A Study of Ladiratuzumab Vedotin in Advanced Solid Tumors

Study Overview
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Brief Summary
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This trial will study ladiratuzumab vedotin (LV) alone and with pembrolizumab to find out if it works to treat different types of solid tumors. It will also find out what side effects may occur. A side effect is anything the drug does besides treating cancer.

Detailed Description
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This trial is designed to assess the antitumor activity, safety, and tolerability of LV alone and with pembrolizumab, for the treatment of solid tumors. Participants with the following advanced solid tumors will be enrolled: Cohort 1: small cell lung cancer (SCLC) Cohort 2: non-small cell lung cancer-squamous (NSCLC-squamous) Cohort 3: non-small cell lung cancer-nonsquamous (NSCLC-nonsquamous) Cohort 4: head and neck squamous cell carcinoma (HNSCC) Cohort 5: esophageal squamous cell carcinoma (esophageal-squamous) Cohort 6: gastric and gastroesophageal junction (GEJ) adenocarcinoma Cohort 7: castration-resistant prostate cancer (CRPC) Cohort 8: melanoma Participants will continue to receive study treatment until disease progression, unacceptable toxicity, investigator decision, consent withdrawal, study termination by the sponsor, pregnancy, or death, whichever comes first.

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

Conditions
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Small Cell Lung Cancer, Non-small Cell Lung Cancer, Squamous, Non-small Cell Lung Cancer, Non-squamous, Head and Neck Squamous Cell Carcinoma, Esophageal Squamous Cell Carcinoma, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Prostate Cancer, Melanoma

Intervention / Treatment
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* Drug: ladiratuzumab vedotin
* Drug: pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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) Exclusion Criteria Active concurrent malignancy or a previous malignancy within the past 3 years Any anticancer therapy within 3 weeks of starting study treatment. Participants who are/were on adjuvant hormonal therapy for the treatment of malignancies with negligible risk of metastases are eligible. Known active central nervous system lesions Any ongoing clinically significant toxicity associated with prior treatment (Grade 2 or higher) Ongoing sensory or motor neuropathy of Grade ≥2 Has received prior radiotherapy within 2 weeks of start of study treatment History of interstitial lung disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Non-randomized LV monotherapy<br>Monotherapy dosing schedule 1. | Drug: ladiratuzumab vedotin<br>* Intravenous (into the vein; IV) infusion<br>* Other names: SGN-LIV1A;|
| Experimental: Part B: Non-randomized LV monotherapy<br>Monotherapy dosing schedule 2. | Drug: ladiratuzumab vedotin<br>* Intravenous (into the vein; IV) infusion<br>* Other names: SGN-LIV1A;|
| Experimental: Part C - Arm 1: Randomized LV monotherapy<br>Monotherapy dosing schedule 3. | Drug: ladiratuzumab vedotin<br>* Intravenous (into the vein; IV) infusion<br>* Other names: SGN-LIV1A;|
| Experimental: Part C - Arm 2: Randomized LV combination therapy<br>Combination dosing schedule 1. | Drug: ladiratuzumab vedotin<br>* Intravenous (into the vein; IV) infusion<br>* Other names: SGN-LIV1A;Drug: pembrolizumab<br>* 200mg given by IV on Day 1 of each 21-day cycle<br>* Other names: Keytruda;|
| Experimental: Part C - Arm 3: Randomized LV combination therapy<br>Combination dosing schedule 2. | Drug: ladiratuzumab vedotin<br>* Intravenous (into the vein; IV) infusion<br>* Other names: SGN-LIV1A;Drug: pembrolizumab<br>* 200mg given by IV on Day 1 of each 21-day cycle<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed objective response rate (ORR) as determined by investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) | Confirmed ORR is defined as the proportion of participants who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST v1.1 as assessed by the investigator. | Up to approximately 1 year | 
| Prostate-specific antigen (PSA) response rate as determined by investigator according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria (Cohort 7 only) | Confirmed PSA response rate is defined as the proportion of participants with a reduction from baseline PSA level of at least 50%, measured twice ≥3 weeks apart. | Up to approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) | An AE is any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. | Up to approximately 1 year | 
| Disease control rate (DCR) as determined by investigator according to RECIST v1.1 | DCR is defined as the proportion of participants who achieve a confirmed CR or PR according to RECIST v1.1 as assessed by the investigator, or meet the stable disease (SD) criteria at least once after start of study treatment at a minimum interval of 5 weeks or 7 weeks for prostate cancer subjects. | Up to approximately 1 year | 
| Duration of response (DOR) as determined by investigator according to RECIST v1.1 | DOR is defined as the time from the first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD) or death due to any cause, whichever comes first. | Up to approximately 1 year | 
| PSA-DOR as determined by investigator assessment (Cohort 7 only) | PSA-DOR is defined as the time from the first documentation of PSA response to the first documentation of PSA progression or death, whichever comes first | Up to approximately 1 year | 
| Progression-free survival (PFS) as determined by investigator according to RECIST v1.1 | PFS is defined as the time from the start of study treatment to the first documentation of PD by RECIST v1.1 or clinical PD or by PSA progression (prostate cancer cohort) or death due to any cause, whichever comes first. | Up to approximately 1 year | 
| PSA-PFS as determined by investigator assessment (Cohort 7 only) | PSA-PFS is defined as the time from the start of study treatment to first occurrence of PSA progression or death, whichever comes first | Up to approximately 1 year | 
| Overall survival (OS) | OS is defined as the time from the start of study treatment to date of death due to any cause. | Up to approximately 1 year | 
| Maximum observed concentration (Cmax) | Pharmacokinetic (PK) endpoint of LV | Up to approximately 1 year | 
| Area under the concentration-time curve (AUC) | PK endpoint of LV | Up to approximately 1 year | 
| Incidence of antitherapeutic antibodies (ATAs) to LV |  | Up to approximately 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Seattle Genetics, SCLC, NSCLC-squamous, NSCLC-nonsquamous, HNSCC, GEJ adenocarcinoma