Clinical trial NCT03260322: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: Pembrolizumab
Oncology
Tumors
ASP8374
Locally advanced or metastatic solid tumor malignancies
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-08-24
Enrollment: 169
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants with Dose Limiting Toxicities (DLTs)
timeFrame: Up to 21 Days (For ASP8374 0.5 mg: Up to 7 days)
measure: Number of Participants with Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose up to 90 days after last dose (maximum duration: 938 days)
measure: Number of Participants with Infusion Related Reactions
timeFrame: From first dose up to 90 days after last dose (maximum duration: 938 days)
measure: Number of Participants with Immune- Related Treatment Emergent Adverse Events (IrTEAEs)
timeFrame: From first dose up to 90 days after last dose (maximum duration: 938 days)
measure: Number of Participants with Eastern Cooperative Oncology Group (ECOG) Performance status
timeFrame: End of treatment ASP8374 (Up to 427 days)
measure: Pharmakokinetics (PK) of ASP8374 (Cycle 1): Area Under the Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: Pharmakokinetics (PK) of ASP8374 (Cycle 7): Area Under the Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUClast) (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: 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)
timeFrame: Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: 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)
timeFrame: Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: 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)
timeFrame: Cycle 7: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle= 21 days)
measure: PK of ASP8374 (Cycle 1): Maximum Plasma concentration (Cmax) (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 7): Cmax (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 7): Trough concentration (Ctrough) (Monotherapy Dose Escalation Cohort)
timeFrame: Cycle 7: predose
measure: PK of ASP8374 (Cycle 1): Time of Maximum Concentration (Tmax) (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 7): Tmax (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 1): Terminal Elimination Half-life (T1/2) of ASP8374 (Monotherapy Dose Escalation Cohort)
timeFrame: Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 1): Time of Last Measurable Concentration (tlast) (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 7): tlast (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 7: predose, end of dosing (within 20 minutes), 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 1): Total Systemic Observed Clearance After Intravenous Dosing (CLobs) of ASP8374 (Monotherapy Dose Escalation Cohort)
timeFrame: Cycles 1: predose, end of dosing (within 20 minutes), 4hr, 24hrt, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 1): Volume of Distribution During the Terminal Elimination Phase (Vz) after Intravenous Dosing (Monotherapy Dose Escalation Cohort)
timeFrame: Cycle 1: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle = 21 days)
measure: PK of ASP8374 (Cycle 7): Apparent Volume of Distribution at Steady State (Vss) after Intravenous Dosing of ASP8374 (Monotherapy Dose Escalation Cohort)
timeFrame: Cycle 7: predose. end of dosing, 4hr, 24hr, 48hr, 168hr, 336hr postdose (each cycle= 21 days)
Secondary outcomes:
measure: Best Overall Response (BOR) as per RECIST as per Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
timeFrame: From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
measure: BOR as per immune Response Evaluation Criteria in Solid Tumors (iRECIST)
timeFrame: From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
measure: Objective Response Rate (ORR) as per RECIST v1.1
timeFrame: From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
measure: ORR as per iRECIST
timeFrame: From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
measure: Duration of Response as per RECIST v1.1
timeFrame: From the date of the first response CR/PR to the date of radiographical progression or date of censoring (maximum 938 days)
measure: DOR as per iRECIST
timeFrame: From the date of the first response iCR/iPR to the date of radiographical progression or date of censoring (maximum 938 days)
measure: Persistence of Response After Discontinuation as per RECIST v1.1
timeFrame: From date of treatment discontinuation to the date of radiographical progression or date of censoring (maximum duration: 938 days)
measure: Persistence of Response After Discontinuation as per iRECIST
timeFrame: From date of treatment discontinuation to the date of radiographical progression or date of censoring (maximum duration: 938 days)
measure: Disease Control Rate (DCR) as per RECIST v1.1
timeFrame: From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
measure: Disease Control Rate (DCR) as per iRECIST
timeFrame: From start of study until radiographical progression or date of censoring (maximum duration: 938 days)
measure: Time to Response as per RECIST v1.1
timeFrame: From first dose date until the first response CR/PR (maximum duration: 938 days)
measure: Time to Response as per iRECIST
timeFrame: From first dose date until the first response iCR/iPR (maximum duration: 938 days)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Honor Health Research Institute
state: Arizona
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Miami Beach
country: United States
facility: Mount Sinai Comprehensive Cancer Center
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Fairway
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: University Hospital of Cleveland
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Research Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Edmonton
country: Canada
facility: Site CA15004
state: Alberta
city: Toronto
country: Canada
facility: Site CA15003
state: Ontario
city: Toronto
country: Canada
facility: Site CA15001
state: Ontario
city: Montreal
country: Canada
facility: Site CA15002
state: Quebec
city: Ancona
country: Italy
facility: Site IT39004
city: Milano
country: Italy
facility: Site IT39002
city: Milano
country: Italy
facility: Site IT39003
city: Milano
country: Italy
facility: Site IT39008
city: Milano
country: Italy
facility: Site IT39009
city: Modena
country: Italy
facility: Site IT39010
city: Monza
country: Italy
facility: Site IT39005
city: Negrar
country: Italy
facility: Site IT39011
city: Chuo-ku
country: Japan
facility: Site JP81001
city: Goyang-si
country: Korea, Republic of
facility: Site KR82004
state: Gyeonggi-do
city: Seongnam-Si
country: Korea, Republic of
facility: Site KR82005
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Site KR82001
city: Seoul
country: Korea, Republic of
facility: SIte KR82002
city: Seoul
country: Korea, Republic of
facility: Site KR82006
city: Lisboa
country: Portugal
facility: Site PT35101
city: Porto
country: Portugal
facility: Site PT35106
city: Barcelona
country: Spain
facility: Site ES34002
city: Barcelona
country: Spain
facility: Site ES34003
city: Barcelona
country: Spain
facility: Site ES34009
city: Barcelona
country: Spain
facility: Site ES34010
city: Madrid
country: Spain
facility: Site ES34001
city: Madrid
country: Spain
facility: Site ES34006
city: Madrid
country: Spain
facility: Site ES34013
city: Valencia
country: Spain
facility: Site ES34014
city: Taichung
country: Taiwan
facility: Site TW88602
city: Tainan
country: Taiwan
facility: Site TW88601
city: Taipei City
country: Taiwan
facility: Site TW88603
city: London
country: United Kingdom
facility: Site GB44003
city: London
country: United Kingdom
facility: Site GB44006
city: Newcastle upon Tyne
country: United Kingdom
facility: Site GB44004
city: Sutton Surry
country: United Kingdom
facility: Site GB44005
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Vice President Medical Sciences - Oncology
role: STUDY_DIRECTOR
References: