A Phase II Study of Radiation Therapy and Pembrolizumab in Patients With Localized Urothelial Bladder Cancer That Are Ineligible or Refusing Chemotherapy
A Phase II Study of Radiation Therapy and Pembrolizumab in Patients With Localized Urothelial Bladder Cancer That Are Ineligible or Refusing Chemotherapy
This randomized phase II trial studies how well radiation therapy and pembrolizumab work in treating patients with urothelial bladder cancer that is restricted to the site of origin, without evidence of spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving radiation therapy and pembrolizumab may work better in treating urothelial bladder cancer.
PRIMARY OBJECTIVES:
I. To determine the maximally tolerated doses of hypofractionated and conventionally fractionated radiation therapy in combination with pembrolizumab and to generate an estimate of the efficacy of this regimen. (Safety Lead-in) II. To estimate the clinical complete response (CR) rate of the primary irradiated tumor in patients receiving radiotherapy and pembrolizumab. (Dose Expansion Cohort)
SECONDARY OBJECTIVES:
I. To estimate the local control rate at 6 and 12 months in each study arm. II. To estimate the distant metastases free survival at 6 and 12 months in each study arm.
III. To estimate progression free survival at 6 and 12 months in each study arm.
IV. To estimate disease-specific survival at 6 and 12 months in each study arm. V. To determine the safety of combining radiotherapy with pembrolizumab in each study arm in the dose expansion phase.
TERTIARY OBJECTIVES:
I. To assess peripheral and tumor-based biomarkers of response and resistance. II. To define the treatment-induced effects on circulating immune cells. III. To explore the remodeling of circulating T cell repertoire.
OUTLINE: Patients are randomized to 1 of 2 cohorts.
COHORT I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients also receive hypofractionated radiation therapy (RT) over 5 fractions for 14 days.
COHORT II: Patients receive pembrolizumab as in Cohort I. Patients also receive conventionally fractionated RT over 30 fractions for 52 weeks.
After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 24 months.
Inclusion Criteria:
Localized, muscle invasive urothelial carcinoma (T2-4, N0-1, M0) (mixed histology acceptable) ineligible for cystectomy
Patients must not be suitable for concurrent cisplatin as determined by the following:
Patients must not be suitable for fluorouracil (5FU)/mitomycin chemotherapy
Subjects with not meeting the above criteria are still eligible provided the patient declines concurrent chemotherapy with radiation, after specific informed consent describing the known benefits of adding chemotherapy to the definitive bladder radiation regimen; the reason for declining must be documented
Life expectancy of at least 3 months or greater
Be willing and able to provide written informed consent/assent for the trial
Be willing to provide tissue from a newly obtained transurethral resection of bladder tumor (TURBT) or biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 8 weeks (56 days) prior to initiation of treatment on say 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor
Have a performance status of 0 - 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
Absolute neutrophil count (ANC) >= 1,500 /mcL, performed within 28 days of treatment initiation
Platelets >= 100,000 / mcL, performed within 28 days of treatment initiation
Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment), performed within 28 days of treatment initiation
Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for subject with creatinine levels > 1.5 X institutional ULN, performed within 28 days of treatment initiation
Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN, performed within 28 days of treatment initiation
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN, performed within 28 days of treatment initiation
Albumin >= 2.5 mg/dL, performed within 28 days of treatment initiation
International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants, performed within 28 days of treatment initiation
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, performed within 28 days of treatment initiation
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
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
Exclusion Criteria:
Non-muscle invasive, localized bladder cancer (Tis, Ta, T1)
Presence of distant metastatic disease or disease not amenable to radiation treatment
Prior radiation treatment to the pelvis
Prior cystectomy
Is currently participating and receiving study therapy, or has participated in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks of the first dose of 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 trial treatment
Has a known history of active tuberculosis (TB) (Mycobacterium tuberculosis)
Hypersensitivity to pembrolizumab or any of its excipients
Has had a prior anti-cancer monoclonal antibody (mAb) 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
Prior systemic chemotherapy for bladder cancer; prior intravesical chemotherapy for the treatment of non-muscle invasive urothelial bladder cancer (UBC) is allowed
Upper tract urothelial carcinoma
Has had prior chemotherapy or targeted small molecule 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
Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
Has known distant metastases; clinically involved pelvic nodes (N1-N3) are allowed
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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; topical and inhaled corticosteroids are allowed
Has known history of, or any evidence of active, non-infectious 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 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 virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans)
Has a history of (non-infectious) pneumonitis that required steroids, or has current pneumonitis
Has received a live vaccine within 30 days of planned start of study therapy