Ensayos clínicos

Inclusion Criteria:

• Patients in Arm A may begin treatment after this registration.
• Patients in Arm B will be required to undergo a second registration by meeting PD-L1  eligibility criteria. A tissue sample must be submitted for central analysis of PD-L1  after eligibility are confirmed.
• Patients must have pathologically confirmed urothelial carcinoma.
  • Note: patients with mixed histology (with predominant urothelial carcinoma) are eligible.
• Patients must have locally advanced or metastatic disease with either:
• Arm A:  Disease progression during or following (within 12 months) platinum-based chemotherapy (cisplatin or carboplatin).
  • Note: no minimum number of cycles on platinum-based chemotherapy are required.
• Patients who have had multiple rounds of platinum-based  chemotherapy with events of intermittent progressive disease (PD) are eligible as long as progression has been confirmed while on or within 12 months from platinum based therapy OR
• Arm B:  Cisplatin ineligible as defined.
• Patients in Arm B must also: 
  • Undergo central analysis of tissue for PD-L1 status; Be positive for PD-L1; 
  • If archival tissue is unavailable or insufficient for PD-L1 central analysis, a new biopsy must be performed;
  • Alternatively, patients who previously have had PD-L1 testing performed as standard of care via the Food and Drug Administration (FDA)-approved Dako PD-L1 immunohistochemistry (IHC) 22C3 PharmDx Assay companion diagnostic test and who have a combined positive score (CPS) of >= 10 may be eligible. In these cases, PD-L1 testing does not need to be repeated, and tissue does not need to be sent for central analysis.
• All patients must have measurable disease in accordance with RECIST criteria version  (v) 1.1.
  • Note: radiological evaluation should occur within 28 days prior to study registration.
• Patients must be naive to prior PD-L1 or EZH2 inhibitors.
  • Note: patients in Arm A should have received platinum-based chemotherapy only.  
• Patients ≥ 18 years of age.
• ECOG performance status ≤ 2.
• Patients must have a blood smear or manual differential performed at screening showing  no significant morpholic abnormalities on complete blood count (CBC) testing.  
• Leukocytes ≥ 3000/mcL (performed within 14 days prior to registration).  
• Absolute neutrophil count (ANC) ≥ 1500/mcL (performed within 14 days prior to  registration).
• Platelets ≥ 100 000/mcL (performed within 14 days prior to registration).
• Hemoglobin ≥ 9 g/dL or ≥ 4.9 mmol/L (performed within 14 days prior to registration).
• Creatinine ≤ 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine  clearance (CrCl) ≥ 30 mL/min for patient with creatinine levels > 1.5 x institutional  ULN (performed within 14 days prior to registration).
• Creatinine clearance (CrCl) should be calculated per institutional standard.  
• Glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl. 
• Total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patients with total  bilirubin levels > 1.5 x ULN (performed within 14 days prior to registration).
• 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 patients with liver metastases (performed within 14 days prior  to registration).
• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin  time (PTT) is within therapeutic range of intended use of anticoagulants (performed  within 14 days prior to registration)  
• Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless patient is receiving  anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 14 days prior to registration).
• The effects of MK-3475 and tazemetostat on the developing human fetus are unknown. For  this reason and because PD-1 inhibitors as well as EZH2 inhibitors are known to be  teratogenic, women of child-bearing potential and men must agree to use adequate  contraception (hormonal or barrier method of birth control; abstinence) prior to study  entry and for the duration of study participation. 
• Female patients of childbearing potential must have a negative urine or serum pregnancy test 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 patients 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 patient. 
• Male patients 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 patient.
• Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MK-3475 or tazemetostat administration.
• Participants who have the ability to understand and the willingness to sign an  Institutional Review Board (IRB) approved written informed consent document are  eligible OR Participants with impaired decision-making capacity (IDMC) who have a  legally authorized representative (LAR) or caregiver are eligible.  

Exclusion Criteria:  

• Patients with disease that is suitable for local therapy administered with curative intent are not eligible.
• Patients who have had chemotherapy, targeted small molecule therapy, or radiotherapy  within 4 weeks prior to entering the study are not eligible.
• Patients who have not recovered from adverse events due to prior anti-cancer therapy  (i.e., have residual toxicities > grade 1 per Common Terminology Criteria for Adverse Events [CTCAE] v.5 ) are not eligible.
  • Note: patients with ≤ grade 2 neuropathy or ≤ grade 2 alopecia or ≤ grade 3 audiometric hearing loss are an exception to this criterion and may qualify for the study.
  • Note: if patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Patients are not eligible who are currently participating and receiving study therapy  or have 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.
• Patients who have received transfusion of blood products (including platelets or red  blood cells) or administration of colony stimulating factors (including granulocyte  colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor  [GM-CSF], or recombinant erythropoietin) within 4 weeks prior to the first dose of  treatment are not eligible.
• Patients with a diagnosis of immunodeficiency or are receiving systemic steroid  therapy or any other form of immunosuppressive therapy within 7 days prior to the  first dose of trial treatment are not eligible.  
  • Note: the use of physiologic doses of corticosteroids may be approved after consultation with the study principal investigator (PI).
• Patients with thrombocytopenia, neutropenia, or anemia of grade 3 (per CTCAE 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic  syndrome (MDS) are not eligible. 
• Patients with abnormalities known to be associated with MDS (e.g., del 5q, chr 7 abn)  and myeloproliferative neoplasms (MPN, e.g. JAK2 V617F) observed in cytogenetic  testing and deoxyribonucleic acid (DNA) sequencing are not eligible.
• Patients with a prior history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute  lymphoblastic leukemia (T-ALL) are not eligible.
• Patients who have received prior PD-L1/PD-1/PD-L2 or EZH2 inhibitor therapy are not eligible.
• Patients who have had a prior monoclonal antibody within 4 weeks prior to study day 1 are not eligible.
• Patients with a known additional malignancy that is progressing or requires active  treatment are not eligible. Exceptions include basal cell carcinoma of the skin,  squamous cell carcinoma of the skin that has undergone potentially curative therapy,  or in situ cervical cancer.
• Patients with known brain metastases or carcinomatous meningitis are excluded from  this clinical trial because of their poor prognosis and because they often develop  progressive neurologic dysfunction that would confound the evaluation of neurologic  and other adverse events.  
  • Note: patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either magnetic resonance imaging [MRI] or computed tomography [CT] scan, for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
• Patients with a history of allergic reactions attributed to compounds of similar  chemical or biologic composition to MK-3475 or tazemetostat are not eligible.
• Patients with an 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) are not eligible.
  • Note: 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.
  • Patients with a history of (non-infectious) pneumonitis that required steroids or  current pneumonitis are not eligible.
• Patients with a prolongation of corrected QT interval (Fridericia's correction formula  [QTcF]) of > 450 msec are not eligible.
• Patients with major surgery within 3 weeks before the first dose of study drugs.  
  • Note: minor surgery (e.g., minor biopsy of an extracranial site, central venous catheter placement, shunt revision) has no restriction.
• Patients must not have a history or current evidence of any condition, therapy, or  laboratory abnormality that might confound the results of the trial, interfere with  the patient's participation for the full duration of the trial, or is not in the best  interest of the patient to participate, in the opinion of the treating investigator.
• Patients receiving any medications or substances that are strong inhibitors or  inducers of CYP3A =< 14 days prior to study treatment are not eligible .
  • Note: The study team should check a frequently-updated medical reference for a list of drugs to avoid or minimize use of. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients who are unable to take oral medication OR have malabsorption syndrome or any  other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, vomiting) that  might impair the bioavailability of tazemetostat are not eligible.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing  or active infection, interstitial lung disease or active, non-infectious pneumonitis,  symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,  uncontrolled arterial hypertension, stroke within 6 months prior to starting study  treatment, or psychiatric illness/social situations that would limit compliance with  study requirements are not eligible.
• Pregnant women are excluded from this study because MK-3475 and tazemetostat are  agents with the potential for teratogenic or abortifacient effects. Because there is  an unknown but potential risk for adverse events in nursing infants secondary to  treatment of the mother with MK-3475 and tazemetostat, breastfeeding should be  discontinued if the mother is treated with MK-3475 or tazemetostat.
• MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not known if MK-3475 has transient adverse effects on the composition of sperm. Patients are excluded from this study if pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
• Patients who are human immunodeficiency virus (HIV) positive may participate IF they  meet the following eligibility requirements:
  • They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective;
  • They must have a CD4 count of greater than 250 cells/mcL; 
  • They must not be receiving prophylactic therapy for an opportunistic infection.
• Patients with a known history of hepatitis B (defined as hepatitis B surface antigen  [HBsAg] reactive) or known hepatitis C virus (defined as HCV ribonucleic acid [RNA]  [qualitative] is detected) infection are not eligible   -Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority.
• Patients who have received a live vaccine within 30 days of planned treatment start  are not eligible.
  • Note: seasonal flu vaccines that do not contain live virus are permitted.

PD-L1 ELIGIBILITY (ARM B ONLY):

• Patients in Arm B must have positive PD-L1 status as confirmed by central analysis  prior to second step registration and treatment initiation.
  • Note: positive PD-L1 expression is defined as a combined positive score (CPS) ≥ 10 and will be confirmed in a report from HistoGeneX.  Alternatively, patients who previously have had PD-L1 testing performed as standard of care via the FDA-approved Dako PD-L1 IHC 22C3 PharmDx Assay companion diagnostic test and who have a combined positive score (CPS) of ≥ 10 may be eligible. In these cases, PD-L1 testing does not need to be repeated, and tissue does not need to be sent for central analysis.