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

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

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.

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%).