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

• ClinicalTrials.gov Identifier: NCT01938573
• Recruitment Status: Completed
• First Posted: September 10, 2013
• Results First Posted: October 20, 2017
• Last Update Posted: October 20, 2017
• Sponsor: University of Washington
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Bruce Montgomery, University of Washington

Tracking Information

• First Submitted Date: September 4, 2013
• First Posted Date: September 10, 2013
• Results First Submitted Date: August 18, 2017
• Results First Posted Date: October 20, 2017
• Last Update Posted Date: October 20, 2017
• Study Start Date: October 2013
• Actual Primary Completion Date: August 18, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 20, 2017)

• Patients With Dose Limiting Toxicity [ Time Frame: 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).
• Percent of Patients With Pathologic Complete Response (Phase II) [ Time Frame: 12 weeks ]
  The study will follow an optimal two-stage Simon design based on pathologic complete response rate.

Original Primary Outcome Measures (submitted: September 4, 2013)

• 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 ]
  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 ]
  The study will follow an optimal two-stage Simon design based on pathologic complete response rate.

Current Secondary Outcome Measures (submitted: September 20, 2017)

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 ]

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.

Original Secondary Outcome Measures (submitted: September 4, 2013)

• DNA microenvironment damage response proteins using immunohistochemistry (IHC) assay [ Time Frame: Up to 28 days after completion of study treatment ]
  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 ]
  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 ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Sirolimus, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Bladder Cancer
• Official Title: A Phase 1-2 Study of Rapamycin and Cisplatin/Gemcitabine for Treatment of Patients With Bladder Cancer
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent Bladder Carcinoma
• Stage II Bladder Cancer
• Stage III Bladder Cancer
• Stage IV Bladder Cancer

Intervention

• 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

Study Arms

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)

Interventions:

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 9, 2017): 21
• Original Estimated Enrollment (submitted: September 4, 2013): 45
• Actual Study Completion Date: August 18, 2016
• Actual Primary Completion Date: August 18, 2016 (Final data collection date for primary outcome measure)

Eligibility 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 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01938573
• Other Study ID Numbers: 8027; NCI-2013-01614 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 8027 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium ); P30CA015704 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bruce Montgomery, University of Washington
• Original Responsible Party: University of Washington
• Current Study Sponsor: University of Washington
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

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

• PRS Account: University of Washington
• Verification Date: September 2017