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

Advanced Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03260322
• Other study ID #: 8374-CL-0101
• Secondary ID: 2018-001146-34KE
• Status: Completed
• Phase: Phase 1
• Start date: September 8, 2017
• Est. completion date: May 10, 2022

Study information

• Verified date: April 2023
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 169
• Est. completion date: May 10, 2022
• Est. primary completion date: May 10, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subject has locally-advanced (unresectable) or metastatic solid tumor malignancy (no limit to the number of prior treatment regimens) that is confirmed by available pathology records or current biopsy as well as:

• Subject in the escalation cohort has received all standard therapies (unless the therapy is contraindicated or intolerable) felt to provide clinical benefit for the subject's specific tumor type. OR

• Subject in an expansion cohort has received at least one standard therapy for the subject's specific tumor type.

• For Korea, Italy and Portugal only: Subject has locally-advanced (unresectable) or metastatic solid tumor malignancy (no limit to the number of prior treatment regimens) that is confirmed by available pathology records or current biopsy and has received all standard therapies (unless the therapy is contraindicated or intolerable) felt to provide clinical benefit for the subject's specific tumor type.

• Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2.

• Subject's last dose of prior antineoplastic therapy, including any immunotherapy, was 21 days or 5 half-lives, whichever is shorter, prior to initiation of study drug administration. A subject with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation-positive NSCLC is allowed to remain on EGFR tyrosine kinase inhibitor (TKI) therapy or ALK inhibitor until 4 days prior to the start of study drug administration.

• For Korea only: Subject's last dose of prior antineoplastic therapy, including any immunotherapy, was at least 21 days or 5 half-lives, whichever is shorter, prior to initiation of study drug administration. For drugs with a half-life greater than or equal to 21 days, the investigator should consider if this washout is sufficient. A subject with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is allowed to remain on EGFR tyrosine kinase inhibitor (TKI) therapy until 7 days prior to the start of study drug administration.

• Subject has completed any radiotherapy (including stereotactic radiosurgery) at least 2 weeks prior to study drug administration.

• Subject's adverse events (excluding alopecia) from prior therapy have improved to grade 1 or baseline within 14 days prior to start of study treatment.

• Subject with metastatic castration resistant prostate cancer (mCRPC) (positive bone scan and/or soft tissue disease documented by computed tomography (CT) / magnetic resonance imaging (MRI)) meets both of the following:

• Subject has serum testosterone = 50 ng/dL at screening.

• Subject has had an orchiectomy or plans to continue androgen deprivation therapy (ADT) for the duration of study treatment.

• Subject has adequate organ function prior to start of study treatment as indicated by the following laboratory values. If a subject has received a recent blood transfusion, the laboratory tests must be obtained = 4 weeks after any blood transfusion.

• Female subject 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)

• WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 6 months after the final study drug administration.

• Female subject must agree not to breastfeed starting at screening and throughout the study treatment, and for 6 months after the final study drug administration.

• Female subject must not donate ova starting at screening and throughout the study treatment, and for 6 months after the final study drug administration.

• A male subject with female partner(s) of childbearing potential must agree to use contraception as detailed during the treatment period and for at least 6 months after the final study drug administration.

• Male subject must not donate sperm starting at screening and throughout the study treatment, and for 6 months after the final study drug administration.

• Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study treatment and for 6 months after the final study drug administration.

• Subject agrees not to participate in another interventional study while receiving study drug (subjects who are currently in the follow-up period of an interventional clinical trial are allowed).

Additional Inclusion Criteria for Subjects in the Expansion Cohorts:

• Subject meets one of the following:

• Subject has the tumor type for which a confirmed response was observed in a monotherapy or combination therapy dose escalation cohort; or

• For an expansion cohort opened due to achieving predicted efficacious exposure, subject has squamous cell carcinoma of the head and neck (SCCHN); or

• For tumor specific expansion cohorts of ASP8374 with pembrolizumab, subject has the applicable tumor type (e.g., non-small cell lung cancer (NSCLC), bladder cancer, gastric cancer, metastatic castration resistant prostate cancer (MCRPC) or colorectal cancer (CRC)).

• Subject has at least 1 measureable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Subjects with mCRPC who do not have measurable lesions must have at least one of the following:

• Progression with 2 or more new bone lesions; or

• Prostate-specific antigen (PSA) progression (defined as a minimum of three rising PSA levels with an interval of = 1 week between each determination) within 6 weeks prior to study drug administration and a PSA value at the screening visit = 2 ng/mL.

• Subject consents to provide an available tumor specimen in a tissue block or unstained serial slides obtained within 56 days prior to first dose of study treatment, or subject is an appropriate candidate for tumor biopsy and is amenable to undergoing a tumor biopsy (core needle biopsy or excision) during the screening period.This does not apply to subjects with mCRPC without measurable disease.

• Subject in any expansion cohort, is an appropriate candidate for tumor biopsy and consents to undergoing a tumor biopsy (core needle biopsy or excision) during the treatment period as indicated in the Schedule of Assessments.

Exclusion:

• Subject weighs < 45 kg at screening.

• Subject has received investigational therapy (other than an investigational epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in a subject with EGFR activating mutations or ALK inhibitor in a subject with an ALK mutation) within 21 days or 5 half-lives, whichever is shorter, prior to start of study drug.

• Subject requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to study drug administration. Subjects 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.

• Subject has symptomatic central nervous system (CNS) metastases or subject has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Subjects with previously treated CNS metastases are eligible, if subject is clinically stable and have no evidence of CNS progression by imaging for at least 4 weeks prior to start of study treatment 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.

• Subject has an active autoimmune disease. Subjects 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.

• Subject was discontinued from prior immunomodulatory therapy due to a grade = 3 toxicity that was mechanistically related (e.g., immune related) to the agent.

• Subject has known history of serious hypersensitivity reaction to a known ingredient of ASP8374 or pembrolizumab or severe hypersensitivity reaction to treatment with another monoclonal antibody.

• Subject has a known history of Human Immunodeficiency Virus.

• Subject with positive for Hepatitis B virus (HBV) antibodies and surface antigen (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 subjects with negative Hepatitis C antibody testing.

• Subject has received a live vaccine against infectious diseases within 28 days prior to initiation of study treatment.

• Subject 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.

• Subject has an infection requiring systemic therapy within 14 days prior to study drug treatment.

• Subject has received a prior allogeneic bone marrow or solid organ transplant.

• Subject is expected to require another form of antineoplastic therapy while on study treatment.

• Subject has had a myocardial infarction or unstable angina within 6 months prior to the start of study treatment 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.

• Any condition that makes the subject unsuitable for study participation.

• Subject has had a major surgical procedure and has not completely recovered within 28 days prior to the start of study treatment.

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Neoplasms

Intervention

Drug:
• ASP8374
intravenous
• Pembrolizumab
intravenous

Locations

Country	Name	City	State
Canada	Site CA15004	Edmonton	Alberta
Canada	Site CA15002	Montreal	Quebec
Canada	Site CA15001	Toronto	Ontario
Canada	Site CA15003	Toronto	Ontario
Italy	Site IT39004	Ancona
Italy	Site IT39002	Milano
Italy	Site IT39003	Milano
Italy	Site IT39008	Milano
Italy	Site IT39009	Milano
Italy	Site IT39010	Modena
Italy	Site IT39005	Monza
Italy	Site IT39011	Negrar
Japan	Site JP81001	Chuo-ku
Korea, Republic of	Site KR82004	Goyang-si	Gyeonggi-do
Korea, Republic of	Site KR82005	Seongnam-Si	Gyeonggi-do
Korea, Republic of	Site KR82001	Seoul
Korea, Republic of	SIte KR82002	Seoul
Korea, Republic of	Site KR82006	Seoul
Portugal	Site PT35101	Lisboa
Portugal	Site PT35106	Porto
Spain	Site ES34002	Barcelona
Spain	Site ES34003	Barcelona
Spain	Site ES34009	Barcelona
Spain	Site ES34010	Barcelona
Spain	Site ES34001	Madrid
Spain	Site ES34006	Madrid
Spain	Site ES34013	Madrid
Spain	Site ES34014	Valencia
Taiwan	Site TW88602	Taichung
Taiwan	Site TW88601	Tainan
Taiwan	Site TW88603	Taipei City
United Kingdom	Site GB44003	London
United Kingdom	Site GB44006	London
United Kingdom	Site GB44004	Newcastle upon Tyne
United Kingdom	Site GB44005	Sutton Surry
United States	University Hospital of Cleveland	Cleveland	Ohio
United States	Mary Crowley Research Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	University of Kansas Cancer Center	Fairway	Kansas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of California Los Angeles	Los Angeles	California
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania
United States	University of California, Davis	Sacramento	California
United States	Huntsman Cancer Institute	Salt Lake City	Utah
United States	University of California, San Francisco	San Francisco	California
United States	Honor Health Research Institute	Scottsdale	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Canada,  Italy,  Japan,  Korea, Republic of,  Portugal,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants with Dose Limiting Toxicities (DLTs)	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	Up to 21 Days (For ASP8374 0.5 mg: Up to 7 days)
Primary	Number of Participants with Treatment Emergent Adverse Events (TEAEs)	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.	From first dose up to 90 days after last dose (maximum duration: 938 days)
Primary	Number of Participants with Infusion Related Reactions	Number of participants with infusion related reactions are reported.	From first dose up to 90 days after last dose (maximum duration: 938 days)
Primary	Number of Participants with Immune- Related Treatment Emergent Adverse Events (IrTEAEs)	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).	From first dose up to 90 days after last dose (maximum duration: 938 days)
Primary	Number of Participants with Eastern Cooperative Oncology Group (ECOG) Performance status	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; Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature; Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours; Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.	End of treatment ASP8374 (Up to 427 days)
Primary	Pharmakokinetics (PK) of ASP8374 (Cycle 1): Area Under the Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) (Monotherapy Dose Escalation Cohort)	Area under the concentration-time curve from the time zero to the last measurable concentration was derived from the plasma samples.	Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	Pharmakokinetics (PK) of ASP8374 (Cycle 7): Area Under the Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) (Monotherapy Dose Escalation Cohort)	Area under the concentration-time curve from the time zero to the last measurable concentration was derived from the plasma samples.	Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 1): Area Under the Concentration-Time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) (Monotherapy Dose Escalation Cohort)	Area under the concentration-time curve from the time of dosing extrapolated to time infinity was derived from the plasma samples.	Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 1): Percentage of AUCinf due to extrapolation from the last measurable concentration to time infinity [AUCinf(%extrap)] (Monotherapy Dose Escalation Cohort)	Percentage of AUCinf due to extrapolation from the last measurable concentration to time infinity was derived from the plasma samples.	Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 7): Area Under the Concentration-Time Curve From the Time of Dosing to the Start of the Next Dosing Interval at Multiple Dose Conditions (AUCtau) (Monotherapy Dose Escalation Cohort)	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.	Cycle 7: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle= 21 days)
Primary	PK of ASP8374 (Cycle 1): Maximum Plasma concentration (Cmax) (Monotherapy Dose Escalation Cohort)	Maximum plasma concentration of ASP8374 was derived from the plasma samples.	Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 7): Cmax (Monotherapy Dose Escalation Cohort)	Maximum plasma concentration of ASP8374 was derived from the plasma samples.	Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 7): Trough concentration (Ctrough) (Monotherapy Dose Escalation Cohort)	Trough Concentration was derived from the PK samples.	Cycle 7: predose
Primary	PK of ASP8374 (Cycle 1): Time of Maximum Concentration (Tmax) (Monotherapy Dose Escalation Cohort)	Time of maximum plasma concentration of ASP8374 was derived from the plasma samples.	Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 7): Tmax (Monotherapy Dose Escalation Cohort)	Time of maximum plasma concentration of ASP8374 was derived from the plasma samples.	Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 1): Terminal Elimination Half-life (T1/2) of ASP8374 (Monotherapy Dose Escalation Cohort)	Terminal half life of ASP8374 was derived from the plasma samples.	Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 1): Time of Last Measurable Concentration (tlast) (Monotherapy Dose Escalation Cohort)	Time of last measurable concentration was derived from the plasma samples.	Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 7): tlast (Monotherapy Dose Escalation Cohort)	Time of last measurable concentration was derived from the plasma samples.	Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 1): Total Systemic Observed Clearance After Intravenous Dosing (CLobs) of ASP8374 (Monotherapy Dose Escalation Cohort)	Total systemic observed clearance after intravenous dosing was derived from the plasma samples	Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hrt, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 1): Volume of Distribution During the Terminal Elimination Phase (Vz) after Intravenous Dosing (Monotherapy Dose Escalation Cohort)	Volume of distribution after intravenous dosing during the terminal elimination phase was derived from plasma samples.	Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
Primary	PK of ASP8374 (Cycle 7): Apparent Volume of Distribution at Steady State (Vss) after Intravenous Dosing of ASP8374 (Monotherapy Dose Escalation Cohort)	Volume of distribution at steady state after intravenous dosing was derived from plasma samples.	Cycle 7: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle= 21 days)
Secondary	Best Overall Response (BOR) as per RECIST as per Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)	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.	From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	BOR as per immune Response Evaluation Criteria in Solid Tumors (iRECIST)	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.	From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	Objective Response Rate (ORR) as per RECIST v1.1	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.	From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	ORR as per iRECIST	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.	From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	Duration of Response as per RECIST v1.1	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.	From the date of the first response CR/PR to the date of radiographical progression or date of censoring (maximum 938 days)
Secondary	DOR as per iRECIST	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.	From the date of the first response iCR/iPR to the date of radiographical progression or date of censoring (maximum 938 days)
Secondary	Persistence of Response After Discontinuation as per RECIST v1.1	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.	From date of treatment discontinuation to the date of radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	Persistence of Response After Discontinuation as per iRECIST	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.	From date of treatment discontinuation to the date of radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	Disease Control Rate (DCR) as per RECIST v1.1	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.	From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	Disease Control Rate (DCR) as per iRECIST	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.	From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
Secondary	Time to Response as per RECIST v1.1	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.	From first dose date until the first response CR/PR (maximum duration: 938 days)
Secondary	Time to Response as per iRECIST	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.	From first dose date until the first response iCR/iPR (maximum duration: 938 days)

External Links

•   Link to plain language summary of the study on the Trial Results Summaries website
•   Link to results and other applicable study documents on the Astellas Clinical Trials website