A phase I trial of docetaxel/estramustine/imatinib in patients with hormone-refractory prostate cancer

Background

Docetaxel/estramustine was a commonly used regimen to treat metastatic hormone-refractory prostate cancer. Imatinib inhibits the platelet-derived growth factor receptor that is expressed in prostate cancer and is synergistic with taxanes in preclinical prostate cancer models.

Patients and Methods

A phase I trial of docetaxel/estramustine/imatinib was undertaken to determine the safety and maximum tolerated dose of this combination. Patients with progressive, metastatic, hormone-refractory prostate cancer were treated every 21 days with fixed doses of estramustine (280 mg orally 3 times a day on days 1-5), imatinib (400 mg orally daily on days 1-21), dexamethasone (8 mg orally twice daily on days 1-3), and prophylactic warfarin (2 mg orally daily on days 1-21). Cohorts of 3-6 patients were enrolled to receive escalating doses of docetaxel on day 2 from 50 mg/m² to 60 mg/m² to 70 mg/m². Thirteen patients were treated.

Results

On dose level 3 (docetaxel 70 mg/m² and imatinib 400 mg daily), 2 patients experienced grade 3 elevations in prothrombin time, attributed to the interaction between imatinib and warfarin. The protocol was amended to include an intermediate dose level (docetaxel 60 mg/m² and imatinib 300 mg daily). However, in the overall study, there were 5 unacceptable toxicities (2 cerebrovascular accidents, 1 myocardial infarction, 1 mesenteric ischemia, and 1 deep venous thrombosis) in 13 patients; 2 of those toxicities resulted in death. The study was closed early to further accrual.

Conclusion

The high incidence of thromboembolic events observed when imatinib was combined with docetaxel/estramustine precludes further exploration of this regimen.     

Weekly docetaxel/estramustine phosphate in patients with increasing serum prostate- specific antigen levels after primary treatment for prostate cancer: a phase II trial of the Minnie Pearl Cancer Research Network

Purpose

Docetaxel alone or in combination with estramustine prolongs survival in patients with metastatic hormone-refractory prostate cancer. The role of chemotherapy is undefined in the treatment of patients who develop an increasing serum prostate-specific antigen (PSA) level after primary therapy but have no detectable metastases. This phase II study was performed as a preliminary evaluation of the feasibility and efficacy of weekly docetaxel/estramustine in patients with prostate cancer and increasing serum PSA levels.

Patients and Methods

Between March 2001 and September 2003, 34 patients entered this phase II trial. All patients had biopsy-proven adenocarcinoma of the prostate and had increasing PSA levels but no clinically or radiographically detected metastases after primary therapy. All patients received docetaxel 35 mg/m² intravenously on days 1, 8, and 15 and estramustine phosphate 140 mg 3 times daily for 7 doses, beginning the evening before each dose of docetaxel. Treatment courses were repeated at 28-day intervals, and responding patients received a total of 6 courses.

Results

Thirty-one patients (91%) completed 6 courses of treatment. Thirty-two of 33 evaluable patients (97%) had a decrease in serum PSA level of > 50% during treatment, and 27 patients (82%) had normalization of serum PSA level. The median progression-free survival was 28 months, with 33% of patients progression free at 3 years. This treatment regimen was well tolerated with no myelosuppression-related complications or uncommon grade 3 nonhematologic toxicity.

Conclusion

Treatment with weekly docetaxel and estramustine is feasible and active in patients with prostate cancer and increasing serum PSA levels. However, the benefit of early treatment versus treatment when clinical metastases are detected requires demonstration in a randomized phase III trial.     

Phase II trial of docetaxel/capecitabine in hormone-refractory prostate cancer

Background

Docetaxel is the most active single agent in the treatment of hormone-refractory prostate cancer (HRPC). Because of the preclinical and clinical evidence of synergy of capecitabine and docetaxel, it was hypothesized that this combination would be active and tolerable in HRPC.

Patient and Methods

Patients received docetaxel 60 mg/m² intravenously over 60 minutes on day 1 of each 21-day cycle and capecitabine 1000 mg/m² administered orally twice daily on days 1-14 of each cycle for a maximum of 8 cycles or until disease progression or intolerable toxicity. Seventy-seven patients were enrolled at 43 US Oncology sites. The median age was 69.3 years (range, 48-86 years); 86% were white, and the Eastern Cooperative Oncology Group performance status scores of 0 and 1 were 49% and 51%, respectively. Sixty-nine (90%) patients were evaluable for prostate-specific antigen response.

Results

Overall, 41% of patients had a decreased prostate-specific antigen level ≥ 50%. There were 4 complete responses (6%), 24 partial responses (35%), 29 incidences of stable disease (43%), and 11 incidences of progressive disease (16%). Nine patients had stable disease ≥ 6 months, and the clinical benefit rate was 54%. The median time to response was 1.5 months (range, 1-6 months), and the median duration of response was 5.2 months (range, 1-16.9 months). The estimated survival at 12 and 24 months was 65% and 22%, respectively, with a median survival of 17 months (range, < 1-27 months). There were no treatment-related deaths. Grade 3/4 toxicities included neutropenia (50%), leukopenia (22%), hand-foot syndrome (17%), fatigue (11%), and nausea (11%).

Conclusion

Docetaxel/capecitabine is an active and tolerable combination in HRPC. Toxicity was acceptable and anticipated. Response rate and survival are comparable with other docetaxel combinations.     

A phase II trial of docetaxel and estramustine in patients with refractory metastatic breast carcinoma

BACKGROUND: The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC). METHODS: Thirty-six patients with MBC were treated with estramustine 900 mg/m(2) per day divided into 3 doses given on Days 1-3 and docetaxel 70 mg/m(2) given by intravenous administration over 1 hour on Day 3 after the first dose of estramustine, every 21 days. Patients may have received any number of prior chemotherapy regimens for MBC. RESULTS: Nine partial responses were observed in 31 assessable patients, for an objective response rate of 29% (95% confidence interval, 14-48%). The median progression free survival was 4 months (range, 1-41 months), and the median overall survival was 17 months (range, 2-45 months). Severe toxicities (Grade 3 or 4) were neutropenia, hypophosphatemia, and thrombosis. Seventy-five percent of patients experienced either an improvement or no change in quality of life. CONCLUSIONS: The combination of docetaxel and estramustine produced responses in heavily pretreated women with MBC while maintaining quality of life.     

Sequential mitoxantrone/prednisone followed by docetaxel/estramustine in patients with hormone refractory metastatic prostate cancer: results of a phase II study.

BACKGROUND: Mitoxantrone/prednisone ameliorates symptoms in hormone refractory prostate cancer (HRPC) but has no effect on survival. Docetaxel (Taxotere)/estramustine improves response but with significant toxicity. We reasoned that a sequential administration of the two regimens could be a viable alternative for delivering full doses of chemotherapy, avoiding overlapping toxicity and preserving dose intensity. PATIENTS AND METHODS: Thirty HRPC patients were treated with mitoxantrone 10 mg/m(2), day 1, every 3 weeks, plus prednisone 5 mg twice daily, for three cycles, followed by estramustine phosphate, 280 mg three times daily, days 1 to 5, plus docetaxel 75 mg/m(2), day 2, every 3 weeks for a maximum of 10 cycles. RESULTS: All patients were assessable for response and toxicity. After mitoxantrone/prednisone treatment, the prostate-specific antigen (PSA) response rate was 23%, which increased to 63% after completion of sequential mitoxantrone/prednisone and docetaxel/estramustine treatment (12 partial and 7 complete responses). With a median follow-up of 18 months, median survival for all patients was 18 months, and median progression-free survival was 10 months. The mitoxantrone/prednisone regimen was well tolerated, and the only grade 3-4 toxicity was grade 3 neutropenia in four (13%) patients. Twenty-nine patients received a total of 173 cycles of docetaxel/estramustine (median, 6 cycles/patient). Six (20%) patients had grade 3-4 neutropenia and two (6%) patients had febrile neutropenia episodes. The most frequent non-hematological toxic effects were asthenia, nausea and vomiting, edemas and onycholysis. Two (6%) patients had deep venous thrombosis. CONCLUSIONS: Mitoxantrone/prednisone followed by docetaxel/estramustine is a well-tolerated and active regimen in HRPC. Sequential therapy is feasible and can be used to integrate novel, more active regimens.     

Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC. PATIENTS AND METHODS: Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE). RESULTS: Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups. CONCLUSION: Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.     

A phase 2 study of estramustine,docetaxel, and bevacizumab in men with castrate‐resistant prostate cancer

BACKGROUND:

The use of docetaxel prolongs survival for patients with castrate‐resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC.

METHODS:

This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m² docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate‐specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression‐free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival.

RESULTS:

Seventy‐nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty‐three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty‐four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity.

CONCLUSIONS:

The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing. Cancer 2011. © 2010 American Cancer Society.     

The AKT inhibitor perifosine in biochemically recurrent prostate cancer: a phase II California/Pittsburgh cancer consortium trial

BACKGROUND: Perifosine is an oral alkylphospholipid that inhibits cancer cell growth through decreased Akt phosphorylation. We conducted a phase II trial of perifosine in patients with biochemically recurrent, hormone-sensitive prostate cancer. PATIENTS AND METHODS: Eligible patients had histologically confirmed prostate cancer, previous prostatectomy and/or radiation therapy, and rising prostate-specific antigen (PSA) without radiographic evidence of metastasis. Previous androgen deprivation therapy < 9 months in duration (completed >or= 1 year before registration) was allowed. The primary endpoint was PSA response, defined as a decrease by >or= 50% from the pretreatment value. Treatment was composed of a loading dose of perifosine 900 mg orally on day 1, then 100 mg daily starting 24 hours later. RESULTS: Of 25 patients, 24 were evaluable for response. After a median follow-up of 8 months, 5 patients (20%) had a reduction in serum PSA levels, but none met criteria for PSA response. Three patients immediately progressed with no response to therapy. Median progression-free survival was 6.64 months (range, 4.53-12.81 months). No change in the PSA doubling time (7 months) was observed before and after treatment initiation. Dose-limiting toxicities (all grade 3) included hyponatremia, arthritis, hyperuricemia, and photophobia. CONCLUSION: Although well tolerated, perifosine did not meet prespecified PSA criteria for response as a single agent in biochemically recurrent prostate cancer. However, 20% of patients had evidence of PSA reduction, suggesting modest single-agent clinical activity. The role of perifosine in combination with androgen deprivation or chemotherapy is currently under investigation.     

A phase II study of vinorelbine and estramustine in patients with hormone-resistant prostate cancer

Introduction

This phase II study was designed to evaluate the efficacy of vinorelbine in combination with estramustine in patients with chemotherapy-naïve hormone-refractory prostate cancer.

Material and methods

Patients received vinorelbine (i.v. 25 mg/m²) on days 1 and 8 every 3 weeks and estramustine (oral, 600 mg/m²) daily. Eligible patients were required to have progressive metastatic disease following the first hormonal manipulation.

Results

Of the 51 patients enrolled (median age=69 years), 84% presented bone involvement and 75% had at least two organs involved at the time of study entry and 47 were evaluable for treatment efficacy. Prostate specific antigen (PSA) response (≥50% decrease) which was the primary efficacy criterion was reported in 21 patients (41.2%) in the intent-to-treat (ITT) population and in 20 patients (48.8%) in the perprotocol (PP) population. Of the 7 patients with measurable disease, 2 achieved partial response. Median progression-free survival and overall survival were 4.7 months (range: 1.9–8.6) and 14.3 months (range: 4.2–21.2), respectively. grade 3–4 neutropenia was reported in 6.1% of patients and in 1% of cycles. The incidence of complicated neutropenia (febrile neutropenia reported in 1 patient and septic shock with severe neutropenia reported in 2 patients) was 5.8%. The most frequent grade 3–4 non-haematological events (% of patients ≥5%) included anorexia (10%), thrombosis/embolism (8%), vomiting and hypotension (6% each). There were 3 toxic deaths (5.9%) resulting from pulmonary embolism, angina pectoris, and septic shock. The impact of combined chemotherapy on the quality-of-life (QL) of the patients was assessed between baseline and the first evaluation scheduled at 6 weeks indicated a marked reduction in pain while the rest of the symptoms remained stable. Overall, health status improved slightly over the treatment period.

Conclusions

This study confirmed that the combination of vinorelbine and estramustine is an active regimen in patients with hormone-resistant prostate cancer who had not been treated previously with chemotherapy. Main toxicities included complicated neutropenia even though the incidence of severe neutropenia was low. We observed a higher incidence of toxic deaths which could have been related to the regimen of estramustine used in the study.     

A phase II trial of docetaxel and vinorelbine in patients with hormone-refractory prostate cancer

Recent studies of docetaxel have demonstrated improved survival over mitoxantrone and prednisone in patients with hormone-refractory prostate cancer (HRPC), supporting the study of novel docetaxel-containing regimens as primary therapy or following initial docetaxel-based therapy. To evaluate the combination of docetaxel and vinorelbine in the treatment of patients with HRPC, 40 patients with proven adenocarcinoma of the prostate with progressive metastatic disease despite androgen ablation were enrolled onto this phase II trial. Patients were treated with docetaxel 60 mg/m² on day 1 and vinorelbine 15 mg/m² on days 1 and 8 of a 21-day cycle. All patients received dexamethasone 8 mg twice daily for 4 days starting 1 day prior to the docetaxel infusion. After the first three patients were enrolled, filgrastim was added on days 2–6 and 9–13. Of the 40 patients enrolled, 19 had no prior chemotherapy and 21 had received at least one prior chemotherapy regimen. Of the 19 patients without prior chemotherapy and the 21 with prior chemotherapy, 7 (37%) and 6 (29%) , respectively, demonstrated a decrease in prostate specific antigen by >50% maintained for at least 4 weeks. Out of eight patients with measurable disease, one achieved a partial response and four demonstrated stable disease. There was one patient with deep vein thrombosis, and febrile neutropenia was noted in only three patients after the protocol was modified to include filgrastim support. The combination of docetaxel and vinorelbine with filgrastim was well tolerated and active against HRPC in patients with or without prior chemotherapy.This trial was supported in part by research grants from Aventis, Amgen, and P30 CA72720-01-03.     

Weekly administration of docetaxel in combination with estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer: final results from a phase II study

The objective of this study was to evaluate the efficacy and safety profile of weekly docetaxel, estramustine and celecoxib in patients with advanced hormone-refractory prostate cancer. Forty-eight patients received 35 mg m(-2) of weekly docetaxel for 3 out of every 4 weeks, 280 mg of estramustine twice daily on days 1-3, 8-10, 15-17 and 400 mg of celecoxib twice daily until progression or toxicity. Cycles were repeated every 28 days for at least six cycles. Patients were evaluated for response and toxicity. Patients received a median of four cycles (range: 1-9). On an intention-to-treat analysis, prostate-specific antigen (PSA) was decreased greater than 50% in 28 out of 48 patients (overall response rate: 58%, 95% confidence interval (CI): 44-72) and median duration of PSA response was 8.0 months (95% CI: 6.9-9.0). After a median follow-up of 11.3 months, the median time to progression was 7.1 months and the median overall survival was 19.2 months. The most frequent severe toxicity was asthenia (15% of patients), diarrhoea and stomatitis (8% of patients, each). Grade 3/4 neutropenia was reported in two patients. There was a toxic death during the study due to a gastric perforation. Celecoxib with weekly docetaxel and estramustine is an effective and safe treatment for patients with hormone-refractory prostate cancer, but it does not seem to add any benefit to docetaxel.     

Gemcitabine and docetaxel in metastatic, castrate-resistant prostate cancer: results from a phase 2 trial

BACKGROUND:

Docetaxel is the standard of care for patients with metastatic, castrate‐resistant prostate cancer (CRPC). Gemcitabine is a nucleoside analogue with broad antitumor activity. In a phase 2 study of combined docetaxel and gemcitabine, the authors assessed its safety and activity in patients with chemotherapy‐naive, metastatic CRPC.

METHODS:

Eligible patients had untreated, metastatic CRPC with radiologic and/or biochemical evidence of progression after antiandrogen withdrawal with castrate testosterone levels, an Eastern Cooperative Oncology performance status (ECOG PS) of 0 to 2, and adequate organ function; no previous chemotherapy was permitted. Patients received gemcitabine (800 mg/m²) Days 1 and 8 and docetaxel (75 mg/m²) on Day 8 every 21 days for a maximum of 6 cycles. Response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) for measurable disease. A prostate‐specific antigen (PSA) response was defined as a decline ≥50% in baseline PSA level.

RESULTS:

Thirty‐five patients with chemotherapy‐naive, metastatic CRPC were enrolled. The median age was 67 years, and 60% of patients had an ECOG PS of 0. PSA responses were observed in 49% of patients. Among the patients who had measurable disease (n = 25), 3 patients (12%) had a confirmed, RECIST‐defined partial response (PR); 4 patients (16%) had an unconfirmed PR; and 15 patients (60%) achieved stable disease. The most common adverse events included grade 1 and 2 fatigue (69%), alopecia (80%), and nausea/vomiting (54%). No treatment‐related deaths were noted, but an unusually high incidence of grade 3 and 4 neutropenia was observed.

CONCLUSIONS:

The efficacy of combined gemcitabine and docetaxel in metastatic CRPC was similar to that observed with single‐agent docetaxel. In contrast to single‐agent docetaxel, the combination was moderately toxic and had an impact primarily on bone marrow reserve. Cancer 2011. © 2010 American Cancer Society.     

A phase I study of estramustine, weekly docetaxel, and carboplatin chemotherapy in patients with hormone-refractory prostate cancer.

PURPOSE: To define the maximal tolerated dose, safety, and efficacy of docetaxel, carboplatin, and estramustine in patients with hormone-refractory prostate cancer (HRPC). METHODS: Patients with HRPC received docetaxel for 3 weeks, followed by a rest week. Docetaxel (20, 25, 30, 36, or 43 mg/m2) was given on days 2, 9, and 16 of a 28-day cycle. Patients also received estramustine (140 mg p.o. three times daily on days 1-5, 8-12, and 15-19) and carboplatin [area under the curve, AUC (5) or (6) on day 2]. RESULTS: Thirty patients were treated. Five patients received carboplatin [AUC (6)] but experienced delayed thrombocytopenia. After a protocol amendment, 25 subsequent patients received carboplatin [AUC (5)]. Median age was 64 years. Median prostate-specific antigen (PSA) was 117 ng/mL. Fifty-three percent received prior ketoconazole and 10% had mitoxantrone. No dose-limiting toxicities were noted. Although maximal tolerated dose was not reached, docetaxel dose escalation was stopped at 43 mg/m2. Significant myelosuppression was not seen until the highest dose level, when seven and four patients experienced grade 3 and 4 toxicities, respectively. Among all patients, PSA declines of > or =50% occurred in 63%. At the recommended phase II dose, PSA declines of > or =50% occurred in 75% (95% confidence interval, 43-95). Four of 14 (29%) patients with measurable disease had partial responses. Median survival was 14.6 months. CONCLUSIONS: Estramustine, docetaxel, and carboplatin are well tolerated and active in HRPC. Myelosuppression is the primary toxicity. The recommended phase II dose of docetaxel is 43 mg/m2 combined with estramustine and carboplatin. PSA declines were seen at every dose level.     

Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study

BACKGROUND: Nearly all cases of metastatic prostate carcinoma progress, after hormonal ablation, to a hormone refractory status. To the authors' knowledge no standard chemotherapy for patients with hormone refractory prostate carcinoma (HRPC) exists. In a prospective study, the efficacy and toxicity of an oral combination of estramustine and cyclophosphamide were evaluated. METHODS: Between March 1996 and April 1998, 32 consecutive patients (median age 74 years; range, 53-84 years) with metastatic HRPC were treated with oral estramustine (10 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day) for 14 days every 28 days. Inclusion criteria were previous complete androgen blockade, antiandrogen withdrawal evaluation, and clinical or biochemical disease progression. Response assessment was based on a decrease > or =50% in the prostate specific antigen (PSA) level associated with improvement (or no worsening) in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and relief of bone pain (if present). RESULTS: All patients were evaluable for efficacy and toxicity. PSA levels decreased by at least 50% in 14 patients (43.7%) (95% confidence interval, 26.5-60.9), remained stable in 12 patients (37.5%), and rose in 6 patients (18.8%). ECOG PS was 0 in 5 of 14 patients, improved from 1 to 0 in 7 patients, and remained unchanged in 2 patients. Bone pain, present in 8 of 14 patients, disappeared in 7 and was partially relieved in 1. The median duration of response was 30 weeks (range, 8-88+ weeks). An objective partial response was obtained in two cases. Toxicity was mild and mainly gastrointestinal (World Health Organization [WHO] Grade 1). No cases of WHO Grade 3-4 hematologic toxicity occurred. CONCLUSIONS: The oral combination of estramustine and cyclophosphamide appears to be safe and effective in patients with HRPC. In responding patients its use shows a clinical benefit in terms of improvement of ECOG PS and pain control.     

A phase II study of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor support in patients with hormone-refractory prostate carcinoma: Cancer and Leukemia Group B 99813

BACKGROUND: The authors determined the safety and efficacy of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor (G-CSF) support in patients with hormone-refractory prostate carcinoma. METHODS: In the current multicenter, cooperative group study, patients with advanced prostate carcinoma whose disease progressed despite androgen deprivation therapy were treated with a combination of oral estramustine(240 mg three times per day for 5 days), 70 mg/m2 of docetaxel, and carboplatin at a dose of (area under the curve) 5. G-CSF was used to minimize the neutropenia associated with this regimen. Each cycle was repeated every 21 days. RESULTS: Forty patients were treated with a median of 7 cycles of therapy. Of the 34 evaluable patients with elevated pretreatment prostate-specific antigen (PSA) levels, 23 (68%) had a > or = 50% decline in PSA and 20 (59%) had a > or = 75% decline. Twenty-one patients had measurable disease, with 1 complete response (5%) and 10 partial responses (47%), for an overall measurable response rate of 52% (95% confidence interval [95% CI], 30-74%). The most common Grade 3 or Grade 4 toxicities (according to the National Cancer Institute Common Toxicity Criteria) included neutropenia in 23% of patients, thrombocytopenia in 13%, and fatigue in 13%. Febrile neutropenia occurred in 1 patient (3%). The overall median time to disease progression was 8.1 months (95% CI, 6-10 months) and the overall survival period was 19 months (95% CI, 13-26 months). CONCLUSIONS: The combination of estramustine, docetaxel, and carboplatin with G-CSF support was found to have significant clinical activity with an acceptable toxicity profile in patients with progressive hormone-refractory prostate carcinoma.     

A phase I study of paclitaxel/doxorubicin/ thalidomide in patients with androgen- independent prostate cancer

Purpose

The antiangiogenic and immunomodulatory effects of thalidomide induce responses in patients with androgen-independent prostate cancer (AIPC). Paclitaxel and doxorubicin also have significant antitumor activity. A phase I dose-escalation study was conducted to evaluate the use of these agents in combination to enhance the chemotherapeutic effects of treatment for refractory cancer.

Patients and Methods

Twelve men with AIPC (mean age, 64.5 years) and a median prostate-specific antigen (PSA) level of 30 ng/mL were enrolled. Patients received starting doses of weekly paclitaxel (100 mg/m²) as a 1-hour intravenous infusion, weekly doxorubicin (20 mg/m²) as a 24-hour intravenous infusion, and daily oral thalidomide at escalating dose levels of 200 mg (dose level 0), 300 mg (dose level +1), and 400 mg (dose level +2). Paclitaxel and doxorubicin were administered for 3 consecutive weeks of a 5-week cycle. Exposure to thalidomide was daily. Patients were evaluated weekly for dose-limiting toxicities to determine the maximum tolerated dose. In addition, PSA levels were measured before each cycle of treatment. Response to treatment was defined as a ≥ 50% decrease in baseline PSA levels associated with stable radiographic disease, improvement of bone scan results with plain radiograph correlation, or improvement in soft tissue disease.

Results

Four patients were treated on dose level 0, 5 were treated on dose level +1, and 3 were treated on dose level +2. The thalidomide 400-mg dose level resulted in 3 of 3 patients experiencing grade 3 leukopenia. The maximum tolerated dose was 300 mg of thalidomide in combination with paclitaxel/doxorubicin. Nine of the 12 patients were evaluable for PSA response, with 88% exhibiting partial responses or stable disease. One patient (11%) had a significant response, with PSA levels decreasing > 90% from baseline values. Overall, PSA-level decreases ranged from 0.5 ng/mL to 39.5 ng/mL among the 9 evaluable patients. A maximum of 7 cycles of therapy were administered. Twelve patients were evaluable for toxicity: neutropenia (grade 3, 27%; grade 4, 54%), leukopenia (grade 3, 63%), constipation (grade 3, 27%), fatigue (grade 3, 27%), nausea (grade 3, 9%), and deep vein thrombosis (grade 3, 9%) were reported.

Conclusion

The combined dosing of paclitaxel (100 mg/m² weekly), doxorubicin (20 mg/m² weekly), and thalidomide (300 mg daily) is tolerated by men with AIPC and merits continued phase II study.     

Southwest Oncology Group phase II study of ispinesib in androgen-independent prostate cancer previously treated with taxanes

PURPOSE: The mitotic spindle has proven to be an effective therapeutic target in antineoplastic efforts. In this study, we sought to assess the efficacy of ispinesib, a mitotic kinesin spindle protein (KSP) inhibitor in androgen-independent prostate cancer progressing after docetaxel. PATIENTS AND METHODS: Patients were treated with ispinesib 18 mg/m2 every 21 days and assessed for prostate-specific antigen (PSA) and measurable disease response at regular intervals. Kinesin spindle protein expression in archival tumors, population ispinesib pharmacokinetics, and pharmacodynamic assessments of circulating lymphocytes were included. RESULTS: The study was terminated after first stage because no responses were seen in the first 21 patients. Median duration of PSA or clinical progression-free survival was 9 weeks. Plasma concentrations of ispinesib were comparable with those observed in previous phase I investigations. Immunohistochemical analysis of archival tumor specimens did not demonstrate significant KSP expression in most of the prostate cancer cases studied. Pharmacodynamic assessments of circulating lymphocytes from patients receiving ispinesib showed an absence of monopolar spindle formation, as would be expected if the drug were having its expected effects. CONCLUSION: Ispinesib was inactive in this study of patients with androgen-independent, and largely docetaxelresistant, prostate cancer. The lack of efficacy might be explained by the low expression of the drug target seen in prostate cancer, whereas not detecting monopolar spindles in circulating lymphocytes with drug treatment likely reflects the lack of dividing cells in peripheral blood.     

Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design

Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgenindependent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective αvβ3 and αvβ5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit αvβ3- and αvβ5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor- and vascular endothelial growth factor-mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program-sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer.     

Weekly docetaxel and bortezomib as first-line treatment for patients with hormone-refractory prostate cancer: a Minnie Pearl Cancer Research Network phase II trial

Background

Docetaxel is currently the standard first-line treatment in patients with hormone-refractory prostate cancer (HRPC). Bortezomib, the first proteasome inhibitor in clinical use, demonstrated activity against prostate cancer in phase I trials. For this reason, we evaluated the efficacy of docetaxel plus bortezomib in the first-line treatment of patients with HRPC.

Patients and Methods

Between February 2004 and May 2005, 63 eligible patients entered this phase II trial. All patients had metastatic adenocarcinoma of the prostate that had progressed on hormonal therapy. All patients received docetaxel 30 mg/m² and bortezomib 1.6 mg/m² on days 1, 8, and 15 of a 28-day cycle. Patients were reevaluated after 8 weeks of treatment; responding and stable patients continued treatment until tumor progression.

Results

Sixty patients (95%) received ≤ 2 courses of treatment and were evaluable for response. Fifteen patients (25%; 95% confidence interval, 15%-38%) had a > 50% decrease in serum prostate-specific antigen level with treatment; the median response duration was 8 months. The median progression-free and overall survival times for the entire group were 4.1 months and 13.8 months, respectively; 20% of patients were alive at 2 years. The regimen was well tolerated, with uncommon grade 3/4 toxicity.

Conclusion

Treatment with this combination of weekly docetaxel and bortezomib showed no suggestion of improved efficacy versus previous results with docetaxel alone. Bortezomib has minimal activity in patients with HRPC and is unlikely to make any impact on treatment efficacy.