Purpose

This phase II trial studies how well gemcitabine together with pembrolizumab works in treating patients with non-muscle invasive bladder cancer who are unresponsive to the BCG vaccine. Drugs used in chemotherapy, such as gemcitabine, 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. 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. Adding pembrolizumab to gemcitabine may delay the return of bladder cancer for longer than gemcitabine alone.

Conditions

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • High grade Ta, T1 or CIS urothelial carcinoma. Accrual of patients with Ta or T1 disease may be closed to ensure adequate patients enrollment to meet the primary endpoint
  • Persistent disease after completing therapy with at least induction BCG (>= 5 doses) and the first round of maintenance or second induction course (>= 2 doses)
  • Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above
  • High grade T1 after completing therapy with at least induction BCG (>= 5 doses) or after completing therapy with at least induction BCG (>=5 doses) and first round of maintenance or second induction course (>= 2 doses)
  • Persistent high risk NMIBC (T1, high grade Ta and/or CIS) must be within 9 months of the last BCG instillation despite having received adequate BCG as defined above
  • Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible
  • Patients who are disease free at 6 months after starting BCG but have high grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible
  • The recurrence must be within 6 months of the last BCG dose
  • Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy
  • All visible tumor must be completely resected 60 days prior to registration (residual pure CIS is permitted)
  • All patients must have histologically confirmed urothelial cancer of the bladder within 60 days prior to registration.

All patients must have had a cystoscopy without papillary tumor and negative urinary cytology within 21 days of registration. (positive cytology is allowed in patients with pure CIS)

- All patients with T1 tumors must undergo a re-staging transurethral resection of bladder tumor (TURBT) within 60 days of registration. There must be uninvolved muscularis propria present in the re-staging TURBT. The initial TURBT prior to re-staging TURBT may be greater than 60 days prior to registration

- Patients must have had imaging with computed tomography (CT) or magnetic resonance imaging (MRI) abdomen/pelvis within 90 days of registration demonstrating no evidence of metastasis.

- Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects

- Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 9.0 g/dL

- Creatinine =< 1.5 x upper limit of normal (ULN)

- In patients with creatinine > 1.5 x ULN, if measured or calculated creatinine clearance > 30 mL/min, then patient is eligible

- Total Bilirubin =< 1.5 x ULN

- In patients with a total bilirubin > 1.5 x ULN, if direct bilirubin < 1.0 X ULN, then patient is eligible

- Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 2.5 x ULN

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN

- Unless patient is receiving anticoagulant therapy, then PT or partial thromboplastin time (PTT) must be within the therapeutic range of intended use of the anticoagulant(s)

- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN

- Unless patient is receiving anticoagulant therapy, then PT or PTT must be within the therapeutic range of intended use of the anticoagulant(s)

- Patients with human immunodeficiency virus (HIV) are eligible with the following:

- On stable regimen of anti-retroviral therapy (highly active anti-retroviral therapy [HAART]).

- No requirement for antibiotic or antifungal for prevention of opportunistic infections.

- A CD4 count about 250 cells/mcl and undetectable HIV viral load by PCR

- Has no known additional malignancy that has had progression or has required active treatment in the last three years. Exceptions include basal or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with definitive intent is allowed, provided that the prostate-specific antigen (PSA) is undetectable for at least 1 year while off androgen deprivation therapy

- No live vaccines or BCG within 30 days prior to registration

- Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable: Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom).

Exclusion Criteria

  • Patients cannot have had a history of urothelial carcinoma in the ureters or prostatic urethra 24 months prior to registration
  • Patients must not have received any prior or concurrent systemic chemotherapy or immunotherapy (prior intravesical chemotherapy and interferon is permitted). Single dose chemotherapy post TURBT is permitted
  • Patients must not have received any prior bladder radiation
  • Patients must not have had an active autoimmune disease requiring systemic treatment within 24 months prior to registration. Autoimmune diseases include, but not limited to, lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis
  • Patients must not have undergone prior organ or bone marrow transplant
  • Patients must not have active tuberculosis
  • Patients must not have been treated with antibiotics for an active infection within 14 days prior to registration. Prophylactic antibiotics are permitted
  • Patients must not have a history of idiopathic pulmonary fibrosis, pneumonitis, organizing pneumonia, or active pneumonitis
  • Patients must not have active hepatitis B or C (resolved disease with positive anti-hepatitis B core [HBc] antibody or negative polymerase chain reaction [PCR] for hepatitis C [HCV] RNA permitted)
  • Glucocorticoids for any purpose other than to modulate symptoms from an adverse event of suspected immunologic etiology. Physiologic doses of corticosteroids are allowed
  • Physicians should consider whether any of the following may render the patient inappropriate for this protocol:
  • Psychiatric illness which would prevent the patient from giving informed consent.
  • Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

Study Design

Phase
Phase 2
Study Type
Interventional
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Treatment (pembrolizumab, gemcitabine hydrochloride)
INDUCTION: Patients receive pembrolizumab IV over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Drug: Gemcitabine Hydrochloride
    Given intravesically
    Other names:
    • dFdCyd
    • Difluorodeoxycytidine Hydrochloride
    • FF 10832
    • FF-10832
    • FF10832
    • Gemcitabine HCI
    • Gemzar
    • LY-188011
    • LY188011
  • Biological: Pembrolizumab
    Given IV
    Other names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475

Recruiting Locations

University of Texas Medical Branch
Galveston, Texas 77555-0565
Contact:
Site Public Contact
409-772-1950
clinical.research@utmb.edu

UTMB Cancer Center at Victory Lakes
League City, Texas 77573
Contact:
Site Public Contact
800-917-8906

More Details

Status
Recruiting
Sponsor
National Cancer Institute (NCI)

Study Contact

Detailed Description

CO-PRIMARY OBJECTIVES:

I. Estimate the 6-month complete response rate of treatment with intravesical gemcitabine hydrochloride (gemcitabine) in combination with MK-3475 (pembrolizumab) in patients with Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) that have a carcinoma in situ (CIS) component.

II. Estimate the 18 month event-free survival (EFS) rate for all patients with BCG-unresponsive NMIBC receiving intravesical gemcitabine in combination with MK-3475 (pembrolizumab).

SECONDARY OBJECTIVES:

I. To characterize the safety profile of the combination of intravesical gemcitabine with MK-3475 (pembrolizumab) with BCG-unresponsive NMIBC (CIS or high grade Ta and T1 with or without a CIS component).

II. To estimate progression-free survival (PFS) of patients with BCG-unresponsive NMIBC treated with intravesical gemcitabine in combination with MK-3475 (pembrolizumab).

III. To estimate overall survival (OS) of patients with BCG-unresponsive NMIBC treated with intravesical gemcitabine in combination with MK-3475 (pembrolizumab).

IV. To estimate cystectomy-free survival of patients with BCG-unresponsive NMIBC treated with intravesical gemcitabine in combination with MK-3475 (pembrolizumab).

V. To estimate recurrence-free survival (RFS) for patients with a CIS component only and those without a CIS component.

EXPLORATORY OBJECTIVES:

I. To assess correlation between tumor mutation burden (TMB) and EFS and 6-month complete response (CR) rate.

II. To assess correlation between specific genomic alterations (single nucleotide variant [SNV] and copy number gains/loss) and EFS and 6-month complete response rate.

III. To assess correlation between APOBEC mutational signature and EFS and 6-month complete response rate.

IV. To assess correlation between immune gene signatures (IGS) and EFS and 6-month complete response rate.

V. To assess correlation between PD-L1 ribonucleic acid (RNA) levels and EFS and 6-month complete response rate.

VI. To assess correlation between RNA molecular subtype and EFS and 6-month complete response rate.

VII. To assess correlation between intratumoral T-cell receptor (TCR) clonality and EFS and 6-month complete response rate.

VIII. To assess correlation between changes in peripheral blood TCR clonality and EFS and 6-month complete response rate.

IX. To assess EFS in patients with urine cell free deoxyribonucleic acid (DNA) (cfDNA) + versus (vs.) patients with cfDNA.

OUTLINE:

INDUCTION: Patients receive pembrolizumab intravenously (IV) over 25-40 minutes on day 1 of cycles 1-4. Patients also receive gemcitabine hydrochloride intravesically on days 1, 8 and 15 of cycles 1 and 2. Treatment repeats every 3 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Beginning cycle 5, patients with no evidence of disease after induction receive pembrolizumab IV over 25-40 minutes and gemcitabine intravesically on day 1. Treatment repeats every 3 weeks for 12 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years, until disease progression or recurrence, or until 5 years from study registration or . After documentation of disease progression or recurrence, patients are followed every 6 months for up to 5 years total from study registration.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.