Open-Label Phase 2 Study of Ladiratuzumab Vedotin (LV) for Unresectable Locally Advanced or Metastatic Solid Tumors

• All Cohorts

‣ Measurable disease according to RECIST v1.1 as assessed by the investigator

⁃ Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1

• Cohort 1: SCLC (Parts A and B)

‣ Must have extensive stage disease

⁃ Must have disease progression during or following prior platinum-based systemic chemotherapy for extensive stage disease;

⁃ No more than 1 prior line of cytotoxic chemotherapy for extensive disease stage

⁃ May have received prior anti-PD(L)1 therapy

• Cohort 2: NSCLC-squamous (Parts A and B)

‣ Must have unresectable locally advanced or metastatic disease

⁃ Must have disease progression during or following systemic therapy

• Participants must have progressed during or after a platinum-based combination therapy administered for the treatment of metastatic disease, OR

∙ Participants must have progressed within 6 months of last dose of platinum-based adjuvant, neoadjuvant, or definitive chemotherapy, or concomitant chemoradiation regimen for early stage or locally advanced stage disease.

⁃ Participants with known epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), reactive oxygen species (ROS), BRAF, or other actionable mutations are not eligible

⁃ No more than 1 prior line of cytotoxic chemotherapy for their advanced disease

⁃ Must have received prior anti-PD(L)1 therapy, unless contraindicated

• Cohort 3: NSCLC-nonsquamous (Parts A and B)

‣ Must have unresectable locally advanced or metastatic disease

⁃ Must have disease progression during or following systemic therapy

• Participants must have progressed during or after a platinum-based combination therapy administered for the treatment of metastatic disease, OR

∙ Participants must have progressed within 6 months of last dose of platinum-based adjuvant, neoadjuvant, or definitive chemotherapy, or concomitant chemoradiation regimen for early stage or locally advanced state disease.

⁃ Participants with known EGFR, ALK, ROS, BRAF, tropomyosin receptor kinase (TRK), or other actionable mutations are not eligible

⁃ Must have had prior platinum-based chemotherapy

⁃ No more than 1 prior line of cytotoxic chemotherapy for their advanced disease

⁃ Must have received prior anti-PD(L)1 therapy, unless contraindicated

• Cohort 4: HNSCC (Parts A and B)

‣ Must have unresectable locally recurrent or metastatic disease

• Must have disease progression during or following prior line of systemic therapy

∙ Disease progression after treatment with a platinum-containing regimen for recurrent/metastatic disease; OR

∙ Recurrence/progression within 6 months of last dose of platinum therapy given as part of a multimodal therapy in the curative setting

⁃ No more than 1 line of cytotoxic chemotherapy for their advanced disease

⁃ May have received prior anti-PD(L)1 therapy, unless contraindicated

• Cohort 5: esophageal-squamous (Parts A and B)

‣ Must have unresectable locally advanced or metastatic disease

⁃ Must have disease progression during or following systemic therapy

⁃ Must have had prior platinum-based chemotherapy

⁃ No more than 1 line of cytotoxic chemotherapy for their advanced disease

• Cohort 6: gastric and GEJ adenocarcinoma (Parts A and B)

‣ Must have unresectable locally advanced or metastatic disease

⁃ Must have received prior platinum-based therapy

⁃ Must have disease progression during or following systemic therapy

⁃ Participants with known human epidermal growth factor receptor 2 (HER2) overexpression must have received prior HER2-targeted therapy

⁃ No more than 1 line of prior cytotoxic chemotherapy for their advanced disease

⁃ Participants may have received prior anti-PD(L)1 therapy, unless contraindicated

• Cohort 7: CRPC (Part B only)

‣ Must have histologically or cytologically confirmed adenocarcinoma of the prostate

• Participants with components of small cell of neuroendocrine histology are excluded

⁃ Must have metastatic castration-resistant disease

⁃ Must have been ≥28 days between cessation of androgen receptor-targeted therapy and start of study treatment

⁃ Must have received no more than 1 prior line of androgen receptor-targeted therapy for metastatic castration-sensitive prostate cancer or CRPC

⁃ No prior cytotoxic chemotherapy in the metastatic CRPC setting

• For participants who received cytotoxic chemotherapy in CSPC, at least 6 months must have elapsed between last dose of chemotherapy and start of study treatment

∙ No more than 1 prior line of cytotoxic chemotherapy for CSPC

⁃ Participants with measurable disease are eligible if the following criteria are met:

• A minimum starting PSA level ≥1.0 ng/mL

∙ Participants with measurable soft tissue disease must have evidence of measurable soft tissue disease according to PCWG3 criteria.

⁃ Participants with known breast cancer gene (BRCA) mutations are excluded

⁃ No prior radioisotope therapy or radiotherapy to ≥30% of bone marrow

• Cohort 8: Melanoma (Parts B and C)

‣ Must have histologically or cytologically confirmed cutaneous malignant melanoma

• Participants with mucosal, acral, or uveal melanoma are excluded

⁃ Must have locally advanced unresectable or metastatic stage disease

⁃ Must have progressive disease following anti-PD(L)1 therapy

⁃ Must have received BRAF +/- MEK inhibitor therapy if BRAF mutated (Part C)