Antineoplastic Agents

All Drugs and Chemicals

Immune Checkpoint Inhibitors

Pembrolizumab

Antineoplastic Agents, Immunological

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.

ASP8374

Vice President Medical Sciences - Oncology

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

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.

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

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

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.

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.

Merck Sharp & Dohme LLC

Astellas Pharma Global Development, Inc.

Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Digestive System Diseases

Gland and Hormone Related Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Carcinoma

Breast Neoplasms

Pancreatic Neoplasms

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Pancreatic Cancer

Ovarian Cancer

Ovarian Epithelial Cancer

Nivolumab

Participants have received ASP1948 70 mg intravenously, on day 1 of every 2-week (Q2W) cycle for a period of up to 24 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 200 mg intravenously, on day 1 of Q2W cycle for a period of up to 24 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 700 mg intravenously, on day 1 of every 2 week cycle for a period of up to 24 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 1200 mg intravenously, on day 1 of every 2 week cycle for a period of up to 24 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 2000 mg intravenously, on day 1 of every 2 week cycle for a period of up to 24 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 3000 mg intravenously, on day 1 of every 3-week (Q3W) cycle for a period of up to 16 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received treatment for an additional 16 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 2000 mg intravenously, on day 1 of Q2W cycle for a period of up to 24 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 1200 mg intravenously in combination with nivolumab 240 mg administered as a 30 minute intravenous infusion, on day 1 of Q2W cycle for a period of up to 24 cycles or until a discontinuation criterion is met. Qualifying participants have entered a re-treatment period and have received combination treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 2000 mg intravenously in combination with nivolumab 240 mg administered as a 30 minute intravenous infusion, on day 1 of Q2W cycle for a period of up to 24 cycles or until a discontinuation criterion is met. Qualifying participants have entered a re-treatment period and have received combination treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 2000 mg intravenously in combination with nivolumab 240 mg administered as a 30 minute intravenous infusion, on day 1 of every 2 week cycle for a period of up to 24 cycles or until a discontinuation criterion is met. Qualifying participants have entered a re-treatment period and have received combination treatment for an additional 24 cycles or until a discontinuation criteria is met.

Participants have received ASP1948 2000 mg intravenously on day 1 of Q2W cycle in combination with pembrolizumab 400 mg administered as a 30 minute intravenous infusion, on day 1, once every 6 weeks (Q6W) for a period of up to 24 cycles or until a discontinuation criterion is met. Qualifying participants have entered a re-treatment period and have received combination treatment for an additional 24 cycles or until a discontinuation criteria is met. Participants who completed 24 cycles of treatment and have entered the follow-up period with PR or SD are allowed to continue on pembrolizumab alone for a period of up to an additional 10 doses of pembrolizumab. If the participant is eligible for a re-treatment period during follow up, administration of pembrolizumab alone is discontinued and combination therapy with ASP1948 is resumed per the protocol.

Participants have received ASP1948 3000 mg intravenously in combination with pembrolizumab 200 mg administered as a 30 minute intravenous infusion, on day 1 of Q3W cycle for a period of up to 16 cycles or until a discontinuation criterion is met during treatment period. Qualifying participants have entered a re-treatment period and have received combination treatment for an additional 16 cycles or until a discontinuation criteria is met. Participants who completed 16 cycles of treatment and have 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 is eligible for a re-treatment period during follow up, administration of pembrolizumab alone is discontinued and combination therapy with ASP1948 is resumed per the protocol.

ASP1948

nivolumab

pembrolizumab

Medical Monitor

The purpose of this study is to evaluate the tolerability and safety profile of ASP1948 when administered as a single agent and in combination with nivolumab or pembrolizumab in participants with locally advanced (unresectable) or metastatic solid tumors; characterize the pharmacokinetic profile of ASP1948 when administered as a single agent and in combination with nivolumab or pembrolizumab and determine the recommended Phase 2 dose (RP2D) of ASP1948 when administered as a single agent and in combination with nivolumab or pembrolizumab. This study will also evaluate the antitumor effect of ASP1948 when administered as a single agent and in combination with nivolumab or pembrolizumab.

This is a dose-escalation and expansion study of ASP1948 as a single agent and in combination with nivolumab or pembrolizumab. The study consists of 3 periods for monotherapy and combination therapy: screening, treatment and follow up, followed by an optional Re-treatment period for participants that qualify.

The escalation cohorts will evaluate escalating dose levels of ASP1948 in participants with locally advanced (unresectable) or metastatic solid tumor malignancies.

After discontinuation of study drug, 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 study drug.

For dose expansion, the tumor-specific cohorts will include participants with squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), metastatic castration-resistant prostate cancer (mCRPC), ovarian cancer, pancreatic cancer and breast cancer, as well as any tumor types that respond to study drug treatment during dose escalation.

A Study of ASP1948, Targeting an Immune Modulatory Receptor as a Single Agent and in Combination With a PD-l Inhibitor (Nivolumab or Pembrolizumab) in Subjects With Advanced Solid Tumors

A Phase 1b Study of ASP1948, Targeting an Immune Modulatory Receptor as a Single Agent and in Combination With a PD-l Inhibitor (Nivolumab or Pembrolizumab) in Subjects With Advanced Solid Tumors

DLT is any AE that cannot be attributed 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 requires transfusion Gr 4 anemia or Gr 3 anemia requiring transfusion Gr ≥ 3 NHAE Gr ≥ 2 pneumonitis 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) Gr ≥ 2 encephalopathy, meningitis, or motor or sensory neuropathy Gr ≥ 2 pulmonary or CNS hemorrhage Gr ≥ 3 hemorrhage GBS or MS/MG IRR leading to infusion discontinuation Prolonged delay in initiating cycle 2 due to TRT Any TRT that caused participant to discontinue treatment during DLT period Missing \>25% of ASP1948 or pembrolizumab doses as a result of drug-related AE(s) during DLT period Gr 5 toxicity.

An AE is 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 \& 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 resulted 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 is defined as an AE observed after starting administration of the study drug.

Immune-related AEs observed with currently approved checkpoint inhibitors (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). TEAE is defined as an AE observed after starting administration of the study drug.

The ECOG is 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.

Negative change scores indicate an improvement. Positive scores indicate a decline in performance.

AUClast is derived from the PK serum samples collected.

AUCinf is derived from the PK serum samples collected.

AUCinf %extrap is derived from the PK serum samples collected.

AUCtau is derived from the PK serum samples collected.

Cmax is derived from the PK serum samples collected.

Ctrough is derived from the PK serum samples collected.

tmax is derived from the PK serum samples collected

tmax is derived from the PK serum samples collected.

t1/2 is derived from the PK serum samples collected.

tlast is derived from the PK serum samples collected.

CL is derived from the PK serum samples collected.

Vz is derived from the PK serum samples collected.

Vss is derived from the PK serum samples collected.

ORR as per RECIST 1.1 is defined as the percentage of participants for each dose level whose best overall response is rated as confirmed CR or PR. CR is 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 is 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 is defined as the percentage of participants for each dose level whose best overall response is rated as confirmed iCR or iPR. iCR is 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 is 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 1.1 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. CR is 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 is defined as at least a 30% decrease in the sum of diameters (longest for non nodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

DOR as per iRECIST is 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 is 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 is 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 1.1 is defined as the time from the date of treatment discontinuation to the date of radiographical progression or date of censoring. Persistence of response is derived for participants who at the time of treatment discontinuation had a confirmed response of CR or PR based on RECIST 1.1. CR is 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 is 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 is defined as the time from the date of treatment discontinuation to the date of radiographical progression or date of censoring. Persistence of response is derived for participants who at the time of treatment discontinuation had a confirmed response of iCR or iPR. iCR is 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 is 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 1.1 is defined as percentage of participants for each dose level whose BOR is rated as confirmed CR, PR or Stable Disease (SD). CR is 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 is 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 is 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. Progressive disease (PD): \>= 20% increase in sum of diameters of target lesions taking as reference the smallest sum, and sum must also demonstrate an absolute increase of \>= 5 mm. Appearance of 1 or more new lesions is also considered progression.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT03260322	Advanced Solid ...	ASP8374 Pembrolizumab	18 Years -	Astellas Pharma Inc
A Study of ASP1948, Targeting an Immune Modulatory Receptor as a Single Agent and in Combination With a PD-l Inhibitor (Nivolumab or Pembrolizumab) in Subjects With Advanced Solid Tumors	NCT03565445	Advanced Solid ...	ASP1948 nivolumab pembrolizumab	18 Years -	Astellas Pharma Inc

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