The purpose of this study was to evaluate the safety, tolerability, and clinical response of ASP7517, and determine the Recommended Phase 2 Dose (RP2D) and/or the Maximum Tolerated Dose (MTD) of ASP7517 when administered as a single agent and in combination with pembrolizumab. This study also evaluated other measures of anticancer activity of ASP7517 when administered as a single agent and in combination with pembrolizumab based on central and local assessment.
This study consisted of arms receiving ASP7517 monotherapy and arms receiving ASP7517 and pembrolizumab combination therapy in Phase 1 (dose escalation cohort) and Phase 2 (dose expansion cohort). Phase 2 monotherapy and combination dose expansion cohorts were opened after the phase 1 escalation cohort was completed.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Intravenous (IV)
Intravenous (IV)
Emory University
Atlanta, Georgia, United States
University of Chicago
Chicago, Illinois, United States
University of Iowa Hospitals
Iowa City, Iowa, United States
UPCI Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events: Monotherapy
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the study drug. An AE could therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An AE was considered "serious" if, it resulted in any of the following outcomes: resulted in death; was life-threatening; resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions; resulted in congenital anomaly, or birth defect; required inpatient hospitalization; or led to prolongation of hospitalization; other medically important events. A treatment-emergent adverse event (TEAE) was defined as an AE observed after the date of first dose until 30 days after the last dose.
Time frame: From first dose up to 30 days after last dose (maximum treatment duration: approximately 534[504+30] days)
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events: Combination Therapy
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the study drug. An AE could therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An AE was considered "serious" if, it resulted in any of the following outcomes: resulted in death; was life-threatening; resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions; resulted in congenital anomaly, or birth defect; required inpatient hospitalization; or led to prolongation of hospitalization; other medically important events. A treatment-emergent adverse event (TEAE) was defined as an AE observed after the date of first dose until 30 days after the last dose.
Time frame: From first dose up to 30 days after last dose (maximum treatment duration: approximately 847[817+30] days)
Number of Participants With ECOG Performance Status at Cycle (C) 1 Day (D) 1
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C1D1
Number of Participants With ECOG Performance Status at C1D2
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C1D2
Number of Participants With ECOG Performance Status at C1D4
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C1D4
Number of Participants With ECOG Performance Status at C1D8
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C1D8
Number of Participants With ECOG Performance Status at C1D15
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C1D15
Number of Participants With ECOG Performance Status at C2D1
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C2D1
Number of Participants With ECOG Performance Status at C2D4
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C2D4
Number of Participants With ECOG Performance Status at C2D8
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C2D8
Number of Participants With ECOG Performance Status at C2D15
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C2D15
Number of Participants With ECOG Performance Status at C3D1
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C3D1
Number of Participants With ECOG Performance Status at C3D8
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C3D8
Number of Participants With ECOG Performance Status at C3D15
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C3D15
Number of Participants With ECOG Performance Status at C4D1
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C4D1
Number of Participants With ECOG Performance Status at C4D8
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C4D8
Number of Participants With ECOG Performance Status at C4D15
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C4D15
Number of Participants With ECOG Performance Status at C5D1
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C5D1
Number of Participants With ECOG Performance Status at C5D8
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C5D8
Number of Participants With ECOG Performance Status at C5D15
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C5D15
Number of Participants With ECOG Performance Status at C6D1
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C6D1
Number of Participants With ECOG Performance Status at C6D8
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C6D8
Number of Participants With ECOG Performance Status at C6D15
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At C6D15
Number of Participants With ECOG Performance Status at End of Treatment (EOT): Monotherapy
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead. EOT visit was conducted for all participants after 7 days of last dose.
Time frame: At EOT (Approximately 511 [504 +7] days)
Number of Participants With ECOG Performance Status at End of Treatment (EOT): Combination Therapy.
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead. EOT visit was conducted for all participants after 7 days of last dose.
Time frame: At EOT (Approximately 824 [817 +7] days)
Number of Participants With ECOG Performance Status at 30 Day Follow Up: Monotherapy
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At 30 days safety Follow Up (Approximately 541 [511+30] days)
Number of Participants With ECOG Performance Status at 30 Day Follow Up: Combination Therapy
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At 30 days safety Follow Up (Approximately 854 [824+30 ] days)
Number of Participants With ECOG Performance Status at 60 Day Follow Up: Monotherapy
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At 60 days safety Follow Up (Approximately 571 [511+60] days)
Number of Participants With ECOG Performance Status at 60 Day Follow Up: Combination Therapy
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At 60 days safety Follow Up (Approximately 884 [824+60] days)
Number of Participants With ECOG Performance Status at 90 Day Follow Up: Monotherapy
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At 90 days safety follow up (Approximately 601 [511+90] days)
Number of Participants With ECOG Performance Status at 90 Day Follow Up: Combination Therapy
The ECOG Scale was used to assess performance status. Grade Description: 0 - Fully active, able to carry on all pre disease performance without restriction. 1 - Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2 - Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 -Dead.
Time frame: At 90 days safety follow up (Approximately 914 [824+90] days)
Number of Participants With Dose Limiting Toxicities (DLTs)
DLT: any event occurring within 28 days of first dose on C1D1 and graded as: \*Non-hematologic AEs \>= grade 3 and not resolving to \<= grade 2 within 72 hours. \*Confirmed Hy's law case. \*Infusion-related reactions requiring infusion discontinuation, prolonged delay (\> 2 weeks) in initiating C2 due to treatment-related toxicity. \*Any treatment-related toxicity causing discontinuation in C1. \*Grade \>= 3 thrombocytopenia/bleeding requiring transfusion/hospitalization, grade \>= 3 anemia requiring transfusion, grade 3 febrile neutropenia with/without infection and grade 5 treatment-related toxicity, grade \>= 2 pneumonitis, grade \>= 2 encephalopathy, meningitis or motor/sensory neuropathy. \*Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) \> 5 × upper limit of normal (ULN) in participants without liver metastases, AST/ALT \> 8×ULN in participants with liver metastases, total bilirubin \> 3×ULN (grade \>= 3). \*Guillain-Barré syndrome/myasthenic syndrome/myasthenia gravis.
Time frame: From C1D1 up to C1D28
Objective Response Rate (iORR) Per Immune Response Evaluation Criteria in Solid Tumors (iRECIST) by Investigator Assessment
iORR was defined as the percentage of participants for each dose level whose best overall response was rated as confirmed iCR or iPR per iRECIST by independent central review. iCR was complete response based on iRECIST and defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. iPR was partial response based on iRECIST was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. iORR assessments included: * iORR with confirmed response by investigator assessment * iORR with unconfirmed response by investigator assessment For confirmed response for iCR/iPR, scan had to be done 4 weeks after iPR/iCR was first observed. Participants who had iCR/iPR were considered as having confirmed response and those that did not fulfil this criteria were considered as having unconfirmed response.
Time frame: From first dose up to 954 days
Objective Response Rate (ORR) Per RECIST v1.1 by Investigator Assessment
ORR was defined as the percentage of participants for each dose level whose best overall response is rated as complete response (CR) or partial response (PR) per RECIST v1.1. CR was complete response based on RECIST and defined as disappearance of all target and non-target lesions and any pathological lymph nodes must be \<10 mm in the short axis. PR was partial response based on RECIST and defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. ORR assessment included: * ORR with confirmed response by investigator assessment * ORR with unconfirmed response by investigator assessment For confirmed response for CR/PR, scan had to be done 4 weeks after PR/CR was first observed. Participants who had CR/PR were considered as having confirmed response and those that did not fulfil this criteria were considered as having unconfirmed response.
Time frame: From first dose up to 954 days
Disease Control Rate Per iRECIST (iDCR) by Investigator Assessment
iDCR: Percentage of participants for each dose level whose best overall response is rated as confirmed iCR, iPR or iSD per iRECIST. iCR: Complete response based on iRECIST, defined as disappearance of all target/non target lesions and pathological lymph nodes must be \<10 millimeter (mm) in the short axis. iPR: Partial response based on iRECIST, defined as at least 30% decrease in the sum of diameters of target lesions, with reference to the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for iPR nor sufficient increase to qualify for PD. PD: Defined as at least 20% increase in the sum of diameters of target lesions, with reference to the smallest sum of diameters recorded since the treatment started. For confirmed response for iCR/iPR, scan had to be done 4 weeks after iPR/iCR was first observed. Participants who had iCR/iPR were considered as having confirmed response and those that did not fulfil this criteria were considered as having unconfirmed response.
Time frame: From first dose up to 954 days
Disease Control Rate (DCR) Per RECIST v1.1 by Investigator Assessment
DCR: Percentage of participants for each dose level whose best overall response is rated as confirmed CR, PR or SD per RECIST v1.1. CR: Complete response based on RECIST and defined as disappearance of all target/non target lesions and any pathological lymph nodes must be \<10 mm in the short axis. PR: Partial response based on RECIST and defined as at least a 30% decrease in the sum of diameters of target lesions, with reference to, the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for iPR nor sufficient increase to qualify for PD. PD: At least a 20% increase in the sum of diameters of target lesions, with reference to, the smallest sum of diameters recorded since treatment started. For confirmed response for CR/PR, scan had to be done 4 weeks after PR/CR was first observed. Participants who had CR/PR were considered as having confirmed response and those that did not fulfil this criteria were considered as having unconfirmed response.
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Time frame: From first dose up to 954 days
Progression-Free Survival Per iRECIST (iPFS) Using Investigator Assessment
iPFS was defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed per iRECIST by independent central review and investigator assessment, whichever occurs first. Progressive Disease was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. Kaplan Meier estimate was used for analysis of time-to-event endpoints.
Time frame: From first dose until death from any cause or radiographic disease progression (up to 954 days)
Progression-Free Survival Per RECIST (PFS) Using Investigator Assessment
PFS was defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed per RECIST by independent central review and investigator assessment, whichever occurred first. Progressive Disease was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. Kaplan Meier estimate was used for analysis of time-to-event endpoints.
Time frame: From first dose until death from any cause or radiographic disease progression (up to 954 days)
Overall Survival (OS)
OS was defined as the time from the date of first dose until the date of death from any cause (death date - first dose date + 1). For a participant who is not known to have died by the end of study follow-up, OS is censored at the date of last contact (date of last contact - first dose date + 1). Kaplan Meier estimate was used for analysis of time-to-event endpoints.
Time frame: From first dose until death from any cause (up to 954 days)
Duration of Response Per iRECIST (iDOR)
iDOR was defined as the time from the date of the first response iCR/iPR (whichever was first recorded) to the date of radiographical progression or date of censoring. iCR was complete response based on iRECIST and defined as disappearance of all target and non target lesions and any pathological lymph nodes must be \<10 millimeter (mm) in the short axis. iPR was partial response based on iRECIST was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. Progressive Disease was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
Time frame: From first response up to the date of radiographical progression (up to 954 days)
Duration of Response (DOR) Per RECIST v1.1
DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression or date of censoring. DOR will be calculated only for the subgroup of participants with confirmed response CR/PR per RECIST v1.1, separately for independent central review and for investigator assessment. CR was complete response based on RECIST and defined as disappearance of all target and non target lesions and any pathological lymph nodes must be \<10 mm in the short axis. PR was partial response based on RECIST and defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. Progressive Disease was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started.
Time frame: From first response up to the date of radiographical progression (up to 954 days)