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

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01938573
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 21
• Locations: 2
• Arm: 1
• Duration (Months): 34.6
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Bladder Carcinoma; Stage II Bladder Cancer; Stage III Bladder Cancer; Stage IV Bladder Cancer	Drug: Cisplatin; Drug: Gemcitabine Hydrochloride; Drug: Sirolimus; Procedure: Cystectomy	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

2. 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:

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

2. 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)

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

4. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1-2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Bladder Cancer
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Aug 18, 2016
• Actual Study Completion Date: Aug 18, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Sirolimus, cisplatin, gemcitabine 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)

Drug: Cisplatin; Given IV; Other Names: Abiplatin Blastolem Briplatin Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroamine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin ; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride Gemzar ; Drug: Sirolimus; Given PO; Other Names: Rapamune (RAPA) RAPAMYCIN ; Procedure: Cystectomy; Undergo cystectomy when appropriate

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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.

Secondary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Puget Sound Health Care System	Seattle	Washington	United States	98101
2	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert Montgomery, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bruce Montgomery, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT01938573
• Other Study ID Numbers: 8027; NCI-2013-01614; 8027; P30CA015704
• First Posted: Sep 10, 2013
• Last Update Posted: Oct 20, 2017
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Urinary Bladder Neoplasms; Gemcitabine; Sirolimus; Cisplatin

Study Results

Participant Flow

Arm/Group Title	Phase 2	Phase I
Arm/Group Description	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) Cisplatin: Given IV Gemcitabine Hydrochloride: Given IV Sirolimus: Given PO Cystectomy: Undergo cystectomy when appropriate	Sirolimus 35 mg PO day -2, cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1 and 8, every 21 days
Period Title: Overall Study
STARTED	15	6
COMPLETED	13	6
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Sirolimus, Cisplatin, Gemcitabine
Arm/Group Description	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) Cisplatin: Given IV Gemcitabine Hydrochloride: Given IV Sirolimus: Given PO Cystectomy: Undergo cystectomy when appropriate
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	1 4.8%
Male	20 95.2%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Patients With Dose Limiting Toxicity
Description	Safety will be assessed through summaries of adverse events, vital signs, physical examinations, and clinical laboratory test data (including change from baseline).
Time Frame	Up to 28 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1 - Sirolimus, Cisplatin, Gemcitabine
Arm/Group Description	Sirolimus day -2, cisplatin 70 mg/m2 IV Day 1 and gemcitabine hydrochloride 1000 mg/m2 IV days 1 and 8 every 21 days Cisplatin: Given IV Gemcitabine Hydrochloride: Given IV Sirolimus: Given PO Cystectomy: Undergo cystectomy when appropriate
Measure Participants	6
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Percent of Patients With Pathologic Complete Response (Phase II)
Description	The study will follow an optimal two-stage Simon design based on pathologic complete response rate.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Patients treated in phase 2

Arm/Group Title	Sirolimus, Cisplatin, Gemcitabine
Arm/Group Description	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) Cisplatin: Given IV Gemcitabine Hydrochloride: Given IV Sirolimus: Given PO Cystectomy: Undergo cystectomy when appropriate
Measure Participants	15
Count of Participants [Participants]	4 19%

3. Secondary Outcome

Title	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)
Description	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.
Time Frame	Up to 28 days after completion of study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sirolimus, Cisplatin, Gemcitabine
Arm/Group Description	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) Cisplatin: Given IV Gemcitabine Hydrochloride: Given IV Sirolimus: Given PO Cystectomy: Undergo cystectomy when appropriate
Measure Participants	21
Number [Number of events]	45

Adverse Events

Time Frame	4 months (neoadjuvant therapy (3 months) and 1 month after completion)
Arm/Group Title	Sirolimus, Cisplatin, Gemcitabine
Arm/Group Description	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) Cisplatin: Given IV Gemcitabine Hydrochloride: Given IV Sirolimus: Given PO Cystectomy: Undergo cystectomy when appropriate
All Cause Mortality
	Sirolimus, Cisplatin, Gemcitabine
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Serious Adverse Events
	Sirolimus, Cisplatin, Gemcitabine
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Other (Not Including Serious) Adverse Events
	Sirolimus, Cisplatin, Gemcitabine
	Affected / at Risk (%)	# Events
Total	21/21 (100%)
Blood and lymphatic system disorders
Neutropenia	5/21 (23.8%)	5
Thrombocytopenia	8/21 (38.1%)	8
Anemia	4/21 (19%)	4
General disorders
Fatigue	10/21 (47.6%)	10

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.