Proliposomal Intravesical Paclitaxel for Treatment of Low-Grade, Stage Ta, Non Muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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This is a single-arm, phase 1/2a study of formulated paclitaxel in subjects with low-grade, noninvasive papillary carcinoma (stage Ta) of the bladder. Part 1 of the study will enroll 6 subjects (3 per cohort) with low-grade, stage Ta transitional cell carcinoma (TCC) of the bladder who will receive escalating doses of paclitaxel formulated as TSD-001 every 2 weeks for 6 treatments until Dose Limiting Toxicity (or until the Maximum Deliverable Dose) is observed (Maximum Tolerated Dose established). Part 2 of the study will enroll an additional 10 subjects with low-grade, stage Ta (uni-or multifocal) TCC of the bladder who will receive weekly TSD-001 for 6 weeks at the highest nontoxic dose (i.e., MTD) established in part 1 of the study. May meet definition of low grade without histological tissue diagnosis if on cystoscopic assessment they have a solitary papillary tumor. Part 3 of the study will continue to track subjects enrolled in Parts 1 and 2 to determine rates of disease-free survival.

Official Title
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A Phase 1/2a Pilot Study of Intravesical TSD-001 for Treatment of Low-Grade, Stage Ta, Non Muscle Invasive Bladder Cancer

Conditions
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Bladder Cancer Cell Transitional, Non-Muscle Invasive Bladder Cancer, Bladder Cancer, Urinary Bladder, Transitional Cell Carcinoma of the Bladder, Urinary Bladder Neoplasms, Urologic Neoplasms, Urogenital Neoplasms, Urinary Bladder Diseases, Urologic Diseases

Intervention / Treatment
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* Drug: TSD-001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of low grade (G1 or G2), uni- or multifocal papillary appearing bladder tumor, stage Ta. For part 1, subject will have ≥ 1 and ≤ 5 tumors (prior to TURBT), none of which exceeds 3.0 cm in diameter; for part 2, patient will have ≥ 2 and ≤ 5 tumors (prior to TURBT), none of which exceeds 3.0 cm in diameter (resection loop  1 cm), OR, for part 2, subject meets this inclusion if on cystoscopic assessment they have a solitary papillary tumor (> 0.5 cm and ≤ 2.0 cm in diameter).. Subject is surgical candidate for TURBT as part of normal NMIBC treatment plan. For part 1, successful completion of TURBT procedure. For part 2, successful completion of cystoscopic assessment/TURBT procedure with one marker lesion left intact; the marker lesion should be > 0.5 cm and < 2.0 cm in diameter. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Peripheral neuropathy grade 1 or less. Adequate hematological, hepatic, and renal parameters; i.e., hemoglobin > 10 g/dL, creatinine < 3.5 mg/dL, bilirubin < 1.5 mg/dL , and aspartate aminotransferase, alanine aminotransferase < 50 U/L, and alkaline phosphatase < 130 U/L. All sexually active subjects of reproductive potential are required to use or start using a reliable method of birth control at least 2 weeks prior to study enrollment, throughout the study, and for at least 3 months following completion of study therapy. Females of childbearing potential must have a negative pregnancy test within 30 days prior to enrollment. Females who are postmenopausal for at least 1 year (defined as more than 12 months since last menses) or are surgically sterilized do not require this test. For male subjects, the digital rectal examination must not be suspicious for carcinoma of the prostate. Able to retain bladder instillations for up to 120 minutes (± 15 minutes). Exclusion Criteria: Has an active concurrent malignancy/life-threatening disease. If there is a history of prior malignancies/life-threatening diseases, the subject is to be disease free for at least 5 years. Subjects with other prior malignancies less than 5 years before study entry may still be enrolled if they have received treatment resulting in complete resolution of the cancer and currently have no clinical, radiologic, or laboratory evidence of active or recurrent disease. Subjects will not be excluded for recurrent NMIBC, basal or squamous cell skin cancers, or noninvasive cancer of the cervix. Has positive urine cytology for urothelial malignancy at screening. Has an active uncontrolled infection, including a urinary tract infection, underlying medical condition, or other serious illness that would impair the ability of the subject to receive protocol treatment. Previous intravesical therapy within 6 months of study entry. Prior radiation to the pelvis. Participated in a previous clinical trial or used any investigational drugs, biologics, or devices within 90 days prior to study treatment or plans to use any of these during the course of the study. Has had any previous exposure to paclitaxel or docetaxel in the last 5 years. Has or has ever had: upper tract TCC; urethral tumor (prostatic urethra included); any invasive bladder tumor known to be other than tumor Ta, low-grade (G1-G2); any evidence of lymph node or distant metastasis; any bladder tumor with histology other than TCC; or carcinoma in situ (CIS). Has a tumor in a bladder diverticulum Concurrent treatment with any chemotherapeutic agent. History of vesicoureteral reflux. An indwelling ureteral stent. Has received any pelvic radiotherapy (including external beam and/or brachytherapy.) Has a bleeding disorder or a screening platelet count < 100×109/L. Has an active diagnosis of interstitial cystitis. For subjects with recurrent tumor, the subject had at least a 6-month cystoscopically confirmed tumor-free interval between the last tumor recurrence and screening cystoscopic examination. Presence of poorly controlled diabetes mellitus (glycated hemoglobin [HgbA1c] > 9.0%).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TSD-001 Administration Part 1, Cohort 2<br>Part 1, Cohort 1: For the next 3 subjects enrolled, the initial dose will be 90 mg in SWFI. TSD-001 will be retained in the bladder for 2 hours (1 hour or more will be acceptable, depending on subject's tolerability of the procedure). If DLT does not develop, intravesical instillation 14 days later will be titrated up according to the schedule (180, 270, 360, 450, and 540 mg in SWFI) until DLT (defined as any grade 3 or 4 toxicity or prolonged [greater than 14 days] grade 2 toxicity) is observed. If no DLT is observed in the first 6 subjects (cohorts 1 and 2) after titration up to 540 mg, then the maximum deliverable dose (MDD) will be defined and dose recommended for part 2 of the study. | Drug: TSD-001<br>* Administered via intravesical instillation.<br>* Other names: Proliposomal Intravesical Paclitaxel;|
| Experimental: TSD-001 Administration Part 2<br>In part 2, the dose will be selected as the MTD/MDD, established in part 1 and provided weekly via the intravesical route. During part 2, up to 10 additional subjects will receive intravesical instillations of TSD-001 via urethral catheterization of the urinary bladder at the MTD/MDD established in part 1 at weekly intervals for 6 consecutive weeks. TSD-001 will be retained in the bladder for 2 hours (1 hour or more will be acceptable, depending on subject's tolerability of the procedure). | Drug: TSD-001<br>* Administered via intravesical instillation.<br>* Other names: Proliposomal Intravesical Paclitaxel;|
| Experimental: TSD-001 Administration Part 1, Cohort 1<br>Part 1, Cohort 1: For the first 3 subjects enrolled, the initial dose will be 10 mg in Sterile Water for Injection (SWFI). TSD-001 will be retained in the bladder for 2 hours (1 hour or more will be acceptable, depending on subject's tolerability of the procedure). If Dose Limiting Toxicity(DLT) does not develop, intravesical instillation 14 days later will be titrated up according to the schedule (25, 50, 75, 100, 150 mg in SWFI) until DLT (defined as any grade 3 or 4 toxicity or prolonged [greater than 14 days] grade 2 toxicity) is observed. | Drug: TSD-001<br>* Administered via intravesical instillation.<br>* Other names: Proliposomal Intravesical Paclitaxel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Maximum Tolerated Dose | Dose immediately preceding the dose at which DLT occurs or when a MDD is reached. | 12 weeks | 
| Part 2: Marker Lesion Response Rate | Determine the marker lesion response rate using the MTD established in part 1. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Determine paclitaxel concentrations | Determine the local (bladder urine) and systemic (peripheral blood) paclitaxel concentrations before and after intravesical exposure to TSD-001 at all doses. Blood and urine samples will be collected 15 (± 15) minutes before and 2 hours (± 10 minutes) after each instillation. | 10 weeks | 
| Part 2: Determine paclitaxel concentrations | Determine the local (bladder urine) paclitaxel concentrations 15 (± 15) minutes before, and 2 hours (± 10 minutes) after the third intravesical instillation of TSD-001. Determine the systemic (peripheral blood) paclitaxel concentration 2 hours (± 10 minutes) after the first intravesical instillation of TSD-001. Determine the systemic (peripheral blood) paclitaxel concentrations 15 (± 15) minutes before, and 2 hours (± 10 minutes) after the third intravesical instillation of TSD-001. | 5 weeks | 
| Severity and Frequency of Adverse Events | Characterize the severity and frequency of AEs following intravesical administration of TSD-001. | Part 1: 16 weeks, Part 2: 13 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NMIBC, Paclitaxel, Antineoplastic Agents