Thalidomide/Estramustine/Paclitaxel in Metastatic Androgen-Independent Prostate Cancer

BackgroundThis is a phase I/II trial of thalidomide with estramustine and paclitaxel in men with androgen-independent prostate cancer (AIPC) who underwent previous chemotherapy.Patients and MethodsMen with progressive AIPC were treated with oral thalidomide (200 mg, 400 mg, or 600 mg daily), intravenous paclitaxel (100 mg/m² over 3 hours on days 3 and 10), and oral estramustine (140 mg 3 times daily on days 1-5 and days 8-12) every 21 days.ResultsPhase I: first cycle dose-limiting toxicity occurred in 0 of 3 patients at 200 mg thalidomide daily, 0 of 3 at 400 mg daily, and 1 of 3 at 600 mg daily (the designated maximum tolerated dose). Phase II: twenty-nine of 38 evaluable patients (76%; 95% confidence interval, 67%-87%) experienced a 50% decrease in prostate-specific antigen level. Five of 18 patients (28%) with measurable disease exhibited an objective response. Nine of 14 patients (64%) with disease refractory to previous taxane therapy had 50% decreases in prostate-specific antigen level. Grade 3/4 adverse events included neutropenia (9 of 39 [23%]), fatigue (9 of 39 [23%]), dyspnea (8 of 39 [21%]), and thromboembolic events (7 of 39 [18%]). Cumulative dose-limiting toxicity rates were minimal (13%) with thalidomide at 200 mg daily.ConclusionThe profile of activity of thalidomide/paclitaxel/estramustine in taxane-refractory AIPC warrants further investigation.     

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.     

A phase II study of weekly paclitaxel/estramustine/carboplatin in hormone-refractory prostate cancer

Purpose

The objective of this phase II study was to determine the response rate in patients with hormone-refractory prostate cancer given paclitaxel/estramustine/carboplatin for weeks 1, 2, and 3 of a 4-week cycle.

Patients and Methods

Eighty-four patients were registered into the trial. Paclitaxel 80 mg/m² and carboplatin area under the curve of 2 were administered intravenously on days 2, 9, and 16, and oral estramustine 280 mg 3 times daily was given on days 1-3, 8-10, and 15-17 for 6 cycles. Eastern Cooperative Oncology Group performance status 0, 1, and 2 was 46%, 41%, and 13%, respectively, and median age was 70 years (range, 53-82 years), with 58 patients (69%) aged > 65 years. The majority of patients (83%) were white. Fifteen patients (18%) had received previous chemotherapy, 61 patients (73%) had undergone previous surgery, and 51 patients (61%) had received previous external-beam radiation therapy.

Results

Intent-to-treat analysis revealed a ≥ 50% prostate-specific antigen decrease rate of 61%. Median survival was 15.3 months. The most frequent grade ≥ 3 toxicities included fatigue (11%), nausea (10%), neutropenia (9%), anemia (6%), and vomiting (6%).

Conclusion

Paclitaxel/estramustine/carboplatin administered in a weekly regimen is highly effective in the treatment of hormone-refractory prostate cancer and can be administered with reasonable safety in an outpatient setting.     

Phase II evaluation of oral estramustine, oral etoposide, and intravenous paclitaxel in patients with hormone-sensitive prostate adenocarcinoma

Purpose

The primary objective of this study was to assess the feasibility and efficacy of administering etoposide/estramustine/paclitaxel in hormone-sensitive metastatic prostate cancer responding to hormonal therapy.

Patients and Methods

Eligible patients had metastatic prostate cancer and had received combined androgen blockade for 6-8 months with a ≤ 80% decrease in prostate-specific antigen from pretreatment. They received 4 cycles of chemotherapy consisting of estramustine 280 mg orally 3 times daily, etoposide 50 mg/m² orally on days 1-14, and paclitaxel 135 mg/m² intravenously for 1 hour on day 2 of each 21-day cycle and were then followed until time to treatment failure (TTF).

Results

Twenty-six patients were evaluable for response and toxicity. Median TTF was 21.7 months (range, 11.9-64.5 months; 95% confidence interval, 15.3-26.2 months). Median survival from time of initiation of hormone therapy was 5.1 years. Neutropenia was the most common grade 3/4 toxicity, occurring in 3 patients. Significant toxicities were limited to nausea, diarrhea, and febrile neutropenia in 3 patients, respectively.

Conclusion

The administration of paclitaxel/estramustine/etoposide in this setting is feasible and well tolerated. Although the TTF of 21.7 months by prostate-specific antigen criteria is similar to historical controls in the emergence of clinically evident androgen-independent disease after starting hormone therapy, direct comparisons cannot be made. More trials are needed to investigate the timing of chemotherapy in patients with prostate cancer.     

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.     

Phase II study of low-dose docetaxel/estramustine in elderly patients or patients aged 18-74 years with hormone-refractory prostate cancer

Purpose

Chemotherapy is often poorly tolerated in elderly patients or patients with poor performance status. This trial was designed to determine whether low-dose weekly docetaxel/estramustine was efficacious with acceptable toxicity.

Patients and Methods

Dexamethasone was administered as premedication. Subjects received docetaxel 25 mg/m² intravenously on days 2, 9, and 16 and estramustine 140 mg orally twice daily on days 1-3, 8-10, and 15-17. Cycles were 28 days. Participants received ≤ 6 cycles unless progression or intolerable toxicity occurred.

Results

Fifty-eight subjects were enrolled at 31 sites in the US Oncology Network. Median age was 78 years (range, 64-92 years); performance status scores (0, 1, 2, and 3) were 36%, 38%, 24%, and 2%, respectively; 55 subjects received ≤ 1 cycle of treatment; and 4 participants were nonevaluable because they completed < 2 cycles. Among the 56 treated subjects, 38 (68%) had a decreased prostate-specific antigen level (≤ 50% compared with baseline level and maintained for ≤ 4 weeks). There were 40 subjects with measurable tumor(s). Responses, assessed using Response Evaluation Criteria in Solid Tumors, were 1 complete response (2.5%), 7 partial responses (17.5%), 26 stable diseases (65%), and 6 progressive diseases (15%). At 1 year, 17% of participants were progression free; median progression-free survival was 5.3 months (range, 1-14.5 months); estimated 1-year survival was 65%. There were no grade 4 treatment-related events. Grade 3 treatment-related events included fatigue/asthenia (11%) and arrhythmia, dehydration, cerebral ischemia, thrombocytopenia, and dyspnea (4% each). There was 1 treatment-related death (acute respiratory distress syndrome).

Conclusion

These findings suggest that elderly men with advancedstage prostate cancer tolerate this regimen, with significant responses and prolonged progression-free survival. These patients should not be excluded from chemotherapeutic interventions based on age alone.     

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.     

A Phase I Study of Paclitaxel/Doxorubicin/Thalidomide in Patients with Androgen-Independent Prostate Cancer

PurposeThe 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 MethodsTwelve 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.ResultsFour 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.ConclusionThe 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.     

Phase II Trial of Carboplatin and Paclitaxel in Papillary Renal Cell Carcinoma

Background

Cytotoxic chemotherapy has not been well investigated in non-clear-cell renal cell carcinoma (RCC). A phase II study was thus conducted to assess the efficacy of carboplatin and paclitaxel in such patients.

Patients and Methods

Patients were treated with carboplatin (area under the curve of 6) and paclitaxel 225 mg/m² every 21 days and assessed for measurable disease response every 2 cycles. An initial 20 patients were planned to be enrolled to rule out a null hypothesized 15% response rate.

Results

Seventeen patients were enrolled, of which 16 patients had papillary and 1 had collecting duct histology. The patient with collecting duct histology had a complete response, but no responses were observed in patients with papillary histology and the trial was thus terminated early. Toxicities were as expected for the carboplatin and paclitaxel regimen.

Conclusion

Carboplatin and paclitaxel is not an active regimen in patients with metastatic papillary RCC. Future studies should explore the role of this or similar regimens in collecting duct carcinoma.     

Weekly paclitaxel with concurrent radiotherapy followed by adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma

Purpose

To evaluate the efficacy and toxicity of weekly paclitaxel with concurrent radiotherapy followed by adjuvant chemotherapy (AC) in patients with locally advanced nasopharyngeal carcinoma (NPC).

Methods and materials

Between 2004 and 2007, 54 patients with locally advanced NPC were included in this protocol. Patient characteristics: median age 48; 69% male; 52% World Health Organization (WHO) III; 50% stage III, 50% stage IV. The patients underwent a course of definitive conventional radiotherapy (70 Gy in 7 weeks with 2 Gy/fraction), with concurrent weekly paclitaxel 35 mg/m² from the first to the sixth week of radiation. AC was started 4 weeks after the end of the radiotherapy (RT), paclitaxel 135 mg/m² on day 1 and cisplatin 30 mg/m² on days 1-3 were administered every 4 weeks for two cycles.

Results

Median follow-up was 32 months. Eighty-five percentage of complete response and 15% partial response were achieved at the time of one month after AC. The 3-year actuarial rate of local regional control was 86%; distant metastases-free survival, progression-free survival and overall survival at 3 years were 81%, 69% and 76%, respectively. Forty-nine (91%) patients completed six courses of concurrent chemotherapy with weekly paclitaxel, and 4 (7%) patients delayed at the second cycle of AC. No patient developed severe acute toxicities.

Conclusions

Weekly paclitaxel with concurrent RT followed by AC is a potentially effective and toxicity tolerable method for locally advanced NPC. Further studies are needed to identify the optimal dose of weekly paclitaxel in this strategy.     

Preoperative concomitant boost intensity-modulated radiotherapy with oral capecitabine in locally advanced mid-low rectal cancer: A phase II trial

Purpose

We aimed to assess the safety and efficacy of preoperative intensity-modulated radiotherapy (IMRT) with oral capecitabine in patients with locally advanced mid-low rectal cancer using a concomitant boost technique.

Materials and methods

Patients with resectable locally advanced mid-low rectal cancer (node-negative ?T3 or any node-positive tumor) were eligible. The eligible patients received IMRT to 2 dose levels simultaneously (50.6 and 41.8 Gy in 22 fractions) with concurrent capecitabine 825 mg/m² twice daily 5 days/week. The primary end point included toxicity, postoperative complication, and pathological complete response rate (ypCR). The secondary endpoints included local recurrence rate, progression-free survival (PFS), and overall survival (OS).

Results

Sixty-three eligible patients were enrolled; five patients did not undergo surgery. Of the 58 patients evaluable for pathologic response, the ypCR rate was 31.0% (95% CI 19.1-42.9). Grade 3 toxicities included diarrhea (9.5%), radiation dermatitis (3.2%), and neutropenia (1.6%). There was no Grade 4 toxicity reported. Four (6.9%) patients developed postoperative complications. Two-year local recurrence rate, PFS, and OS were 5.7%, 90.5%, and 96.0%, respectively.

Conclusions

The design of preoperative concurrent boost IMRT with oral capecitabine could achieve high rate of ypCR with an acceptable toxicity profile.     

Phase 2 Study of Weekly Paclitaxel Plus Estramustine in Metastatic Hormone-Refractory Prostate Carcinoma: ECOG-ACRIN Cancer Research Group (E1898) Trial

Introduction

This multicenter phase 2 study assessed the combination of estramustine and weekly paclitaxel with metastatic castration-resistant prostate cancer (CRPC).

Pre-operative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer: a phase II trial

Background

To evaluate the safety and efficacy of pre-operative chemoradiation, using capecitabine, oxaliplatin and bevacizumab with standard doses of radiation, in patients with high-risk rectal cancer.

Methods

Patients with locally advanced or low rectal cancer were treated with capecitabine 825 mg/m² twice daily on days 1-14 and 22-35, oxaliplatin 50 mg/m² on days 1, 8, 22 and 29, bevacizumab 5 mg/kg on days 14, 1, 15 and 29, and radiation 50.4 Gy in 28 fractions including boost. Total mesorectal excision was performed 7-9 weeks after chemoradiation. The primary end-point was complete tumour regression (ypT0NX) by central review.

Findings

Forty-two evaluable patients were enrolled, and 38 proceeded to definitive surgery. Eighteen patients (43%) had clinical T4 tumours and/or N2 tumours. Mean relative dose intensity was >90% for all systemic agents, and 97% for radiation. Grade 3/4 diarrhoea occurred in 10 patients (24%) and pain in 4 patients (10%) pre-operatively, while grade 3/4 pain, fatigue and infection were each reported among 5 patients (13%) post-operatively. Re-operation due to complications occurred in 4 patients (11%). Complete tumour regression (ypT0) was seen in 9 patients (23.7%) of which two had N1 disease and the pathological complete response (pCR) rate (ypT0N0) was 18.4%. Central review changed pathologic stage in six cases (16%).

Interpretation

In this study, pre-operative bevacizumab added to oxaliplatin, capecitabine and radiation was safe and resulted in a promising tumour regression rate. Surgical complications were closely monitored and occurred with the expected frequency. Central pathology review should be considered for trials with pathologic response as the primary end-point.

Funding

British Columbia Cancer Agency, Hoffmann-La Roche Canada and Sanofi-Aventis.     

Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer

Aim

Registered dose capecitabine monotherapy is active against metastatic breast cancer (MBC), but retrospective analyses indicate that lower doses may be as effective and better tolerated. This study was conducted to assess the safety and efficacy of metronomic capecitabine in heavily pretreated patients with MBC.

Patients and methods

In this phase II study 60 MBC patients received continuous metronomic capecitabine monotherapy (1500 mg once a day). Primary endpoint was clinical benefit rate, secondary end points were clinical benefit rates (CBRs), tumour response rates (RRs), overall survival (OS), time to progression (TTP), duration of response (DOR) and toxicity.

Results

Fifty eight assessable patients received two or more 28-day cycles of metronomic capecitabine. The CBR was 62%. Median DOR was 7 months. Median TTP and OS were 7 and 17 months, respectively. Two partial responses and 7 cases of stable disease were recorded in 13 patients who had previously received capecitabine intermittently (2000 mg/m²/day on days 1-14 every 21 days) as first- or subsequent-line treatment for MBC. Grade 3-4 adverse events were uncommon; haematologic toxicity was infrequent (5%) and consistently mild.

Conclusion

This regimen of metronomic capecitabine displayed good activity and excellent tolerability in MBC patients, including those who had previously received the drug at standard doses.     

Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors

Purpose.

To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.

Patients and Methods.

Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m²) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.

Results.

Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m² paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m². At the MTR, coadministration of 800 mg pazopanib and 80 mg/m² paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.

Conclusion.

Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m² when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.     

A modular Phase I study of lenalidomide and paclitaxel in metastatic castration-resistant prostate cancer following prior taxane therapy

Purpose

Lenalidomide, a highly potent immunomodulatory derivative of thalidomide, potentiates the action of paclitaxel in vitro against prostate cancer cell lines in co-culture with mononuclear cells. A modular Phase I study of lenalidomide and paclitaxel in men with metastatic castration-resistant prostate cancer (CRPC) was conducted to assess PSA kinetics with lead-in lenalidomide and the feasibility of the combination.

Methods

Men with metastatic CRPC with prior taxane chemotherapy were planned for single-agent “lead-in” lenalidomide for 21/28 days at dose-levels: ?1 (5 mg), 0 (10 mg), +1 (15 mg), +2 (20 mg), +3 (25 mg); followed by lenalidomide at the same dose and schedule in combination with weekly intravenous paclitaxel 100 mg/m² over 3 h on days 1, 8, 15 every 28 days utilizing a 3 + 3 dose-escalation design.

Results

Dose-limiting toxicity was observed in 4/6 patients with first-cycle combination therapy at the 10 mg dose-level and 3/6 patients at the 5 mg dose-level of lenalidomide, respectively. These included Grade 3 neutropenia precluding planned paclitaxel therapy (n = 3), grade 3 gastrointestinal toxicity (n = 2), chest pain (n = 1) and pulmonary embolism (n = 1). With lead-in lenalidomide, two patients with lymph-node dominant CRPC had a PSA-decline and regression in lymph node disease, respectively. Two of seven evaluable patients had PSA declines by 50% with combination therapy. Progression-free survival was 13 weeks (range 4–35 weeks).

Conclusions

The high dose-limiting toxicity rates observed with lenalidomide and weekly paclitaxel require exploration of alternate dose-schedules of the combination in the second-line setting of CRPC. These early observations suggest distinctive toxicity and efficacy outcomes from thalidomide in combination with paclitaxel.     

Multicenter Phase II study of estramustine phosphate plus weekly paclitaxel in patients with androgen-independent prostate carcinoma

BACKGROUND: The current study determined the efficacy and toxicity of weekly paclitaxel in combination with estramustine phosphate (EMP) in patients with androgen-independent prostate carcinoma (AIPC). METHODS: Patients with progressive AIPC received 90 mg/m2 paclitaxel by 1-hour intravenous infusion weekly for 3 weeks, followed by a 1-week treatment rest. Patients received 140 mg EMP orally 3 times daily on the day before, the day of, and the day after paclitaxel administration. Patients received 1 mg warfarin daily to prevent thromboembolism. RESULTS: Sixty-six patients with progressive AIPC received treatment at 29 centers. Forty-two percent of patients had a 50% decline in prostate-specific antigen (PSA; 95% confidence interval [CI], 30-54%). For 26 patients with bidimensionally measurable disease, the objective response rate was 15% (95% CI, 1-30%). The median time to disease progression was 6.3 months, and the median time to PSA progression was 11.4 months. The median survival period was 15.6 months. Grade 3-4 toxicities were uncommon and included thromboembolism (8%), anemia (3%), neutropenia (3%), and peripheral neuropathy (2%). There was one treatment-related death. CONCLUSIONS: This regimen of EMP plus weekly paclitaxel was an active and well tolerated treatment for patients with AIPC.     

Safety and Efficacy of PF-3512676 for the Treatment of Stage IV Renal Cell Carcinoma: An Open-Label, Multicenter Phase I/II Study

Purpose

Single-agent PF-3512676 (agatolimod), a Toll-like receptor 9 agonist, was examined in an open-label, single-arm, multicenter phase I/II study to determine its maximum tolerated dose (MTD), safety profile, antitumor activity, pharmacokinetics, and immunologic effects in patients with advanced metastatic renal cell carcinoma (RCC).

Patients and Methods

PF-3512676 was administered subcutaneously weekly for up to 24 weeks to 39 adults with stage IV RCC. Patients were excluded if they had received previous therapy other than surgery. Phase I dose escalation began at 0.08 mg/kg, with phase II expansion to 20 patients to estimate objective response rates at 0.16 mg/kg. Doses were subsequently escalated to 0.81 mg/kg according to the phase I design.

Results

An MTD was not reached. One patient who received 0.54 mg/kg had dose-limiting toxicities (grade 3 nonhematologic adverse events [AEs], including anorexia). The most commonly reported AEs were flu-like symptoms and local injection-site reactions of mild-to-moderate severity. The most commonly reported serious AE was grade 3 fatigue in 4 patients (10%). Grade 4 AEs included anemia, exacerbated dyspnea, and polyarthralgia in 1 patient each. Two patients (5%), 1 each in the 0.16-mg/kg and 0.54-mg/kg cohorts, achieved a partial response. Both responses were durable (35 and 40 months).

Conclusion

This was the first study to examine PF-3512676 safety and antitumor activity in patients with advanced RCC. Single-agent treatment was tolerable. At the doses tested, PF-3512676 had modest antitumor activity. Additional studies in combination with other agents or at higher monotherapy doses might be warranted.     

Phase I Study Combining Treatment with Temsirolimus and Sunitinib Malate in Patients with Advanced Renal Cell Carcinoma

Purpose

Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC.

Patients and Methods

Eligibility included advanced RCC and ≤ 2 previous systemic regimens. At the starting dose, temsirolimus 15 mg was administered by intravenous (I.V.) infusion once weekly, and sunitinib 25 mg was administered orally once daily for 4 weeks, followed by a 2-week rest period.

Results

In the first cohort, dose-limiting toxicities (grade 3 treatment-related toxicities that lasted ≤ 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/μL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/μL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents.

Conclusion

Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.     

A phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer

Introduction

Pomalidomide is an investigational immunomodulating drug (IMiD®) that also inhibits angiogenesis and has direct anti-tumour effects. This phase I study was performed to identify the optimal dose of pomalidomide to be used in combination with gemcitabine in the treatment of patients with metastatic pancreatic cancer.

Methods

Eligible patients had histologically documented metastatic adenocarcinoma of the pancreas. No prior gemcitabine for metastatic disease or for primary treatment of locally advanced disease was allowed although prior radiation therapy with 5-flourouracil (5-FU) or gemcitabine as a radiosensitizer was allowed. All patients received gemcitabine 1000 mg/m² IV on days 1, 8 and 15 of a 28 day cycle. Pomalidomide was administered orally on days 1−21 at doses escalated from 2 to 10 mg daily. Patients were re-evaluated every 8 weeks; treatment continued until disease progression or intolerable toxicity occurred.

Results

Twenty-three patients were enrolled with a median age of 62 and Eastern Cooperative Oncology Group (ECOG) performance status 0 (87%) and 1 (13%). The maximum tolerated dose (MTD) was 10 mg/day on days 1−21. Neutropaenia was the most common grade 3/4 toxicity (38%); other grade 3/4 toxicity included deep vein thrombosis (DVT) (22%) and anaemia (9%). While efficacy was not a primary end-point of this study, 3 of 20 evaluable patients (15%) had partial responses and 10 patients (50%) had >50% decrease in CA 19-9 levels.

Conclusions

The combination of pomalidomide and gemcitabine was feasible and safe in most patients receiving first-line chemotherapy for metastatic pancreatic cancer. Neutropaenia, the dose-limiting toxicity, was brief and reversible. Intermittent dosing of pomalidomide allowed substantially higher doses than were previously reported with a continuous schedule. This combination merits further evaluation in the treatment of metastatic pancreatic cancer.