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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 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: May 28, 2014
Last verified: May 2014

September 4, 2013
May 28, 2014
December 2013
October 2014   (final data collection date for primary outcome measure)
  • MTD of sirolimus based on the incidence of dose-limiting toxicity (DLT) graded according to the National Cancer Institute (NCI) Common Terminology Criterial 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.
Same as current
Complete list of historical versions of study NCT01938573 on ClinicalTrials.gov Archive Site
  • 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.
Same as current
Not Provided
Not Provided
 
Sirolimus, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Bladder Cancer
A Phase 1-2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Bladder Cancer

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 the immune system in different ways and stop cancer 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.

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 T2-4, N0 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) with 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.

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • 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
    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
Experimental: Treatment (sirolimus, cisplatin, gemcitabine hydrochloride)
Patients receive sirolimus PO with 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.
Interventions:
  • Drug: sirolimus
  • Drug: cisplatin
  • Drug: gemcitabine hydrochloride
  • Other: laboratory biomarker analysis
  • Procedure: therapeutic conventional surgery
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
45
Not Provided
October 2014   (final data collection date for primary outcome measure)

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 cisplatin 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), and bilirubin levels =< 1.5 x upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x ULN
  • Serum creatinine < 1.5 mg/DL OR creatinine clearance >= 50 mL/min

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
Both
18 Years and older
No
United States
 
NCT01938573
8027, NCI-2013-01614, 8027, UW Protocol 8027, P30CA015704
Yes
University of Washington
University of Washington
National Cancer Institute (NCI)
Principal Investigator: Robert B Montgomery Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
University of Washington
May 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP