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A study of mirabegron in young children with neurogenic detrusor overactivity

Mirabegron in Young Children Study | Astellas Clinical Trials

A study to learn how [14C]ASP0367 is processed by the body in healthy men

14C ASP0367 In Males Study | Astellas Clinical Trials

A Study of Gilteritinib (ASP2215) Combined with Chemotherapy in Children, Adolescents and Young Adults with FMS-like Tyrosine Kinase 3 (FLT3)/Internal Tandem Duplication (ITD) Positive Relapsed or Refractory Acute Myeloid Leukemia (AML)

Gilteritnib and Chemotherapy Study | Astellas Clinical Trials

A study to find the best dose of ASP5354 to show lymph nodes in people with breast cancer or melanoma during surgery

ASP5354 to Show Lymph Nodes Study | Astellas Clinical Trials

A Study of Intravesical Enfortumab Vedotin For Treatment of Patients With Non-muscle Invasive Bladder Cancer (NMIBC)

Intravesical Enfortumab Vedotin for Bladder Cancer Study | Astellas Clinical Trials

A study of the safety and tolerability of ASP7317 in adults who are losing their clear, sharp central vision due to geographic atrophy secondary to dry age-related macular degeneration

ASP7317 for Geographic Atrophy Study | Astellas Clinical Trials

A Study to Assess the Antitumor Activity, Safety, Pharmacokinetics and Biomarkers of Zolbetuximab (IMAB362) in Participants with Claudin (CLDN) 18.2 Positive, Metastatic or Advanced Unresectable Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma

Zolbetuximab Study | Astellas Clinical Trials

A Study of an Intratumoral Oncolytic Virus in Patients with Advanced Metastatic Solid Tumors

Intratumoral Oncolytic Virus Study | Astellas Clinical Trials

A Study to Assess ASP0598 Otic Solution Following Topical Application in the Ear in Subjects with Chronic Tympanic Membrane Perforation (CTMP)

ASP058 Otic Solution Study | Astellas Clinical Trials

A study to evaluate ASP0367 in participants with primary mitochondrial myopathy

ASP0367 Study for Primary Mitochondrial Myopathy | Astellas Clinical Trials

A study of ASP2138 in adults with stomach cancer or pancreatic cancer

ASP2138 Study for Stomach or Pancreatic Cancer | Astellas Clinical Trials

A study about how ASP5354 affects the body in healthy adults and in adults whose kidneys do not work well

ASP5354 for Healthy Adults and Adults with Poor Kidneys | Astellas Clinical Trials

A Study for Subjects With Prostate Cancer Who Previously Participated in an Enzalutamide Clinical Study

Prostate Cancer Study for Previous Participation in Enzalutamide  | Astellas Clinical Trials

A Study to Assess the Efficacy and Safety of IMAB362 in Combination with Nab-Paclitaxel and Gemcitabine (Nab-P + GEM) as First Line Treatment in Subjects with Claudin 18.2 (CLDN18.2) Positive, Metastatic Pancreatic Adenocarcinoma

IMAB362 with Nab P and GEM Study for Pancreatic Cancer  | Astellas Clinical Trials

A study of gilteritinib, venetoclax and azacitidine as a combined treatment for people newly diagnosed with acute myeloid leukemia

Gilteritinib Venetoclax and Azacitidine Study for Acute Myeloid Leukemia | Astellas Clinical Trials

A Study Investigating the Safety, Tolerability and Efficacy of ASP7517 in Subjects with Relapsed/Refractory Acute Myeloid Leukemia (AML) and Relapsed/Refractory Higher Risk Myelodysplastic Syndrome (MDS)

ASP7517 for Acute Myeloid Leukimia | Astellas Clinical Trials

A study to evaluate ASP0367 in participants with reduced maximum oxygen uptake due to poor systemic oxygen extraction

ASP0367 for Reduced Maxiumum Oxygen Uptake Study | Astellas Clinical Trials

A study of ASP3082 in adults with previously treated solid tumors

ASP3082 for Solid Tumors Study | Astellas Clinical Trials

A Study of ASP1570 in adults with locally advanced or metastatic solid tumors

ASP1570 for Advanced or Metastatic Tumors Study | Astellas Clinical Trials

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

ASP7517 with Pembrolizumab Study | Astellas Clinical Trials

A Safety Surveillance Study in Subjects with Macular Degenerative Disease Treated with Human Embryonic Stem Cell-derived Retinal Pigment Epithelial Cell Therapy

Macular Degenerative Disease Study | Astellas Clinical Trials

A study to evaluate mirabegron in pediatric participants from 5 to less than 18 years of age with overactive bladder (OAB)

Mirabegron Study in Children with OAB Study | Astellas Clinical Trials

Study of ASP0739 Alone and with Pembrolizumab in Advanced Solid Tumors with NY-ESO-1 Expression Participants

ASP0739 with Pembrolizumab Study For Solid Tumors| Astellas Clinical Trials

A study of ASP0367 in people with kidneys that do not work well and in healthy people

ASP0367 Study for Adults with Poor Kidneys | Astellas Clinical Trials

Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer

Enfortumab Vedotin and Pembrolizumab vs Chemotherapy Study | Astellas Clinical Trials

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Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

Participants received ASP8374 0.5 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 2 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 7 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 20 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 70 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 200 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 700 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 1400 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participant received ASP8374 1400 mg intravenously, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met during treatment period. Qualifying participants entered re-treatment period and received treatment for an additional 16 cycles or until a discontinuation criteria was met.

Participants received ASP8374 20 mg intravenously in combination with pembrolizumab 200 mg adminstered as a 30 minutes intravenous infusion, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met. Qualifying participants received combination treatment for an additional 16 cycles or until a discontinuation criteria was met. Participants who completed 16 cycles of combination treatment who entered the follow-up period with PR or SD were allowed to continue on pembrolizumab alone for a period of up to an additional 19 cycles. If the participant was eligible for the re-treatment period during follow up, administration of pembrolizumab alone was discontinued and combination therapy with ASP8374 was resumed per the protocol.

Participants received ASP8374 70 mg intravenously in combination with pembrolizumab 200 mg adminstered as a 30 minutes intravenous infusion, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met. Qualifying participants received combination treatment for an additional 16 cycles or until a discontinuation criteria was met. Participants who completed 16 cycles of combination treatment who entered the follow-up period with PR or SD were allowed to continue on pembrolizumab alone for a period of up to an additional 19 cycles. If the participant was eligible for the re-treatment period during follow up, administration of pembrolizumab alone was discontinued and combination therapy with ASP8374 was resumed per the protocol.

Participants received ASP8374 200 mg intravenously in combination with pembrolizumab 200 mg adminstered as a 30 minutes intravenous infusion, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met. Qualifying participants received combination treatment for an additional 16 cycles or until a discontinuation criteria was met. Participants who completed 16 cycles of combination treatment who entered the follow-up period with PR or SD were allowed to continue on pembrolizumab alone for a period of up to an additional 19 cycles. If the participant was eligible for the re-treatment period during follow up, administration of pembrolizumab alone was discontinued and combination therapy with ASP8374 was resumed per the protocol.

Participants received ASP8374 700 mg intravenously in combination with pembrolizumab 200 mg adminstered as a 30 minutes intravenous infusion, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met. Qualifying participants received combination treatment for an additional 16 cycles or until a discontinuation criteria was met. Participants who completed 16 cycles of combination treatment who entered the follow-up period with PR or SD were allowed to continue on pembrolizumab alone for a period of up to an additional 19 cycles. If the participant was eligible for the re-treatment period during follow up, administration of pembrolizumab alone was discontinued and combination therapy with ASP8374 was resumed per the protocol.

Participants received ASP8374 1400 mg intravenously in combination with pembrolizumab 200 mg adminstered as a 30 minutes intravenous infusion, on day 1 of every 3 week cycle for a period of up to 16 cycles or until a discontinuation criterion was met. Qualifying participants received combination treatment for an additional 16 cycles or until a discontinuation criteria was met. Participants who completed 16 cycles of combination treatment who entered the follow-up period with PR or SD were allowed to continue on pembrolizumab alone for a period of up to an additional 19 cycles. If the participant was eligible for the re-treatment period during follow up, administration of pembrolizumab alone was discontinued and combination therapy with ASP8374 was resumed per the protocol.

Redacted CSR Synopsis English

Plain Language Summary English

The primary purpose of this study is to evaluate the tolerability and safety profile of ASP8374 when administered as a single agent and in combination with pembrolizumab in participants with locally advanced (unresectable) or metastatic solid tumor malignancies. Also primary purpose is to characterize the pharmacokinetic profile of ASP8374 when administered as a single agent and in combination with pembrolizumab. Last primary purpose of this study is to determine the recommended Phase 2 dose (RP2D) of ASP8374 when administered as a single agent and in combination with pembrolizumab.

The secondary  purpose of this study is to evaluate the anti-tumor effect (objective response rate [ORR], duration of response [DOR], persistence of response after discontinuation, and disease control rate [DCR]) of ASP8374 when administered as a single agent and in combination with pembrolizumab.


NTP: Neutropenia

NHAE:Non-haematological AE

GBS: Guillain-Barré syndrome""

IRR: Infusion-related reaction

AST: Aspartate aminotransferase 

ALT: Alanine aminotransferase

MS/MG: Myasthenia Syndrome/Myasthenia Gravis

TRT: Treatment-related Toxicity

TCP: Thrombocytopenia

A multiple-dose study of ASP8374, an Immune Checkpoint Inhibitor, as a Single Agent and in Combination with Pembrolizumab in Subjects with Advanced Solid Tumors

This is a multi-center, multiple-dose, dose-escalation and expansion study of ASP8374 as a single agent and in combination with pembrolizumab. After discontinuation of study drug treatment (initial treatment and re-treatment), all participants will complete an end of treatment visit along with 30-day and 90-day safety follow-up visits from the last dose of ASP8374. Participants will be enrolled in respectively escalation cohorts or expansion cohorts. The 90-day safety follow-up visit is optional for participants who discontinue due to progressive disease or initiate new anticancer treatment after the last dose of study drug.

Escalation cohorts: Approximately 60 participants may be enrolled in the escalation cohorts (approximately 30 participants for monotherapy and 30 participants for combination therapy).

Expansion cohorts: The total number of subjects in the expansion cohorts will depend on the observed pharmacokinetic and antitumor activity. It is estimated that approximately 240 participants may be enrolled in the monotherapy and combination therapy expansion cohorts.

As the number of participants in the escalation cohorts and the expansion cohorts will depend on the observed Dose Limiting Toxicity (DLT), pharmacokinetics and antitumor activity, approximately 300 participants are expected to be enrolled.

CN CDE Number

EudraCT Number

jRCT Number

NCT ID

Patient Level Data

Product ST Name

Therapeutic Area

Link to results and other applicable study documents on the Astellas Clinical Trials website

Link to plain language summary of the study on the Trial Results Summaries website

Site IT39013

Honor Health Research Institute

Site IT39009

Site GB44006

Site CA15004

Mary Crowley Research Center

Fox Chase Cancer Center

Site KR82001

University of Pittsburgh Cancer Institute

Site GB44001

Site TW88603

Site IT39010

Site TW88602

Site IT39007

Site CA15002

Site IT39008

Huntsman Cancer Institute

Site PT35106

Site ES34009

Henry Ford Health System

Site ES34001

University of California, San Francisco

Site GB44004

Site IT39012

Site GB44005

Icahn School of Medicine at Mount Sinai

Site IT39004

University of Kansas Cancer Center

Virginia Cancer Specialists

Site GB44003

Mount Sinai Comprehensive Cancer Center

Site CA15001

Site KR82005

SIte KR82002

Site KR82004

Site ES34006

Cedars-Sinai Medical Center

Medical College of Wisconsin

University Hospital of Cleveland

Site IT39011

Site ES34002

Columbia University Medical Center

Site KR82006

Site ES34010

Site JP81001

Site ES34013

University of Iowa Hospitals and Clinics

University of Arizona

University of California, Davis

Site ES34003

Site ES34014

Site IT39003

Site PT35101

Sarah Cannon Research Institute

Karmanos Cancer Institute

Site IT39005

Site CA15003

University of California Los Angeles

University of North Carolina

Site TW88601

Site IT39002

A Phase 1b Study of ASP8374, an Immune Checkpoint Inhibitor, as a Single Agent and in Combination with Pembrolizumab in Subjects with Advanced Solid Tumors

DLT was defined as any of the following AE that cannot clearly attribute to a cause other than study drug:
Grade (Gr) 4 NTP or Gr ≥ 3 febrile NTP
Gr 4 TCP; or Gr 3 TCP accompanied by bleeding that required any transfusion
Gr 4 anemia or Gr 3 anemia requiring transfusion
Gr ≥ 3 NHAE
Gr ≥ 2 pneumonitis
Gr ≥ 2 encephalopathy, meningitis, or motor or sensory neuropathy
AST or ALT > 5x upper limit of normal (ULN; Gr ≥ 3) without liver metastases
AST or ALT > 8 x ULN in participants with liver metastases
AST or ALT > 3 x ULN & total bilirubin > 2 x ULN (in participant with Gilbert syndrome: AST or ALT > 3x ULN & direct bilirubin > 1.5 x ULN)
Total bilirubin > 3x ULN (Gr ≥ 3)
GBS or MS/MG
IRR that required the infusion to be discontinued
Prolonged delay (> 2 weeks) in initiating cycle 2 due to TRT
Any TRT that caused the participant to discontinue treatment during cycle 1
Missing >25% of ASP8374 or pembrolizumab doses as a result of drug-related AE(s) during the 1st cycle
Gr 5 toxicity

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 medicinal product. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An AE is considered “serious” if, it results in any of the following outcomes:
results in death; is life-threatening; results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly, or birth defect; requires inpatient hospitalization; or leads to prolongation of hospitalization; other medically important events. TEAE was defined as an AE observed after starting administration of the study drug.

Number of participants with infusion related reactions are reported.

AEs associated with pembrolizumab exposure may represent an immune-related response. Immune-related AEs observed with currently approved check point inhibitor CPIs include rash, oral mucositis, dry mouth, colitis/diarrhea, hepatitis, pneumonitis, and endocrinopathies (hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency and Type 1 diabetes mellitus). Other less frequent irAEs associated with CPIs include: nephritis; pancreatitis; myositis; arthritis; neurologic toxicities (Guillain-Barre syndrome, myasthenia gravis, posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis, and autoimmune encephalitis), cardiotoxicity (myocarditis and conduction abnormalities); hematologic toxicity (red cell aplasia, neutropenia, thrombo-cytopenia, acquired hemophilia A, and cryoglobulinemia); and eye inflammation (episcleritis, conjunctivitis, uveitis or orbital inflammation).

The ECOG was used to assess performance status. Number of participants in each of the ECOG PS grade were reported.
0 = Fully active, able to carry on all predisease performance without restriction;
1=Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature; 
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.

Area under the concentration-time curve from the time zero to the last measurable concentration was derived from the plasma samples.

Area under the concentration-time curve from the time of dosing extrapolated to time infinity was derived from the plasma samples.

Percentage of AUCinf due to extrapolation from the last measurable concentration to time infinity was derived from the plasma samples.

AUCtau: Area under the concentration-time curve from the time of dosing to the start of the next dosing interval was derived from plasma samples.

Maximum plasma concentration of ASP8374 was derived from the plasma samples.

Trough Concentration was derived from the PK samples.

Time of maximum plasma concentration of ASP8374 was derived from the plasma samples.

Terminal half life of ASP8374 was derived from the plasma samples.

Time of last measurable concentration was derived from the plasma samples.

Total systemic observed clearance after intravenous dosing was derived from the plasma samples

Volume of distribution after intravenous dosing during the terminal elimination phase was derived from plasma samples.

Volume of distribution at steady state after intravenous dosing was derived from plasma samples.

The BOR rate was defined as the percentage of participants whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1 criteria. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

The BOR rate was defined as the percentage of participants whose best response was immune complete response (iCR) or immune partial response (iPR) as defined by RECIST v1.1 criteria.  immune complete response (iCR) or immune partial response (iPR). iCR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. iPR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

ORR as per RECIST v1.1 was defined as the percentage of participants for each dose level whose best overall response was rated as confirmed CR or PR. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

ORR as per iRECIST was defined as the percentage of participants for each dose level whose best overall response was rated as confirmed iCR or iPR. iCR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. iPR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

DOR as per RECIST v1.1 was 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. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

DOR as per iRECIST was defined as the time from the date of the first response iCR/iPR (whichever is first recorded) to the date of radiographical progression or date of censoring. iCR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. iPR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

Persistence of response as per RECIST v1.1 was defined as the time from the date of treatment discontinuation to the date of radiographical progression or date of censoring. Persistence of response was derived for participants who at the time of treatment discontinuation had a confirmed response of CR or PR based on RECIST 1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

Persistence of response as per iRECIST was defined as the time from the date of treatment discontinuation to the date of radiographical progression or date of censoring. Persistence of response was derived for participants who at the time of treatment discontinuation had a confirmed response of iCR or iPR. iCR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. iPR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

DCR as per RECIST v1.1 was defined as the percentage of participants for each dose level whose best overall response is rated as confirmed CR, PR or Stable Disease (SD). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters.

DCR as per iRECIST was defined as the perccentage of participants for each dose level whose best overall response is rated as confirmed iCR, iPR or immune Stable Disease (iSD). iCR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. iPR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. iSD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters.

Time to response was defined as the time from first dose date until the first response CR/PR (whichever is first recorded). CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. Time to response was calculated for objective responders only. Confirmation response is required.

Time to response was defined as the time from first dose date until the first response iCR/iPR (whichever is first recorded). iCR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. iPR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.Time to response was calculated for objective responders only. Confirmation response is required.