Gemcitabine Hydrochloride, Cisplatin, and Pembrolizumab before Surgery in Treating Patients with Muscle-Invasive Bladder Cancer
This phase II trial studies how well gemcitabine hydrochloride, cisplatin, and pembrolizumab work before surgery in treating patients with bladder cancer that has spread to the muscle. 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. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving gemcitabine hydrochloride, cisplatin, and pembrolizumab before surgery may make the tumor smaller and reduce the amount of tissue that needs to be removed by surgery.
Inclusion Criteria
- Be able to give written Institutional Review Board (IRB) approved informed consent and be able to follow protocol requirements
- Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- Has histologically confirmed urothelial carcinoma of the bladder; those with mixed histology, including a component of urothelial carcinoma, are eligible; pure small cell carcinoma, pure adenocarcinoma, and pure squamous cell carcinoma are excluded
- Has clinical stage T2-T4a N0/X M0 urothelial carcinoma; clinical T stage is based on the pre-study standard of care transurethral resection of the bladder tumor (TURBT) sample and imaging studies
- Absolute neutrophil count (ANC) >= 1500/mcL (within 10 days of treatment initiation)
- Platelets >= 100,000/mcL(within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 10 days of treatment initiation)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR estimated glomerular filtration rate (GFR) per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days of treatment initiation)
- Serum total bilirubin =< 1.5 X ULN (=< 3 X ULN if Gilbert’s syndrome) OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN (within 10 days of treatment initiation)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy; if subject receiving anticoagulants, PT or partial thromboplastin time (PTT) should be within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- Activated partial thromboplastin Time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy; if subject receiving anticoagulants, PT or PTT should be within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- Has staging scans with abdominal/pelvic computed tomography (CT) or magnetic resonance imaging (MRI) scan and CT scan or x-ray of the chest within 4 weeks prior to treatment initiation
- Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of pembrolizumab; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Be a medically appropriate candidate for radical cystectomy as determined by an attending urologist and be planning to receive cystectomy
- Has had no prior systemic cytotoxic chemotherapy for urothelial carcinoma (prior intravesicular chemotherapies are permitted)
- Patients must agree to submission of tumor tissue from transurethral resection of the bladder tumor (TURBT) including a paraffin block or 20 formalin-fixed paraffin embedded (FFPE) slides of 5-10 microns in thickness; patients must also agree to submission of tissue from cystectomy
- Female subjects of childbearing potential must be willing to use adequate method of contraception; contraception, for the course of the study through 120 days after the last dose of study medication; Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Male subjects of childbearing potential must agree to use an adequate method of contraception; contraception, starting with the first dose of study therapy; Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Life expectancy greater than 3 months
- Consents to whole blood collection prior to initiating therapy, on cycle 2 day 1, and at cystectomy for support of correlative research studies
Exclusion Criteria
- Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of pembrolizumab
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; inhaled and topical steroids are allowed
- Has a known history of active TB (bacillus tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients
- Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
- Has an active infection requiring systemic therapy
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- Has received prior therapy with an PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
- Has received prior radiation therapy to the bladder for the purpose of treating urothelial carcinoma
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Has clinically relevant hearing impairment > grade 2
- Has received a live vaccine within 30 days prior to the first dose of trial treatment
Additional locations may be listed on ClinicalTrials.gov for NCT02690558.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To estimate the proportion of patients with pathological downstaging to < pT2 after neoadjuvant therapy with pembrolizumab in combination with gemcitabine hydrochloride (gemcitabine) and cisplatin in patients with muscle-invasive bladder cancer (MIBC).
SECONDARY OBJECTIVES:
I. To estimate the proportion of patients with pT0 after neoadjuvant therapy with pembrolizumab when administered in combination with gemcitabine and cisplatin in patients with MIBC.
II. To estimate event free survival (EFS).
III. To estimate overall survival (OS).
IV. To estimate the proportion of patients who are alive at 3 years (OS at 3 years).
V. To characterize the toxicity profile for the combination of pembrolizumab, gemcitabine, and cisplatin.
TERTIARY OBJECTIVES:
I. To explore the association of biological markers including PD-L1 expression and immune gene expression signatures with pathological downstaging to < pT2, pT0, EFS, and OS.
II. To explore associations between bladder cancer analysis of subtypes by gene expression using a 47-geen signature (BASE47) “basal,” “claudin-low,” and “luminal” subtypes of MIBC and pathological downstaging to < pT2, pT0, EFS, and OS.
III. To characterize the change in phenotype of tumor infiltrating lymphocytes (TILs), including delineation of effector and regulatory T cells, before and after neoadjuvant treatment.
IV. To define T cell receptor (TCR) and B cell receptor (BCR) repertoire profiles that are associated with pathological downstaging to < pT2, pT0, EFS, and OS.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, gemcitabine hydrochloride IV over 1 hour on days 1 and 8, and cisplatin IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients undergo radical cystectomy.
After completion of study treatment, patients are followed up for 30 days, every 3 months for 12 months, every 6 months for 24 months, then annually for 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUNC Lineberger Comprehensive Cancer Center
Principal InvestigatorMatthew Ivan Milowsky
- Primary IDLCCC1520
- Secondary IDsNCI-2016-00790
- ClinicalTrials.gov IDNCT02690558