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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by University of Washington
Sponsor:
Collaborator:
Information provided by (Responsible Party):
University of Washington
ClinicalTrials.gov Identifier:
NCT01938573
First received: September 4, 2013
Last updated: November 17, 2014
Last verified: November 2014
  Purpose

This phase I/II trial studies the side effects and the best dose of sirolimus when given together with cisplatin and gemcitabine hydrochloride and to see how well it works 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 or by stopping them from dividing. Giving sirolimus together with cisplatin and gemcitabine hydrochloride may be an effective treatment for bladder cancer.


Condition Intervention Phase
Adenocarcinoma of the Bladder
Recurrent Bladder Cancer
Stage II Bladder Cancer
Stage III Bladder Cancer
Stage IV Bladder Cancer
Transitional Cell Carcinoma of the Bladder
Drug: sirolimus
Drug: cisplatin
Drug: gemcitabine hydrochloride
Other: laboratory biomarker analysis
Procedure: therapeutic conventional surgery
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1-2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Bladder Cancer

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • MTD of sirolimus based on the incidence of dose-limiting toxicity (DLT) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
    Safety will be assessed through summaries of adverse events, vital signs, physical examinations, and clinical laboratory test data (including change from baseline).

  • Percent of patients with pathologic complete response (Phase II) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    The study will follow an optimal two-stage Simon design based on pathologic complete response rate.


Secondary Outcome Measures:
  • DNA microenvironment damage response proteins using immunohistochemistry (IHC) assay [ Time Frame: Up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]
    IHC will be performed and evaluated using antibodies to interleukin 6 (IL6), Wingless-Type MMTV Integration Site Family, Member 16 (WNT16B) and will assess mammalian target of rapamycin (mTOR) blockade using antibodies to S6.

  • DNA microenvironment damage-responsive transcripts by polymerase chain reaction (PCR) [ Time Frame: Up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]
    Panels of microenvironment transcripts will be quantitated including WNT16B, serine protease inhibitor Kazal-type 1 (SPINK1), IL6, Matrix metalloproteinases (MMPs), and Amphiregulin. Tumor cell transcripts will include Ki67, p16, p27, myelocytomatosis oncogene (Myc) and epithelial-mesenchymal transition (EMT) markers including vimentin and Snail.

  • 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) [ Time Frame: Up to 28 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 45
Study Start Date: December 2013
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (sirolimus, cisplatin, gemcitabine hydrochloride)
Patients receive sirolimus PO two hours before or after grapefruit juice on day -2, cisplatin 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.
Drug: sirolimus
Given PO
Other Names:
  • AY 22989
  • Rapamune
  • rapamycin
  • SLM
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Drug: gemcitabine hydrochloride
Given IV
Other Names:
  • dFdC
  • difluorodeoxycytidine hydrochloride
  • gemcitabine
  • Gemzar
Other: laboratory biomarker analysis
Correlative studies
Procedure: therapeutic conventional surgery
Undergo cystectomy when appropriate

Detailed Description:

PRIMARY OBJECTIVES:

I. To define the maximum-tolerated dose (MTD) of rapamycin (sirolimus) 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 metastasis (M)1 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 mg/DL OR creatinine clearance >= 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
  • Estimated creatinine clearance less than 50 ml/minute
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01938573

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Robert B. Montgomery    206-616-8289      
Principal Investigator: Robert B. Montgomery         
Sponsors and Collaborators
University of Washington
Investigators
Principal Investigator: Robert Montgomery Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT01938573     History of Changes
Other Study ID Numbers: 8027, NCI-2013-01614, 8027, P30CA015704
Study First Received: September 4, 2013
Last Updated: November 17, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Urogenital Neoplasms
Urologic Neoplasms
Everolimus
Sirolimus
Adenocarcinoma
Carcinoma, Transitional Cell
Carcinoma
Urinary Bladder Diseases
Urologic Diseases
Cisplatin
Gemcitabine
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 27, 2014