A Phase 1/2, Open-label Study Investigating the Safety, Tolerability and Efficacy of ASP7517 as a Single Agent and in Combination With Pembrolizumab in Patients With Advanced Solid Tumors Known to Express WT1 Antigen
Overview
- Phase
- Phase 1
- Intervention
- ASP7517
- Conditions
- Advanced Malignancies
- Sponsor
- Astellas Pharma Global Development, Inc.
- Enrollment
- 24
- Locations
- 4
- Primary Endpoint
- Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events: Monotherapy
- Status
- Completed
- Last Updated
- 8 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participant has locally-advanced (unresectable) or metastatic solid tumor malignancy that is confirmed by available pathology records or current biopsy. Participant must also have received all standard therapies (unless the therapy is contraindicated or intolerable) appropriate to provide clinical benefit for his/her specific tumor type. However, participants with metastatic melanoma who have not received checkpoint inhibitors \[CPIs\] (i.e., CPIs naive) may enroll in the Phase 2 Combination Therapy Arm Dose Expansion Cohort to receive CPI: Pembrolizumab.
- •Participant must be diagnosed with solid tumor known to express WT1 antigen such as, but not limited to melanoma, ovarian cancer or Colorectal Cancer (CRC).
- •Participant consents to provide an archival tumor specimen in a tissue block or unstained serial slides, if available, prior to study treatment.
- •Participant has an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤
- •Participant's last dose of prior antineoplastic therapy, including any immunotherapy, was 21 days or 5 half-lives, whichever is shorter, prior to initiation of IP administration. A participant with BRAF gene, epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation positive non-small cell lung carcinoma is allowed to remain on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) or anaplastic lymphoma kinase (ALK) or BRAF inhibitor therapy until 4 days prior to the start of Investigational Product (IP) administration.
- •Participant has completed any radiotherapy (including stereotactic radiosurgery) at least 2 weeks prior to IP administration.
- •Participant's Adverse Events (AEs) (excluding alopecia) from prior therapy have improved to grade 1 or baseline within 14 days prior to start of IP.
- •Participant has adequate organ function prior to start of IP. If a participant has received a recent blood transfusion, the laboratory tests must be obtained ≥ 4 weeks after any blood transfusion.
- •A female participant is eligible to participate if she is not pregnant and at least 1 of the following conditions applies:
- •Not a woman of childbearing potential (WOCBP) OR
Exclusion Criteria
- •Participant weighs \< 45 kg at screening.
- •Participant has received investigational therapy (other than an investigational EGFR TKI in a participant with EGFR activating mutations or ALK or BRAF inhibitor in a participant with an ALK mutation) within 21 days or 5 half-lives, whichever is shorter, prior to start of IP.
- •Participant requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to Cycle 1 Day
- •Participants using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone up to 10 mg per day of prednisone) are allowed.
- •Participant has symptomatic central nervous system (CNS) metastases or participant has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Participants with previously treated CNS metastases are eligible, if they are clinically stable and have no evidence of CNS progression by imaging for at least 4 weeks prior to start of IP and are not requiring immunosuppressive doses of systemic steroids (\> 30 mg per day of hydrocortisone or \> 10 mg per day of prednisone or equivalent) for longer than 2 weeks.
- •Participant has an active autoimmune disease. Participants with type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy or skin disorders (e.g., vitiligo, psoriasis or alopecia) not requiring systemic treatment are allowed.
- •Participant was discontinued from prior immunomodulatory therapy due to a grade ≥ 3 toxicity that was mechanistically related (e.g., immune related) to the agent.
- •Participant has known history of serious hypersensitivity reaction to a known ingredient of ASP7517 or pembrolizumab or severe hypersensitivity reaction to treatment with another monoclonal antibody.
- •Participant has a known history of human immunodeficiency virus.
- •Participant with known history of positive hepatitis B surface antigen or isolated hepatitis B core antibody (including acute HBV or chronic HBV) or hepatitis C (\[HCV\] ribonucleic acid \[RNA\] detected by qualitative assay). Hepatitis C RNA testing is not required in participants with negative hepatitis C antibody testing.
Arms & Interventions
Phase 1: Monotherapy Dose Escalation (ASP7517 1x10^7 cells/dose)
Participants received one dose of ASP7517 1x10\^7 cells/dose for up to 6 doses (168 days) by intravenous (IV) infusion (4 to 6 mL/minute) on Day 1 of each cycle (1 Cycle=28 days). Following first 2 cycles, participants not meeting treatment discontinuation criteria and receiving clinical benefit (defined:radiological response/SD/reduction of disease-related symptoms) continued treatment with ASP7517. After 4 cycles of treatment, participants achieving confirmed CR discontinued ASP7517, and participants who achieved PR or SD received an additional 2 doses. Participants entered an Observation Period except those with iCPD, iUPD and those not clinically stable or clinical progression was confirmed by investigator and followed up to 48 weeks until iCPD per independent central review, initiation of new anticancer therapy or meeting 1 of Observation Period discontinuation criteria, whichever occurred first. After EOT visit, participants completed Safety follow-up visits 30, 60 and 90 days.
Intervention: ASP7517
Phase 1: Monotherapy dose escalation (ASP7517 1x10^8 cells/dose)
Participants received one dose of ASP7517 1x10\^8 cells/dose by IV infusion (4 to 6 mL/minute) on Day 1 of each cycle (1 Cycle=28 days). Following first 2 cycles, participants not meeting treatment discontinuation criteria and receiving clinical benefit (defined as radiological response/ SD, or reduction of disease-related symptoms) continued treatment with ASP7517. After 4 cycles of treatment, participants achieving confirmed CR discontinued ASP7517, and any participants who achieved PR or SD received an additional 2 doses. Participants entered an Observation Period except those with iCPD, iUPD and those not clinically stable or clinical progression was confirmed by the investigator and followed for up to 48 weeks until iCPD per independent central review, initiation of a new anticancer therapy or meeting 1 of the Observation Period discontinuation criteria, whichever occurred first. After EOT visit, participants completed Safety follow-up visits 30, 60 and 90 days
Intervention: ASP7517
Phase 2:Monotherapy dose expansion (ASP7517 1x10^8 cells/dose)
Participants received ASP7517 1x10\^8 cells/dose by IV infusion (4 to 6 mL/minute) on Day 1 of each cycle (1 Cycle=28 days).Following the first 2 cycles, participants not meeting discontinuation criteria and were receiving clinical benefit (defined as radiological response/SD, or reduction of disease-related symptoms) continued treatment with ASP7517. After 4 cycles of treatment, participants achieving confirmed CR discontinued ASP7517, and any participants who achieved PR or SD received an additional 2 doses. Participants entered an Observation Period except those with iCPD, iUPD and who were not clinically stable or clinical progression was confirmed by the investigator and followed up to 48 weeks until iCPD per independent central review, initiation of a new anticancer therapy or meeting 1 of the Observation Period discontinuation criteria, whichever occurred first. After the EOT visit, participants completed the Safety follow-up visits 30, 60 and 90 days.
Intervention: ASP7517
Phase1:Combination Therapy dose Escalation (ASP7517 1x10^7 cells/dose) and Pembrolizumab
Participants received ASP7517 1x10\^7 cells/dose for up to 6 doses (168 days) on Day 1 of each cycle by IV infusion (4-6 mL/min) (1 Cycle = 28 days) with 400 mg pembrolizumab infusion (over 30 min) for up to 4 doses every 6 weeks. After 2 cycles, those not meeting discontinuation criteria and receiving clinical benefit continued ASP7517 and pembrolizumab. Participants with confirmed CR within 4 cycles did not receive ASP7517 at cycles 5-6; those with PR/SD after 4 doses received 2 more ASP7517 doses with pembrolizumab. After Treatment Period, all except those with iCPD, iUPD, or clinical progression entered Observation Period and continued pembrolizumab alone (up to 17 doses) to monitor response up to 96 weeks until iCPD, new therapy, or discontinuation criteria. After EOT visit, participants completed Safety follow-up at 30, 60, and 90 days.
Intervention: ASP7517
Phase1:Combination Therapy dose Escalation (ASP7517 1x10^7 cells/dose) and Pembrolizumab
Participants received ASP7517 1x10\^7 cells/dose for up to 6 doses (168 days) on Day 1 of each cycle by IV infusion (4-6 mL/min) (1 Cycle = 28 days) with 400 mg pembrolizumab infusion (over 30 min) for up to 4 doses every 6 weeks. After 2 cycles, those not meeting discontinuation criteria and receiving clinical benefit continued ASP7517 and pembrolizumab. Participants with confirmed CR within 4 cycles did not receive ASP7517 at cycles 5-6; those with PR/SD after 4 doses received 2 more ASP7517 doses with pembrolizumab. After Treatment Period, all except those with iCPD, iUPD, or clinical progression entered Observation Period and continued pembrolizumab alone (up to 17 doses) to monitor response up to 96 weeks until iCPD, new therapy, or discontinuation criteria. After EOT visit, participants completed Safety follow-up at 30, 60, and 90 days.
Intervention: Pembrolizumab
Phase 1:Combination Therapy dose Escalation (ASP7517 1x10^8cells/dose) and Pembrolizumab
Participants received ASP7517 1x10\^8 cells/dose for up to 6 doses (168 days) on Day 1 of each cycle by IV infusion (4-6 mL/min) (1 Cycle = 28 days) with 400 mg pembrolizumab infusion (over 30 min) for up to 4 doses every 6 weeks. After 2 cycles, those not meeting discontinuation criteria and receiving clinical benefit continued ASP7517 and pembrolizumab. Participants with confirmed CR within 4 cycles did not receive ASP7517 at cycles 5-6; those with PR/SD after 4 doses received 2 more ASP7517 doses with pembrolizumab. After Treatment Period, all except those with iCPD, iUPD, or clinical progression entered Observation Period and continued pembrolizumab alone (up to 17 doses) to monitor response up to 96 weeks until iCPD, new therapy, or discontinuation criteria. After EOT visit, participants completed Safety follow-up at 30, 60, and 90 days.
Intervention: ASP7517
Phase 1:Combination Therapy dose Escalation (ASP7517 1x10^8cells/dose) and Pembrolizumab
Participants received ASP7517 1x10\^8 cells/dose for up to 6 doses (168 days) on Day 1 of each cycle by IV infusion (4-6 mL/min) (1 Cycle = 28 days) with 400 mg pembrolizumab infusion (over 30 min) for up to 4 doses every 6 weeks. After 2 cycles, those not meeting discontinuation criteria and receiving clinical benefit continued ASP7517 and pembrolizumab. Participants with confirmed CR within 4 cycles did not receive ASP7517 at cycles 5-6; those with PR/SD after 4 doses received 2 more ASP7517 doses with pembrolizumab. After Treatment Period, all except those with iCPD, iUPD, or clinical progression entered Observation Period and continued pembrolizumab alone (up to 17 doses) to monitor response up to 96 weeks until iCPD, new therapy, or discontinuation criteria. After EOT visit, participants completed Safety follow-up at 30, 60, and 90 days.
Intervention: Pembrolizumab
Outcomes
Primary Outcomes
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events: Monotherapy
Time Frame: From first dose up to 30 days after last dose (maximum treatment duration: approximately 534[504+30] days)
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.
Number of Participants With ECOG Performance Status at Cycle (C) 1 Day (D) 1
Time Frame: At C1D1
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.
Number of Participants With ECOG Performance Status at C2D4
Time Frame: 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.
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events: Combination Therapy
Time Frame: From first dose up to 30 days after last dose (maximum treatment duration: approximately 847[817+30] days)
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.
Number of Participants With ECOG Performance Status at C1D2
Time Frame: 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.
Number of Participants With ECOG Performance Status at C4D15
Time Frame: 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.
Number of Participants With ECOG Performance Status at C1D4
Time Frame: 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.
Number of Participants With ECOG Performance Status at C5D8
Time Frame: 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.
Number of Participants With ECOG Performance Status at C1D8
Time Frame: 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.
Number of Participants With ECOG Performance Status at C1D15
Time Frame: 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.
Number of Participants With ECOG Performance Status at C2D1
Time Frame: 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.
Number of Participants With ECOG Performance Status at C2D8
Time Frame: 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.
Number of Participants With ECOG Performance Status at C2D15
Time Frame: 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.
Number of Participants With ECOG Performance Status at C3D1
Time Frame: 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.
Number of Participants With ECOG Performance Status at C3D8
Time Frame: 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.
Number of Participants With ECOG Performance Status at C3D15
Time Frame: 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.
Number of Participants With ECOG Performance Status at C4D1
Time Frame: 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.
Number of Participants With ECOG Performance Status at C4D8
Time Frame: 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.
Number of Participants With ECOG Performance Status at C5D1
Time Frame: 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.
Number of Participants With ECOG Performance Status at 30 Day Follow Up: Combination Therapy
Time Frame: At 30 days safety Follow Up (Approximately 854 [824+30 ] days)
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.
Number of Participants With ECOG Performance Status at 90 Day Follow Up: Monotherapy
Time Frame: At 90 days safety follow up (Approximately 601 [511+90] days)
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.
Number of Participants With ECOG Performance Status at C5D15
Time Frame: 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.
Number of Participants With ECOG Performance Status at C6D1
Time Frame: 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.
Number of Participants With ECOG Performance Status at C6D8
Time Frame: 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.
Number of Participants With ECOG Performance Status at C6D15
Time Frame: 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.
Number of Participants With ECOG Performance Status at End of Treatment (EOT): Monotherapy
Time Frame: At EOT (Approximately 511 [504 +7] days)
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.
Number of Participants With ECOG Performance Status at End of Treatment (EOT): Combination Therapy.
Time Frame: At EOT (Approximately 824 [817 +7] days)
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.
Number of Participants With ECOG Performance Status at 30 Day Follow Up: Monotherapy
Time Frame: At 30 days safety Follow Up (Approximately 541 [511+30] days)
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.
Number of Participants With ECOG Performance Status at 60 Day Follow Up: Monotherapy
Time Frame: At 60 days safety Follow Up (Approximately 571 [511+60] days)
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.
Number of Participants With ECOG Performance Status at 60 Day Follow Up: Combination Therapy
Time Frame: At 60 days safety Follow Up (Approximately 884 [824+60] days)
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.
Number of Participants With ECOG Performance Status at 90 Day Follow Up: Combination Therapy
Time Frame: At 90 days safety follow up (Approximately 914 [824+90] days)
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.
Number of Participants With Dose Limiting Toxicities (DLTs)
Time Frame: From C1D1 up to C1D28
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.
Objective Response Rate (iORR) Per Immune Response Evaluation Criteria in Solid Tumors (iRECIST) by Investigator Assessment
Time Frame: From first dose up to 954 days
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.
Secondary Outcomes
- Objective Response Rate (ORR) Per RECIST v1.1 by Investigator Assessment(From first dose up to 954 days)
- Disease Control Rate Per iRECIST (iDCR) by Investigator Assessment(From first dose up to 954 days)
- Disease Control Rate (DCR) Per RECIST v1.1 by Investigator Assessment(From first dose up to 954 days)
- Progression-Free Survival Per iRECIST (iPFS) Using Investigator Assessment(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(From first dose until death from any cause or radiographic disease progression (up to 954 days))
- Overall Survival (OS)(From first dose until death from any cause (up to 954 days))
- Duration of Response Per iRECIST (iDOR)(From first response up to the date of radiographical progression (up to 954 days))
- Duration of Response (DOR) Per RECIST v1.1(From first response up to the date of radiographical progression (up to 954 days))