Esophageal Squamous Cell Carcinoma, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Head and Neck Squamous Cell Carcinoma, Melanoma, Non-small Cell Lung Cancer, Non-squamous, Non-small Cell Lung Cancer, Squamous, Prostate Cancer, Small Cell Lung Cancer
Conditions
Keywords
SCLC, NSCLC-squamous, NSCLC-nonsquamous, HNSCC, GEJ adenocarcinoma, Seattle Genetics
Brief summary
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
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.
Interventions
Intravenous (into the vein; IV) infusion
DRUGpembrolizumab
200mg given by IV on Day 1 of each 21-day cycle
Sponsors
Merck Sharp & Dohme LLC
Seagen Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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) | 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. |
| Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 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) | 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. |
| 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 | From the first dose of study treatment up to the date of last response assessment (maximum up to 13.5 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 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) | 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. |
| Part A: Confirmed Investigator Determined Duration of Response (DOR) According to RECIST v1.1 | From the first documentation of CR or PR to PD or death or censoring whichever occurred first (maximum up to 5.7 months) | 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. |
| Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | 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) | 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. |
| Part B: Confirmed Investigator Determined PSA-DOR, for Prostate Cancer | From the first documentation of CR or PR to PD or death or censoring whichever occurred first (maximum up to 3 months) | 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. |
| Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1 | 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) | 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. |
| Part A: AUC21 of Monomethyl Auristatin E (MMAE) | 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) | Area under the observed concentration-time curve from the time of dosing to Day 21 of MMAE was calculated by noncompartmental analysis. |
| Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 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) | 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. |
| Part B: Confirmed Investigator Determined PSA-PFS, for Prostate Cancer | 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) | 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. |
| Part A: Overall Survival (OS) | From first dose of study treatment to the date of death or censoring whichever occurred first (maximum up to 27.5 months) | 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. |
| Part B: Overall Survival | 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) | 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. |
| Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin | 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) | Area under the observed concentration-time curve from the time of dosing to Day 21 of LV was calculated by noncompartmental analysis. |
| Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | From start of study treatment up to 30 days after last dose of study treatment (maximum up to 37.5 months) | 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). |
| Part A: AUC21 of Total Antibody (TAB) | 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) | 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 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) | Cmax according to TAB pharmacokinetic parameters was reported. |
| Part A: Cmax According to MMAE Pharmacokinetic Parameters | 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) | Cmax according to MMAE pharmacokinetic parameters was reported. |
| Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 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) | Area under the observed concentration-time curve from the time of dosing to Day 7 of ADC was calculated by noncompartmental analysis. |
| Part B: Cmax According to ADC Pharmacokinetic Parameters | 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) | Cmax according to ADC pharmacokinetic parameters was reported. |
| Part B: AUC7 of TAB | 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) | 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 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) | Cmax according to TAB pharmacokinetic parameters was reported. |
| Part B: AUC7 OF MMAE | 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) | 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 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) | Cmax according to MMAE pharmacokinetic parameters was reported. |
| Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | From first ATA draw to last ATA draw (maximum up to 8.8 months) | 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. |
| Part B: Number of Participants With Positive Post-Baseline ATA Incidence | From first ATA draw to last ATA draw (maximum up to 22.1 months for 1.25 mg/kg and 5.1 months for 1 mg/kg) | 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. |
| Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters | 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) | Cmax according to ADC pharmacokinetic parameters was reported. |
| Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | From start of study treatment up to 30 days after last dose of study treatment (maximum up to 37.5 months) | 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). |
| Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1 | 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 4.1 months) | 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. |
Countries
Australia, Italy, South Korea, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
This study had Parts A, B and C. Study was terminated and Part C was not opened. A total of 205 participants were enrolled in Part A (49 participants) and Part B (156 participants) of this study. In Part A all enrolled participants received study intervention while in Part B, 2 participants did not receive study intervention.
Pre-assignment details
Cohorts of study: Cohort 1: small cell lung cancer (SCLC) (Part A, B); Cohort 2: non-SCLC-squamous (NSCLC-squamous) (Part A, B); Cohort 3: NSCLC-nonsquamous (Part A, B); Cohort 4: head & neck squamous cell carcinoma (HNSCC) (Part A, B); Cohort 5: esophageal squamous cell carcinoma (esophageal-squamous) (Part A, B); Cohort 6: gastric & gastroesophageal junction (GEJ) adenocarcinoma (Part A, B); Cohort 7: castration-resistant prostate cancer (CRPC) (Part B); Cohort 8: melanoma (Part B).
Participants by arm
| Arm | Count |
|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg Participants with SCLC were administered ladiratuzumab vedotin (LV) 2.5 milligram per kilogram (mg/kg) as intravenous (IV) fusion on Day 1 of each 21-day cycle (q3wk). | 10 |
| Part A: Cohort 2, LV 2.5 mg/kg Participants with NSCLC-squamous were administered LV 2.5 mg/kg as IV fusion q3wk. | 2 |
| Part A: Cohort 3, LV 2.5 mg/kg Participants with NSCLC-nonsquamous were administered LV 2.5 mg/kg as IV fusion q3wk. | 13 |
| Part A: Cohort 4, LV 2.5 mg/kg Participants with HNSCC were administered LV 2.5 mg/kg as IV fusion q3wk. | 7 |
| Part A: Cohort 5, LV 2.5 mg/kg Participants with esophageal-squamous were administered LV 2.5 mg/kg as IV fusion q3wk. | 5 |
| Part A: Cohort 6, LV 2.5 mg/kg Participants with GEJ were administered LV 2.5 mg/kg as IV fusion q3wk. | 12 |
| Part B: Cohort 1, LV 1.25 mg/kg Participants with SCLC were administered LV 1.25 mg/kg on Days 1, 8 and 15 of each 21-day cycle (q1wk) as a 30-minute IV infusion. | 16 |
| Part B: Cohort 2, LV 1.25 mg/kg Participants with NSCLC-squamous were administered LV 1.25 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 16 |
| Part B: Cohort 3, LV 1.25 mg/kg Participants with NSCLC-nonsquamous were administered LV 1.25 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 19 |
| Part B: Cohort 4, LV 1.25 mg/kg Participants with HNSCC were administered LV 1.25 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 14 |
| Part B: Cohort 5, LV 1.25 mg/kg Participants with esophageal-squamous were administered LV 1.25 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 17 |
| Part B: Cohort 6, LV 1.25 mg/kg Participants with GEJ were administered LV 1.25 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 21 |
| Part B: Cohort 7, LV 1.25 mg/kg Participants with CRPC were administered LV 1.25 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 13 |
| Part B: Cohort 8, LV 1.25 mg/kg Participants with melanoma were administered LV 1.25 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 30 |
| Part B: Cohort 1, LV 1.0 mg/kg Participants with SCLC were administered LV 1.0 mg/kg q1wk on Days 1, 8 and 15 as a 30-minute IV infusion. | 2 |
| Part B: Cohort 3, LV 1.0 mg/kg Participants with NSCLC-nonsquamous were administered LV 1.0 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 2 |
| Part B: Cohort 4, LV 1.0 mg/kg Participants with HNSCC were administered LV 1.0 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 2 |
| Part B: Cohort 6, LV 1.0 mg/kg Participants with GEJ were administered LV 1.0 mg/kg on Days 1, 8 and 15 q1wk as a 30-minute IV infusion. | 2 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part A | Death | 9 | 2 | 10 | 7 | 4 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part A | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part A | Withdrawal by Subject | 0 | 0 | 3 | 0 | 1 | 7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part B | Death | 0 | 0 | 0 | 0 | 0 | 0 | 13 | 13 | 14 | 12 | 12 | 13 | 7 | 17 | 2 | 1 | 2 | 2 |
| Part B | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part B | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 | 1 | 1 | 1 | 5 | 13 | 0 | 0 | 0 | 0 |
| Part B | Study termination by Sponsor | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part B | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 2 | 2 | 1 | 4 | 6 | 2 | 1 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part B: Cohort 6, LV 1.0 mg/kg | Total | Part A: Cohort 1, LV 2.5 mg/kg | Part A: Cohort 2, LV 2.5 mg/kg | Part A: Cohort 3, LV 2.5 mg/kg | Part A: Cohort 4, LV 2.5 mg/kg | Part A: Cohort 5, LV 2.5 mg/kg | Part A: Cohort 6, LV 2.5 mg/kg | Part B: Cohort 1, LV 1.25 mg/kg | Part B: Cohort 2, LV 1.25 mg/kg | Part B: Cohort 3, LV 1.25 mg/kg | Part B: Cohort 4, LV 1.25 mg/kg | Part B: Cohort 5, LV 1.25 mg/kg | Part B: Cohort 6, LV 1.25 mg/kg | Part B: Cohort 7, LV 1.25 mg/kg | Part B: Cohort 8, LV 1.25 mg/kg | Part B: Cohort 1, LV 1.0 mg/kg | Part B: Cohort 3, LV 1.0 mg/kg | Part B: Cohort 4, LV 1.0 mg/kg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 77.5 Years STANDARD_DEVIATION 6.4 | 64.7 Years STANDARD_DEVIATION 10.5 | 63.7 Years STANDARD_DEVIATION 9.5 | 80.5 Years STANDARD_DEVIATION 4.9 | 67.2 Years STANDARD_DEVIATION 13.7 | 63.1 Years STANDARD_DEVIATION 12.3 | 70.8 Years STANDARD_DEVIATION 11.2 | 64.7 Years STANDARD_DEVIATION 10.3 | 65.0 Years STANDARD_DEVIATION 10.7 | 67.3 Years STANDARD_DEVIATION 8.8 | 63.9 Years STANDARD_DEVIATION 9.3 | 63.8 Years STANDARD_DEVIATION 9.9 | 60.5 Years STANDARD_DEVIATION 8.3 | 60.9 Years STANDARD_DEVIATION 8.9 | 71.9 Years STANDARD_DEVIATION 8.5 | 63.4 Years STANDARD_DEVIATION 12.2 | 61.0 Years STANDARD_DEVIATION 1.4 | 66.0 Years STANDARD_DEVIATION 2.8 | 56.0 Years STANDARD_DEVIATION 2.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 185 Participants | 10 Participants | 2 Participants | 13 Participants | 7 Participants | 5 Participants | 12 Participants | 15 Participants | 13 Participants | 18 Participants | 14 Participants | 14 Participants | 16 Participants | 12 Participants | 27 Participants | 2 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 15 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 4 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 41 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants | 8 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 9 Participants | 4 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 17 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 5 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 140 Participants | 5 Participants | 2 Participants | 10 Participants | 6 Participants | 1 Participants | 4 Participants | 14 Participants | 13 Participants | 14 Participants | 11 Participants | 5 Participants | 12 Participants | 10 Participants | 25 Participants | 2 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 0 Participants | 46 Participants | 2 Participants | 1 Participants | 8 Participants | 2 Participants | 1 Participants | 0 Participants | 7 Participants | 4 Participants | 5 Participants | 3 Participants | 2 Participants | 3 Participants | 0 Participants | 7 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 157 Participants | 8 Participants | 1 Participants | 5 Participants | 5 Participants | 4 Participants | 12 Participants | 9 Participants | 12 Participants | 14 Participants | 11 Participants | 15 Participants | 18 Participants | 13 Participants | 23 Participants | 2 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 10 | 2 / 2 | 10 / 13 | 7 / 7 | 4 / 5 | 5 / 12 | 13 / 16 | 13 / 16 | 14 / 19 | 12 / 14 | 12 / 17 | 13 / 21 | 7 / 13 | 16 / 30 | 2 / 2 | 1 / 2 | 2 / 2 | 2 / 2 |
| other Total, other adverse events | 10 / 10 | 2 / 2 | 13 / 13 | 6 / 7 | 5 / 5 | 12 / 12 | 15 / 16 | 16 / 16 | 19 / 19 | 14 / 14 | 17 / 17 | 19 / 21 | 13 / 13 | 30 / 30 | 2 / 2 | 2 / 2 | 2 / 2 | 2 / 2 |
| serious Total, serious adverse events | 5 / 10 | 1 / 2 | 7 / 13 | 2 / 7 | 3 / 5 | 3 / 12 | 6 / 16 | 5 / 16 | 9 / 19 | 8 / 14 | 9 / 17 | 12 / 21 | 4 / 13 | 11 / 30 | 1 / 2 | 2 / 2 | 1 / 2 | 0 / 2 |
Outcome results
Primary
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)
Population: The full analysis set (FAS) included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | 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) | 10 Percentage of participants |
| Part A: Cohort 2, LV 2.5 mg/kg | 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) | 0 Percentage of participants |
| Part A: Cohort 3, LV 2.5 mg/kg | 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) | 8 Percentage of participants |
| Part A: Cohort 4, LV 2.5 mg/kg | 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) | 14 Percentage of participants |
| Part A: Cohort 5, LV 2.5 mg/kg | 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) | 20 Percentage of participants |
| Part A: Cohort 6, LV 2.5 mg/kg | 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) | 8 Percentage of participants |
Primary
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)
Population: The FAS included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 6 Percentage of participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 13 Percentage of participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 11 Percentage of participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 0 Percentage of participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 18 Percentage of participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 14 Percentage of participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 0 Percentage of participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 20 Percentage of participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 0 Percentage of participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 0 Percentage of participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 0 Percentage of participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Confirmed ORR as Determined by Investigator According to RECIST v1.1 | 50 Percentage of participants |
Primary
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)
Population: The FAS included all participants who received any amount of study drug. As prespecified in protocol, this outcome measure was planned to be analyzed only in the Part B: Cohort 7, LV 1.25 mg/kg arm. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | 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 | 23 Percentage of participants |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin | 142.5 Day*micrograms per milliliter | Geometric Coefficient of Variation 18.9 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin | 175.6 Day*micrograms per milliliter | Geometric Coefficient of Variation 16.5 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin | 145.3 Day*micrograms per milliliter | Geometric Coefficient of Variation 35.1 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin | 146.6 Day*micrograms per milliliter | Geometric Coefficient of Variation 28.3 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin | 123.2 Day*micrograms per milliliter | Geometric Coefficient of Variation 21.7 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Area Under the Serum Concentration Time Curve Between Days 0 to 21 (AUC21) of Ladiratuzumab Vedotin | 132.0 Day*micrograms per milliliter | Geometric Coefficient of Variation 26 |
Secondary
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.
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: AUC21 of Monomethyl Auristatin E (MMAE) | 34.1 Day*nanogram per milliliter | Geometric Coefficient of Variation 21.1 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: AUC21 of Monomethyl Auristatin E (MMAE) | 50.5 Day*nanogram per milliliter | — |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: AUC21 of Monomethyl Auristatin E (MMAE) | 62.9 Day*nanogram per milliliter | Geometric Coefficient of Variation 79.3 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: AUC21 of Monomethyl Auristatin E (MMAE) | 66.2 Day*nanogram per milliliter | Geometric Coefficient of Variation 45.6 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: AUC21 of Monomethyl Auristatin E (MMAE) | 91.0 Day*nanogram per milliliter | Geometric Coefficient of Variation 19.3 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: AUC21 of Monomethyl Auristatin E (MMAE) | 35.2 Day*nanogram per milliliter | Geometric Coefficient of Variation 36.9 |
Secondary
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.
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: AUC21 of Total Antibody (TAB) | 302.4 Day*micrograms per milliliter | Geometric Coefficient of Variation 19.7 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: AUC21 of Total Antibody (TAB) | 328.5 Day*micrograms per milliliter | Geometric Coefficient of Variation 17.8 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: AUC21 of Total Antibody (TAB) | 280.3 Day*micrograms per milliliter | Geometric Coefficient of Variation 34.1 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: AUC21 of Total Antibody (TAB) | 292.3 Day*micrograms per milliliter | Geometric Coefficient of Variation 28.2 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: AUC21 of Total Antibody (TAB) | 219.8 Day*micrograms per milliliter | Geometric Coefficient of Variation 28.5 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: AUC21 of Total Antibody (TAB) | 258.9 Day*micrograms per milliliter | Geometric Coefficient of Variation 31.6 |
Secondary
Part A: Cmax According to MMAE Pharmacokinetic Parameters
Cmax according to MMAE 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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Cmax According to MMAE Pharmacokinetic Parameters | 2.8 Nanogram per milliliter | Geometric Coefficient of Variation 15.7 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Cmax According to MMAE Pharmacokinetic Parameters | 5.7 Nanogram per milliliter | — |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Cmax According to MMAE Pharmacokinetic Parameters | 6.4 Nanogram per milliliter | Geometric Coefficient of Variation 83.1 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Cmax According to MMAE Pharmacokinetic Parameters | 6.3 Nanogram per milliliter | Geometric Coefficient of Variation 10.6 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Cmax According to MMAE Pharmacokinetic Parameters | 11.3 Nanogram per milliliter | Geometric Coefficient of Variation 12.6 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Cmax According to MMAE Pharmacokinetic Parameters | 3.6 Nanogram per milliliter | Geometric Coefficient of Variation 41.8 |
Secondary
Part A: Cmax According to TAB Pharmacokinetic Parameters
Cmax according to TAB 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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Cmax According to TAB Pharmacokinetic Parameters | 61.6 Micrograms per milliliter | Geometric Coefficient of Variation 23.7 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Cmax According to TAB Pharmacokinetic Parameters | 66.1 Micrograms per milliliter | Geometric Coefficient of Variation 20.8 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Cmax According to TAB Pharmacokinetic Parameters | 68.2 Micrograms per milliliter | Geometric Coefficient of Variation 30.5 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Cmax According to TAB Pharmacokinetic Parameters | 61.4 Micrograms per milliliter | Geometric Coefficient of Variation 16.1 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Cmax According to TAB Pharmacokinetic Parameters | 50.7 Micrograms per milliliter | Geometric Coefficient of Variation 38.3 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Cmax According to TAB Pharmacokinetic Parameters | 57.2 Micrograms per milliliter | Geometric Coefficient of Variation 24.1 |
Secondary
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.
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 4.1 months)
Population: The FAS included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1 | 40 Percentage of participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1 | 50 Percentage of participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1 | 46 Percentage of participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1 | 57 Percentage of participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1 | 60 Percentage of participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Disease Control Rate (DCR) According to RECIST v1.1 | 33 Percentage of participants |
Secondary
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)
Population: The FAS included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. No participant had CR or PR in Part A: Cohort 2, LV 2.5 mg/kg arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Duration of Response (DOR) According to RECIST v1.1 | 5.7 Months |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Duration of Response (DOR) According to RECIST v1.1 | 5.5 Months |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Duration of Response (DOR) According to RECIST v1.1 | 3.7 Months |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Duration of Response (DOR) According to RECIST v1.1 | 2.7 Months |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Duration of Response (DOR) According to RECIST v1.1 | NA Months |
Secondary
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)
Population: The FAS included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1 | 1.4 Months |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1 | 1.5 Months |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1 | 2.5 Months |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1 | 2.3 Months |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1 | 2.9 Months |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Confirmed Investigator Determined Progression Free Survival (PFS) According to RECIST v1.1 | 1.4 Months |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters | 50.4 Micrograms per milliliter | Geometric Coefficient of Variation 31.2 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters | 58.6 Micrograms per milliliter | Geometric Coefficient of Variation 1 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters | 55.8 Micrograms per milliliter | Geometric Coefficient of Variation 29.6 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters | 52.3 Micrograms per milliliter | Geometric Coefficient of Variation 23.6 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters | 39.6 Micrograms per milliliter | Geometric Coefficient of Variation 14.7 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Maximum Serum Concentration (Cmax) According to Antibody-Drug Conjugate (ADC) Pharmacokinetic Parameters | 55.2 Micrograms per milliliter | Geometric Coefficient of Variation 64.9 |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Negative post-baseline | 8 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Positive post-baseline | 0 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Negative post-baseline | 2 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Negative post-baseline | 2 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Negative post-baseline | 9 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Negative post-baseline | 4 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Negative post-baseline | 1 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Positive post-baseline | 0 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Negative post-baseline | 4 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Negative post-baseline | 1 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Positive Post-Baseline Antitherapeutic Antibody (ATA) Incidence | Baseline Negative and Negative post-baseline | 10 Participants |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 10 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 5 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 9 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 7 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 2 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 1 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 2 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 1 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 9 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 11 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 7 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 13 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 7 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 4 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 2 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 7 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 5 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 4 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 3 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 5 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 3 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 11 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 6 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs), Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 12 Participants |
Secondary
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)
Population: The FAS included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part A: Overall Survival (OS) | 6.1 Months |
| Part A: Cohort 2, LV 2.5 mg/kg | Part A: Overall Survival (OS) | 2.5 Months |
| Part A: Cohort 3, LV 2.5 mg/kg | Part A: Overall Survival (OS) | 6.5 Months |
| Part A: Cohort 4, LV 2.5 mg/kg | Part A: Overall Survival (OS) | 4.8 Months |
| Part A: Cohort 5, LV 2.5 mg/kg | Part A: Overall Survival (OS) | 7.2 Months |
| Part A: Cohort 6, LV 2.5 mg/kg | Part A: Overall Survival (OS) | 8.7 Months |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. There were insufficient samples to provide pharmacokinetic (PK) estimates for analytes in Part B: Cohort 6, LV 1.0 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 57.3 Day*micrograms per milliliter | Geometric Coefficient of Variation 23.2 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 51.7 Day*micrograms per milliliter | Geometric Coefficient of Variation 16.9 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 59.5 Day*micrograms per milliliter | Geometric Coefficient of Variation 29.7 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 60.6 Day*micrograms per milliliter | Geometric Coefficient of Variation 36.7 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 43.3 Day*micrograms per milliliter | Geometric Coefficient of Variation 12.6 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 50.7 Day*micrograms per milliliter | Geometric Coefficient of Variation 27.2 |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 66.0 Day*micrograms per milliliter | Geometric Coefficient of Variation 42.8 |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 46.8 Day*micrograms per milliliter | Geometric Coefficient of Variation 25 |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 42.1 Day*micrograms per milliliter | Geometric Coefficient of Variation 0.5 |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 52.0 Day*micrograms per milliliter | Geometric Coefficient of Variation 0.1 |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Area Under the Concentration Time Curve Between Day 0 to 7 (AUC7) of ADC | 44.8 Day*micrograms per milliliter | — |
Secondary
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.
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. There were insufficient samples to provide PK estimates for analytes in Part B: Cohort 6, LV 1.0 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: AUC7 OF MMAE | 14.6 Day*micrograms per milliliter | Geometric Coefficient of Variation 63.1 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: AUC7 OF MMAE | 16.5 Day*micrograms per milliliter | Geometric Coefficient of Variation 55.6 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: AUC7 OF MMAE | 11.9 Day*micrograms per milliliter | Geometric Coefficient of Variation 51.5 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: AUC7 OF MMAE | 15.6 Day*micrograms per milliliter | Geometric Coefficient of Variation 51 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: AUC7 OF MMAE | 17.3 Day*micrograms per milliliter | Geometric Coefficient of Variation 67.6 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: AUC7 OF MMAE | 13.7 Day*micrograms per milliliter | Geometric Coefficient of Variation 83 |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: AUC7 OF MMAE | 10.7 Day*micrograms per milliliter | Geometric Coefficient of Variation 57.3 |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: AUC7 OF MMAE | 13.8 Day*micrograms per milliliter | Geometric Coefficient of Variation 45.2 |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: AUC7 OF MMAE | 10.8 Day*micrograms per milliliter | Geometric Coefficient of Variation 64.1 |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: AUC7 OF MMAE | 12.4 Day*micrograms per milliliter | Geometric Coefficient of Variation 25.9 |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: AUC7 OF MMAE | 8.5 Day*micrograms per milliliter | — |
Secondary
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.
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. There were insufficient samples to provide PK estimates for analytes in Part B: Cohort 6, LV 1.0 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: AUC7 of TAB | 101.1 Day*micrograms per milliliter | Geometric Coefficient of Variation 29.4 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: AUC7 of TAB | 92.7 Day*micrograms per milliliter | Geometric Coefficient of Variation 18.7 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: AUC7 of TAB | 106.9 Day*micrograms per milliliter | Geometric Coefficient of Variation 29.8 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: AUC7 of TAB | 91.2 Day*micrograms per milliliter | Geometric Coefficient of Variation 30.9 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: AUC7 of TAB | 73.9 Day*micrograms per milliliter | Geometric Coefficient of Variation 20.7 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: AUC7 of TAB | 85.7 Day*micrograms per milliliter | Geometric Coefficient of Variation 26 |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: AUC7 of TAB | 106.5 Day*micrograms per milliliter | Geometric Coefficient of Variation 28.2 |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: AUC7 of TAB | 74.7 Day*micrograms per milliliter | Geometric Coefficient of Variation 26.3 |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: AUC7 of TAB | 76.6 Day*micrograms per milliliter | Geometric Coefficient of Variation 22.6 |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: AUC7 of TAB | 88.6 Day*micrograms per milliliter | Geometric Coefficient of Variation 11.1 |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: AUC7 of TAB | 71.4 Day*micrograms per milliliter | — |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. There were insufficient samples to provide PK estimates for analytes in Part B: Cohort 6, LV 1.0 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 35.3 Micrograms per milliliter | Geometric Coefficient of Variation 35 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 27.8 Micrograms per milliliter | Geometric Coefficient of Variation 19.7 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 30.9 Micrograms per milliliter | Geometric Coefficient of Variation 19.2 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 28.7 Micrograms per milliliter | Geometric Coefficient of Variation 28.6 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 25.0 Micrograms per milliliter | Geometric Coefficient of Variation 28.8 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 28.0 Micrograms per milliliter | Geometric Coefficient of Variation 17.2 |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 30.5 Micrograms per milliliter | Geometric Coefficient of Variation 15.1 |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 25.4 Micrograms per milliliter | Geometric Coefficient of Variation 21.9 |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 29.5 Micrograms per milliliter | Geometric Coefficient of Variation 20.3 |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 24.3 Micrograms per milliliter | Geometric Coefficient of Variation 10.2 |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Cmax According to ADC Pharmacokinetic Parameters | 24.1 Micrograms per milliliter | Geometric Coefficient of Variation 6.2 |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. There were insufficient samples to provide PK estimates for analytes in Part B: Cohort 6, LV 1.0 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 2.8 Nanograms per milliliter | Geometric Coefficient of Variation 60.7 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 4.5 Nanograms per milliliter | Geometric Coefficient of Variation 50.4 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 2.6 Nanograms per milliliter | Geometric Coefficient of Variation 59.1 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 2.7 Nanograms per milliliter | Geometric Coefficient of Variation 39.9 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 3.3 Nanograms per milliliter | Geometric Coefficient of Variation 65.8 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 2.9 Nanograms per milliliter | Geometric Coefficient of Variation 114.9 |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 1.7 Nanograms per milliliter | Geometric Coefficient of Variation 28.9 |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 2.4 Nanograms per milliliter | Geometric Coefficient of Variation 52.7 |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 1.4 Nanograms per milliliter | — |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Cmax According to MMAE Pharmacokinetic Parameters | 1.7 Nanograms per milliliter | — |
Secondary
Part B: Cmax According to TAB Pharmacokinetic Parameters
Cmax according to TAB 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)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. There were insufficient samples to provide PK estimates for analytes in Part B: Cohort 6, LV 1.0 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 38.3 Micrograms per milliliter | Geometric Coefficient of Variation 17.9 |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 31.6 Micrograms per milliliter | Geometric Coefficient of Variation 16.6 |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 36.8 Micrograms per milliliter | Geometric Coefficient of Variation 21.8 |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 32.1 Micrograms per milliliter | Geometric Coefficient of Variation 26.2 |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 27.4 Micrograms per milliliter | Geometric Coefficient of Variation 28.9 |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 31.3 Micrograms per milliliter | Geometric Coefficient of Variation 19.7 |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 32.6 Micrograms per milliliter | Geometric Coefficient of Variation 25.9 |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 32.5 Micrograms per milliliter | Geometric Coefficient of Variation 73.8 |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 26.8 Micrograms per milliliter | Geometric Coefficient of Variation 15.6 |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 30.6 Micrograms per milliliter | Geometric Coefficient of Variation 14.8 |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Cmax According to TAB Pharmacokinetic Parameters | 27.9 Micrograms per milliliter | Geometric Coefficient of Variation 2 |
Secondary
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)
Population: The FAS included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 19 Percentage of participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 50 Percentage of participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 58 Percentage of participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 64 Percentage of participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 59 Percentage of participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 52 Percentage of participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 62 Percentage of participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 77 Percentage of participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 50 Percentage of participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 50 Percentage of participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 0 Percentage of participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined DCR According to RECIST v1.1 | 100 Percentage of participants |
Secondary
Part B: Confirmed Investigator Determined 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 32.0 months for 1.25 mg/kg and 4.2 months for 1 mg/kg dose level)
Population: The FAS included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure. No participant had CR or PR in Part B: Cohort 4, LV 1.25 mg/kg arm, Part B: Cohort 7, LV 1.25 mg/kg arm, Part B: Cohort 1, LV 1.0 mg/kg arm, Part B: Cohort 3, LV 1.0 mg/kg arm and Part B: Cohort 4, LV 1.0 mg/kg arm.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | NA Months |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | 7.5 Months |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | NA Months |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | NA Months |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | 3.9 Months |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | 8.3 Months |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined DOR According to RECIST v1.1 | 4.2 Months |
Secondary
Part B: Confirmed Investigator Determined 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 34.7 months for 1.25 mg/kg and 5.7 months for 1 mg/kg dose level)
Population: The FAS included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 1.4 Months |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 1.8 Months |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 2.4 Months |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 2.7 Months |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 2.8 Months |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 2.3 Months |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 4.9 Months |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 4.2 Months |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 1.9 Months |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | NA Months |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 1.5 Months |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Confirmed Investigator Determined PFS According to RECIST v1.1 | 4.2 Months |
Secondary
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)
Population: The FAS included all participants who received any amount of study drug. As prespecified in protocol, this outcome measure was planned to be analyzed only in the Part B: Cohort 7, LV 1.25 mg/kg arm. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PSA-DOR, for Prostate Cancer | 3.0 Months |
Secondary
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)
Population: The FAS included all participants who received any amount of study drug. As prespecified in protocol, this outcome measure was planned to be analyzed only in the Part B: Cohort 7, LV 1.25 mg/kg arm. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Confirmed Investigator Determined PSA-PFS, for Prostate Cancer | 3.7 Months |
Secondary
Part B: Number of Participants With Positive Post-Baseline 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 22.1 months for 1.25 mg/kg and 5.1 months for 1 mg/kg)
Population: The safety analysis set included all participants who received any amount of study drug. Here, 'Number of Participants Analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 1 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 10 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 11 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 1 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 13 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 4 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 2 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 12 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 0 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 2 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 1 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 11 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 10 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 1 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 9 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 1 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 4 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 24 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 1 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 0 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 2 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 0 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 2 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 0 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 1 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Negative post-baseline | 2 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Negative post-baseline | 0 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Negative and Positive post-baseline | 0 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With Positive Post-Baseline ATA Incidence | Baseline Positive and Positive post-baseline | 0 Participants |
Secondary
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)
Population: The safety analysis set included all participants who received any amount of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 13 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 15 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 6 Participants |
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 12 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 11 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 16 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 16 Participants |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 5 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 19 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 14 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 9 Participants |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 18 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 11 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 14 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 12 Participants |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 8 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 17 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 17 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 9 Participants |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 13 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 12 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 17 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 21 Participants |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 19 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 12 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 13 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 4 Participants |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 8 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 11 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 30 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 17 Participants |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 28 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 2 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 1 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 1 Participants |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 2 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 2 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 2 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 2 Participants |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 2 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 1 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 2 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 2 Participants |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 1 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs | 2 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | Treatment Related TEAEs | 2 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TESAEs | 0 Participants |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Number of Participants With TEAEs, TESAEs, Treatment Related TEAEs and >= Grade 3 TEAE | TEAEs (>= Grade 3) | 0 Participants |
Secondary
Part B: Overall Survival
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 37.5 months for 1.25 mg/kg and 20.9 months for 1 mg/kg dose level)
Population: The FAS included all participants who received any amount of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Cohort 1, LV 2.5 mg/kg | Part B: Overall Survival | 4.7 Months |
| Part A: Cohort 2, LV 2.5 mg/kg | Part B: Overall Survival | 9.0 Months |
| Part A: Cohort 3, LV 2.5 mg/kg | Part B: Overall Survival | 9.3 Months |
| Part A: Cohort 4, LV 2.5 mg/kg | Part B: Overall Survival | 5.2 Months |
| Part A: Cohort 5, LV 2.5 mg/kg | Part B: Overall Survival | 12.7 Months |
| Part A: Cohort 6, LV 2.5 mg/kg | Part B: Overall Survival | 3.8 Months |
| Part B: Cohort 7, LV 1.25 mg/kg | Part B: Overall Survival | 10.1 Months |
| Part B: Cohort 8, LV 1.25 mg/kg | Part B: Overall Survival | 11.5 Months |
| Part B: Cohort 1, LV 1.0 mg/kg | Part B: Overall Survival | 11.1 Months |
| Part B: Cohort 3, LV 1.0 mg/kg | Part B: Overall Survival | NA Months |
| Part B: Cohort 4, LV 1.0 mg/kg | Part B: Overall Survival | 5.6 Months |
| Part B: Cohort 6, LV 1.0 mg/kg | Part B: Overall Survival | 14.2 Months |