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

Advanced Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03565445
• Other study ID #: 1948-CL-0101
• Secondary ID: 2018-003873-82KE
• Status: Completed
• Phase: Phase 1
• Start date: July 2, 2018
• Est. completion date: March 27, 2023

Study information

• Verified date: April 2024
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 190
• Est. completion date: March 27, 2023
• Est. primary completion date: March 27, 2023
• 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, and has received all standard therapies (unless the therapy is contraindicated or intolerable) felt to provide clinical benefit.

• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, or 1.

• Subject's last dose of prior antineoplastic therapy, including any immunotherapy, was at least 21 days 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) or ALK inhibitor therapy until 4 days prior to the start of study drug administration.

• Subject has completed any radiotherapy (including stereotactic radiosurgery) at least 14 days prior to study drug administration.

• Subject with metastatic castration-resistant prostate cancer (mCRPC) (positive scan and/or soft tissue disease documented by computed tomography/magnetic resonance imaging) 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 as indicated by laboratory values. (If a subject has received a recent blood transfusion, the laboratory tests must be obtained = 28 days after any blood transfusion.) Subjects can be on a stable dose of erythropoietin (= approximately 3 months). Note: Growth factors, colony stimulating factors are not permitted in the screening period.

• Female subject must either:

• Be of non-childbearing potential: post-menopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to screening, or; documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy).

• Or, if of childbearing potential: Agree not to try to become pregnant during the study treatment and for 6 months after the final study drug administration; and have a negative urine or serum pregnancy test prior to study drug administration; and if heterosexually active, agree to consistently use 1 form of highly effective birth control starting at screening and throughout the study treatment and 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 sexually active male subject with female partner(s) who are of childbearing potential is eligible if :

• The male subject agrees to use a male condom starting at screening and continues throughout the study treatment, and for 6 months after the final study drug administration.

• The male subject has not had a vasectomy or is not sterile, as defined below and the subject's female partner(s) is utilizing 1 form of highly effective birth control starting at screening and continuing throughout the study treatment and for 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 has at least 1 measurable lesion per RECIST 1.1. The measureable lesion must be outside the field of radiation if subject had prior radiotherapy. 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 1 of the following:

• Progression with 2 or more new bone lesions, or

• Prostate specific antigen (PSA) progression (defined as a minimum of 3 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 available tumor specimen in a tissue block or unstained serial slides obtained within 8 to 56 days prior to first dose of study treatment. Note: This does not apply to subjects with mCRPC who do not have measurable disease.

• Subject is an appropriate candidate for tumor biopsy and consents to undergoing a tumor biopsy (core needle biopsy or excision) during the treatment period. Note: This does not apply to subjects with mCRPC who do not have measurable disease.

• Subject meets one of the following:

• Subject has the tumor type for which a confirmed response was observed in a monotherapy or in combination with nivolumab dose escalation or RP2D cohort; or

• ASP1948 monotherapy or in combination with pembrolizumab expansion cohort is opened due to achieving predicted efficacious exposure, subject has squamous cell carcinoma of the head and neck (SCCHN); or

• RP2D monotherapy cohort is opened and subject has NSCLC, mCRPC, ovarian cancer, pancreatic cancer or breast cancer; or

• RP2D combination with pembrolizumab expansion cohort, is opened and subject has NSCLC (all PD-L1 status), NSCLC PD-L1 high*, ovarian cancer, colorectal cancer, or breast cancer.

• NSCLC with PD-L1 high expressing tumor as determined by immunohistochemistry at a central laboratory during the screening period.

Additional Inclusion Criteria for Re-treatment:

Subjects may be eligible for study drug re-treatment if the study remains open and the subject continues to meet all of the eligibility criteria above (except prior use of this drug) and the following conditions:

• Subject stopped initial treatment with ASP1948 or ASP1948 in combination with nivolumab or pembrolizumab after attaining a confirmed CR or PR or SD.

• Subject experienced a confirmed disease progression by iRECIST (iCPD) after stopping their initial treatment with ASP1948 or ASP1948 in combination with nivolumab or pembrolizumab.

• Subject did not receive any prohibited anti-cancer treatment since the last dose of ASP1948 or ASP1948 in combination with nivolumab or pembrolizumab.

• Subject did not experience a toxicity that met the discontinuation criteria during the initial treatment with ASP1948 or ASP1948 in combination with nivolumab or pembrolizumab.

Exclusion Criteria:

• Subject weighs < 45 kg.

• Subject has received investigational therapy (other than an investigational epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in a subject with EGFR mutations or ALK inhibitor in a subject with an ALK mutation) within 21 days 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, 2 mg per day of dexamethasone or up to 10 mg per day of prednisone) are allowed. Note: Corticosteroids for prophylaxis (e.g., contrast dye allergy) or for brief treatment of conditions not related to study treatment (e.g., delayed-type hypersensitivity reaction caused by a contact allergen) is also 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 the subject is clinically stable and has no evidence of CNS progression by imaging for at least 28 days prior to start of study treatment and are not requiring immunosuppressive doses of systemic steroids (> 30 mg per day of hydrocortisone, > 2 mg per day of dexamethasone or > 10 mg per day of prednisone or equivalent) for longer than 14 days.

• Subject has leptomeningeal disease as a manifestation of the current malignancy.

• Subject has an active autoimmune disease that has required systemic treatment in the past 2 years. Subjects with type 1 diabetes mellitus, stable endocrinopathies maintained on appropriate replacement therapy and 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 ASP1948, nivolumab or pembrolizumab or severe hypersensitivity reaction to treatment with another monoclonal antibody.

• Subject with positive Hepatitis B virus antibodies and surface antigen (indicating acute Hepatitis B virus (HBV) or chronic HBV) or Hepatitis C (HCV ribonucleic acid (RNA) [(qualitative or quantitative)]. Hepatitis C RNA testing is not required in subjects with negative Hepatitis C antibody testing. Hepatitis B virus antibodies are not required in subjects with negative Hepatitis B surface antigen.

• 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 active infection requiring systemic therapy within 14 days prior to study drug treatment.

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

• Subject has an uncontrolled intercurrent illness including, but not limited to cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements.

• Subject's AEs (excluding alopecia) from prior therapy have not improved to Grade 1 or baseline within 14 days prior to start of study treatment.

• Subject has significant cardiovascular disease including:

• Subject has inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications).

• Subject has a history of myocardial infarction or unstable angina within 6 months prior to day 1.

• Subject has New York Heart Association Class II or greater chronic heart failure (CHF).

• History of cerebrovascular accident (CVA) or transient ischemic attack (TIA) within 6 months prior to study treatment.

• Subject has significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to study treatment.

• Subject has a history of hemoptysis (bright red blood of ½ teaspoon or more per episode) within 12 weeks prior to study treatment.

• Subject has evidence of a bleeding diathesis or significant coagulopathy.

• Subject has inadequate recovery from prior surgical procedure or has had a major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to day 1, or anticipates the need for a major surgical procedure during the course of the study or minor surgery within 7 days of starting study treatment.

• Subject has initiated new treatment with medications that affect the coagulation cascade with an international normalized ratio (INR) = 2 such as vitamin K antagonists, heparins and direct thrombin inhibitors or the use of factor Xa inhibitors within 28 days prior to the start of study treatment. Note: If the subject started receiving such medications more than 28 days prior to the start of study treatment and needs to continue, this is allowed. However, new anticoagulation may not be initiated within 28 days prior to the start of study treatment.

• Subject has any condition that makes the subject unsuitable for study participation.

• Subject has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.

• Subject has had an allogeneic tissue solid organ transplant.

• Subject has known history of COVID-19 positive polymerase chain reaction (PCR) test within 4 weeks prior to start of study treatment.

Additional Exclusion Criteria for Subjects in Expansion Cohorts:

• Subject has a prior malignancy active (i.e., requiring treatment or intervention) within the previous 2 years, except for locally curable malignancies that have been apparently cured, which are allowed, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast.

• Subject has received prior treatment with a neuropilin-1 (NRP1) inhibitor.

Additional Exclusion Criteria for Re-treatment:

• Subjects who have completed 40 weeks (ASP1948 monotherapy or combination therapy with nivolumab cohorts) or 57 weeks (ASP1948 combination therapy with pembrolizumab) of follow-up with disease control are not eligible for retreatment.

• Subject currently has an ongoing Adverse Event (AE) related to the initial ASP1948 or ASP1948 in combination with nivolumab or pembrolizumab treatment that meets the criteria for treatment interruption or discontinuation.

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Neoplasms

Intervention

Drug:
• ASP1948
Intravenously (IV)
• nivolumab
Intravenously (IV)
• pembrolizumab
Intravenously (IV)

Locations

Country	Name	City	State
Canada	Site CA15002	Edmonton
Canada	Site CA15004	Montreal
Italy	Site IT39008	Milano
Italy	Site IT39006	Modena
Japan	Site JP81002	Chiba
Japan	Site JP81001	Tokyo
Korea, Republic of	Site KR82001	Seoul
Korea, Republic of	Site KR82002	Seoul
Korea, Republic of	Site KR82003	Seoul
Korea, Republic of	Site KR82004	Seoul
Korea, Republic of	Site KR82005	Seoul
Korea, Republic of	Site KR82006	Seoul
Korea, Republic of	Site KR82007	Seoul
Portugal	Site PT35104	Porto
Spain	Site ES34002	Barcelona
Spain	Site ES34006	Barcelona
Spain	Site ES34010	Barcelona
Spain	Site ES34014	Barcelona
Spain	Site ES34003	Cataluna
Spain	Site ES34004	Cataluna
Spain	Site ES34007	Madrid
Spain	Site ES34012	Madrid
Taiwan	Site TW88601	Taipei
Taiwan	Site TW88602	Taipei
United Kingdom	Site GB44006	Manchester
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Cancer Center at Greater Baltimore Medical	Baltimore	Maryland
United States	University of South Carolina	Charleston	South Carolina
United States	Mary Crowley Cancer Research Center	Dallas	Texas
United States	Virginia Cancer Care Specialist, PC	Fairfax	Virginia
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Henry-Joyce Cancer Center	Nashville	Tennessee
United States	Sarah Cannon Research Institute - SCRI	Nashville	Tennessee
United States	Yale Center for Clinical Investigation	New Haven	Connecticut
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	University of Oklahoma	Oklahoma City	Oklahoma
United States	Oncology Hematology West P.C. dba Nebraska Cancer Specialists	Omaha	Nebraska
United States	UPMC- Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Washington University	Saint Louis	Missouri
United States	South Texas Accelerated Research Therapeutics	San Antonio	Texas
United States	University of Washington-Seattle Cancer Care Alliance	Seattle	Washington

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 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.	Up to 28 days
Primary	Number of Participants with Adverse Events (AEs)	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.	From first dose until 90 days after last dose (up to 823 days)
Primary	Number of Participants with Immune-related AEs	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.	From first dose until 30 days after last dose (up to 763 days)
Primary	Number of Participants with Eastern Cooperative Oncology Group (ECOG) performance status	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; 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.; Negative change scores indicate an improvement. Positive scores indicate a decline in performance.	End of Treatment (Baseline up to 733 days)
Primary	Pharmacokinetics (PK) of ASP1948 (Cycle 1): Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast)	AUClast is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): AUClast	AUClast is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Area Under the Concentration-Time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf)	AUCinf is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Percentage of AUCinf Due to Extrapolation From Time of The Last Measurable Concentration To Time Infinity (AUCinf %extrap)	AUCinf %extrap is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Area Under The Concentration-Time Curve From The Time of Dosing to The Start of Next Dosing Interval (AUCtau)	AUCtau is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Maximum Concentration (Cmax)	Cmax is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): Cmax	Cmax is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): Trough Concentration (Ctrough)	Ctrough is derived from the PK serum samples collected.	Cycle 10: Predose
Primary	PK of ASP1948 (Cycle 1): Time of The Maximum Concentration (tmax)	tmax is derived from the PK serum samples collected	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): tmax	tmax is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): AUCtau	AUCtau is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Terminal Elimination Half-Life ( t1/2)	t1/2 is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Time of Last Measurable Concentration (tlast)	tlast is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): Terminal Elimination Half-Life ( t1/2)	t1/2 is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): tlast	tlast is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Total Clearance (CL) after Intravenous Dosing	CL is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): CL after Intravenous Dosing	CL is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Volume of Distribution During the Terminal Elimination Phase (Vz) After Intravenous Dosing	Vz is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): Vz After Intravenous Dosing	Vz is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 1): Apparent Volume of Distribution at Steady State (Vss) after Intravenous Dosing	Vss is derived from the PK serum samples collected.	Cycle 1: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Primary	PK of ASP1948 (Cycle 10): Vss After Intravenous Dosing	Vss is derived from the PK serum samples collected.	Cycle 10: pre-dose, within 20 minutes after end of dosing, 4 hours, 24 hours, 48 hours, 168 hours post dose
Secondary	Objective Response Rate (ORR) as per RECIST V1.1	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.	From start of study until radiographical progression or date of censoring (maximum treatment duration: up to 733 days)
Secondary	ORR as per iRECIST V1.1	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.	From start of study until radiographical progression or date of censoring (maximum treatment duration: up to 733 days)
Secondary	Duration of Response (DOR) as per RECIST V1.1	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.	From the date of the first response CR/PR to the date of radiographical progression or date of censoring (maximum treatment duration: up to 733 days)
Secondary	DOR as per iRECIST	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.	From the date of the first response CR/PR to the date of radiographical progression or date of censoring (maximum treatment duration: up to 733 days)
Secondary	Persistence of response after discontinuation per RECIST V1.1	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.	From date of treatment discontinuation to the date of radiographical progression or date of censoring (maximum duration: up to 733 days)
Secondary	Persistence of response after discontinuation per iRECIST	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.	From date of treatment discontinuation to the date of radiographical progression or date of censoring (maximum treatment duration: up to 733 days)
Secondary	Disease Control Rate (DCR) by RECIST 1.1	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.	From start of study until radiographical progression or date of censoring (maximum treatment duration: up to 733 days)
Secondary	DCR by iRECIST	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.	From start of study until radiographical progression or date of censoring (maximum treatment duration: up to 733 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