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

Phase 2Active Not RecruitingNCT03288545

Astellas Pharma Global Development, Inc.348 enrolled

Overview

This study will test an experimental drug (enfortumab vedotin) alone and with different combinations of anticancer therapies. Pembrolizumab is an immune checkpoint inhibitor (CPI) that is used to treat patients with cancer of the urinary system (urothelial cancer). This type of cancer includes cancer of the bladder, renal pelvis, ureter or urethra. Some parts of the study will look at locally advanced or metastatic urothelial cancer (la/mUC), which means the cancer has spread to nearby tissues or to other areas of the body. Other parts of the study will look at muscle-invasive bladder cancer (MIBC), which is cancer at an earlier stage that has spread into the muscle wall of the bladder. This study will look at the side effects of enfortumab vedotin alone and with other anticancer therapies. A side effect is a response to a drug that is not part of the treatment effect. This study will also test if the cancer shrinks with the different treatment combinations.

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Type, incidence, severity, seriousness, and relatedness of adverse events (Dose escalation and Expansion Parts 1 to 3 cohorts only)

Descriptive statistics will be used to summarize results.

Time frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.

Type, incidence, and severity of laboratory abnormalities (Dose escalation and Expansion Parts 1 to 3 cohorts only)

Descriptive statistics will be used to summarize results.

Time frame: Through 1 month following last dose, or end-of-treatment visit whichever is later, approximately 3 years anticipated.

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)

The proportion of patients with confirmed complete response (CR) or partial response (PR) according to RECIST 1.1

Time frame: Up to 3 years

Pathological complete response (pCR) rate per central pathology review (MIBC cohorts only)

The proportion of patients with absence of viable tumor tissue at the time of radical cystectomy.

Time frame: Up to approximately 5 months

Secondary Outcomes

Incidence of dose-limiting toxicity (DLT)

Incidence of DLTs (dose-escalation expansion Cohorts D, E, F, and the first 6 patients of Cohort G).

Time frame: 21 days

Confirmed ORR by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

The proportion of patients with confirmed CR or PR according to RECIST 1.1.

Time frame: Up to 3 years

Confirmed ORR by BICR according to RECIST 1.1 (Dose escalation and Cohort A only)

The proportion of patients with confirmed CR or PR according to RECIST 1.1

Time frame: Up to 3 years

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)

The proportion of patients with confirmed CR or PR according to iRECIST.

Time frame: Up to 3 years

Disease control rate (DCR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1.

Time frame: Up to 5 years

DCR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)

Proportion of patients with CR, PR, or stable disease (SD) according to RECIST 1.1

Time frame: Up to 3 years

DCR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts using pembrolizumab only)

Proportion of patients with CR, PR, or SD according to iRECIST.

Time frame: Up to 3 years

Duration of response (DOR) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

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.

Time frame: Up to 5 years

DOR by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)

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

Time frame: Up to 5 years

DOR by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)

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.

Time frame: Up to 5 years

Progression free survival on study therapy (PFS) by investigator assessment according to RECIST 1.1 (la/mUC cohorts only)

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.

Time frame: Up to 5 years

PFS by BICR according to RECIST 1.1 (Dose escalation, Cohort A, and randomized Cohort K only)

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

Time frame: Up to 5 years

PFS by investigator assessment according to iRECIST (Dose escalation and Part 1-3 cohorts with pembrolizumab only)

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.

Time frame: Up to 5 years

Event-free (EFS) on study therapy by BICR (Cohort L only)

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.

Time frame: Up to 3 years

Event-free (EFS) on study therapy by investigator assessment (MIBC cohorts only)

Time frame: Up to 3 years

Overall survival (OS) (all cohorts)

The time from start of study treatment to date of death due to any cause.

Time frame: Up to 5 years

Pharmacokinetics (PK) parameter for enfortumab vedotin: Maximum concentration (Cmax) (Dose escalation and Expansion Parts 1 to 3; non-randomized la/mUC cohorts only)

Cmax will be derived from the PK blood samples collected.