Phase I-II Study of Paclitaxel, Cisplatin, and Gemcitabine in Advanced Transitional-Cell Carcinoma of the Urothelium

2000 ◽  
Vol 18 (18) ◽  
pp. 3247-3255 ◽  
Author(s):  
J. Bellmunt ◽  
V. Guillem ◽  
L. Paz-Ares ◽  
J.L. González-Larriba ◽  
J. Carles ◽  
...  
Keyword(s):  
Phase I ◽  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Early Onset ◽  
Group Performance ◽  
Locally Advanced ◽  
Transitional Cell ◽  
Fixed Dose ◽  
Grade 3 ◽  
Dose Levels

PURPOSE: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium. PATIENTS AND METHODS: Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance status ≤ 2 and creatinine clearance ≥ 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m2. Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a maximum of six cycles. RESULTS: Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m2 and gemcitabine 1,000 mg/m2 was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up. CONCLUSION: This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.

Phase I Evaluation of Sequential Doxorubicin Gemcitabine Then Ifosfamide Paclitaxel Cisplatin for Patients With Unresectable or Metastatic Transitional-Cell Carcinoma of the Urothelial Tract

2000 ◽  
Vol 18 (4) ◽  
pp. 840-840 ◽  
Author(s):  
Paul M. Dodd ◽  
John A. McCaffrey ◽  
Susan Hilton ◽  
Madhu Mazumdar ◽  
Harry Herr ◽  
...  
Keyword(s):  
Phase I ◽  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Phase I Trial ◽  
Transitional Cell ◽  
Drug Regimen ◽  
Maximum Tolerated Dose ◽  
Major Response ◽  
Grade 3 ◽  
Dose Levels

PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma. PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m2 and gemcitabine 2,000 mg/m2, to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m2 (days 1 to 3); paclitaxel 200 mg/m2 (day 1); and cisplatin 70 mg/m2 (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy. RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses). CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.

Gemcitabine Plus Cisplatin, an Active Regimen in Advanced Urothelial Cancer: A Phase II Trial of the National Cancer Institute of Canada Clinical Trials Group

1999 ◽  
Vol 17 (9) ◽  
pp. 2876-2876 ◽  
Author(s):  
Malcolm J. Moore ◽  
Eric W. Winquist ◽  
Nevin Murray ◽  
Ian F. Tannock ◽  
Susan Huan ◽  
...  
Keyword(s):  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Urothelial Cancer ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Transitional Cell ◽  
Grade 3 ◽  
Intent To Treat ◽  
To Receive

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2′,2′-difluorodeoxycytidine) plus cisplatin in previously untreated patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS: Thirty-one patients with measurable advanced transitional-cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 70 mg/m2 over 1 hour on day 2 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed more than 1 year before study entry. RESULTS: There were six complete responses and 10 partial responses in 28 assessable patients, for anoverall response rate of 16 of 28 (57%). The response rate on an intent-to-treat basis was 16 of 31 patients (52%). The median survival is 13.2 months, with 18 patients still alive at this time. Toxicity was primarily hematologic, with 12 of 31 patients (39%) having ≥ grade 3 granulocytopenia and 17 of 31 (55%) having ≥ grade 3 thrombocytopenia. Two patients had febrile neutropenia. All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia. CONCLUSION: Gemcitabine plus cisplatin is an active regimen for the treatment of urothelial cancer.

Phase I Trial of Intravesical Gemcitabine in Bacillus Calmette-Guérin–Refractory Transitional-Cell Carcinoma of the Bladder

2002 ◽  
Vol 20 (15) ◽  
pp. 3193-3198 ◽  
Author(s):  
Guido Dalbagni ◽  
Paul Russo ◽  
Joel Sheinfeld ◽  
Madhu Mazumdar ◽  
William Tong ◽  
...  
Keyword(s):  
Phase I ◽  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Transitional Cell ◽  
Response Assessment ◽  
Complete Response ◽  
Bacillus Calmette Guerin ◽  
Mixed Response ◽  
Bcg Therapy ◽  
Grade 3

PURPOSE: The aim of this phase I study was to determine the safety and toxicity profile of gemcitabine administered as an intravesical agent in patients with transitional-cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Patients with superficial bladder cancer refractory to intravesical bacillus Calmette-Guérin (BCG) therapy and refusing a cystectomy were considered eligible for the trial. Gemcitabine was given in the bladder for 1 hour twice weekly in 100 mL sodium chloride for a total of six treatments. After a 1-week break, a second course of six treatments over 3 weeks was given, followed by response assessment. Four dose levels were explored: 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg. RESULTS: Eighteen patients completed therapy: three at 500 mg, six at 1,000 mg, three at 1,500 mg, and six at 2,000 mg. No grade 3 or 4 toxicity was observed at 500 mg. At 1,000 mg, three patients developed hematuria and one had a skin reaction resembling grade 3 hand-foot syndrome. Three patients at 1,500 mg had no grade 3 or 4 toxicity. Of six patients at 2,000 mg, one had grade 3 thrombocytopenia and neutropenia without infection. Seven patients had a complete response (negative cytology and posttreatment biopsy), and four patients had a mixed response (negative bladder biopsy but positive cytology). CONCLUSION: Gemcitabine has substantial activity as an intravesical agent in BCG-refractory TCC and warrants further investigation. Therapy given twice weekly was associated with minimal bladder irritation and tolerable myelosuppression. The recommended phase II dose for twice-weekly therapy is 2,000 mg.

Combination Paclitaxel, Carboplatin, and Gemcitabine Is an Active Treatment for Advanced Urothelial Cancer

2001 ◽  
Vol 19 (9) ◽  
pp. 2527-2533 ◽  
Author(s):  
Maha Hussain ◽  
Ulka Vaishampayan ◽  
Wei Du ◽  
Bruce Redman ◽  
David C. Smith
Keyword(s):  
Urothelial Carcinoma ◽  
Cell Carcinoma ◽  
Group Performance ◽  
Locally Advanced ◽  
Transitional Cell ◽  
Target Area ◽  
Number Of Patients ◽  
Visceral Metastases ◽  
Advanced Urothelial Carcinoma ◽  
Grade 3

PURPOSE: To determine the efficacy and toxicity of the drug combination of carboplatin, paclitaxel, and gemcitabine in patients with advanced urothelial carcinoma. PATIENTS AND METHODS: Patients eligible included those with advanced urothelial malignancy of any histology, no previous chemotherapy for metastatic disease, Southwest Oncology Group performance status of 2 or less, serum creatinine levels of 2 mg/dL or less, and adequate bone marrow and hepatic function. Treatment consisted of paclitaxel 200 mg/m2, carboplatin (target area under the curve = 5) on day 1, and gemcitabine 800 mg/m2 on days 1 and 8, repeated every 21 days. RESULTS: Forty-nine patients (44 men and five women) were enrolled; the patients’ median age was 63 years, and their median creatinine clearance was 78 mL/min (range, 26 to 165 mL/min). Forty-three patients had transitional cell carcinoma, and six had squamous cell carcinoma or mixed histology. Ten patients had metastases to lymph nodes only, six had locally advanced disease, four had locally recurrent disease, 24 patients had visceral metastases, and five had soft tissue metastases. Twenty-one patients had disease in one site, 16 in two sites, and 12 in three sites. A total of 272 cycles were administered (median, six cycles; range, 1 to 15 cycles). Major toxicities were grade 3 and 4 neutropenia in 17 and 19 patients, respectively; grade 3 and 4 thrombocytopenia in 15 and six patients, respectively; grade 3 and 4 anemia in 10 and two patients, respectively; grade 3 neuropathy in four patients; and diarrhea in two patients. The incidence of febrile neutropenia was 1.4%; no patients died of drug toxicity. Forty-seven of the 49 patients were assessable for response. Fifteen (32%) patients experienced a complete response, and 17 (36%) patients experienced a partial response (32 of 47 patients, 68%; 95% confidence interval, 56.27 to 82.86). Responses were seen in all sites, including 15 (68%) of 22 patients with visceral metastases. The median survival was 14.7 months, with a 1-year survival of 59%. CONCLUSION: Combination paclitaxel, carboplatin, and gemcitabine is active; an encouraging number of patients with advanced urothelial carcinoma treated with this regimen experienced complete remission.

Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group.

1994 ◽  
Vol 12 (11) ◽  
pp. 2264-2270 ◽  
Author(s):  
B J Roth ◽  
R Dreicer ◽  
L H Einhorn ◽  
D Neuberg ◽  
D H Johnson ◽  
...  
Keyword(s):  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Transitional Cell ◽  
Survival Duration ◽  
Hematologic Toxicity ◽  
Significant Activity ◽  
Grade 3

PURPOSE To assess the efficacy and toxicity of single-agent paclitaxel as first-line chemotherapy in patients with locally advanced or metastatic transitional-cell carcinoma of the urothelium. PATIENTS AND METHODS Twenty-six eligible patients were enrolled onto this cooperative group study and treated with paclitaxel at a dosage of 250 mg/m2 by 24-hour continuous infusion every 21 days until progression or patient intolerance. All patients received recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 5 micrograms/kg/d for at least 10 days during each cycle. RESULTS Eleven of 26 patients (42%; 95% confidence interval [CI], 23% to 63%) demonstrated an objective response, with seven achieving a complete clinical response (CR) (27%; 95% CI, 12% to 48%) and four (15%) a partial response (PR). The median duration of response in the 11 responders is 7+ months (range, 4 to 17), with five responders (four CRs, one PR) remaining progression-free at 5, 6, 10, 12, and 16 months from the start of therapy. The estimated median survival duration for all patients is 8.4 months. Hematologic toxicity consisted of anemia (12% grade 3) and granulocytopenia (4% grade 3, 19% grade 4), with two patients developing granulocytopenic fevers. Nonhematologic toxicity included grade 3 mucositis in 11%, grade 3 neuropathy in 11%, and grade 4 diarrhea in 4%. CONCLUSION Single-agent paclitaxel at this dosage and schedule is one of the most active single agents in previously untreated patients with advanced urothelial carcinoma, and is well tolerated by this patient population when given with hematopoetic growth factor support.

Gemcitabine: a promising new agent in the treatment of advanced urothelial cancer.

1997 ◽  
Vol 15 (12) ◽  
pp. 3441-3445 ◽  
Author(s):  
M J Moore ◽  
I F Tannock ◽  
D S Ernst ◽  
S Huan ◽  
N Murray
Keyword(s):  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Locally Advanced ◽  
Transitional Cell ◽  
Outpatient Basis ◽  
Nonhematologic Toxicity ◽  
Grade 3 ◽  
To Receive

PURPOSE To evaluate the efficacy and toxicity of gemcitabine (2',2'-difluorodeoxycytidine) in previously untreated patients with advanced transitional cell carcinoma. PATIENTS AND METHODS Forty-one patients with measurable advanced transitional cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,200 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed greater than 1 year prior to study entry. All patients were treated on an outpatient basis. RESULTS There were three complete responses and six partial responses seen in 37 assessable patients, for an overall response rate of nine of 37 (24.3%; 95% confidence interval, 12 to 41). Four patients remain in remission at 14, 23, 24, and 31 months. The median survival was 8 months with 17% of patients alive at 2 years. Treatment generally was well-tolerated with three patients having > or = grade 3 nonhematologic toxicity, five having grade 3 neutropenia, two having grade 3 thrombocytopenia, and two episodes of febrile neutropenia. Most patients were able to receive the drug as scheduled with the primary reason for dose reduction or dose delay being neutropenia. CONCLUSION Gemcitabine has promising single-agent activity against urothelial cancer with a favorable toxicity profile. Further studies in combination with other active agents are warranted.

Phase I/II study of vicinium given by intravesical administration in patients with superficial transitional cell carcinoma of the bladder: Phase I results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4580-4580
Author(s):  
D. Fitsialos ◽  
S. Seitz ◽  
E. Wiecek ◽  
M. Rasamoelisolo ◽  
J. Entwistle ◽  
...  
Keyword(s):  
Phase I ◽  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Transitional Cell ◽  
Pharmacokinetic Analysis ◽  
Intravesical Administration ◽  
Bcg Therapy ◽  
Carcinoma Of The Bladder ◽  
Dose Levels

4580 Background: Vicinium is a fusion protein comprised of a humanized scFv, specific for Ep-CAM (epithelial cell adhesion molecule), and a truncated fragment of Pseudomonas exotoxin A. Ep-CAM is highly expressed on carcinoma cells including superficial transitional cell carcinomas (TCC) of the bladder. Vicinium targets and kills Ep-CAM-positive tumors. Results from the Phase I arm of a Phase I/II trial where Vicinium was instilled into the bladders of patients with superficial TCC of the bladder showed the drug to be very well tolerated and showed promising clinical results. Methods: 64 patients with Ep-CAM positive superficial TCC of the bladder, Ta, Tis or T1, Grades 2 or 3 who were refractory or intolerant to BCG therapy were admitted into the study. Dosing comprised a minimum of 3 subjects per dose level through 12 escalating doses. Vicinium was given once/week for 6 consecutive weeks by intravesical administration into the bladder via a catheter at escalating dose levels of 0.1, 0.2, 0.33, 0.66, 1.32, 2.64, 5.28, 10.56, 13.73, 17.85, 23.2 and 30.16 mg/week. All toxicities were assessed according to the NCI CTC v3. Blood samples were collected at different times in the study to determine systemic drug exposure and to assess immunogenicity. Efficacy was explored via biopsy, cystoscopy, urine cytology and FISH. Results: Vicinium was very well tolerated at all doses. Almost all (64/65) patients were positive for the Ep-CAM antigen. Pharmacokinetic analysis showed no evidence of Vicinium in the circulation of any of the patients; however, the majority of patients developed an anti-Vicinium response. Most patients, in particular at the higher doses, showed decreased tumor cell numbers by FISH analysis by the final day of treatment with the greatest sustained effect being observed in patients with the higher percentage Ep-CAM-positive tumors. Conclusions: Vicinium dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels. The early clinical benefit observed with Vicinium strongly supports its development as a promising therapy for superficial transitional cell carcinoma of the bladder. The phase II arm of the trial will confirm the safety and further assess the efficacy of Vicinium at a recommended Phase II dose. [Table: see text]

Repeated Intravesical Instillations of an Adenoviral Vector in Patients With Locally Advanced Bladder Cancer: A Phase I Study of p53 Gene Therapy

2003 ◽  
Vol 21 (12) ◽  
pp. 2247-2253 ◽  
Author(s):  
Lance C. Pagliaro ◽  
Afsaneh Keyhani ◽  
Dallas Williams ◽  
Denise Woods ◽  
Baoshun Liu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bladder Cancer ◽  
Gene Transfer ◽  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Locally Advanced ◽  
Transitional Cell ◽  
P53 Gene ◽  
Advanced Bladder Cancer ◽  
Intravesical Instillations

Purpose: We investigated the feasibility, safety, and biologic activity of adenovirus-mediated p53 gene transfer in patients with locally advanced bladder cancer. Patients and Methods: Patients with measurable, locally advanced transitional-cell carcinoma of the bladder who were not candidates for cystectomy were eligible. On a 28-day cycle, intravesical instillations of INGN 201 (Ad5CMV-p53) were administered on days 1 and 4 at three dose levels (1010 particles to 1012 particles) or on either 4 or 8 consecutive days at a single dose level (1012 particles). Results: Thirteen patients received a total of 22 courses without dose-limiting toxicity. Specific transgene expression was detected by reverse transcriptase polymerase chain reaction in bladder biopsy tissue from two of seven assessable patients. There were no changes in p53, p21waf1/cip1, or bax protein levels in bladder epithelium evident from immunohistochemical analysis of 11 assessable patients. Outpatient administration of multiple courses was feasible and well tolerated. A patient with advanced superficial bladder cancer showed evidence of tumor response. Conclusion: Intravesical instillation of Ad5CMV-p53 is safe, feasible, and biologically active when administered in multiple doses to patients with bladder cancer. Observations from this study indicate that this treatment has an antitumor effect in superficial transitional-cell carcinoma. Improvements in the efficiency of gene transfer and the levels of gene expression are required to develop more effective gene therapy for bladder cancer.

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