Study of ASP7517 Alone and With Pembrolizumab in Participants With Advanced Solid Tumors Expressing WT1 Antigen

Phase 1

Completed

Conditions: Advanced Malignancies
Advanced Cancer

Interventions: Drug: ASP7517
Drug: Pembrolizumab

Registration Number: NCT04837196

Lead Sponsor: Astellas Pharma Global Development, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

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 ≤ 2.
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
- WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 6 months after the final IP administration.
Female participant must agree not to breastfeed starting at screening and throughout the IP and for 180 days after the final IP administration.
Female participant must not donate ova starting at screening and throughout the IP and for 180 days after the final IP administration.
A male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for at least 180 days after the final IP administration.
Male participant must not donate sperm during the treatment period and for 180 days after the final IP administration.
Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 180 days after the final IP administration.
Participant agrees not to participate in another interventional study while receiving IP.

Additional Inclusion Criteria for Participants in the Expansion Cohorts:

Participant meets one of the following:
- Participant has the tumor type for which a confirmed response was observed in a monotherapy dose escalation cohort (monotherapy arm only) cohort; OR
- For tumor specific expansion cohorts of ASP7517 or ASP7517 with pembrolizumab, participant has the applicable tumor type; CPI refractory metastatic melanoma (monotherapy and combination arms), CPI naïve melanoma (combination arm only), ovarian cancer, colorectal cancer (CRC).
Participant has at least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
Participant consents to provide a tumor specimen in a tissue block or unstained serial slides obtained within 56 days prior to first dose of IP. If a recent tissue sample cannot be provided due to medical or safety concerns, enrollment into the study must be discussed with the medical monitor.
Participant consents to undergoing a tumor biopsy (core tissue biopsy or excision) during the treatment period as indicated in the schedule of assessments if predose biopsy is available and if medically feasible.

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 1. 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.
Participant has received a live vaccine against infectious diseases within 28 days prior to initiation of IP.
Participant has a history of drug-induced pneumonitis (interstitial lung disease), a history of (non-infectious) pneumonitis that required steroids, radiation pneumonitis or currently has pneumonitis.
Participant has an infection requiring systemic therapy within 14 days prior to IP.
Participant has received a prior allogeneic bone marrow or solid organ transplant.
Participant is expected to require another form of antineoplastic therapy while on IP.
Participant has had a myocardial infarction or unstable angina within 6 months prior to the start of IP or currently has an uncontrolled illness including, but not limited to symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Participant has a clinically significant abnormal electrocardiogram at screening.
Participant has symptomatic cardiovascular disease within the preceding 12 months unless cardiology consultation and clearance has been obtained for study participation, including but not limited to the following: significant coronary artery disease (e.g., requiring angioplasty or stenting), acute myocardial infarction or unstable angina pectoris < 3 months prior screening, uncontrolled hypertension, clinically significant arrhythmia or congestive heart failure (New York Heart Association grade ≥ 3).
Any condition that makes the participant unsuitable for study participation.
Participant has had a major surgical procedure and has not completely recovered within 28 days prior to the start of IP.
Participant has a prior malignancy active (i.e., requiring treatment of intervention) within the previous 2 years prior to the screening visit, except for locally curable malignancies that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast. Participants with organ confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy.
Participant has International Normalized Ratio (INR) > 1.5 x Upper Limits of Normal (ULN) and/or activated partial thromboplastin time (aPTT) > 1.5 x institutional normal limits.

Additional Exclusion Criteria for Participants in Combination Expansion Cohorts:

Participants with metastatic CRC with documented microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient who have received prior treatment with PD-1 or programmed death-ligand (PD-L1) inhibitors such as nivolumab or pembrolizumab.
CPI naïve metastatic melanoma participants who have received PD-1 or PD-L1 inhibitors, such as nivolumab or pembrolizumab.
Participants with metastatic ovarian cancer with documented MSI-H or MMR deficient who have received PD-1or PD-L1 inhibitors, such as nivolumab or pembrolizumab.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1: Monotherapy Dose Escalation (ASP7517 1x10^7 cells/dose)	ASP7517	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.
Phase 1: Monotherapy dose escalation (ASP7517 1x10^8 cells/dose)	ASP7517	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
Phase1:Combination Therapy dose Escalation (ASP7517 1x10^7 cells/dose) and Pembrolizumab	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.
Phase 2:Monotherapy dose expansion (ASP7517 1x10^8 cells/dose)	ASP7517	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.
Phase 1:Combination Therapy dose Escalation (ASP7517 1x10^8cells/dose) and Pembrolizumab	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.
Phase1:Combination Therapy dose Escalation (ASP7517 1x10^7 cells/dose) and Pembrolizumab	ASP7517	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.
Phase 1:Combination Therapy dose Escalation (ASP7517 1x10^8cells/dose) and Pembrolizumab	ASP7517	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment Emergent Adverse Events and Serious Adverse Events: Monotherapy	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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	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.	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	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	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	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	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)	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	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 Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) Per RECIST v1.1 by Investigator Assessment	From first dose up to 954 days	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.
Disease Control Rate Per iRECIST (iDCR) by Investigator Assessment	From first dose up to 954 days	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.
Disease Control Rate (DCR) Per RECIST v1.1 by Investigator Assessment	From first dose up to 954 days	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.
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)	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.
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)	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.
Overall Survival (OS)	From first dose until death from any cause (up to 954 days)	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.
Duration of Response Per iRECIST (iDOR)	From first response up to the date of radiographical progression (up to 954 days)	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.
Duration of Response (DOR) Per RECIST v1.1	From first response up to the date of radiographical progression (up to 954 days)	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.

Trial Locations

Locations (4): Emory University
🇺🇸
Atlanta, Georgia, United States
University of Chicago
🇺🇸
Chicago, Illinois, United States
University of Iowa Hospitals
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Iowa City, Iowa, United States
UPCI Hillman Cancer Center
🇺🇸
Pittsburgh, Pennsylvania, United States
Emory University
🇺🇸Atlanta, Georgia, United States