A combined phase I/II trial of intravesical nanoparticle albumin-bound paclitaxel in the treatment of refractory non–muscle- invasive transitional cell bladder cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16047-e16047
Author(s):  
L. Barlow ◽  
M. Laudano ◽  
M. Mann ◽  
M. Desai ◽  
D. Petrylak ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Transitional Cell ◽  
Intravesical Therapy ◽  
Systemic Absorption ◽  
Imaging Results ◽  
Muscle Invasive ◽  
Ongoing Phase

e16047 Background: Up to 50% of patients treated with intravesical agents for non-muscle-invasive bladder cancer will recur. Response rates to current second line intravesical therapies average less than 20%. For these high risk patients, novel agents are necessary. Our previously completed phase I trial showed docetaxel to be a safe and efficacious agent for intravesical therapy. Nanoparticle albumin-bound (nab-) paclitaxel has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy and is therefore an appropriate candidate for further investigation as an intravesical agent. Methods: The ongoing phase I component of this combined phase I/II trial began enrollment on 1/1/08 and has reached 72% accrual as of 1/1/09. Inclusion criteria include recurrent high grade (HG) Ta, T1 and Tis transitional cell carcinoma failing at least one prior regimen with any intravesical agent. In phase I, 6 weekly instillations of nab-paclitaxel were administered beginning at a dose of 150 mg with a dose escalation model used until a maximal tolerated dose (MTD) was achieved. The primary endpoints were dose- limiting toxicity (DLT) and MTD; the secondary endpoint was response rate. Efficacy was evaluated by cystoscopy with biopsy, cytology, and CT imaging. Results: 13/18 patients have enrolled in this phase I trial to date, and the distribution of stages included 5 patients with Tis, 4 patients with HGTa, and 4 patients with HGT1. No patient has had any systemic absorption of nab-paclitaxel as measured by HPLC assays, and no grade 3 or 4 DLT has been encountered. Fifty-four percent (7/13) patients were noted to experience grade 1 toxicities, with dysuria being the most common. Forty-two percent (5/12) of completed patients had no evidence of disease at their post-treatment cystoscopy. None of the patients who developed recurrent disease have had disease progression. Conclusions: Intravesical nab-paclitaxel has exhibited minimal toxicity and no systemic absorption in the first ever human intravesical dose escalation trial. Upon completion of this ongoing phase I trial, we plan to evaluate this agent in a larger phase II efficacy study. No significant financial relationships to disclose.

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.

The Use of DT388-IL3 Fusion Protein in Patients with Refractory Acute Myeloid Leukemia(AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4513-4513
Author(s):  
Debashish Misra ◽  
Arthur Frankel ◽  
Philip Hall ◽  
Tie Fu Liu ◽  
Jennifer Black ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Phase I ◽  
Cell Lines ◽  
Dose Level ◽  
Dose Escalation ◽  
Preliminary Data ◽  
Phase I Trial ◽  
Progression Of Disease ◽  
Post Infusion ◽  
Ongoing Phase

Abstract Background: Although complete remission rates for AML are near 70% with combination induction and consolidation chemotherapy, most patients will relapse and die from the disease or treatment complications. New agents with unique mechanisms are needed. One such class of therapeutics are fusion proteins consisting of protein synthesis inactivating peptide toxins fused to tumor cell selective ligands. DT388-IL3 is one such fusion protein. Rationale: In preclinical studies, DT388-IL3 was cytotoxic to the IL3 receptor expressing leukemia cell lines but not toxic to IL3 receptor negative cell lines. This agent was less toxic to normal progenitors and not toxic to early hematopoietic stem cells. The majority of AML progenitors overexpress IL3 receptors. Animal model work in mice bearing human leukemia cells has demonstrated anti-leukemia efficacy which is dose dependent with this agent. Toxicities in monkeys include vascular leak syndrome and pancytopenia observed only at the highest doses. The MTD in monkeys was estimated at 60mcg/kg/day. We report preliminary data on the use of DT388-IL3 fusion protein in humans from an ongoing phase I trial. Pharmacokinetics; clinical and immune response to this novel fusion protein are also being followed. Patients and Methods: Patients with refractory AML were eligible. The first dose level was qd M-W-F X six doses of DT388-IL3 at 4mcg/kg/day with dose escalation planned for subsequent patients. Patients with progression of disease or unacceptable study drug toxicity were to be removed from the study. Toxicity was graded according to NCI CTCAE version 3.0. Three patients have been treated with DT388-IL3. Serum samples were collected and will be assayed for anti-DT388-IL3 antibodies prior to and after treatment. Blood samples were obtained to measure circulating levels of active DT388-IL3 and its half life. Patient blasts were also collected prior to treatment for later analysis of expression of IL3 receptors. Result: Two patients tolerated the treatment schedule(of six doses) without any significant toxicities. Mild fever, headaches, nausea were noted. Both of these patients had progression of disease-one during treatment and one on day 15 bone marrow biospy. The above mentioned patients died secondary to disease complications at 2 weeks and 18 weeks after their last dose of the study agent respectively. DT388-IL3 levels on these two patients post infusion were below the the reliable detectable limits of the assay. The third patient became febrile and hypotensive after the first dose. The hypotension persisted and she did not receive any further doses. This patient is alive 5 weeks later with supportive care alone. DT388-IL3 levels following this patient’s dose are as follows: 2min post infusion 34.3ng/ml, 30min post infusion 1.9ng/ml, 60min post infusion 0.075ng/ml, 120min post infusion 0.003ng/ml, 240min post infusion undetectable. Conclusion: Preclinical/animal studies suggest that DT388-IL3 has anti-leukemia efficacy. Preliminary data from our ongoing phase I trial reveals minimal study agent related toxicity and no life threatening complications at this first dose level. Dose escalation is planned as per protocol.

Results of the phase I trial of cetuximab with mitomycin c and 5-fluorouracil concurrent with radiotherapy treatment in patients with muscle-invasive bladder cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 368-368
Author(s):  
Syed A. Hussain ◽  
Carey Hendron ◽  
Laura Buckley ◽  
Lynne Dickinson ◽  
Isabel Syndikus ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Mitomycin C ◽  
Phase I Trial ◽  
Disease Free Survival ◽  
Dose Intensity ◽  
Complete Response ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

368 Background: Synchronous chemo-radiotherapy is an alternative to cystectomy in patients with muscle invasive bladder cancer (MIBC). BC2001 trial reported improved local control in patients randomised to synchronous chemo-radiotherapy compared to radiotherapy alone (James, Hussain, Hall et al NEJM 2012). TUXEDO trial reports phase I trial results with additional weekly cetuximab (Cet) in combination with Mitomycin c (MMC), 5-Fluouracil (5-FU) and concurrent radiotherapy (RT). Methods: This two centre phase I trial recruited 7 patients with MIBC in Queen Elizabeth Hospital Birmingham and Clatterbridge Cancer Centre Liverpool to synchronous chemotherapy using Loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2, continuous infusion 5-FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC12mg/m2on day 1 in combination with radical RT treatment 64 Gys in 32 fractions. The primary endpoint was to assess toxicity. Secondary end- points included 3 months pathological complete response, loco-regional disease-free survival and overall survival. Results: Median age of patients was 70 (range: 60-75) years, all were male, 6 had received prior neoadjuvant chemotherapy. Two patients had T2B, 3 T3A and 2 T3B disease, all had G3, TCC disease, 6 patients had neo-adjuvant chemotherapy. All 7 patients completed RT as planned except for 1 who withdrew from trial after 5 weeks of protocol treatment due to relocation. Median dose intensity for Cet and MMC was 97.6% and for 5-FU was 99.4%. Grade 3 toxicity to report was maculopapular rash in 3 patients. Grade 2 toxicities include UTI/ frequency/ nocturia / fatigue /constipation / hypokalemia/epistaxis/palmar-plantar reported in 3/1/1/1/1/1/1/2 cases respectively. Grade 2 maculo-papular rash was reported in 3 cases. All seven patients have achieved complete responses at 3 months cystoscopic assessment. Patients continue on surveillance as per TUXEDO trial protocol. Conclusions: Synchronous chemotherapy with Cet and 5FU/MMC concurrent with radical RT is safe to deliver. Complete response rates are encouraging and a phase II trial with added centres within UK is being launched. Clinical trial information: NOT KNOWN.

Single-arm phase I/II study of the safety and efficacy of OncoTherad immunomodulator in patients BCG-refractory or relapsed non-muscle invasive bladder cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16000-e16000
Author(s):  
Wagner José Fávaro ◽  
Sonia Regina Iantas ◽  
Juliana Mattoso Gonçalves ◽  
Eduardo Augusto Rabelo Socca ◽  
Nelson Duran ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Tumor Recurrence ◽  
Invasive Bladder Cancer ◽  
Intravesical Therapy ◽  
Urinary Cytology ◽  
Effective Treatment Option ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

e16000 Background: There is no effective intravesical second-line therapy for high-grade non-muscle-invasive bladder cancer (HGNMIBC) when Bacillus Calmette-Guerin (BCG) fails. In this scenario, a new perspective is represented by OncoTherad immunomodulator. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits antitumor properties. The aims of the study were to evaluate the efficacy and safety of OncoTherad immunomodulator for BCG-refractory or relapsed HGNMIBC. Methods: We carried out a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/II study in 15 (10 male, 5 female) consecutive patients with HGNMIBC-refractory or relapsed (≥ 1 previous course of BCG intravesical therapy). Patients with muscle-invasive disease were excluded. OncoTherad regimen consisted of an induction course of 6 weekly intravesical instillations followed by a maintenance course of 1 monthly instillation until completing 1 year of treatment. Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy, ultrasound and urinary cytology. The primary endpoint was recurrence-free survival (RFS) rate, and secondary endpoint was safety response. The recurrence was defined as histology proven tumor recurrence (any grade), and monitored at 3-month intervals. Results: The median age and follow-up were 71 years and 14.0 months, respectively. A 14-months RFS rate in all patients was 86.7%. Only 2 patients (13.3%) showed recurrence during follow-up, however these patients showed incipient malignant lesions (downstaging of pT1G3 to pTaG1). Regarding toxicity, we reported moderate adverse systemic event of hypersensitivity to OncoTherad in 2 patients (13.3%), and minimal local side effects (dysuria and cystitis)in 6 patients (40.0%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-refractory or relapsed HGNMIBC patients and may provide benefit for preventing tumor recurrence. We report a RFS rate of 86.7% (14.0 months), potentially avoiding or postponing the need for radical surgery in these patients. Clinical trial information: CAAE: 93619718.7.0000.5404.

scholarly journals Phase I Trial of an ICAM-1-Targeted Immunotherapeutic-Coxsackievirus A21 (CVA21) as an Oncolytic Agent Against Non Muscle-Invasive Bladder Cancer

2019 ◽  
Vol 25 (19) ◽  
pp. 5818-5831 ◽  
Author(s):  
Nicola E. Annels ◽  
David Mansfield ◽  
Mehreen Arif ◽  
Carmen Ballesteros-Merino ◽  
Guy R. Simpson ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Coxsackievirus A21 ◽  
Muscle Invasive

Intravesical Gemcitabine Therapy for Superficial Transitional Cell Carcinoma of the Bladder: A Phase I and Pharmacokinetic Study

2003 ◽  
Vol 21 (4) ◽  
pp. 697-703 ◽  
Author(s):  
Menachem Laufer ◽  
Sakkaraiappan Ramalingam ◽  
Mark P. Schoenberg ◽  
Mary Ellen Haisfield-Wolf ◽  
Eleanor G. Zuhowski ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Superficial Bladder Cancer ◽  
Transitional Cell ◽  
Maximum Tolerated Dose ◽  
Intravesical Therapy ◽  
Systemic Absorption ◽  
Therapy Failure ◽  
Low Concentrations ◽  
Transitional Cell Bladder Carcinoma ◽  
Carcinoma Of The Bladder

Purpose: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer. Patients and Methods: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy. Results: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine (≤ 1 μg/mL) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients. dFdU was undetectable in plasma of patients receiving less than 1,500 mg. At doses ≥ 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine. Conclusion: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.

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