Pembrolizumab in Treating Patients With Bladder Cancer Undergoing Radical Cystectomy

Phase 2

Completed

Conditions: Stage II Bladder Cancer AJCC v8
Stage IIIB Bladder Cancer AJCC v8
Stage I Bladder Cancer AJCC v8
Stage III Bladder Cancer AJCC v8
Stage IIIA Bladder Cancer AJCC v8

Interventions: Biological: Pembrolizumab

Registration Number: NCT03319745

Lead Sponsor: M.D. Anderson Cancer Center

Brief Summary: This phase II trial studies the side effects of pembrolizumab and to see how well it works in treating patients with bladder cancer who are undergoing surgery to remove the bladder. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description: PRIMARY OBJECTIVE:

I. To characterize the safety profile of pembrolizumab in patients with urothelial carcinoma undergoing radical cystectomy.

SECONDARY OBJECTIVES:

I. To explore a signal of anti-cancer immunological activity by evaluating surgical specimens for evidence of post-treatment lymphocytic infiltration and residual tumor compared to pre-treatment biopsy samples.

II. To explore a signal of biomarker activity by evaluating surgical specimens and blood samples for established and not-so-established markers of response to pembrolizumab.

III. To report the tumor yield and sufficiency of tumor for immunological and biomarker activity.

IV. To examine the interaction of the human microbiome and pathologic response to pembrolizumab.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. About 4 weeks after treatment, patients then undergo radical cystectomy per standard of care.

After completion of study treatment, patients are followed up to 30 and 90 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

Inclusion Criteria

Be willing and able to provide written informed consent.
Have absence of metastatic disease as determined by conventional imaging studies and be considered a good surgical candidate by the treating physician.
Be willing to participate in the collection of blood and tissue for banking and future correlative studies.
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.
Absolute neutrophil count (ANC) >= 1,500 /mcL.
Platelets >= 100,000/mcL.
Hemoglobin (Hgb) >= 9 g/dL or >= 5.6 mmol/L without (w/o) transfusion within 7 days of assessment.
Creatinine OR calculated creatinine clearance =< 1.5 x upper limit of normal (ULN) OR >= 30 mL/min for subject with creatinine levels > 1.5 x institutional ULN. Creatinine clearance should be calculated per institutional standard.
Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases.
Albumin > 2.5 mg/dL.
Coagulation international normalized ratio (INR) or prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Female subjects of childbearing potential must be willing to use an adequate method of 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, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria

Is currently participating and receiving pembrolizumab or has participated in a study of an investigational agent and received pembrolizumab or used an investigational device within 4 weeks of the first dose of study treatment.
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 study treatment.
Has a known history of active TB (Bacillus tuberculosis).
Has a known history of hypersensitivity to pembrolizumab or any of its excipients.
Has had prior systemic anti-cancer therapy for the treatment of bladder cancer. Prior intravesical therapies, whether Bacillus Calmette-Guerin (BCG) (including but not limited to: persistent high-grade disease or recurrence within 6 months of receiving at least two courses of intravesical BCG [at least five of six induction doses and at least two of three maintenance doses]; or T1 high-grade disease at the first evaluation following induction BCG alone [at least five of six induction doses]), chemotherapy or otherwise, will remain eligible.
Has any other malignancy diagnosed within 2 years of screening with the exception of basal or squamous cell skin cancer, or non-invasive cancer of the cervix, or any other cancer deemed by the treating physician to be of low-risk for progression or patient morbidity during the study period.
Has known metastatic disease as determined by conventional staging studies.
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 known history of, or any evidence of active, non-infectious pneumonitis.
Has a clinically significant 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 physician.
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 anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
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 received a live vaccine within 30 days of initiation of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pembrolizumab)	Pembrolizumab	Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. About 4 weeks after treatment, patients then undergo radical cystectomy per standard of care.

Primary Outcome Measures

Name	Time	Method
Toxicity for Safety Monitoring (TOX)	From initiation of pembrolizumab, until 90 days post-surgery, up to a maximum of 5.5 months	The primary endpoint is a joint endpoint classifying patients as having a toxicity of concern (TOX), defined as the presence of any of these: 1) any 30-day grade 3 or higher surgical complication at least possibly related to the treatment, 2) any toxicity at least possibly related to the treatment that prevents surgery, or 3) death between the start of the study and the 30-day post-surgical assessment as long as it is at least possibly related to pembrolizumab or surgery.

Secondary Outcome Measures

Name	Time	Method
Efficacy Endpoint	Efficacy endpoint will be measured at time of surgery	To explore anti-cancer immunological activity by evaluating surgical specimens for evidence of post-treatment and residual tumor compared to pre-treatment biopsy samples. The main mechanism for doing so will be via histopathologic review of the radical cystectomy specimen. MIBC participants are defined as responders if they achieve a pT1 stage or less. In the case of NMIBC a pT0 status will be used to identify complete response.