Gemcitabine Hydrochloride, Cisplatin, and AGS-003-BLD in Treating Patients With Muscle-Invasive Bladder Cancer Undergoing Surgery

Sponsor

Mayo Clinic (Other)

Overall Status

Withdrawn

CT.gov ID

NCT02944357

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

10.1

Actual Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This pilot clinical trial studies how well gemcitabine hydrochloride, cisplatin, and AGS-003-BLD work in treating patients with bladder cancer that has spread to the muscle and who are undergoing surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride and cisplatin, 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. Vaccines made from a person's tumor cells may help the body build an effective immune response to kill tumor cells. Giving gemcitabine hydrochloride, cisplatin, and AGS-003-BLD before surgery may make the tumor smaller and reduce the amount of tissue that needs to be removed by surgery.

Condition or Disease	Intervention/Treatment	Phase
Infiltrating Bladder Urothelial Carcinoma Stage II Bladder Urothelial Carcinoma Stage III Bladder Urothelial Carcinoma Stage IV Bladder Urothelial Carcinoma	Drug: Cisplatin Drug: Gemcitabine Hydrochloride Procedure: Radical Cystectomy Biological: Tumor Cell-Derived Vaccine Therapy	N/A

Detailed Description

PRIMARY OBJECTIVES:

To assess the immunogenicity of AGS-003-BLD in subjects with muscle invasive bladder cancer.

SECONDARY OBJECTIVES:

To assess 1-year disease-free survival rate of patients with muscle-invasive bladder cancer who receive cisplatin/gemcitabine chemotherapy plus AGS-003-BLD.
To determine the time to first metastatic lesion. III. To explore the disease-free and overall survival of patients treated with this treatment combination.
To evaluate the pathologic complete response (pCR) rate and identify any activity of this treatment combination.
To evaluate toxicities and tolerability associated with this treatment combination.
To assess the success rate of tumor procurement and AGS-003-BLD production of >= 5 doses.

TERTIARY OBJECTIVES:

To evaluate the relationships between pathologic complete response with the change in CD28+ T cell levels.
To evaluate the change in frequency of CD11a highPD-1+ CD8+ T cells (and their expression of Bim) in peripheral blood.

OUTLINE:

NEOADJUVANT PHASE: Patients receive gemcitabine hydrochloride intravenously (IV) on days 1 and 8, AGS-003-BLD intradermally (ID) on day 1, and cisplatin IV on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive AGS-003-BLD ID on day 1. Treatment repeats every 14 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo cystectomy during course 8.

ADJUVANT PHASE: Patients continue AGS-003-BLD ID on day 1 of course 9. Treatment repeats every 12 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pilot Study of Gemcitabine and Cisplatin Plus AGS-003-BLD in Patients With Muscle-Invasive Bladder Cancer Undergoing Neoadjuvant Cisplatin-Based Chemotherapy

Actual Study Start Date :

Nov 1, 2016

Actual Primary Completion Date :

Sep 5, 2017

Actual Study Completion Date :

Sep 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (gemcitabine hydrochloride, cisplatin, AGS-003-BLD) NEOADJUVANT PHASE: Patients receive gemcitabine hydrochloride IV on days 1 and 8, AGS-003-BLD ID on day 1, and cisplatin IV on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive AGS-003-BLD ID on day 1. Treatment repeats every 14 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. SURGERY: Patients undergo cystectomy during course 8. ADJUVANT PHASE: Patients continue AGS-003-BLD ID on day 1 of course 9. Treatment repeats every 12 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.	Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP 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 DDP (diamminedichloroplatinum) Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin Drug: Gemcitabine Hydrochloride Given IV Other Names: dFdCyd Difluorodeoxycytidine Hydrochloride Gemzar LY-188011 LY188011 Procedure: Radical Cystectomy Undergo cystectomy Other Names: Complete Cystectomy Biological: Tumor Cell-Derived Vaccine Therapy Given AGS-003-BLD ID

Arm

Intervention/Treatment

Experimental: Treatment (gemcitabine hydrochloride, cisplatin, AGS-003-BLD)

NEOADJUVANT PHASE: Patients receive gemcitabine hydrochloride IV on days 1 and 8, AGS-003-BLD ID on day 1, and cisplatin IV on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive AGS-003-BLD ID on day 1. Treatment repeats every 14 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. SURGERY: Patients undergo cystectomy during course 8. ADJUVANT PHASE: Patients continue AGS-003-BLD ID on day 1 of course 9. Treatment repeats every 12 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.

Drug: Cisplatin

Given IV

Other Names:

Abiplatin

Blastolem

Briplatin

CDDP

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

DDP (diamminedichloroplatinum)

Lederplatin

Metaplatin

Neoplatin

Peyrone's Chloride

Peyrone's Salt

Placis

Plastistil

Platamine

Platiblastin

Platiblastin-S

Platinex

Platinol

Platinol- AQ

Platinol-AQ

Platinol-AQ VHA Plus

Platinoxan

Platinum

Platinum Diamminodichloride

Platiran

Platistin

Platosin

Drug: Gemcitabine Hydrochloride

Given IV

Other Names:

dFdCyd

Difluorodeoxycytidine Hydrochloride

Gemzar

LY-188011

LY188011

Procedure: Radical Cystectomy

Undergo cystectomy

Other Names:

Complete Cystectomy

Biological: Tumor Cell-Derived Vaccine Therapy

Given AGS-003-BLD ID

Outcome Measures

Primary Outcome Measures

Change in the frequency of CD11a high PD-1+ CD8+ T cells [Baseline, before systemic therapy with chemotherapy]
Descriptive statistics (mean, standard deviation [sd], median, interquartile range [iqr]) will be used to summarize change from baseline in the frequency of CD11a high PD-1+ CD8+ T cells following five doses of AGS-003-BLD.
Change in the frequency of CD11a high PD-1+ CD8+ T cells [Prior to 1st dose of AGS-003-Bladder therapy]
Descriptive statistics (mean, standard deviation [sd], median, interquartile range [iqr]) will be used to summarize change from baseline in the frequency of CD11a high PD-1+ CD8+ T cells following five doses of AGS-003-BLD.
Change in the frequency of CD11a high PD-1+ CD8+ T cells [Treatment visit 7 (Cycle 3) After 3rd dose of AGS-003-Bladder therapy, up to 7 days]
Descriptive statistics (mean, standard deviation [sd], median, interquartile range [iqr]) will be used to summarize change from baseline in the frequency of CD11a high PD-1+ CD8+ T cells following five doses of AGS-003-BLD.
Change in the frequency of CD11a high PD-1+ CD8+ T cells [Treatment visit 15 (Cycle 6) - After the 5th dose of neoadjuvant AGS-003-Bladder therapy, up to 14 days]
Descriptive statistics (mean, standard deviation [sd], median, interquartile range [iqr]) will be used to summarize change from baseline in the frequency of CD11a high PD-1+ CD8+ T cells following five doses of AGS-003-BLD.
Change in the frequency of CD11a high PD-1+ CD8+ T cells [Treatment visit 20 (Cycle 8) - After the 8th dose (3rd adjuvant) of AGS-003 - Bladder therapy, up to 12 weeks]
Descriptive statistics (mean, standard deviation [sd], median, interquartile range [iqr]) will be used to summarize change from baseline in the frequency of CD11a high PD-1+ CD8+ T cells following five doses of AGS-003-BLD.

Secondary Outcome Measures

1-year survival rate [1 year]
2-year disease-free survival rate [2 years]
2-year survival rate [2 years]
Disease-free survival rate [1 year]
Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events [Up to 2 years]
The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns.
Manufacturing success rate and successful manufacture of > 5 doses and administration of 1 or more doses of AGS-003-BLD [Up 2 years]
Descriptive statistics (frequency table) and histogram will be used to summarize the success rate.
Proportion of pathologic complete responses [Up to 2 years]
Descriptive statistics (frequency table) and histogram will be used to summarize the pathologic complete response rate.
Time to first metastatic lesion [Time from randomization to first recognition of metastases, assessed up to 2 years]
Will be estimated using the Kaplan-Meier method.

Other Outcome Measures

Change in CD28 + T cell level with pathological complete response [Baseline up to 2 years]
Descriptive statistics (mean, sd, median, iqr) and longitudinal plots (raw value, change, and change in percentage) will be used to summarize the correlative endpoints. Further analysis will depend on the amount of data received and will be mainly exploratory.
Change in frequency of CD11a high PD-1+ CD8+ T cells (and their expression of Bim) in peripheral blood [Baseline up to 2 years]
Descriptive statistics (mean, sd, median, iqr) and longitudinal plots (raw value, change, and change in percentage) will be used to summarize the correlative endpoints. Further analysis will depend on the amount of data received and will be mainly exploratory.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

PRE-REGISTRATION INCLUSION CRITERIA: Diagnosis or clinical signs of urothelial carcinoma with clinical stage T2 or greater disease without lymph node involvement where neoadjuvant chemotherapy of cisplatin and gemcitabine are indicated
PRE-REGISTRATION INCLUSION CRITERIA: Scheduled for a transurethral resection of bladder tumor (TURBT)
PRE-REGISTRATION INCLUSION CRITERIA: Be a candidate for radical cystectomy
PRE-REGISTRATION INCLUSION CRITERIA: Signed and dated informed consent document for study participation
PRE-REGISTRATION INCLUSION CRITERIA: Willing to submit tissue for required correlative research
REGISTRATION INCLUSION CRITERIA
TURBT successfully completed
Verification received from Argos Therapeutics that ribonucleic acid (RNA) successfully collected from TURBT procedure
Be a candidate for radical cystectomy
Diagnosis of urothelial carcinoma with stage T2 or greater disease without lymph node involvement where neoadjuvant chemotherapy of cisplatin and gemcitabine are indicated
Absolute neutrophil count (ANC) >= 1500/uL
Platelet count >= 100,000/uL
Total bilirubin =< 1.5 x institutional upper normal limit (UNL) or =< 3 x institutional UNL if known Gilbert's syndrome
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x UNL
Alkaline phosphatase =< 5 x UNL
Hemoglobin >= 9.0 g/dL
International normalized ratio (INR) and partial thromboplastin time (PTT) =< 3.0 x UNL; NOTE: anticoagulation is allowed if target INR =< 3.0 x UNL on a stable dose of warfarin or on a stable dose of low molecular weight heparin for > 2 weeks at time of registration
Calculated creatinine clearance must be >= 50 ml/min using the applicable Cockcroft-Gault formula
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Ability to provide written informed consent
Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
Willing to provide tissue and blood samples for correlative research purposes
Negative serum pregnancy test for female subjects with reproductive potential =< 7 days prior to registration, for women of childbearing potential only
Able to abstain from taking prohibited drugs, either prescription or non-prescription, during the treatment phase of the study

Exclusion Criteria:

RE-REGISTRATION EXCLUSION CRITERIA
Requirement for systemic chronic immunosuppressive drugs or systemic chronic corticosteroids for active autoimmune disorder(s) or other conditions (e.g.: rheumatoid arthritis, systemic lupus erythematous, multiple sclerosis, organ transplant recipient, etc.)
Known inability to undergo neoadjuvant gemcitabine and cisplatin combination treatment due to pre-existing medical conditions in the opinion of the treating physician or investigator
Immunotherapy =< 28 days prior to pre-registration (e.g. intravesical Bacillus Calmette-Guerin [BCG])
Any of the following prior therapies:
Systemic chemotherapy for bladder cancer at any time; NOTE: intravesical chemotherapy is allowed
Systemic chemotherapy for other malignancies =< 3 years prior to pre-registration
REGISTRATION EXCLUSION CRITERIA
Lymph node positive urothelial carcinoma
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements in the opinion of the investigator
Treatment with oral/systemic corticosteroids =< 14 days prior to registration, with the exception of topical or inhaled steroids or steroids given for the purpose of antiemetics during chemotherapy
New York Heart Association classification III or IV congestive heart failure
Central nervous system (CNS) metastases or seizure disorder
Any of the following:
Pregnant women
Nursing women
Men or women of childbearing potential who are unwilling to employ adequate contraception
Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) with the exception of intravesical therapy at the time of TURBT
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Clinically significant infections including human immunodeficiency virus (HIV), syphilis, and active hepatitis B or C
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Prior history of malignancy =< 3 years prior to registration, except for adequately treated non-melanoma skin cancer, adequately treated early stage breast cancer, adequately treated cervical cancer and non-metastatic prostate cancer under clinical control as deemed by treating physician or investigator
History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
History of major surgery or traumatic injury =< 28 days prior to registration or other major anticipated procedures requiring general anesthesia during study participation