Cabazitaxel, Gemcitabine, and Cisplatin in Treating Patients with BCG Solution-Refractory Non-muscle Invasive Urothelial Carcinoma of the Bladder
This phase I/II trial studies the side effects and best dose of cabazitaxel and gemcitabine, when given together with cisplatin in treating patients with non-muscle invasive urothelial carcinoma of the bladder that has not responded to Bacillus Calmette-Guerin (BCG) solution (refractory). Drugs used in chemotherapy, such as cabazitaxel, gemcitabine, and cisplatin work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
Inclusion Criteria
- Patients must have a histologically confirmed diagnosis of non- muscle invasive urothelial carcinoma of the bladder at the study institution prior to the beginning of the study; this includes patients with: * High grade Ta papillary lesion(s) * High or low grade T1 papillary lesion(s) * Carcinoma in situ (CIS), with or without Ta or T1 papillary tumor(s) of any grade
- The patient must have BCG refractory or recurrent non-muscle invasive bladder cancer * Refractory disease is defined as evidence of persistent high risk bladder cancer (high grade Ta, T1 and/or CIS) at the first cystoscopic exam after the initial 6 week induction course of BCG or at the 6 month cystoscopic exam * Recurrent disease is defined as reappearance disease after achieving a tumor- free status by 6 months following a full induction course of BCG with or without maintenance BCG; participants must have recurred within 18 months following the last dose of BCG ** Low-grade superficial (Ta) disease will not be considered recurrent ** Patients must exhibit disease recurrence receiving some form of standard intravesical therapy that must include a minimum of one induction course of BCG exposure to mitomycin, interferon, single agent gemcitabine or taxane therapy or maintenance
- Patients must be eligible for radical cystectomy and refuse this standard of care treatment or not be a surgical candidate for radical cystectomy based on other comorbidities
- All grossly visible disease in the bladder must be fully resected and pathologic stage will be confirmed at the study institution
- Patients enrolled in other clinical trials must have received their last treatment at least 6 weeks prior to enrollment
- Age > 18 and must be able to read, understand and sign informed consent
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status: ECOG of 0 or 1 including patients who are not surgical candidates due to comorbid conditions
- Women of childbearing potential must have a negative pregnancy test
- All patients of childbearing potential must be willing to consent to using effective contraception, i.e., intrauterine device (IUD), birth control pills, Depo-Provera, and condoms while on treatment and for 3 months after their participation in the study ends
- No experimental intravesical therapy within 6 weeks of study entry
Exclusion Criteria
- History of severe hypersensitivity reaction (>= grade 3) to docetaxel
- History of severe hypersensitivity reaction (>= grade 3) to polysorbate 80 containing drugs
- Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are already on 1 these treatments)
- Concurrent malignancy diagnosed within 6 months of entry to the study
- Concurrent treatment with any systemic chemotherapeutic agent
- Hemoglobin =< 8.0 g/dL
- Absolute neutrophil count =< 1.5 x 10^9/L
- Platelet count =< 80 x 10^9/L
- Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) >= 2.5 x upper limit of normal (ULN)
- Total bilirubin > 1.5 x ULN
- Serum creatinine > 2.0 x ULN; if creatinine 1.5 - 2.0 x ULN, creatinine clearance will be calculated according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and patients with creatinine clearance < 30 mL/min should be excluded
- Women who are pregnant or lactating
- Documented history of vesicoureteral reflux
- Current indwelling urinary stent
- Participation in any other research protocol involving administration of an investigational agent within 6 weeks prior to study entry
- No Institutional Review Board (IRB) approved signed consent form
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT02202772.
PRIMARY OBJECTIVES:
I. To assess the safety and toxicity profiles of intravesically administered cabazitaxel, gemcitabine, and cisplatin (CGC). (Phase Ia)
II. To assess the safety and toxicity profiles of intravesically administered CGC using a condensed, two day per week infusion schedule in an additional 9 patients. (Phase Ib)
III. To evaluate the efficacy of intravesically administered cabazitaxel, gemcitabine and cisplatin administered at the maximum tolerated dose (MTD) on a two day per week treatment schedule, defined as the number of complete responders after six weeks of the instillation. (Phase II)
SECONDARY OBJECTIVES:
I. To assemble a tissue bank (with pre and post treatment samples) to assess molecular correlates for response to intravesical CGC. (Phase Ia)
II. To evaluate the efficacy of intravesically administered cabazitaxel, gemcitabine and cisplatin, defined as the number of complete responders after completion of six weeks of the instillation. (Phase Ia)
III. To assess the long term durability of response following monthly maintenance therapy using the cabazitaxel and gemcitabine in a single day infusion schedule. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of cabazitaxel and gemcitabine followed by a phase II study.
Patients receive cabazitaxel intravesically over less than 1 hour once weekly on Monday and gemcitabine intravesically once weekly on Wednesday. Patients may also receive cisplatin intravesically bi-weekly on Fridays. Treatment repeats for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients with complete response may then receive an additional 24 months of treatment. Cycles repeat every 4 weeks for months 1-12 and every 8 weeks for months 13-24 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 5 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationNYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
Principal InvestigatorGuarionex Joel DeCastro
- Primary IDAAAM8506
- Secondary IDsNCI-2015-00757
- ClinicalTrials.gov IDNCT02202772