administered in PCMPC (Ann Oncol 14:1518, 2003). Subsequently, we initiated a multi-institutional phase II study to determine the efficacy and toxicity of BMS-247550 +/- EMP. Methods: Chemotherapy-naïve patients with PCMPC were eligible. Patients were randomized to BE: BMS-247550 (35 mg/m2 IV over 3 hours every 3 weeks on day 2) + EMP (280 mg PO TID day 1–5) + Coumadin (2 mg daily) or B: BMS-247550 (35 mg/m2 IV over 3 hours every 3 weeks). Results: Accrual has completed with 92 patients enrolled (BE: 45, B: 47). Patients have received a median of 5 cycles (range, 1–12) on BE and 4 cycles (range, 1–25) on B. Twenty-two patients continue on treatment. The major adverse events are detailed in the table. Neuropathy developed after a median of 3 cycles (range, 1–7). On BE, 22/32 (69%; 95% CI, 53–85%) have achieved a ≥ 50% decline in PSA and 8/18 (44%; 95% CI, 21–69%) have had a partial regression (PR) of measurable disease. On B, 18/32 (56%; 95% CI, 39–73%) have achieved a ≥ 50% decline in PSA and 6/26 (23%; 95% CI, 7–40%) have had a PR. At a median follow-up of 6.5 months (range, 0–23), 81 patients are alive and 11 have died. Conclusions: BMS-247550, alone or in combination with EMP, has significant activity in PCMPC. Neuropathy is prominent, has proven manageable, yet requires further characterization. Phase III studies are needed to determine if BMS-247550 confers a survival benefit. Support: CTEP, Prostate Cancer Foundation, NIH N01-CM17105 Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Cell Therapeutics; Pfizer Cell Therapeutics AstraZeneca Speakers Bureau Aventis; AstraZeneca; Prostate Cancer Foundation; Millennium Pharmaceuticals ProQuest Investments ProQuest Investments

Multi-institutional trial of the epothilone B analogue BMS-247550 with or without estramustine phosphate (EMP) in patients with progressive castrate-metastatic prostate cancer (PCMPC): Updated results

4509 Background: BMS-247550 is a semi-synthetic analogue of epothilone B with preclinical activity in taxane-resistant cell lines. We have previously shown that BMS-247550 + EMP could be safely administered in PCMPC (Ann Oncol 14:1518, 2003). Subsequently, we initiated a multi-institutional phase II study to determine the efficacy and toxicity of BMS-247550 +/- EMP. Methods: Chemotherapy-naïve patients with PCMPC were eligible. Patients were randomized to BE: BMS-247550 (35 mg/m2 IV over 3 hours every 3 weeks on day 2) + EMP (280 mg PO TID day 1–5) + Coumadin (2 mg daily) or B: BMS-247550 (35 mg/m2 IV over 3 hours every 3 weeks). Results: Accrual has completed with 92 patients enrolled (BE: 45, B: 47). Patients have received a median of 5 cycles (range, 1–12) on BE and 4 cycles (range, 1–25) on B. Twenty-two patients continue on treatment. The major adverse events are detailed in the table. Neuropathy developed after a median of 3 cycles (range, 1–7). On BE, 22/32 (69%; 95% CI, 53–85%) have achieved a ≥ 50% decline in PSA and 8/18 (44%; 95% CI, 21–69%) have had a partial regression (PR) of measurable disease. On B, 18/32 (56%; 95% CI, 39–73%) have achieved a ≥ 50% decline in PSA and 6/26 (23%; 95% CI, 7–40%) have had a PR. At a median follow-up of 6.5 months (range, 0–23), 81 patients are alive and 11 have died. Conclusions: BMS-247550, alone or in combination with EMP, has significant activity in PCMPC. Neuropathy is prominent, has proven manageable, yet requires further characterization. Phase III studies are needed to determine if BMS-247550 confers a survival benefit. Support: CTEP, Prostate Cancer Foundation, NIH N01-CM17105 Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb; Cell Therapeutics; Pfizer Cell Therapeutics AstraZeneca Speakers Bureau Aventis; AstraZeneca; Prostate Cancer Foundation; Millennium Pharmaceuticals ProQuest Investments ProQuest Investments

Phase I trial of MLN2704 in patients with castrate-metastatic prostate cancer (CMPC)

4592 Background: MLN2704 is an immunoconjugate designed to deliver the maytansinoid anti-microtubule agent DM1 directly to prostate cancer cells through the prostate-specific membrane antigen (PSMA) targeted monoclonal antibody MLN591. Preclinical models have indicated significant activity in human prostate cancer xenografts. We report the results of the first phase I trial of MLN2704 in patients with CMPC. Methods: The study was designed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and immunogenicity of a single ascending dose of MLN2704 administered intravenously over 2.5 hours. Based on emerging safety and PK data, repeat dosing at 4-week intervals was subsequently permitted. Patients with progressive CMPC and adequate organ function were eligible for enrollment. Results: 23 patients have received MLN2704 at doses ranging from 18 to 343 mg/m2 in this ongoing trial. 17 patients have received ≥ 3 doses. PK of antibody related analytes (J591-DM1, Total J591 and free J591) has been typical of monoclonal antibodies. Plasma levels of free DM1 have been detectable. No autoantibodies against MLN2704, MLN591 or DM1 have been detected. MLN2704 has been well-tolerated in the majority of patients. Transient elevations in hepatic transaminases, infusion-related fever/chills, nausea, and fatigue have been observed. Only one DLT, an uncomplicated febrile neutropenia, has been reported at the highest dose level (343 mg/m2). This patient also demonstrated a sustained > 50% PSA decline and remains on study at a reduced dose. One patient treated at the 264 mg/m2 dose level has experienced a PR by RECIST, improvement in intradermal metastatic lesions, and a durable 70% decline in PSA. This patient has received 7 doses and remains on study at 24 weeks. Conclusions: Anti-tumor activity has been observed at well tolerated doses of MLN2704. MTD is 343 mg/m2 or higher. Support: T32 CA-09207 Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals Bristol-Myers; Cell Therapeutics; Millennium Pharmaceuticals Cell Therapeutics; Millennium Pharmaceuticals AstraZeneca Speakers Bureau Millennium Pharmaceuticals ProQuest Investments ProQuest Investments

Estimating survival benefit in castrate metastatic prostate cancer: decision making in proceeding to a definitive phase III trial

Objectives In designing a Phase II trial, the acceptable clinical activity region for a new therapy is often developed using data from historically treated patients. This region incorrectly ignores the variability of this estimate, because the efficacy of the prior treatment lies somewhere around the estimate. The size of this interval is dependent on the sample size used. This report illustrates the use of a published method that accounts for this uncertainty and aids in the decision to proceed to a definitive trial. Methods A historical data set of low-risk patients with progressive castrate metastatic prostate cancer and a group of similar patients treated in a Phase II chemotherapy trial were used. The 1-year Kaplan-Meier estimate of survival was obtained for both. This approach uses the 75% upper confidence bound of the 1-year survival probability from the historical data set to define the lower limit of acceptable clinical activity. Use of this bound makes the approach more conservative, and hence the decision to proceed to a Phase III trial more difficult. Results In the low-risk historical patients, the 1-year Kaplan-Meier estimate of survival was 66.4% (75% upper confidence bound 71.0%). In the Phase II patients, the 1-year Kaplan-Meier estimate of survival was 89.5% (95% lower confidence bound 78.2%). Conclusions A hypothesis test using the 75% upper confidence bound to define the lower limit of acceptable clinical activity demonstrates that the 1-year survival probability on Taxol/estramustine/carboplatin is greater than that of the historical population, and hence should be taken into a definitive trial. The design provides investigators increased confidence in making this decision.