Study of 2141-V11 in People With Non-muscle Invasive Bladder Cancer That Did Not Respond to Standard Treatment

Inclusion Criteria:

Cohorts A and B Part 1

* High-grade (HG) NMIBC (HG Ta, CIS, and/or T1) of urothelial histology that is unresponsive to adequate BCG therapy.
* Stage, grade, and histology must be confirmed by the MSK Department of Pathology
* Subjects with tumors of mixed urothelial/non-urothelial histology may be included, but urothelial carcinoma must be the predominant histology; subjects with predominant or exclusively non-urothelial histology are excluded
* In those subjects with CIS, the CIS must be present on the tumor sample from the most recent cystoscopy/TURBT
* In this context, adequate BCG therapy is defined as at least one of the following:
* At least five of six doses of an initial induction course plus at least two of three doses of maintenance therapy
* At least five of six doses of an initial induction course plus at least two of six doses of a second induction course
* Disease unresponsive to adequate BCG therapy is defined as the following. Suspected recurrence from suspicious cytology or cystoscopy, and later confirmed via TURBT, is acceptable:
* Persistent or recurrent CIS alone or with recurrent Ta/T1 disease (noninvasive papillary disease/tumor invades the subepithelial connective tissue) within 12 months of completion of adequate BCG therapy
* Recurrent HG Ta/T1 disease within 6 months of completion of adequate BCG therapy
* HG T1 disease at the first evaluation following an induction BCG course

Cohort C:

* Muslce invasive bladder cancer cT2-T4aN0-2 that has a predominant urothelial histology.
* Stage, grade, and histology must be confirmed by the MSK Department of Pathology
* Subjects with tumors of mixed urothelial/non-urothelial histology may be included, but urothelial carcinoma must be the predominant histology; subjects with predominant or exclusively non-urothelial histology are excluded

Cohort A and B Only:

* In subjects with papillary tumors (Ta and T1), a complete TURBT must have been performed.

This is characterized by:

* Attainment of a visually complete resection of all papillary tumors (Ta and T1)
* Residual CIS not amenable to complete transurethral resection is acceptable
* Receipt of restaging transurethral resection for any tumor with invasion into the lamina propria (HG T1) as part of standard care, with documented presence of uninvolved detrusor muscle.
* Most recent cystoscopy/TURBT must have been performed within 6 months of the first dose of trial treatment.
* Absence of urothelial carcinoma involving the upper urinary tract (documented by radiological imaging or ureteroscopy).
* Have elected not to undergo or are considered ineligible for radical cystectomy, as determined by the treating surgeon. Reasons for ineligibility or refusal of radical cystectomy should be discussed with the subject as part of the informed consent process.
* Ineligibility factors for radical cystectomy may include, but are not limited to:
* Cardiovascular disease (e.g., recent acute coronary syndrome, arrhythmia, heart failure)
* Chronic obstructive pulmonary disease that would preclude a safe surgical procedure, as determined by the treating surgeon
* Poor performance status
* Prior major abdominal and pelvic surgery that would preclude a safe surgical procedure, as determined by the treating surgeon

Cohort C Only:

\- Are willing to undergo a standard of care examination under anesthesia or cystoscopy within four weeks of scheduled radical cystetomy.

* Patients must have received 3-4 cycles of neoadjuvant Enfortumab Vedotin and pembrolizumab
* Age ≥18 years on day of signing informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status ≤2 / Karnofsky performance status ≥60%, as assessed within 28 days prior to treatment initiation.
* Required values for screening laboratory tests, performed within 28 days prior to treatment initiation:

Absolute neutrophil count (ANC) ≥1000/mm3

* Platelets \>75,000/mm3 without
* Hemoglobin \>8 g/dL
* Creatinine clearance \>40 mL/min for the dose-escalation phases, \>25 mL/min for the dose expansion phases (estimated GFR can also be used in place of creatinine clearance)
* AST/ALT ≤3 times the institutional upper limit of normal (ULN)
* Total bilirubin ≤1.5 times the institutional ULN

  * Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment.
  * Female subjects will be considered of non-reproductive potential if any of the following:
  * Postmenopausal \[defined as at least 12 months with no menses without an alternative medical cause; in women \<45 years of age a high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
  * Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening
  * Has a congenital or acquired condition that prevents childbearing
  * Male and female subjects of childbearing potential must agree, if participating in sexual activity that could lead to pregnancy, to use of an adequate method of contraception from the day of study medication initiation (or 14 days prior to the initiation of study medication for oral contraception) throughout the study period up to 120 days after the last dose of trial therapy. Subjects should be informed that taking the study medication(s) may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study.

    o Male subjects will be considered of non-reproductive potential if they have azoospermia (whether due to vasectomy or an underlying medical condition). Female subjects will be considered of non-reproductive potential if as described above. Acceptable methods of contraception:
  * Single method (one of the following is acceptable): intrauterine device, vasectomy of a female subject's male partner, or contraceptive rod implanted into the skin
  * Combination method (requires use of two of the following): diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), or hormonal contraceptive \[oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection
  * Male subjects must agree not to donate sperm during and after the study
  * Able to comply with the treatment schedule as determined by the participant and the licensed practitioner.

Cohort B Part 2

* Subjects with BCG-naïve High-grade Ta NMIBC are eligible. BCG-naïve NMIBC is defined as patients with no prior BCG exposure or no BCG treatment within 2 years of trial start.

  * Stage, grade, and histology must be confirmed by the MSK Department of Pathology
  * Subjects with tumors of mixed urothelial/non-urothelial histology may be included, but urothelial carcinoma must be the predominant histology; subjects with predominant or exclusively non-urothelial histology are excluded
* A complete TURBT must have been performed, as characterized by:

  o Attainment of a visually complete resection of all tumors
* Most recent cystoscopy/TURBT must have been performed within 60 days of the first dose of trial treatment
* Absence of urothelial carcinoma involving the upper urinary tract (documented by radiological imaging or ureteroscopy)
* Eastern Cooperative Oncology Group (ECOG) performance status ≤2 / Karnofsky performance status ≥60%, as assessed within 28 days prior to treatment initiation
* Required values for screening laboratory tests, performed within 28 days prior to treatment initiation:

  o Absolute neutrophil count (ANC) ≥1000/mm3 independent of growth factor support

  o Platelets \>75,000/mm3 without receiving transfusion within 4 weeks prior to screening

  o Hemoglobin \>8 g/dL without receiving transfusion within 4 weeks prior to screening

  o Creatinine clearance (measured or calculated per institutional standard) \>40mL/min; estimated GFR can also be used in place of creatinine clearance

  o AST/ALT ≤3 times the institutional upper limit of normal (ULN)

  o Total bilirubin ≤1.5 times the institutional ULN (except for participants with Gilbert's Syndrome or of non-hepatic origin)
* Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment.

  o Female subjects will be considered of non-reproductive potential if any of the following: oPostmenopausal \[defined as at least 12 months with no menses without an alternative medical cause; in women \<45 years of age a high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.\] Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening
* Has a congenital or acquired condition that prevents childbearing
* Male and female subjects of childbearing potential must agree, if participating in sexual activity that could lead to pregnancy, to use of an adequate method of contraception from the day of study medication initiation (or 14 days prior to the initiation of study medication for oral contraception) throughout the study period up to 120 days after the last dose of trial therapy. Subjects should be informed that taking the study medication(s) may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study.

  * Male subjects will be considered of non-reproductive potential if they have azoospermia (whether due to vasectomy or an underlying medical condition). Female subjects will be considered of non-reproductive potential if as described above.
  * Acceptable methods of contraception:
* Single method (one of the following is acceptable): intrauterine device, vasectomy of a female subject's male partner, or contraceptive rod implanted into the skin
* Combination method (requires use of two of the following): diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide), cervical cap with spermicide (nulliparous women only), contraceptive sponge (nulliparous women only), male condom or female condom (cannot be used together), or hormonal contraceptive \[oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection\]
* Male subjects must agree not to donate sperm during and after the study
* Willing and able to provide written informed consent/assent for the trial
* Able to comply with the treatment schedule as determined by the participant and the licensed practitioner

Exclusion Criteria:

(Cohort A and B) Part 1

* History of or currently being treated for muscle-invasive (T2, T3, T4) locally-advanced non-resectable or metastatic urothelial carcinoma.
* Evidence of concurrent extravesical (i.e., urethra, ureter, or renal pelvis) urothelial cell carcinoma.
* Concurrent anti-cancer therapy, including investigational agents

Exceptions include:

* Cohorts A and B Exceptions: Subjects on topical therapy (e.g. topical 5-
* Cohort C Exceptions: Subjects on topical therapy (e.g. topical 5-fluorouracil) and Neoadjuvant chemotherapy (e.g. cisplatin and gemcitabine)
* Has undergone any intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/TURBT to starting trial treatment (a single dose of intravesical treatment given as part of the most recent cystoscopy/TURBT, during the screening period, such as with chemotherapy as per local/regional practices, is acceptable).
* Have received any other neoadjuvant treatment other than Enfortumab Vedotin and pembrolizumab for muscle invasive bladder cancer
* Has had prior chemotherapy, targeted small molecule therapy, cytokine therapy, or radiation therapy within 2 weeks prior to the first dose of trial treatment or who has not recovered (i.e., Grade ≤1 or at baseline) from AEs due to a previously administered agent.

  °Subjects with Grade ≤2 neuropathy or Grade ≤2 alopecia are an exception to this criterion and may qualify for the study
* Major surgery or a wound that has not fully healed within 4 weeks prior to the first dose of trial treatment.

  * If subject has undergone major surgery greater than 4 weeks prior, subject must have recovered adequately from the toxicity and/or complications from the intervention prior to starting trial therapy

    * Refer to detail description for the rest of the Inclusion/Exclusion criteria