Gemcitabine and Cisplatin plus Cemiplimab with or without Fianlimab for Bladder Preserving Treatment of Muscle Invasive Bladder Cancer, The NeoSTOP-IT Trial

Inclusion Criteria

• Be willing and able to provide written informed consent for the trial
• Be age ≥ 18 years of age on day of signing informed consent
• Have life expectancy > 12 months
• Have a performance status of 0-2 using the Eastern Cooperative Oncology Group (ECOG) performance scale
• Have histologically confirmed muscle-invasive urothelial carcinoma of the bladder defined as T2-T3, N0, M0 stage. Mixed histology is permitted if there is a urothelial component. Upper tract disease is not permitted
• Prior Bacillus Calmette-Guerin (BCG) or other intravesical treatment of non-muscle invasive bladder cancer is permitted if completed at least 6 weeks prior to initiating study treatment. Only one course (includes induction + maintenance) of BCG or intravesical therapy is permitted
• Have no metastatic disease based on cross-sectional imaging
• Be considered cisplatin eligible based on: * Creatinine clearance ≥ 50 ml/min * ECOG performance status 0-1 * Grade < 2 hearing loss * Grade < 2 neuropathy
• Have not received any adjuvant or neoadjuvant chemotherapy or immunotherapy
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000
• Hemoglobin ≥ 9.0g/dL (without transfusion in past 2 weeks)
• Prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT) ≤ 1.5 upper limit of normal (ULN) (except if on therapeutic anti-coagulation in which case the patient can be enrolled if stable and anti-coagulation levels are appropriate for their condition per good clinical practice)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3.0 × institutional upper limit of normal
• Total bilirubin ≤ 1.5 x normal institutional limits. * Note: Patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g. Gilbert’s syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator
• Creatinine clearance of ≥ 50 mL/min. Creatinine clearance (CrCl) should be calculated at screening using the Cockcroft-Gault formula
• Agree to pre- and post-treatment TURBT as well as surveillance with cystoscopies, cross-sectional imaging, and urine cytology unless medically contraindicated in the opinion of the treating physician, and discussed with the principal investigator
• The effects of cemiplimab (REGN2810) and fianlimab (REGN3767) on the developing human fetus are unknown. For this reason and because the investigational agents (as well as other therapeutic agents used in this trial) are known to be teratogenic, 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 6 months after completion of cemiplimab (REGN2810) and fianlimab (REGN3767) administration. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately

Exclusion Criteria

• Has concurrent upper urinary tract (i.e., ureter, renal pelvis) invasive urothelial carcinoma. * NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible
• Received prior immune checkpoint inhibitors (including anti–PD-1, anti–PD-L1, anti-CTLA4, anti-LAG-3 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways), as well as cellular vaccines, cellular therapies, or systemic oncolytic virus therapy
• Received bladder-directed radiation therapy previously for bladder cancer
• Has received prior systemic chemotherapy for muscle-invasive bladder cancer
• Is receiving any other investigational agents concurrently or within 4 weeks of start of treatment
• Had a solid organ or hematologic transplant
• Ongoing or recent (within 2 years) evidence of an autoimmune disease that required systemic treatment with immunosuppressive agents. The following are non-exclusionary: vitiligo, childhood asthma that has resolved, residual hypothyroidism that requires only hormone replacement, psoriasis not requiring systemic treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose greater than 10mg/day of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Has a history of myocarditis
• Has Troponin T (TnT) or Troponin I (TnI) > 2 x institutional upper limit of normal at baseline. Patients with TnT or TnI levels between > 1 to 2 x ULN are permitted if repeat levels within 24 hours are ≤ 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on medical judgement in the patient’s best interest
• Patients with another active second malignancy other than non-melanoma skin cancers
• Has a known history of, or any evidence of, interstitial lung disease or active noninfectious pneumonitis
• Has peripheral neuropathy > grade 1
• Has an active infection requiring systemic therapy
• History or current evidence of significant (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥ 2) local or systemic infection (eg, cellulitis, pneumonia, septicemia) requiring systemic antibiotic treatment within 2 weeks prior to the first dose of trial medication
• Has a history of 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, including dialysis
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Uncontrolled infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Notes: * Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable antiviral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. * Patients with known hepatitis B (hepatitis B surface antigen positive [HepBsAg+]) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards and must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug. * Patients who are known hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. * Patients with HIV or hepatitis must be reviewed by a qualified specialist (eg, infectious disease or hepatologist) managing this disease prior to commencing and regularly throughout the duration of their participation in the trial
• Has received a live vaccine within 30 days of planned start of study therapy (Cycle 1, Day 1). Note: The killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. * Live or live attenuated vaccination with replicating potential. If a patient intends to receive a COVID-19 vaccine before the start of study drug, participation in the study should be delayed at least 1 week after any COVID-19 vaccination. During the treatment period, it is recommended to delay COVID-19 vaccination until patients are receiving and tolerating a steady dose of study drug. A vaccine dose should not be less than 48 hours before or after study drug dosing
• Has a history of severe hypersensitivity reaction to gemcitabine or cisplatin
• Has a prior history of hypersensitivity to monoclonal antibody
• Has a history of hypersensitivity to any of the excipients
• Is pregnant or is a breastfeeding woman
• Women of childbearing potential (WOCBP) who are unwilling to practice highly effective contraception prior to initial dose/start of treatment, during study, and for at least 6 months after the last dose. (WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. Pregnancy testing and contraception are not required for women who are post-menopausal or permanently sterile.) Highly-effective contraceptive measures include: * stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; * intrauterine device; intrauterine hormone-releasing system; * bilateral tubal occlusion/ligation; * vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or * sexual abstinence. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactation amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
• Men who do not agree to not to donate sperm during the trial and for 6 months after receiving the last therapy dose
• WOCBP who do not agree to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial and until 6 months after last treatment