Phase I-II evaluation of intravesical novantrone (mitoxantrone) in superficial bladder cancer

1991 ◽  
Vol 2 (2) ◽  
pp. 153-158 ◽  
Author(s):  
R Sharifi ◽  
M Lee ◽  
M Clayton ◽  
D Lamb ◽  
P Siami ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Superficial Bladder Cancer

Phase I Trial of Intravesical Docetaxel in the Management of Superficial Bladder Cancer Refractory to Standard Intravesical Therapy

2006 ◽  
Vol 24 (19) ◽  
pp. 3075-3080 ◽  
Author(s):  
James M. McKiernan ◽  
Puneet Masson ◽  
Alana M. Murphy ◽  
Manlio Goetzl ◽  
Carl A. Olsson ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Superficial Bladder Cancer ◽  
Transitional Cell ◽  
Maximum Tolerated Dose ◽  
Intravesical Therapy ◽  
Systemic Absorption ◽  
Microtubule Depolymerization ◽  
Grade 3

Purpose Up to 50% of patients treated with intravesical agents for superficial bladder cancer will experience recurrence. Response rates to second-line intravesical therapies range from 20% to 40%. For these high-risk patients, novel agents are necessary to prevent recurrence. Docetaxel is a microtubule depolymerization inhibitor with unique physiochemical properties, making it an excellent candidate for investigation as an intravesical agent. Patients and Methods This phase I trial included patients with recurrent Ta, T1, and Tis transitional cell carcinoma who experienced treatment failure with at least one prior intravesical treatment. Docetaxel was administered as six weekly instillations at a starting dose of 5 mg, with a dose-escalation model used until a maximum tolerated dose (MTD) was achieved. Primary end points were dose-limiting toxicity (DLT) and MTD. Efficacy was evaluated by cystoscopy with biopsy, cytology, and computed tomography imaging. Results Eighteen patients (100%) completed the trial, and the distribution of stages included six patients with Tis, seven with Ta, and five with T1 disease. No grade 3 or 4 DLTs occurred in 108 infusions, and no patient had systemic absorption of docetaxel. Eight (44%) of 18 patients experienced grade 1 or 2 toxicities, with dysuria being the most common. Ten (56%) of 18 patients had no evidence of disease at their post-treatment cystoscopy and biopsy. None of the patients who experienced relapse had disease progression. Conclusion Intravesical docetaxel exhibited minimal toxicity and no systemic absorption in the first human intravesical clinical trial. This suggests that docetaxel is a safe agent for further evaluation of efficacy in a phase II trial.

A phase I study of intravesical Ad-IFN in superficial bladder cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16048-e16048
Author(s):  
C. P. Dinney ◽  
W. F. Benedict ◽  
D. L. Cutler ◽  
M. F. Fisher ◽  
M. A. O'Donnell
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Study ◽  
Prolonged Exposure ◽  
Superficial Bladder Cancer ◽  
Response Duration ◽  
Maximum Tolerated Dose ◽  
Interferon Α ◽  
Anticholinergic Medication ◽  
Open Label

e16048 Background: Intravesical BCG (Bacillus Calmette-Guérin) is the gold standard for treatment of superficial bladder cancer. Recurrence is a significant problem. Intravesical interferon α (IFN) demonstrated complete response (CR) in ∼40% patients with most relapsing <1 year. Intravesical Ad-IFN takes advantage of the bladder to allow prolonged exposure to high concentrations of IFN; this is expected to potentiate durable therapeutic responses. Syn3 is an excipient used to increase adenoviral vector (Ad) transfection. Methods: The phase I study is a nonrandomized, open-label, rising-dose, multi-center study of Ad-IFN in patients with papillary bladder cancer, or carcinoma in situ refractory to BCG. Patients with T1 were not enrolled unless they refused cystectomy. A minimum of 3 subjects were enrolled at each dose level. Adverse events and lab abnormalities were graded according to CTC version 3 criteria. The occurrence of treatment-related Grade 3 or Grade 4 toxicity is considered dose-limiting toxicity (DLT). The maximum tolerated dose is defined as the dose which results in DLT in ≤1/6 subjects. Urine from pre-treatment, posttreatment days 0–7, 10, 14, and 28 were tested for IFN, Syn3, Ad-IFN DNA, and research biomarkers. Blood was assayed for IFN, Syn3, Ad-IFN DNA, anti- adenovirus and anti-IFN antibodies. Results: Intravesical administration of 3×109, 1×1010, 3x1010, 1×1011, or 3×1011 particles/ml of Ad-IFN (75ml) in 1mg/ml Syn3 is safe with only minor initial urgency controlled with anticholinergic medication. Of the 13 evaluable patients, 6 are CR, defined as a negative cytology and biopsy at 3 months. CR patients were offered a second dose. Response duration is variable with longest >1 year. Urinary IFN was seen for all patients in a dose-dependent fashion. TRAIL, IP-10, M65, and M30 were also seen. Conclusions: Initial safety and response activity justify further clinical development. [Table: see text]

Phase I/II Marker Lesion Study of Intravesical BC-819 DNA Plasmid in H19 Over Expressing Superficial Bladder Cancer Refractory to Bacillus Calmette-Guerin

2008 ◽  
Vol 180 (6) ◽  
pp. 2379-2383 ◽  
Author(s):  
Abraham Ami Sidi ◽  
Patricia Ohana ◽  
Shalva Benjamin ◽  
Moshe Shalev ◽  
Janet H. Ransom ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Superficial Bladder Cancer ◽  
Bacillus Calmette Guerin ◽  
Dna Plasmid

916: Phase I Trial of Intra Vesical Docetaxel in the Treatment of Superficial Bladder Cancer Resistant to Standard Intra Vesical Therapy

2005 ◽  
Vol 173 (4S) ◽  
pp. 247-247 ◽  
Author(s):  
James M. McKiernan ◽  
Alana M. Murphy ◽  
Manlio Goetzl ◽  
Puneet Masson ◽  
Manisha Desai ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Superficial Bladder Cancer

275: Intravesical Administration of Gemcitabine in Superficial Bladder Cancer: A Phase I Study with Pharmacodynamic Evaluation. A Phase II Study with Chemoresection of the Marker Lesion

2004 ◽  
Vol 171 (4S) ◽  
pp. 72-72 ◽  
Author(s):  
Ettore De Berardinis ◽  
Gabriele Antonini ◽  
Ana Maria Autran Gomez ◽  
Giovanni Codacci Pisanelli ◽  
Franco Di Silverio ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Superficial Bladder Cancer ◽  
Phase Ii Study ◽  
Intravesical Administration

Activity of intravesical CG0070 in Rb-inactive superficial bladder cancer after BCG failure: Updated results of a phase I/II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4593-4593
Author(s):  
Terence W. Friedlander ◽  
Vivian K. Weinberg ◽  
Alex Yeung ◽  
James Burke ◽  
Donald L. Lamm ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Single Dose ◽  
Phase I ◽  
Multiple Dose ◽  
Superficial Bladder Cancer ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Suppressor Activity ◽  
Remission Duration

4593 Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs commonly in bladder cancer and leads to upregulation of the E2F-1 transcription factor. CG0070 is a replication-competent oncolytic adenovirus genetically modified to express GMCSF under control of the human E2F-1 promoter. Updated results from a phase I study of CG0070 in patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG treatment are presented here. Methods: The V-0046 phase I/II study previously reported the safety and evidence of efficacy of single and multiple doses of intravesical CG0070. Efficacy was determined using quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was assessed immunohistochemically in 18 tumors. Results: 35 patients were treated with either a single dose (n=13) of CG0070 ranging from 1x1012 to 3x1013 viral particles (vp) or with weekly x 6 (n=9) or every 4 week x 3-6 doses (n=13) ranging from 1x1012 to 1x1013 vp per dose. The most common adverse events regardless of schedule were flu-like illness, dysuria, hematuria, bladder spasm, and nocturia. No maximum tolerated dose was reached. Urine GMCSF and CG0070 levels were detectable in almost all patients suggesting in-vivo viral replication. The CR rate in the single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose cohorts. The CR rate for patients with either CIS or Ta tumors was 65% (15/23). Of all responders, 11 recurred with a remission duration ranging from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, remain in remission as of last follow-up with a remission duration ranging from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a complete response. All patients (5/5, 100%) with known phosphorylated Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070 was well tolerated with minimal toxicities. Complete responses were more frequently observed in the multiple-dose cohorts, including durable CRs in patients with inactive Rb and in patients with CIS. Further study in Rb-inactive superficial tumors is warranted.

Updated results of a phase I/II trial of intravesical CG0070 in patients with superficial bladder cancer after BCG failure.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 271-271
Author(s):  
Terence W. Friedlander ◽  
Vivian K. Weinberg ◽  
Alex Yeung ◽  
James Burke ◽  
Donald L. Lamm ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Single Dose ◽  
Phase I ◽  
Multiple Dose ◽  
Superficial Bladder Cancer ◽  
Suppressor Activity ◽  
Dose Cohort ◽  
Remission Duration

271 Background: Loss of retinoblastoma (Rb) tumor suppressor activity occurs commonly in bladder cancer and leads to upregulation of the E2F-1 transcription factor. CG0070 is a replication competent oncolytic adenovirus genetically modified to express GMCSF under control of the human E2F-1 promoter. Updated results from a phase I/II study of CG0070 in patients with recurrent superficial bladder cancer (T1, Ta, Tcis) after BCG treatment are presented here. Methods: The V-0046 phase I/II study previously reported the safety and evidence of efficacy of single and multiple doses of intravesical CG0070. Efficacy was determined using quarterly cystoscopy, biopsy, and/or urine cytology. Tumor Rb status was assessed immunohistochemically in 18 tumors. Results: 35 patients were treated with either a single dose (n=13) of CG0070 ranging from 1x1012 to 3x1013 viral particles (vp) or with weekly x 6 (n=9) or every 4 week x 3 doses (n=13) ranging from 1x1012 to 1x1013 vp per dose. Only one dose limiting toxicity, grade 3 lymphopenia in an every 4 week patient, was observed. The most common adverse events regardless of schedule were flu-like illness, dysuria, hematuria, bladder spasm, and nocturia. Urine GMCSF was detectable in 94% of patients and 58% of patients in the single dose cohort had an increase in CG0070 levels suggesting in-vivo viral replication. The CR rate in the single dose cohort was 23% (3/13), and 64% (14/22) in the multi-dose cohorts. Median follow up for all responders is 9.1 months. Of all responders, 11 recurred with a remission duration ranging from 3.0 - 33.4 months and 6 patients, all in the multiple dose cohorts, remain in remission as of last follow-up with a remission duration ranging from 3.3 – 38.2 months. Phosphorylated (inactive) Rb was detected in 13 of the 18 (72%) patients evaluated. Nine of these 13 patients (70%) had a CR. All patients (5/5, 100%) with known phosphorylated Rb treated in the weekly cohort experienced a CR. Conclusions: CG0070 was well tolerated with minimal local and systemic toxicities. Complete responses were more frequently observed in the multiple-dose cohorts, including durable CRs in patients with phosphorylated Rb. Further study in Rb inactivated tumors is warranted.

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