A Study of LY4052031 in Participants With Advanced or Metastatic Urothelial Cancer or Other Solid Tumors

This is a Phase 1a/1b multicenter, open-label study in participants with advanced or metastatic solid tumor malignancies known to express Nectin 4. This study evaluates an antibody-drug conjugate that binds to the protein nectin-4, which is expressed on certain cancer cells, delivering the drug to the cancer. This study is comprised of two phases: Dose Escalation and Dose Optimization (1a), and Dose expansion (1b). Phase 1a will assess the safety, tolerability, and pharmacokinetics of LY4052031 to determine the recommended phase 2 dose (RP2D)/optimal dose. Phase 1b will evaluate efficacy and safety of LY4052031 as monotherapy or in combination with pembrolizumab at the RP2D/optimal dose in expansion cohorts based on tumor type and/or treatment history.

• LY4052031 (Drug): Intravenous
• Pembrolizumab (Drug): Intravenous

Primary outcomes

• Phase 1a: To determine the recommended phase 2 dose (RP2D) optimal dose(s) of LY4052031 [Cycle 1 (21 Days)]: Number of participants with dose-limiting toxicities (DLTs)
• Phase 1b: To assess the antitumor activity of LY4052031 as monotherapy or in combination with pembrolizumab: Overall response rate (ORR) [Up to Approximately 48 Months or 4 Years]: ORR per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1)

Secondary outcomes

• To characterize the pharmacokinetics (PK) properties of LY4052031: Minimum Plasma Concentration (Cmin) [Cycle 1 (21 Days)]: PK: Cmin of LY4052031
• To characterize the PK properties of LY4052031: Area under the concentration versus time curve (AUC) [Cycle 1 (21 Days)]: PK: AUC of LY4052031
• To evaluate the preliminary antitumor activity of LY4052031 monotherapy or in combination with pembrolizumab: Overall response rate (ORR) [Up to Approximately 48 Months or 4 Years]: ORR per investigator assessed Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1))
• To evaluate the preliminary antitumor activity of LY4052031 monotherapy or in combination with pembrolizumab: Duration of response (DOR) [Up to Approximately 48 Months or 4 Years]: DOR per investigator assessed RECIST 1.1
• To evaluate the preliminary antitumor activity of LY4052031 monotherapy or in combination with pembrolizumab: Time to response (TTR) [Up to Approximately 48 Months or 4 Years]: TTR per investigator assessed RECIST 1.1
• To evaluate the preliminary antitumor activity of LY4052031 monotherapy or in combination with pembrolizumab: Progression free survival (PFS) [Up to Approximately 48 Months or 4 Years]: PFS per investigator assessed RECIST 1.1
• To evaluate the preliminary antitumor activity of LY4052031 monotherapy or in combination with pembrolizumab: Disease control rate (DCR) [Up to Approximately 48 Months or 4 Years]: DCR per investigator assessed RECIST 1.1
• To evaluate the preliminary antitumor activity of LY4052031 monotherapy or in combination with pembrolizumab: Overall survival (OS) [Up to Approximately 48 Months or 4 Years]: OS per investigator assessed RECIST 1.1

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Have one of the following solid tumor cancers:

  * Cohort A1: urothelial carcinoma, triple negative breast cancer, non-small cell lung cancer, esophageal cancer, pancreatic cancer, ovarian cancer, cervical cancer (squamous cell carcinoma), head and neck squamous cell carcinoma or prostate cancer
  * Cohort A2/B/D: urothelial carcinoma
  * Cohort C: triple negative breast cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, HNSCC (head and neck squamous cell carcinoma), esophageal cancer, pancreatic cancer, or prostate cancer
* Prior Systemic Therapy Criteria:

  * Cohort A1/C: Individual has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating investigator; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies
  * Cohort A2/B1/B2: Individual must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
  * Cohort D: Treatment-naive for locally advanced or metastatic urothelial cancer.
* Prior enfortumab vedotin specific requirements:

  * Cohorts A1/A2/C/D: prior treatment with enfortumab vedotin is allowed, but not required
  * Cohort B1: individual must be enfortumab vedotin naive in the advanced/metastatic setting
  * Cohort B2: individual must have received enfortumab vedotin in the metastatic/advanced setting.
* Measurability of disease

  * Cohort A1: measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1)
  * Measurable disease is required as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for all Cohorts. Cohort A1 may permit non-measurable disease as defined by RECIST v1.1
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country specific regulations

Exclusion Criteria:

* Individual with known or suspected uncontrolled CNS metastases
* Individual with uncontrolled hypercalcemia
* Individual with uncontrolled diabetes
* Individual with evidence of corneal keratopathy or keratitis, and history of corneal transplant
* Any serious unresolved toxicities from prior therapy
* Significant cardiovascular disease
* Recent thromboembolic event and/or clinically significant bleeding disorder
* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
* History of pneumonitis/interstitial lung disease
* History of Grade ≥3 skin toxicity associated with enfortumab vedotin that required treatment discontinuation
* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention

• Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST), Study director, Eli Lilly and Company