Trial Of Docetaxel Research Articles

Long-term follow-up of phase II trial of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer

Background. Chemoradiation improves survival for patients with locally advanced non-small cell lung cancer (NSCLC), but clinical outcomes beyond five years are rarely reported. The aim of the present study was to identify the long-term results of a phase II study of docetaxel and cisplatin with concurrent thoracic radiation. Methods. We previously reported short-term outcomes from the phase II study, which enrolled 42 patients (aged ≤ 75 years) with unresectable stage III NSCLC. We continued to follow these patients for long-term clinical outcomes. Results. At a median follow-up for all patients of 6.3 years (range: 5.2–7.1 years), the median survival time was 2.1 years and the actual five-year survival rate was 31%. Among 14 patients who were progression-free longer than two years, three patients died due to bacterial or fungal pneumonia and one died due to gall bladder cancer. Conclusions. Thirty-one percent of locally advanced patients having NSCLC treated with docetaxel and cisplatin and concurrent thoracic radiation survived beyond five years. Progression-free patients might be cautiously followed up taking precautions against emerging pneumonia.

Preliminary Result of Phase I/II Clinical Trial of Docetaxel, Cisplatin, and Fluorouracil Regimen Induction Chemotherapy for Primary Locoregionally Advanced Nasopharyngeal Carcinoma

To investigate the tolerable dose and short-term efficacy of docetaxel, cisplatin and fluorouracil (TPF) regimen induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) and concomitant chemotherapy for primary locoregionally advanced nasopharyngeal carcinoma (NPC). Naïve patients with locally advanced NPC were enrolled. The TPF regimen consisted of docetaxel at a dose of 60 mg/m2 and cisplatin 60 mg/m2, administered as intravenous infusion on day 1, fluorouracil as a 120-hour continuous intravenous infusion on days 1 to 5. The starting dose of fluorouracil was 450 mg/(m2·day) with a subsequent dose escalation of 50 mg/(m2·day). The maximum-tolerable dose of fluorouracil was defined as the dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Treatment was administered every 3 weeks (defined as one cycle) for three cycles, and IMRT and concomitant chemotherapy were delivered during a 6-week period within 2 to 3 weeks after the completion of chemotherapy. We delineated the primary gross tumor volume (GTV) into two parts: the post-IC primary GTV (GTVpost-IC-NP), and the region of pre-IC primary GTV minus GTVpost-IC-NP (GTVpre-post-IC-NP), which was prescribed to a total dose of 68.1-Gy and 63-Gy in 2.27-Gy and 2.10-Gy daily fractions, respectively. During radiotherapy, Cisplatin at a dose of 80 mg/m2 was given every 3 weeks. The primary end point was progression-free survival, and the secondary end points were respond rate after IC and radiotherapy, overall survival, time to treatment failure, toxic effects. From December 2007 to October 2010, 80 patients with Stage III – IVb (by the UICC 2002 staging system) primary NPC were treated. The maximum-tolerable dose of fluorouracil was established as 550 mg/(m2·day) by 12 patients' treatment, and 74 patients received IC at the dose, in which, 89.2%(66/74) patients finished 3 cycles of IC. The overall and complete respond rate to IC was 99.8% (1/74) and 16.2% (12/74), respectively. During IC, Grade 3 or 4 hematologic adverse events occurred in 23.3% of patients, Grade 3 or 4 diarrhea 7.1%. Radiotherapy delay was not observed, and all patients finished concurrent chemoradiotherapy per protocol. After a median follow-up of 17.6 (3.3 – 33.9) months, 2 patients had local-regional failure, 3 distant metastasis and 1 died. The 18 months progression-free survival rate was 89.0%, overall survival 96.0%, local-regional failure-free 93.9%, and distant metastasis-free 95.1%. TPF regimen induction chemotherapy has excellent short-term efficacy for primary locoregionally advanced NPC.

Myotax: A phase II trial of docetaxel plus non-pegylated liposomal doxorubicin as first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines

AimNon-pegylated liposomal doxorubicin (NPLD) has demonstrated equivalent antitumour activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as a single agent or in combination with cyclophosphamide. This phase II trial was performed to evaluate the efficacy and the safety of NPLD and docetaxel combination in patients with metastatic breast cancer previously exposed to adjuvant anthracyclines. Patients and methodsThirty-four patients received NPLD 60mg/m2 and docetaxel 75mg/m2 in a 21-day cycle as first-line therapy of metastatic breast cancer. Treatment was planned for six cycles and was continued until progression or toxicity. ResultsObjective response rate among response-assessable patients was 79% (95% CI (confidence interval), 64–94%) and 27% (95% CI, 11–43%) presented a complete response. Median progression free survival was 11.3months (95% CI, 6.2–13.3months) and median overall survival was 28.2months (95% CI, 16–36.4months). Symptomatic grade 3 cardiotoxicity occurred in 15% of cases and febrile neutropenia in 47% of the patients. ConclusionsThe combination of NPLD and docetaxel demonstrated high antitumour activity in a population of metastatic breast cancer patients exposed to adjuvant anthracyclines and showed an unexpected and unexplained 15% symptomatic left ventricular systolic dysfunction rate.

Stromal targeted therapy in bone metastatic prostate cancer: promise delivered

Stromal targeted therapy in bone metastatic prostate cancer: promise delivered

An economic analysis of the INTEREST trial, a randomized trial of docetaxel versus gefitinib as second-/third-line therapy in advanced non-small-cell lung cancer

BackgroundThe INTEREST (IRESSA NSCLC Trial Evaluating Response and Survival against Taxotere) trial compared gefitinib with docetaxel (Taxotere) in pretreated advanced non-small-cell lung cancer (NSCLC). Noninferiority for overall survival was concluded. Gefitinib had a better toxicity profile and greater improvements in quality of life (QoL). We undertook a cost-consequence analysis to estimate the direct medical costs of gefitinib compared with docetaxel. Patients and methodsSummary data from INTEREST were used to derive resource utilization and direct costs from treatment start until drug discontinuation. Costs for treatment, adverse events, outpatient visits and investigations were calculated. Mean total cost-per-patient-per-arm was determined, and incremental cost was calculated. Utility values were generated from Functional Assessment of Cancer Therapy - Lung scores and compared between arms. ResultsIncremental mean overall cost per patient for gefitinib over docetaxel was CAD$5161. Drug was the major contributor to overall cost in both arms. Longer mean duration of gefitinib therapy (134 versus 91 days) contributed to the incremental cost difference. The cost per 21-day cycle was similar in both arms ($1963 docetaxel, $2095 gefitinib). ConclusionThe modest increase in cost associated with gefitinib supports its use as an alternative to docetaxel as second-line treatment of advanced NSCLC, particularly given the improvements in QoL, patient preference for oral therapy and better toxicity profile with gefitinib.

Multicenter Phase I/II Study of Docetaxel, Cisplatin and Fluorouracil Combination Chemotherapy in Patients with Advanced or Recurrent Squamous Cell Carcinoma of the Esophagus

Objective: Esophageal squamous cell carcinoma (ESCC) is refractory to current therapeutic regimens and more effective therapies are imperative. To this end, we conducted a multicenter phase I/II trial of docetaxel, cisplatin, and fluorouracil (DCF) combination chemotherapy for ESCC. Methods: The study subjects were 46 patients with advanced or recurrent ESCC. Treatment included docetaxel at 60, 70, and 75 mg/m², cisplatin at 70 mg/m² on day 1, and daily fluorouracil at 700 mg/m² on days 1 through 5. The recommended dose of docetaxel was determined in phase I, while the response rate (RR) and progression-free survival rates were analyzed in phase II. Results: The recommended dose was determined to be 70 mg/m² in phase I. In phase II, the RR was 72.5%. Interim analysis showed median and 1-year progression-free survival of 14 months and 55.6%, respectively. Grade 3/4 toxicities of leukopenia and neutropenia occurred in 72.5 and 90% of patients, respectively. No treatment-related death was recorded. Surgical resection was subsequently performed in 20 patients after chemotherapy, and curative resection was achieved in 19. Conclusion: DCF was tolerable and effective for advanced and recurrent ESCC. Such findings might encourage a change in the treatment strategy for ESCC.

SCOTCERV: A phase II trial of docetaxel and gemcitabine as second line chemotherapy in cervical cancer

Objective The aim of the study was to determine the response rate and response duration of cervical cancer previously treated by cisplatin (with or without radiation) to a combination of docetaxel and gemcitabine. Secondary endpoints were assessment of toxicity and quality of life (QoL) of patients receiving the treatment. Methods This was a multicentre phase II trial of 3 weekly docetaxel 75 mg/m 2 day 1 (reduced to 60 mg/m 2 after 32 cycles had been administered) and gemcitabine 1000 mg/m 2 (days 1 and 8). A two stage Gehan design was used initially. Twenty-nine patients recruited had disease outside the irradiated pelvis (Group 1), and 21 had disease confined to the irradiated pelvis (Group 2). The target response for the Gehan 2 design was 25% (Group 1) and 10% (Group 2). Results The overall response rate for Group 1 was 21.4% (95% CI 8.3–41.0%). Amongst those who had at least 3 cycles of chemotherapy the response rate was 27.3% (95% CI 10.7–50.2%). The median survival was 7.3 months (95% CI 5.4 to 9.2 months) with 39.3% (95% CI 21.7–56.5%) alive at 1 year. In Group 2 the overall response rate was 9.5% (95% CI 1.2%–30.4%). The response rate for those who had at least 3 cycles of chemotherapy was 12.5% (95% CI 1.6–38.4%). The median survival was 7.9 months (95% CI 2.2–13.6 months). Toxicity was mainly haematological with 51% developing grade 3 or 4 neutropenia after at least 1 cycle of chemotherapy. QoL showed a significant deterioration from baseline for physical and role function but there was an improvement in emotional function during treatment. Conclusion Response rates and survival duration were similar to those reported following treatment with platinum based doublets. In view of the relatively poor response rates (no more than 36%) to conventional chemotherapy future developments should be a combination of chemotherapy and biological agents such as VEGFR inhibitors.

Gefitinib versus Docetaxel for Previously Treated NSCLC—Response

Gefitinib obtained approval in Korea in 2003 based on the result of IDEAL-1, which had shown a higher response rate of 27.5% than that of 7.1% in a docetaxel trial ([1, 2][1]). Therefore, at the time of designing our trial, unlike other new agents waiting for approval, gefitinib was already being

Long-term follow-up of phase III trial of docetaxel and cisplatin (DP) versus mitomycin, vindesine, and cisplatin (MVP) with concurrent thoracic radiation therapy (TRT) for locally advanced non-small cell lung cancer (OLCSG 0007).

7048 Background: Although overall survival (OS) and progression-free survival (PFS) tended to be longer in the DP arm than in the MVP arm, there was no significant difference in the first report (A...

A randomized, double-blind phase II trial of docetaxel plus prednisone (DP) combined with either AT-101 or placebo for the first-line therapy of metastatic castration-resistant prostate cancer (CRPC)

125 Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 protein family has broad preclinical activity including synergy with docetaxel (D). AT-101 has demonstrated activity alone a...

The association of PTEN loss on outcome in patients with early high-risk prostate cancer (CaP) treated with adjuvant docetaxel following radical prostatectomy (RP).

4576 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is common and has potential clinical and therapeutic value in CaP. We examined the PTEN status of primary tumors in pts who underwent adjuvant docetaxel tx in a prospective clinical trial. Methods: Of the 77 pts enrolled in a prospective multi-institutional adjuvant docetaxel trial (TAX 2501, J Urol 2007), we prospectively collected 56 primary tumor pathology specimens suitable for analysis of PTEN status by immunoreactivity (IHC) and/or fluorescence in situ hybridisation (FISH) assay. Protocol defined progression included a PSA of ≥ 0.4 ng/ml, radiological/pathological evidence of recurrent disease or death from any cause. Univariate and multivariable analyses based on the Cox proportional hazards regression model were used to analyze the independent association of PTEN and other known prognostic factors with progression free survival (PFS). Results: PTEN loss was observed in 37/56 pts (66%). Pts with PTEN loss vs detectable PTEN were balanced regarding clinical stage, combined Gleason score, seminal vesicles and surgical margins involvement, and lymph nodes status. Pts with a detectable PTEN had a significantly higher pre-RP PSA (median 14 vs 8.6 ng/ml, p=0.015). 41/56 (73.2%, median followup of 37.5 months, range 10.4 to 44.5) progressed with an overall median PFS of 13 months (mos) (95% CI 9.8-15.8). Independent prognostic factors of progression by multivariate analysis were: seminal vesicles involvement (HR 2.19, p=0.024), combined Gleason score 9-10 (HR 2.46, p=0.027) and PTEN loss (HR 2.36, p=0.037). PFS on pts without PTEN loss (median not reached at a followup time of 37.5 mos, range 10.4 – 44.5 mos) was significantly longer (log rank test, p = 0.026) compared to those with undetectable PTEN (median PFS 12.9 mos, 95% CI 9.7-15.3). Conclusions: PTEN loss may be an independent prognostic factor associated with poorer outcome of pts with early high risk CaP treated with adjuvant docetaxel following RP. These findings may have important prognostic and therapeutic implications in CaP.

A double-blind randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated advanced urothelial cancer.

LBA239 Background: Vandetanib (V) is a novel small-molecule inhibitor that targets key signaling pathways in cancer including VEGF and EGF. V in combination with docetaxel (D) was assessed in patients (pts) who received prior platinum-based chemotherapy for advanced urothelial cancer (UC). Methods: Patients eligible for this randomized, multicenter, double-blind, investigator-initiated trial had metastatic UC after failure of prior platinum-based chemotherapy. Up to 3 prior therapies were allowed including paclitaxel. The primary objective was to determine whether once-daily oral V (100 mg) + D (75 mg/m2 IV q21 days) prolonged progression-free survival (PFS) vs. placebo (P) + D (80% power to detect 60% improvement in median PFS with 1-sided α=0.05). Patients on D+P, had the option to cross over to single agent V. Overall survival (OS), overall response rate (ORR), stable disease (SD), and safety were secondary objectives. Results: One-hundred and forty-two pts were enrolled at 16 institutions, 68% men; median age 65y; ECOG PS 0/1: 52%/48%; visceral involvement: 66%. 80% of patients had ECOG PS 1 and/or visceral metastases. 44% of patients had 2 or more prior systemic therapies and 15% had prior paclitaxel. Baseline characteristics were balanced in both arms. Median PFS was 11.1 weeks (wks) for D+V arm vs. 6.9 wks for D+P arm (HR=1.04, p=0.92). Median OS was 25.4 wks for the D+V arm vs. 30.6 wks for the D+P arm (HR 1.21, p=0.35). ORR was 7.1% for the D+V arm vs. 11.1% for the D+P arm (OR=0.6, 90% CI [0.2–1.6]). SD or better rates were 50.0% vs. 37.5% on D+V and D+P, respectively. As of December 2010, 5 pts were on therapy and 70% of pts died. Median follow-up for pts still alive is 7.2 months. Treatment-related grade >3 toxicities for D+V arm was 60% vs. 36% for the D+P arm (p=0.055) and were generally manageable (grade 4, 14% vs. 11%). Grade >3 toxicities that were more commonly seen in the D+V arm were rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%). Conclusions: In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR or OS. Toxicities were greater but manageable. [Table: see text]

A randomized, double-blind phase II trial of docetaxel plus prednisone (DP) combined with either AT101 or placebo for the first-line therapy of metastatic castration-resistant prostate cancer (CRPC).

125 Background: AT-101 (A), a small molecule oral inhibitor of the Bcl-2 protein family has broad preclinical activity including synergy with docetaxel (D). AT-101 has demonstrated activity alone and in combination with D in D-refractory patients with metastatic CRPC. Methods: A randomized, double-blind, placebo-controlled phase II trial was conducted to compare the combination of DP with either A or placebo in chemo-naive men with progressive metastatic CRPC. A key requirement was progression (bone scan, RECIST or rising PSA ≥ 2 ng/mL) despite androgen deprivation. Stratification factors were pain and performance status. Patients received DP (75mg/m2 day 1; 5mg PO b.i.d.) Q 21 days (1 cycle) with either A (40 mg b.i.d.) or placebo PO on days 1–3. Radiological assessments were performed every 3 cycles. Primary endpoint was overall survival (OS) and 221 patients were planned for 110 events (80% power, HR 0.67, 1-sided alpha 0.1). Results: 221 patients were randomized to ADP or placebo-DP and baseline factors were balanced. Efficacy outcomes (OS, PFS, PSA declines, disease control) were not significantly different ( Table ). In a subgroup of patients with poor-risk CRPC (n=34), efficacy endpoints appeared to favor ADP with a median OS of 19 months vs.14 months for placebo-DP. Grade 3/4 AEs that occurred with higher incidence in the ADP arm compared to placebo-DP included cardiac AEs (5% vs. 2%), lymphopenia (23% vs. 16%), neutropenia (47% vs. 40%), ileus (2% vs. 0%) and pulmonary embolism (6% vs. 2%). Conclusions: The combination of AT-101 with DP in men with chemonaive metastatic CRPC was well tolerated but did not extend OS compared to placebo-DP. There was a potential benefit in a subset of high-risk patients. [Table: see text] [Table: see text]

Caveolin-1 as a biomarker of Src family kinase/Abl inhibition in castrate-resistant prostate cancer.

45 Background: Bone metastases cause significant morbidity in men with castrate-resistant prostate cancer (CRPC). Caveolin-1 (Cav-1), a Src kinase substrate, is overexpressed in primary prostate cancer (PCa) and in PCa bone metastases. In addition, PCa-derived and secreted Cav-1 contributes to malignant progression. We reasoned that Cav-1 may serve as a biomarker of dasatinib (a Src family kinase [SFK]/Abl inhibitor) activity in CRPC patients enrolled in a phase II clinical trial of docetaxel plus dasatinib. Methods: Levels of prostate-specific antigen (PSA), Cav-1, and markers of bone turnover were measured from baseline and cycle-2, day-1 samples from patients (n = 32) enrolled in this trial. Changes in these markers were stratified by response (responders [R] vs. nonresponders [NR]) and by predominant disease site (lymph node vs. bone). We evaluated Cav-1 expression in human PCa bone metastases samples from trial patients by immunohistochemistry. In parallel, Cav-1 secretion in response to dasatinib treatment was analyzed in PCa cells and osteoblasts. Results: Serum Cav-1 levels correlated directly with PSA levels in responding patients with node-positive disease (R vs. NR, p = 0.08) but correlated inversely in responding patients with bone-predominant disease (R vs. NR, p = 0.001). Serum from a separate cohort of patients treated with docetaxel only showed no effect on serum Cav-1 levels (R vs. NR, p = 0.85). Levels of Cav-1 were high in the active OBLs in bone specimens with PCa metastases, but not in bone specimens without metastases. Dasatinib treatment led to reduced secretion of Cav-1 in PC-3 and DU145 PCa cells but to increased secretion of Cav-1 in primary mouse osteoblasts or pre-osteoblast MC3T3-E1 cells. Conclusions: Our results suggest that serum Cav-1 serves as a novel discriminating biomarker for SFK/Abl inhibition in both node-positive and bone-metastatic CRPC. The expression of Cav-1 in OBLs of patients with PCa bone metastases suggests that tumor-associated OBLs are an important source of Cav-1 production in bone marrow. Our data provide evidence that the increase in serum Cav-1 in these patients with bone disease likely occurs through a direct effect of dasatinib on osteoblasts. No significant financial relationships to disclose.

Phase II Trial of docetaxel and bevacizumab in recurrent ovarian cancer within 12 months of prior platinum-based chemotherapy

Objective: Bevacizumab has activity in ovarian cancer (OC). Docetaxel is an active chemotherapeutic in recurrent OC and the combination with bevacizumab appears to be tolerable and efficacious in other cancers. We therefore studied the efficacy and tolerability of combination docetaxel and bevacizumab in patients with recurrence of OC within one year of platinum-based therapy.

Association of PTEN loss with outcome of patients (pts) with early high-risk prostate cancer (CaP) treated with adjuvant docetaxel following radical prostatectomy (RP).

43 Background: Loss of the PTEN tumor suppressor and subsequent activation of the PI3K pathway is common and has potential clinical and therapeutic value in CaP. We examined the PTEN status of primary tumors in pts who underwent adjuvant docetaxel tx in a prospective clinical trial. Methods: Of the 77 pts enrolled in a prospective multi-institutional adjuvant docetaxel trial (TAX 2501, J Urol 2007), we prospectively collected 56 primary tumor pathology specimens suitable for analysis of PTEN status by immunoreactivity (IHC) and/or fluorescence in situ hybridisation (FISH) assay. Protocol defined progression included a PSA of ≥ 0.4 ng/mL, radiological/pathological evidence of recurrent disease or death from any cause. Univariate and multivariable analyses based on the Cox proportional hazards regression model were used to analyze the independent association of PTEN and other known prognostic factors with progression free survival (PFS). Results: PTEN loss was observed in 37/56 pts (66%). Pts with PTEN loss vs detectable PTEN were balanced regarding clinical stage, combined Gleason score, seminal vesicles and surgical margins involvement, and lymph nodes status. Pts with a detectable PTEN had a significantly higher pre-RP PSA (median 14 vs 8.6 ng/mL, p=0.015). 41/56 (73.2%, median followup of 37.5 months, range 10.4 to 44.5) progressed with an overall median PFS of 13 months (mos) (95% CI 9.8–15.8). Independent prognostic factors of progression by multivariate analysis were: seminal vesicles involvement (HR 2.19, p=0.024), combined Gleason score 9–10 (HR 2.46, p=0.027) and PTEN loss (HR 2.36, p=0.037). PFS on pts without PTEN loss (median not reached at a followup time of 37.5 mos, range 10.4–44.5 mos) was significantly longer (log rank test, p = 0.026) compared to those with undetectable PTEN (median PFS 12.9 mos, 95% CI 9.7–15.3). Conclusions: PTEN loss may be an independent prognostic factor associated with poorer outcome of pts with early high-risk CaP treated with adjuvant docetaxel following RP. These findings may have important prognostic and therapeutic implications in CaP. No significant financial relationships to disclose.

Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer

Background:Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy.Methods:Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15–30 mg m−2 per week and cisplatin 15–30 mg m−2 per week in six planned dose levels (DLs) in 3–6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy.Results:A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m−2, cisplatin 15 mg m−2) and grade 3 nausea in DL2 (20 mg m−2, 15 mg m−2). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial).Conclusion:Cisplatin and docetaxel each 30 mg m−2 per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.

A Phase II Trial of Docetaxel With Bevacizumab as First-line Therapy for HER2-Negative Metastatic Breast Cancer (TORI B01)

Introduction Addition of the antiangiogenic agent bevacizumab to paclitaxel significantly improves response rates and progression-free survival for metastatic breast cancer (MBC). To assess the activity of docetaxel plus bevacizumab, a multicenter phase II trial was conducted. Patients and Methods Patients with measurable first-line HER2/ neu—negative MBC were eligible. This trial began as a 2-arm study with a docetaxel-alone arm. When bevacizumab became widely available, it was converted to a 1-arm open-label trial of docetaxel/bevacizumab. Patients enrolled in the docetaxel-alone arm were permitted to cross over to docetaxel/bevacizumab. Patients received bevacizumab 15 mg/kg and docetaxel 75 mg/m 2 intravenously (I.V.) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Results From March 2005 to September 2006, 76 patients were enrolled. Of the 7 patients who were randomized to docetaxel alone, 6 crossed over to docetaxel/bevacizumab (included in the safety analysis only). Two patients were found to be ineligible before receiving drug. Efficacy data are based on the 67 patients who were originally enrolled in the docetaxel/bevacizumab arm and received at least 1 dose of study medication. The confirmed objective response rate is 51% (34 of 67) with 9% complete responses (6 of 67) and 42% partial responses (28 of 67). Nine additional patients (13%) had stable disease lasting ≥ 6 months. With a median follow-up of 21.7 months, the median time to progression is 9.3 months, and median overall survival is 26.3 months. Common grade 3/4 adverse events included neutropenia (33%), leukopenia/lymphopenia (25%), fatigue (22%), infection (17%), pain (16%), and hypertension (9%). Conclusion Docetaxel/bevacizumab was generally well tolerated with manageable toxicity and promising efficacy results.

A phase II trial of docetaxel, cisplatin, and 5-fluorouracil (TPF) in locally advanced and metastatic carcinoma of the penis (CRUK/09/001).

TPS240 Background: Chemotherapy for penile cancer is used mainly as palliation of metastatic disease. It also has a role as treatment for locally advanced disease but the rarity of the disease has hampered attempts to define an evidence base for its use. Combined cisplatin (P) and 5-fluororacil (F) has been used for treatment of squamous cell carcinoma (SCC) of the penis since 1990. Pathological similarities to head and neck SCC suggest that addition of docetaxel (T) to an established platinum-based regimen may lead to improved therapeutic benefits. The purpose of the trial is to determine the activity ofTPF chemotherapy in penile cancer Methods: This single stage phase II trial is the only UK-wide trial for penile cancer. Eligible patients (pts) have histologically proven SCC of the penis staged M1; M0, T4 any N; M0, any T, N3 or inoperable N2; or M0, any T, N1 where chemotherapy is to be offered as first-line therapy. Pts must have measurable disease and be fit to receive TPF as palliative or definitive treatment or as treatment for relapse. All pts receive three 21 day cycles of: T 75mg/m2 day 1, P 60mg/m2 day 1, F 750mg/m2/day (days 1-5). Fourteen or more responses in 26 pts are required to conclude a response rate of 60% or more (p0=0.35, p1=0.60, α=0.1, β=0.2; Fleming-A'Hern exact methods). The primary endpoint is overall response rate (RECIST) assessed by MRI/CT scan at completion/discontinuation of trial treatment. The proportion of pts with inoperable locoregional disease rendered operable following TPF, safety, tolerability, and progression-free and overall survival are secondary endpoints. The trial opened in September 2009. To end 2009, 4 pts have been recruited of which two have completed trial treatment and remain on follow-up. The National Cancer Research Institute's Penile Cancer Studies Group plans further studies. If results suggest a high response rate, they are likely to lead to an expanded phase II TPF programme in two settings: as neoadjuvant therapy (in operable and inoperable disease); and as palliation of metastatic disease. The trial also takes the first steps to defining a standard of care for synchronous chemoradiotherapy as consolidation for inoperable locoregional disease. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Pfizer, Roche, sanofi-aventis sanofi-aventis

A Phase I Clinical Study of High Dose Ketoconazole Plus Weekly Docetaxel for Metastatic Castration Resistant Prostate Cancer

This phase I study of high dose ketoconazole and docetaxel was designed against castration resistant prostate cancer to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of co-administered docetaxel and ketoconazole. Patients with metastatic castration resistant prostate cancer received weekly docetaxel for 3 of every 4 weeks plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole). The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly, increasing from 5 to 43 mg/m(2), with starting doses of 600, 800 or 1,200 mg ketoconazole daily. Decreases in prostate specific antigen of 50% or greater were seen in 62% of patients. Of 25 patients with soft tissue disease 7 (28%) had a partial response. Median overall survival was 22.8 months and was significantly greater in docetaxel naïve patients than in patients pretreated with docetaxel (36.8 vs 10.3 months, p = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (p <0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1,200 mg daily, 1.6-fold with 800 mg daily and approximately 1.3 to 1.5-fold with 600 mg daily. Combination regimens using 600 mg ketoconazole daily were fairly well tolerated and the maximum tolerated dose of docetaxel was 32 mg/m(2). Results suggest that the combination has significant antitumor activity in castration resistant prostate cancer. The long survival in the docetaxel naïve cohort warrants additional, larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.