A Study of Ladiratuzumab Vedotin in Advanced Solid Tumors

Phase 2TerminatedNCT04032704

Seagen Inc.205 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

205

Conditions

Small Cell Lung Cancer Non-small Cell Lung Cancer, Squamous

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (66)

Ironwood Cancer & Research Centers - Chandler

Chandler, Arizona, United States

Adventist Health White Memorial

Los Angeles, California, United States

Providence Medical Foundation

Santa Rosa, California, United States

Eastern CT Hematology and Oncology Associates

Norwich, Connecticut, United States

GenesisCare USA

Jacksonville, Florida, United States

Outcomes

Primary Outcomes

Part A: 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 was defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) per RECIST v.1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than (\<) 10 millimeter (mm). PR was defined as more than or equal to (\>=) 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not have at least 2 post-baseline response assessment (initial response and confirmation scan) were counted as non-responders.

Time frame: From the first dose of study treatment until the first documented CR or PR or new anticancer therapies or death, whichever occurred first (maximum up to 8.3 months)

Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1

Confirmed ORR was defined as the percentage of participants with a confirmed CR or PR per RECIST v.1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR was defined as \>= 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not have at least 2 post-baseline response assessment (initial response and confirmation scan) were counted as non-responders.

Time frame: From the first dose of study treatment until the first documented CR or PR or new anticancer therapies or death, whichever occurred first (maximum up to 34.7 months for 1.25 mg/kg and 5.7 months for 1 mg/kg dose level)

Part B: Confirmed Prostate-Specific Antigen (PSA) Response Rate as Determined by Investigator According to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) Criteria, for Prostate Cancer

Confirmed PSA response rate was defined as the percentage of participants with a reduction from baseline PSA level of at least 50%, measured twice \>= 3 weeks apart. PSA progression was defined as per PCWG3 criteria- a) if a participant presented first a decline from baseline, progression was defined as the first PSA increase that was \>=25% and \>=2 nanograms per milliliter (ng/mL) above the nadir, and which was confirmed by a consecutive second value \>=3 weeks later that fulfilled the same criteria (that is, a confirmed rising trend); b) if a participant did not present a decline from baseline, progression was defined as the first PSA increase that was \>=25% and \>=2 ng/mL increased from baseline beyond 12 weeks.

Time frame: From the first dose of study treatment up to the date of last response assessment (maximum up to 13.5 months)

Secondary Outcomes

Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE

An adverse event (AE) was any untoward medical occurrence in a participant/ clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. AEs included both SAEs ad all non-SAEs. TEAEs were defined as newly occurring (not present at baseline)/worsening after first dose of study treatment. TESAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent/significant disability/incapacity \& may cause congenital anomaly/birth defect. Treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version (v) 4.03 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening).

Time frame: From start of study treatment up to 30 days after last dose of study treatment (maximum up to 37.5 months)

Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE

An AE was any untoward medical occurrence in a participant, or a clinical investigational participant administered a medicinal product, and which does not necessarily have a causal relationship with this treatment. AEs included both SAEs ad all non-SAEs. TEAEs were defined as newly occurring (not present at baseline) or worsening after first dose of study treatment. TESAEs were any untoward medical occurrence at any dose that: suspected to cause death; life-threatening; required hospitalization; persistent or significant disability or incapacity and may cause congenital anomaly or birth defect. Treatment related TEAEs were related to study treatment and relatedness was judged by investigator. TEAEs were graded according to NCI-CTCAE v4.03 (grade 1= mild, grade 2= moderate, grade 3= severe and grade 4= life-threatening).

Time frame: From start of study treatment up to 30 days after last dose of study treatment (maximum up to 37.5 months)

Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1

DCR was defined as percentage of participants who achieved confirmed and unconfirmed CR or PR per RECIST v1.1 or met stable disease (SD) criteria at least once after start of study treatment at minimum interval of 5 weeks. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR was defined as \>= 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference smallest sum diameters while on study. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 0.5 cm. Appearance of one or more new lesions was also considered progression.

Part B: Confirmed Investigator Determined DCR According to RECIST v1.1

DCR was defined as percentage of participants who achieved confirmed and unconfirmed CR or PR per RECIST v1.1 or met SD criteria at least once after start of study treatment at a minimum interval of 5 weeks. CR was defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR was defined as \>= 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: At least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 centimeter (cm). Appearance of one or more new lesions was also considered progression.

Time frame: From the first dose of study treatment until the first documented CR, PR or SD or new anticancer therapies or death, whichever occurred first (maximum up to 5.5 months for 1.25 mg/kg and 1.5 months for 1 mg/kg dose level)

Part A: Confirmed Investigator Determined Duration of Response (DOR) According to RECIST v1.1

DOR:time from 1st documentation of OR(confirmed CR/PR per RECIST Version 1.1) to 1st documentation of PD/death due to any cause,whichever occurred first.CR:disappearance of all target lesions.Any pathological lymph nodes must have reduction in short axis to \<10 mm.PR:\>=30 % decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. Participants do not have PD and are still on study at time of analysis/are removed from study prior to documentation of PD were censored at last disease assessment documenting absence of PD. Participants who started new anticancer treatment prior to documentation of PD were censored at last disease assessment prior to start of new treatment.PD:at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study.In addition to relative increase of 20%, sum must demonstrate absolute increase of 0.5 cm.Appearance of one/more new lesions was considered progression. Kaplan-Meier method was used.

Time frame: From the first documentation of CR or PR to PD or death or censoring whichever occurred first (maximum up to 5.7 months)

Part B: Confirmed Investigator Determined DOR According to RECIST v1.1

Time frame: From the first documentation of CR or PR to PD or death or censoring whichever occurred first (maximum up to 32.0 months for 1.25 mg/kg and 4.2 months for 1 mg/kg dose level)

Part B: Confirmed Investigator Determined PSA-DOR, for Prostate Cancer

PSA-DOR was defined as the time from the first documentation of PSA response (subsequently confirmed at least 3 weeks apart) to the first documentation of PSA progression or death due to any cause, whichever occurred first. Confirmed PSA response rate was defined as the percentage of participants with a reduction from baseline PSA level of at least 50%, measured twice \>= 3 weeks apart. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD was censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. The confidence interval (CI) was calculated using the complementary log-log transformation method.

Time frame: From the first documentation of CR or PR to PD or death or censoring whichever occurred first (maximum up to 3 months)

Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1

PFS: time from start of study treatment to the first documentation of PD by RECIST v1.1 or clinical PD. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD were censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. PD: At least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 0.5 cm. Appearance of one or more new lesions was also considered progression. Median was estimated using the Kaplan-Meier method and the CI was calculated using the complementary log-log transformation method.

Time frame: From first dose of study treatment to the date of PD or clinical PD or censoring whichever occurred first (maximum up to 8.3 months)

Part B: Confirmed Investigator Determined PFS According to RECIST v1.1

Time frame: From first dose of study treatment to the date of PD or clinical PD or censoring whichever occurred first (maximum up to 34.7 months for 1.25 mg/kg and 5.7 months for 1 mg/kg dose level)

Part B: Confirmed Investigator Determined PSA-PFS, for Prostate Cancer

PSA-PFS: time from start of study treatment to first documentation of PSA progression or death due to any cause, whichever occurred first. Participants who do not have PD and are still on study at time of analysis or who are removed from study prior to documentation of PD was censored at date of last disease assessment documenting absence of PD. Participants who started new anticancer treatment prior to documentation of PD were censored at date of last disease assessment prior to the start of new treatment. PD: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that is smallest on study). In addition to relative increase of 20%, sum must also demonstrate absolute increase of at least 0.5 cm. Appearance of one or more new lesions was also considered progression. Median was estimated using Kaplan-Meier method and CI was calculated using the complementary log-log transformation method.

Time frame: From first dose of study treatment to the date of PD or clinical PD or censoring whichever occurred first (maximum up to 5.7 months)

Part A: Overall Survival (OS)

OS was defined as the time from the start of study treatment to date of death due to any cause. Participants who do not have PD and are still on study at the time of an analysis or who are removed from the study prior to documentation of PD was censored at the date of last disease assessment documenting absence of PD. Participants who started a new anticancer treatment prior to documentation of PD were censored at the date of last disease assessment prior to the start of new treatment. Median was estimated using the Kaplan-Meier method.

Time frame: From first dose of study treatment to the date of death or censoring whichever occurred first (maximum up to 27.5 months)

Part B: Overall Survival

Time frame: From first dose of study treatment to the date of death or censoring whichever occurred first (maximum up to 37.5 months for 1.25 mg/kg and 20.9 months for 1 mg/kg dose level)

Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin

Area under the observed concentration-time curve from the time of dosing to Day 21 of LV was calculated by noncompartmental analysis.

Time frame: AUC21 is reported on Day 21 using PK concentrations assessed at Pre-dose, end of infusion, 2 hour, 4 hour, 48 hour, 168 hour and 336 hour post dose of Cycle 1 (each cycle = 21 days, LV administered on Day 1 of cycle)

Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters

Cmax according to ADC pharmacokinetic parameters was reported.

Time frame: Cmax during Day 1 to 21 post LV administration on Day 1 was reported using PK concentration assessed at Pre-dose, end of infusion, 2 hour, 4 hour, 48 hour, 168 hour and 336 hour post-dose of LV administration on Day 1 (each cycle = 21 days)

Part A: AUC21 of Total Antibody (TAB)

Area under the observed concentration-time curve from the time of dosing to Day 21 of TAB was calculated by noncompartmental analysis.

Part A: Cmax According to TAB Pharmacokinetic Parameters

Cmax according to TAB pharmacokinetic parameters was reported.

Part A: AUC21 of Monomethyl Auristatin E (MMAE)

Area under the observed concentration-time curve from the time of dosing to Day 21 of MMAE was calculated by noncompartmental analysis.

Part A: Cmax According to MMAE Pharmacokinetic Parameters

Cmax according to MMAE pharmacokinetic parameters was reported.

Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC

Area under the observed concentration-time curve from the time of dosing to Day 7 of ADC was calculated by noncompartmental analysis.

Time frame: AUC7 is reported at Day 7 using PK concentration assessed at Pre-dose, end of infusion, 2hr, 4hr, 48hr post-dose of LV administration on Day 1; pre-dose PK concentration on Day 8 in Cycle 1 (each cycle=21 days, LV administered on Day 1, 8 and 15 of cycle)

Part B: Cmax According to ADC Pharmacokinetic Parameters

Cmax according to ADC pharmacokinetic parameters was reported.

Time frame: Cmax during Day 1 to 7 post LV administration on Day 1 was reported using PK concentration assessed at Pre-dose, end of infusion, 2 hr, 4 hr, 48 hr post-dose of LV administration on Day 1 (each cycle = 21 days, LV administered on Day 1, 8 and 15 of cycle)

Part B: AUC7 of TAB

Area under the observed concentration-time curve from the time of dosing to Day 7of TAB was calculated by noncompartmental analysis.

Part B: Cmax According to TAB Pharmacokinetic Parameters

Cmax according to TAB pharmacokinetic parameters was reported.

Part B: AUC7 OF MMAE

Area under the observed concentration-time curve from the time of dosing to Day 7 of MMAE was calculated by noncompartmental analysis.

Part B: Cmax According to MMAE Pharmacokinetic Parameters

Cmax according to MMAE pharmacokinetic parameters was reported.

Time frame: Cmax during Day 1 to 7 post LV administration on Day 1 was reported using PK concentration assessed at Pre-dose, end of infusion, 2 hr, 4 hr, 48 hr post-dose of LV administration on Day 1 (each cycle= 21 days, LV administered on Day 1, 8 and 15 of cycle)

Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence

A positive baseline ATA result was considered positive post-baseline if the post-baseline ATA titer result was at least four times higher than the baseline result.

Time frame: From first ATA draw to last ATA draw (maximum up to 8.8 months)

Part B: Number of Participants With Positive Post-Baseline ATA Incidence