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 with evidence of disease (recurrence or
progression) or stop study treatment to receive non-protocol treatment during induction are
followed up every 6 months for 5 years. Patients who go off treatment due to any reason other
than recurrence/progression or receiving subsequent non-protocol treatment during induction
will go to clinical follow-up until evidence of disease progression/recurrence. Thereafter,
patients are followed up every 6 months until 5 years from registration. Patients who
complete scheduled maintenance treatment according to protocol therapy are followed up every
3 months for 2 years and then every 6 months for 3 years until disease progression/recurrence
or receiving subsequent non-protocol treatment. Thereafter, patients are followed up every 6
months until 5 years from registration. Patients who have evidence of disease during
maintenance therapy are followed up every 6 months until 5 years from registration.
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
- 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)
- A woman of childbearing potential (WOCBP) must not have a positive urine
pregnancy test within 7 days prior to registration. If the urine test is positive
or cannot be confirmed as negative, a serum pregnancy test will be required
- Patients must not be pregnant or breastfeeding or expecting to conceive or father
children within the projected duration of the study, starting with registration
through the last dose of treatment
- Age >= 18 years
- 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
- Patients with human immunodeficiency virus (HIV) are eligible with the following:
- On effective anti-retroviral therapy with undetectable viral load within 6 months
of registration
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 be currently participating in or have participated in a study of an
investigational agent or have used an investigational device within 4 weeks prior to
study registration
- Note: Participants who have entered the follow-up phase of an investigational
study may participate as long as it has been more than 4 weeks after the last
dose of the previous investigational agent at time of registration
- Patients must not have prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2
agent or with an agent directed to another stimulatory or co-inhibitory T-cell
receptor (e.g., CTLA-4, OX 40, CD137)
- Patients must not have undergone prior allogeneic hematopoietic stem cell
transplantation within the last 5 years prior to registration. (Participants who have
had a transplant greater than 5 years ago are eligible as long as there are no
symptoms of graft versus host disease [GVHD])
- Patients must not have received prior systemic anti-cancer therapy including
investigational agents within 4 weeks prior to treatment
- Note: Participants must have recovered from all adverse events (AEs) due to
previous therapies to =< grade 1 or baseline. Participants with =< grade 2
neuropathy may be eligible
- Note: If participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
study treatment
- Patients must not have received prior radiotherapy within 2 weeks of study
registration. Participants must have recovered from all radiation-related toxicities,
not require corticosteroids, and not have had radiation pneumonitis
- Patients must not have received radiation therapy to the lung that is > 30 Gy within 6
months prior to trial registration
- Patients must not have had an active autoimmune disease requiring systemic treatment
within 7 days 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 a diagnosis of immunodeficiency or is receiving chronic
systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or
any other form of immunosuppressive therapy within 7 days prior to registration
- Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not
considered a form of systemic treatment and is allowed
- Patients must not have a known psychiatric or substance abuse disorder that would
interfere with the participant's ability to cooperate with the requirements of the
study
- 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. Treatment for a
urinary tract infection (UTI) is allowed but must be deemed adequately treated by the
treating physician prior the start of cycle 1 (C1) day 1 (D1)
- Patients must not have a history of idiopathic pulmonary fibrosis or organizing
pneumonia
- Patients must not have a history of (non-infectious) pneumonitis that required
steroids or have current pneumonitis
- HIV-infected participants must not have a history of Kaposi sarcoma and/or
multicentric Castleman disease
- Patients must not have a 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
- Patients must not have known active CNS metastases and/or carcinomatous meningitis.
Participants with previously treated brain metastases may participate provided they
are radiologically stable, i.e., without evidence of progression for at least 4 weeks
by repeat imaging (note that the repeat imaging should be performed during study
screening), clinically stable and without requirement of steroid treatment for at
least 14 days prior to first dose of study treatment
- Patients must not have severe hypersensitivity (>= grade 3) to pembrolizumab and/or
any of its excipients
- Patients must not have an active infection requiring systemic therapy
- Patients must not have a known history of hepatitis B (defined as hepatitis B surface
antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C
virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection
- Note: No testing for hepatitis B and hepatitis C is required unless mandated by a
local health authority
- Patients must not have received live vaccines within 30 days of study drug
administration. Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever,
rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed; however,
intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not
allowed
- Physicians should consider whether any of the following may render the patient
inappropriate for this protocol:
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, or is not in the
best interest of the participant to participate, in the opinion of the treating
investigator
