Sirolimus, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Bladder Cancer

Phase 1

Completed

Conditions: Stage III Bladder Cancer
Recurrent Bladder Carcinoma
Stage II Bladder Cancer
Stage IV Bladder Cancer

Interventions: Drug: Cisplatin
Drug: Gemcitabine Hydrochloride
Drug: Sirolimus
Procedure: Cystectomy

Registration Number: NCT01938573

Lead Sponsor: University of Washington

Brief Summary: This phase I/II trial studies the side effects and best dose of sirolimus when given together with cisplatin and gemcitabine hydrochloride and to see how well they work in treating patients with bladder cancer. Biological therapies, such as sirolimus, may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cisplatin and gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sirolimus together with cisplatin and gemcitabine hydrochloride may be an effective treatment for bladder cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. To define the maximum-tolerated dose (MTD) of sirolimus (rapamycin) combined with gemcitabine hydrochloride and cisplatin (GC). (Phase I)

II. To determine the pathologic complete response rate at cystectomy in patients with localized, muscle invasive carcinoma of the bladder (clinical tumor \[T\]2-4, node \[N\]0 or N1). (Phase II)

SECONDARY OBJECTIVES:

I. To assess the response rate to rapamycin combined with GC. (Phase I)

II. To assess effect of rapamycin with GC on deoxyribonucleic acid (DNA) damage surrogates in cancer associated stroma compared to untreated and GC treated stroma. (Phase I)

III. To assess effect of rapamycin with GC on DNA damage surrogates in cancer associated stroma compared to untreated and GC treated stroma. (Phase II)

IV. To assess toxicity of the MTD dose of rapamycin with GC. (Phase II)

OUTLINE: This is a phase I, dose de-escalation study of sirolimus followed by a phase II study.

Patients receive sirolimus orally (PO) two hours before or after grapefruit juice on day -2, cisplatin intravenously (IV) on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy as clinically appropriate after 1-4 courses of treatment.

After completion of study treatment, patients are followed up for 28 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Signed informed consent form (ICF) providing agreement to adhere to the dosing schedule, report for all trial visits and authorization, use and release of health and research trial information
Histologically or cytologically confirmed carcinoma of the bladder of all histologies except neuroendocrine differentiation or squamous cell histology
Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
Eligibility for phase 1 and phase 2 components:
- Phase 1 - clinical T3 or T4 or N1 or M1 cancer which is untreated or previously treated with platinum based therapy with primary tumor still present in the bladder and amenable to sampling before and after treatment, as indicated
- Phase 2 - clinical T2-4 N0 or N1 untreated with primary tumor still present in the bladder and amenable to sampling before and after treatment, as indicated
Life expectancy >= 12 weeks
No prior malignancy is allowed except:
- Adequately treated basal cell or squamous cell skin cancer or
- In situ carcinoma of any site or
- Other adequately treated malignancy for which the patient is currently disease free for at least one year
Absolute neutrophil count >= 1.5 x 10^9 cells/L
Hemoglobin (Hgb) >= 9.0 g/dL
Platelets >= 100,000 x 10^9/L
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN)
Bilirubin and total bilirubin levels =< 1.5 x ULN
Serum creatinine < 1.5 X institutional ULN mg/dL OR glomerular filtration rate (GFR) >= 50 mL/min
All pre-study labs required for determination of eligibility are to be completed within 30 days prior to day -2 (or the next business day if falls on a weekend or holiday)
X-rays and/or scans to assess all disease sites are to be completed within 30 days prior to day -2 (or the next business day if falls on a weekend or holiday)

Exclusion Criteria

Patients currently receiving active therapy for other neoplastic disorders
Known parenchymal brain metastasis
Active or symptomatic viral hepatitis or chronic liver disease
Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class II-IV heart disease or cardiac ejection fraction measurement of < 45 % at baseline, if done
Atrial fibrillation, or other cardiac arrhythmia requiring medical therapy
Administration of an investigational therapeutic within 30 days of cycle 1, day 1
Patients with dementia/psychiatric illness/social situations that would limit compliance with study requirements or would prohibit the understanding and/or giving of informed consent
Patients with medical conditions, which, in the opinion of the investigators, would jeopardize either the patient or the integrity of the data obtained will not be eligible
Any condition which, in the opinion of the investigator, would preclude participation in this trial

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sirolimus, cisplatin, gemcitabine	Gemcitabine Hydrochloride	Sirolimus day -2, cisplatin 70 mg/m2 IV Day 1 and gemcitabine hydrochloride 1000 mg/m2 IV days 1 and 8 every 21 days for 4 cycles followed by cystectomy (surgery)
Sirolimus, cisplatin, gemcitabine	Cystectomy	Sirolimus day -2, cisplatin 70 mg/m2 IV Day 1 and gemcitabine hydrochloride 1000 mg/m2 IV days 1 and 8 every 21 days for 4 cycles followed by cystectomy (surgery)
Sirolimus, cisplatin, gemcitabine	Sirolimus	Sirolimus day -2, cisplatin 70 mg/m2 IV Day 1 and gemcitabine hydrochloride 1000 mg/m2 IV days 1 and 8 every 21 days for 4 cycles followed by cystectomy (surgery)
Sirolimus, cisplatin, gemcitabine	Cisplatin	Sirolimus day -2, cisplatin 70 mg/m2 IV Day 1 and gemcitabine hydrochloride 1000 mg/m2 IV days 1 and 8 every 21 days for 4 cycles followed by cystectomy (surgery)

Primary Outcome Measures

Name	Time	Method
Percent of Patients With Pathologic Complete Response (Phase II)	12 weeks	The study will follow an optimal two-stage Simon design based on pathologic complete response rate.
Patients With Dose Limiting Toxicity	Up to 28 days	Safety will be assessed through summaries of adverse events, vital signs, physical examinations, and clinical laboratory test data (including change from baseline).

Secondary Outcome Measures

Name	Time	Method
Incidence of Adverse Events Including Any Unfavorable and Unintended Sign, Symptom, Diagnosis, or Disease Temporally Associated With the Use of a Medicinal Product, Whether or Not Related to the Medicinal Product (Phase I and II)	Up to 28 days after completion of study treatment	Graded according to the NCI CTCAE version 4.0. Safety will be assessed through summaries of adverse events, vital signs, physical examinations, and clinical laboratory test data (including change from baseline). All adverse events resulting in discontinuation, dose modification, dosing interruption, and/or treatment delay of study drug will also be listed and tabulated by preferred term.

Trial Locations

Locations (2): VA Puget Sound Health Care System
🇺🇸
Seattle, Washington, United States
Fred Hutch/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States