A Multiple-dose Study of ASP8374, an Immune Checkpoint Inhibitor, as a Single Agent and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors

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

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

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

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

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.