A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer

This study will examine the safety and anticancer activity of enfortumab vedotin (EV) given intravenously as monotherapy and in combination with other anticancer therapies as first line (1L) and second line (2L) treatment for patients with urothelial cancer. The primary goal of the study is to determine the safety, tolerability, and efficacy of enfortumab vedotin alone and in combination with pembrolizumab and/or chemotherapy. The study will be conducted in multiple parts:

Locally advanced or metastatic urothelial cancer:

* Dose escalation
* Expansion

* Part 1: Cohorts A and Optional B
* Part 2: Cohorts D, E, and Optional F
* Part 3: Cohort G.
* Randomized Cohort K

* EV Monotherapy Arm
* EV Combination Arm

Muscle invasive bladder cancer:

* Cohort H
* Optional Cohort J
* Cohort L

• enfortumab vedotin (EV) (Drug), also known as ASG-22CE, ASG-22ME, PADCEV: Intravenous (IV) infusion on days 1 and 8 every 21 days
• pembrolizumab (Drug), also known as Keytruda: IV infusion on day 1 every 21 days
• cisplatin (Drug): IV infusion on day 1 every 21 days
• carboplatin (Drug): IV infusion on day 1 every 21 days
• gemcitabine (Drug): IV infusion on days 1 and 8 every 21 days

Primary outcomes

• Type, incidence, severity, seriousness, and relatedness of adverse events (Dose escalation and Expansion Parts 1 to 3 cohorts only) [Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.]: Descriptive statistics will be used to summarize results.
• Type, incidence, and severity of laboratory abnormalities (Dose escalation and Expansion Parts 1 to 3 cohorts only) [Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.]: Descriptive statistics will be used to summarize results.
• Confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by blinded independent central review (BICR) (Cohort K only) [Up to 3 years]: The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1
• Pathological complete response (pCR) rate per central pathology review (MIBC cohorts only) [Up to approximately 5 months]: The proportion of patients with absence of viable tumor tissue at the time of radical cystectomy.

Secondary outcomes

• Incidence of dose-limiting toxicity (DLT) [21 days]: Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).
• Confirmed ORR by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [Up to 3 years]: The proportion of patients with confirmed CR or PR according to RECIST 1.1.
• Confirmed ORR by BICR according to RECIST 1.1 (Dose escalation and Cohort A only) [Up to 3 years]: The proportion of patients with confirmed CR or PR according to RECIST 1.1
• Confirmed ORR by investigator assessment per the modified RECIST 1.1 for immune-based therapeutics (iRECIST) (Dose escalation and Part 1-3 cohorts with pembrolizumab only) [Up to 3 years]: The proportion of patients with confirmed CR or PR according to iRECIST.
• Disease control rate (DCR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [Up to 5 years]: Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.
• DCR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only) [Up to 3 years]: Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1
• DCR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts using pembrolizumab only) [Up to 3 years]: Proportion of patients with CR, PR, or SD according to iRECIST.
• Duration of response (DOR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [Up to 5 years]: The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD per RECIST 1.1) or to death due to any cause, whichever comes first.
• DOR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only) [Up to 5 years]: The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per RECIST 1.1 or to death due to any cause, whichever comes first
• DOR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only) [Up to 5 years]: The time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of PD per iRECIST or to death due to any cause, whichever comes first.
• Progression free survival on study therapy (PFS) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only) [Up to 5 years]: The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first.
• PFS by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only) [Up to 5 years]: The time from start of study treatment to first documentation of objective tumor progression (PD per RECIST 1.1) on or following study therapy, or to death due to any cause, whichever comes first
• PFS by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only) [Up to 5 years]: The time from start of study treatment to first documentation of objective tumor progression (PD per iRECIST) on or following study therapy, or to death due to any cause, whichever comes first.
• Event-free (EFS) on study therapy by BICR (Cohort L only) [Up to 3 years]: The time from the start of study treatment to the first occurrence of any of the following events: (1) Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC+PLND. (2) Failure to undergo RC+PLND for participants with residual muscle-invasive disease and/or any radiographic disease present. (3) Gross residual disease left behind at time of RC+PLND. (4) Local or distant recurrence post-RC as assessed by CT or MRI and/or biopsy. (5) Death from any cause.
• Event-free (EFS) on study therapy by investigator assessment (MIBC cohorts only) [Up to 3 years]: The time from the start of study treatment to the first occurrence of any of the following events: (1) Radiographic disease progression precluding a curative intent surgery as assessed by BICR prior to RC+PLND. (2) Failure to undergo RC+PLND for participants with residual muscle-invasive disease and/or any radiographic disease present. (3) Gross residual disease left behind at time of RC+PLND. (4) Local or distant recurrence post-RC as assessed by CT or MRI and/or biopsy. (5) Death from any cause.
• Overall survival (OS) (all cohorts) [Up to 5 years]: The time from start of study treatment to date of death due to any cause.
• Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: Cmax will be derived from the PK blood samples collected.
• PK parameter for monomethyl auristatin E (MMAE): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: Cmax will be derived from the PK blood samples collected.
• PK parameter for total antibody (Tab): Cmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: Cmax will be derived from the PK blood samples collected.
• Incidence of antitherapeutic antibodies (ATA) to enfortumab vedotin (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.]: Blood samples for ATA analysis will be collected.
• PK parameter for enfortumab vedotin: Time to maximum concentration (Tmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: Tmax will be derived from the PK blood samples collected.
• PK parameter for MMAE: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: Tmax will be derived from the PK blood samples collected.
• PK parameter for Tab: Tmax (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: Tmax will be derived from the PK blood samples collected.
• PK parameter for enfortumab vedotin: Area under the concentration-time curve (AUC) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: AUC will be derived from the PK blood samples collected.
• PK parameter for MMAE: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: AUC will be derived from the PK blood samples collected.
• PK parameter for Tab: AUC (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only) [Through 2 cycles of treatment, up to 42 days]: AUC will be derived from the PK blood samples collected.
• Pathologic downstaging (pDS) rate by central pathology review (MIBC cohorts only) [Up to approximately 5 months]: The pDS rate is defined as patients with tumors <pT2 and N0 in examined tissue from radical cystectomy (RC) and pelvic lymph node dissection (PLND).
• Disease-free survival (DFS) by investigator assessment (MIBC cohorts only) [Up to approximately 5 years]: DFS is defined as the time from RC to the time of first occurrence of a DFS event, including local recurrence of urothelial cancer (UC), urinary tract recurrence of UC, distant metastasis of UC, or death from any cause.
• DFS by BICR (Cohort L only) [Up to 3 years]: DFS is defined as the time from RC to the time of first occurrence of a DFS event
• Type, incidence, severity, seriousness, and relatedness of AEs (Randomized Cohort K and MIBC cohorts only) [Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years]: Descriptive statistics will be used to summarize results.
• Type, incidence, and severity of laboratory abnormalities (Randomized Cohort K and MIBC cohorts only) [Through 1 month following last dose, or end-of-treatment visit whichever is later, up to approximately 3 years]: Descriptive statistics will be used to summarize results.
• Percentage of planned radical cystectomy and pelvic lymph node dissections (RC+PLND) delayed due to treatment-related AEs (MIBC cohorts only) [Up to approximately 5 months]: Delayed is defined as greater than 12 weeks after the last dose of treatment.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Locally advanced or metastatic urothelial cancer (la/mUC) - Cohorts A, B, D, E, F, G and K.

  * Histologically documented la/mUC, including squamous differentiation or mixed cell types.
  * An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1 or 2: Participants with ECOG performance status of 2 must meet the following additional criteria: hemoglobin ≥10 g/dL, GFR ≥50 mL/min, may not have NYHA Class III heart failure.
  * Eligible for pembrolizumab (Dose-escalation cohorts, Cohorts A, B, G and K Combination Arm).
  * Dose-escalation cohorts: Ineligible for first-line cisplatin-based chemotherapy and no prior treatment for la/mUC, or have disease progression following at least 1 platinum-containing treatment.
  * Cohort A: Ineligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort B: Must have disease progression during/following treatment with at least 1 platinum-containing regimen for la/mUC or disease recurrence.
  * Cohort D: Eligible for cisplatin-based chemotherapy and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort E: Ineligible for cisplatin-based chemotherapy, eligible for carboplatin, and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort F: Ineligible for platinum-based chemotherapy, or disease progression during/following at least 1 prior treatment for la/mUC. Eligible for gemcitabine.
  * Cohort G: Eligible for platinum-based chemotherapy (either cisplatin or carboplatin) and no prior treatment for la/mUC. No prior adjuvant/neoadjuvant platinum-based therapy in at least 12 months.
  * Cohort K: Ineligible for cisplatin-based chemotherapy due to at least 1 of the following: Glomerular filtration rate (GFR) <60 mL/min and ≥30 mL/min, ECOG performance status of 2, NCI CTCAE Version 4.03 Grade ≥2 hearing loss, New York Heart Association (NYHA) Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease. No adjuvant/neoadjuvant platinum-based therapy within 12 months prior to randomization.
* Muscle Invasive Bladder Cancer (MIBC)- Cohorts H, J and L.

  * Histologically confirmed MIBC with predominant >50% urothelial histology: Cohorts H and J: Clinical stage cT2-T4aN0M0; Cohort L: Clinical stage cT2-T4aN0M0 or cT1-T4aN1M0: Participants with pT1 disease are eligible only if they have N1 disease on imaging. Mixed cell types are eligible if urothelial cancer is predominant (>50%); Participants with plasmacytoid and/or neuroendocrine tumors are ineligible regardless of component percentage. Urothelial tumors not originating in the bladder (eg, upper tract tumors, urethral tumors) are ineligible.
  * Must be cisplatin-ineligible.
  * Cohort-specific eligibility: Cohort J, H, and L: No prior systemic treatment, chemoradiation, or radiation therapy for MIBC. May have received prior intravesical Bacillus Calmette-Guerin (BCG) or intravesical chemotherapy for non-MIBC; Cohort J: Eligible for pembrolizumab.
  * ECOG performance status of 0, 1, or 2.
  * Anticipated life expectancy of ≥3 months.
  * Tumor samples with an associated pathology report from the diagnostic transurethral resection of a bladder tumor done 90 days prior to the first dose of study treatment must be available prior to enrollment and determined to be sufficient for pathology review and biomarker analysis.
  * Participants must be deemed eligible for RC+PLND.

Exclusion Criteria:

* la/mUC - Cohorts A, B, D, E, F, G, and K

  * Received any prior treatment with a PD-1 inhibitor, PD-L1 inhibitor, or PD-L2 inhibitor, except Cohort F.
  * Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, OX-40 agonists, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (except Cohort F).
  * Ongoing sensory or motor neuropathy Grade 2 or higher.
  * Active central nervous system (CNS) metastases.
  * Ongoing clinically significant toxicity (Grade 2 or greater) associated with prior treatment (including radiotherapy or surgery).
  * Conditions requiring high doses of steroids or other immunosuppressive medications.
  * Prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs).
  * Uncontrolled diabetes mellitus.
* MIBC - Cohorts H, J, and L

  * Received prior systemic treatment, chemoradiation, and/or radiation therapy of muscle invasive bladder cancer.
  * Received any prior treatment with a CPI.
  * Received any prior treatment with stimulatory or co-inhibitory T-cell receptor agents, such as CD137 agonists, CTLA-4 inhibitors, or OX-40 agonists.
  * For participants in Cohort H, evidence of nodal disease on imaging. For participants in Cohort L, ≥N2 nodal disease on imaging.
  * Participant has undergone partial cystectomy of the bladder to remove any NMIBC or MIBC.
  * Ongoing sensory or motor neuropathy Grade 2 or higher.
  * Conditions requiring high doses of steroids or other immunosuppressive medications.
  * Prior treatment with enfortumab vedotin or other MMAE-based ADCs for urothelial cancer.
  * Participants with a history of another invasive malignancy within 3 years before first dose of study drug.

6 more sites not listed.

• Results publication: Milowsky MI, O'Donnell PH, Hoimes CJ, Petrylak DP, Flaig TW, Moon HH, Friedlander TW, Mar N, McKay RR, Srinivas S, Gravis G, Ramamurthy C, Bupathi M, Bracarda S, Wright P, Hepp Z, Carret AS, Yu Y, Dillon R, Kataria R, Beaumont JL, Purnajo I, Rosenberg JE. Patient-Reported Outcomes in Patients With Advanced Urothelial Cancer Who Are Ineligible for Cisplatin and Treated With First-Line Enfortumab Vedotin Alone or With Pembrolizumab. J Clin Oncol. 2024 Apr 20;42(12):1403-1414. doi: 10.1200/JCO.23.01547. Epub 2024 Jan 12. PMID 38215355
• Results publication: O'Donnell PH, Milowsky MI, Petrylak DP, Hoimes CJ, Flaig TW, Mar N, Moon HH, Friedlander TW, McKay RR, Bilen MA, Srinivas S, Burgess EF, Ramamurthy C, George S, Geynisman DM, Bracarda S, Borchiellini D, Geoffrois L, Maroto Rey JP, Ferrario C, Carret AS, Yu Y, Guseva M, Homet Moreno B, Rosenberg JE. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023 Sep 1;41(25):4107-4117. doi: 10.1200/JCO.22.02887. Epub 2023 Jun 27. PMID 37369081
• Results publication: Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. doi: 10.1200/JCO.22.01643. Epub 2022 Aug 30. PMID 36041086

• Changting Meng, MD, Study director, Seagen Inc.
• Jason Lukas, MD, PhD, Study director, Seagen Inc.