A phase I trial of chemoimmunotherapy combining bacillus Calmette-Guerin (BCG) and intravesical gemcitabine for patients with BCG-relapsing high-grade nonmuscle-invasive bladder cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS509-TPS509
Author(s):  
Manuel R. De Jesus Escano ◽  
Daniel D. Sjoberg ◽  
Melissa McCarter ◽  
Marlena McGill ◽  
Alvin Goh ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Invasive Bladder Cancer ◽  
High Grade ◽  
Continual Reassessment Method ◽  
Intravesical Treatment ◽  
Continual Reassessment

TPS509 Background: Intravesical BCG is the most effective treatment for high-grade non-muscle invasive bladder cancer (NMIBC), yet recurrences are common. Patients with BCG-relapsing NMIBC are often re-treated with BCG or BCG with interferon (IFN) with an expected response rate of only 40–60%. Several studies show that a major mechanism of resistance to BCG is high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in the pretreatment tumor microenvironment. Gemcitabine is a commonly used intravesical treatment for NMIBC that, in addition to direct anti-tumor cytotoxic effects, may also reduce MDSCs and Tregs. Prior trials combining BCG with intravesical mitomycin C have shown improved efficacy over BCG alone but with higher toxicity. While gemcitabine has been shown to be better tolerated than mitomycin as an intravesical treatment, no study has looked at combined BCG and intravesical gemcitabine. We hypothesize that combining BCG and intravesical gemcitabine will be well tolerated and result in higher response rates by reducing levels of MDSCs and Tregs. A novel aspect of our trial design is the use of a modified continual reassessment method to more accurately identify the maximum tolerated dose instead of the traditional 3 + 3 design used in most NMIBC phase I trials. Methods: This is an investigator-initiated phase I trial (NCT04179162) that will study the safety of alternating intravesical gemcitabine and BCG. Inclusion and exclusion criteria are designed so most patients who would ordinarily be re-treated with BCG or BCG/IFN would be eligible. Patients must have recurrent high-grade NMIBC within 24 months of their last BCG treatment without meeting the criteria for BCG-unresponsive NMIBC. Intravesical gemcitabine is given twice a week on weeks 1, 4, 7, and 10, for a total of 8 doses. BCG (50 mg) is given once a week on weeks 2, 3, 5, 6, 8, and 9, for a total of 6 doses. The trial is monitored using a modified continual reassessment method with increasing dose levels of gemcitabine (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) being evaluated. Adverse events are assessed using the Common Terminology Criteria for Adverse Events version 5.0. The primary objective is to determine the maximum tolerated dose of this combination to inform our planned phase II trial. Correlative studies will look at the immunomodulating effects of gemcitabine by evaluating changes in immune cell populations in serial blood and urine specimens. Tissue and urine will also be evaluated for molecular determinants of response and resistance to the combination. The trial is open to enrollment with 10 of 25 planned patients accrued to date. Clinical trial information: NCT04179162.

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

scholarly journals Phase I cancer clinical trials†

2016 ◽  
Vol 4 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Juan R. Cabrera ◽  
Jennie W. Taylor ◽  
Annette M. Molinaro
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Maximum Tolerated Dose ◽  
Cancer Clinical Trials ◽  
Dose Estimation ◽  
Time To Event ◽  
Timely Manner ◽  
Continual Reassessment Method ◽  
Continual Reassessment

Abstract An efficient phase I trial is a crucial step in developing a new drug in a safe and timely manner. The main objective of a phase I trial is to determine the maximum tolerated dose in order to recommend the dose for a phase II trial. There are many designs that are implemented in phase I trials. Rule-based designs such as the traditional 3 + 3 method and rolling six design are easy to implement and assess for safety using a conservative approach. Model-based designs such as the continual reassessment method and the time-to-event continual reassessment method use mathematical models to increase the precision of dose estimation. The advantages and shortcomings of these designs, along with other designs, are reviewed.

A Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of Bacillus Calmette-Guérin Refractory Nonmuscle Invasive Bladder Cancer

2011 ◽  
Vol 186 (2) ◽  
pp. 448-451 ◽  
Author(s):  
James M. McKiernan ◽  
LaMont J. Barlow ◽  
Melissa A. Laudano ◽  
Mark J. Mann ◽  
Daniel P. Petrylak ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Invasive Bladder Cancer ◽  
Bacillus Calmette Guerin ◽  
Nonmuscle Invasive Bladder Cancer

Oncotherad immunotherapy elicits promising responses in Bacillus Calmette-Guérin-unresponsive non–muscle invasive bladder cancer: Results from phase I/ II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17048-e17048
Author(s):  
João Carlos Cardoso Alonso ◽  
Ianny Brum Reis ◽  
Juliana Mattoso Gonçalves ◽  
Bianca Ribeiro de Souza Sasaki ◽  
Adriano Angelo Cintra ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Adverse Events ◽  
Phase I ◽  
Tumor Recurrence ◽  
Disease Recurrence ◽  
Invasive Bladder Cancer ◽  
Bacillus Calmette Guerin ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive

e17048 Background: Standard treatment for high-grade non-muscle-invasive bladder cancer (HGNMIBC) is transurethral resection of the bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Up to 40% of patients with HGNMIBC will fail intravesical BCG therapy. A promising therapeutic perspective is represented by OncoTherad immunotherapy. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein developed by University of Campinas/Brazil that exhibits antitumor properties. The aims of this study were to evaluate the efficacy and safety of OncoTherad immunotherapy for BCG-refractory or relapsed HGNMIBC. Methods: We conducted a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/ II study of OncoTherad immunotherapy in 29 (18 male, 11 female) patients with BCG-unresponsive HGNMIBC (≥ 1 previous course of BCG intravesical therapy). The schedule was initiated with weekly intravesical (120 mg/mL) and intramuscular (25 mg/mL) OncoTherad treatment for 6 weeks, followed by one every other week application for 3 months and, one monthly application until the end of the treatment (24 months). Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy and ultrasound. The primary endpoint was pathological complete response (pCR) and recurrence-free survival (RFS). The recurrence was defined as histology proven tumor recurrence (any grade) and monitored at 3-month intervals. Secondary endpoints were time to disease recurrence and safety response. Results: The median age of the 29 patients was 64 years (range 34-94). At baseline pTis, pTaG2-3, pT1G2-3 occurred in 10%, 59% and 31% of patients respectively. OncoTherad treatment showed pCR rates (95% CI) of 100% at 3, 6 and 9 months, 89,6% (26/29) at 12 months and, 89,6% (26/29) at 24 months. A 24-months RFS rate in all patients was 79,3%. Also, the median time to disease recurrence for patients was 459 days (15,3 months; 95% CI) at 24-months follow-up. 95% of adverse events were Grade 1 or 2. The most commonly reported treatment-related adverse events were dysuria (51,7%), cystitis (34,5%), pruritus (44,8%), rash (27,6%), arthralgia (27,6%) and fatigue (27,6%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-unresponsive HGNMIBC patients and may provide benefit for preventing tumor recurrence. Clinical trial information: RBR-6swqd2.

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.

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