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

• ClinicalTrials.gov Identifier: NCT03565445
• Recruitment Status: Completed
• First Posted: June 21, 2018
• Last Update Posted: April 28, 2023
• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumors	Drug: ASP1948; Drug: nivolumab; Drug: pembrolizumab	Phase 1

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 190 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: July 2, 2018
• Actual Primary Completion Date: March 27, 2023
• Actual Study Completion Date: March 27, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: ASP1948 Dose Escalation; The monotherapy escalation cohort will evaluate escalating dose levels of ASP1948. Each dose level will enroll approximately 3 or 4 participants. Dose escalation to the next level will be made based on the Bayesian Continual Reassessment Method (CRM). Participants may reinitiate study drug treatment after confirmation that they meet all the re-treatment eligibility criteria.	Drug: ASP1948; Intravenously (IV)
Experimental: ASP1948 Dose Expansion; If a confirmed response (partial response [PR] or confirmed response [CR]) per iRECIST occurs in a monotherapy escalation cohort, a tumor specific expansion cohort may be opened in that tumor type, at the dose level in which the confirmed response was observed and at all subsequent dose levels once each dose level has been cleared. Up to 5 expansion cohorts may be opened. Participants may reinitiate study drug treatment after confirmation that they meet all the re-treatment eligibility criteria.	Drug: ASP1948; Intravenously (IV)
Experimental: ASP1948 plus nivolumab Combination Therapy Dose Escalation; ASP1948 will be administered in combination with a fixed dose of nivolumab every 2 weeks. Participants may reinitiate study drug treatment after confirmation that they meet all the re-treatment eligibility criteria.	Drug: ASP1948; Intravenously (IV); Drug: nivolumab; Intravenously (IV)
Experimental: ASP1948 plus nivolumab Combination Therapy Dose Expansion; If a confirmed response (PR or CR) is observed, a combination expansion cohort may be opened in a tumor type with response. Participants may reinitiate study drug treatment after confirmation that they meet all the re-treatment eligibility criteria.	Drug: ASP1948; Intravenously (IV); Drug: nivolumab; Intravenously (IV)
Experimental: ASP1948 plus pembrolizumab Combination Therapy Dose Escalation; After the completion of the nivolumab combination escalation, a fixed dose of ASP1948 will be administered every 2 weeks in combination with a fixed dose of pembrolizumab every 6 weeks. An every 3 week schedule will also be evaluated with the highest fixed dose of ASP1948 in combination with fixed dose of pembrolizumab after the monotherapy cohort is cleared. Participants may reinitiate study drug treatment after confirmation that they meet all the re-treatment eligibility criteria.	Drug: ASP1948; Intravenously (IV); Drug: pembrolizumab; Intravenously (IV)
Experimental: ASP1948 plus pembrolizumab Combination Therapy Dose Expansion; If a confirmed response (PR or CR) per iRECIST occurs in a combination therapy escalation cohort, a tumor specific expansion cohort may be opened in that tumor type, at the dose level in which the confirmed response was observed and at all subsequent dose levels once each dose level has been cleared. Participants may reinitiate study drug treatment after confirmation that they meet all the re-treatment eligibility criteria.	Drug: ASP1948; Intravenously (IV); Drug: pembrolizumab; Intravenously (IV)

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability assessed by dose limiting toxicities (DLTs) [ Time Frame: Up to 28 days ]
   A DLT is defined as any of the prespecified Adverse Events (AEs) (graded using National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] version 4.03) that the investigator (or sponsor) cannot clearly attribute to a cause other than study drug.
2. Safety and tolerability assessed by Adverse Events (AEs) (Initial Treatment) [ Time Frame: Up to a maximum of 52 weeks ]
   An AE is 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 can 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. AEs will be coded using medical dictionary for regulatory activities (MedDRA) and graded using NCI-CTCAE version 4.03.
3. Safety and tolerability assessed by Adverse Events (AEs) (Retreatment) [ Time Frame: Up to a maximum of 52 weeks ]
   An AE is 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 can 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. AEs will be coded using medical dictionary for regulatory activities (MedDRA) and graded using NCI-CTCAE version 4.03.
4. Safety and tolerability assessed by immune-related Adverse Events (irAEs) (Initial Treatment) [ Time Frame: Up to a maximum of 52 weeks ]
   Most frequent immune-related AEs include rash, oral mucositis, dry mouth, colitis/diarrhea, hepatitis, pneumonitis, and endocrinopathies.
5. Safety and tolerability assessed by immune-related Adverse Events (irAEs) (Retreatment) [ Time Frame: Up to a maximum of 52 weeks ]
   Most frequent immune-related AEs include rash, oral mucositis, dry mouth, colitis/diarrhea, hepatitis, pneumonitis, and endocrinopathies.
6. Safety and tolerability assessed by infusion-related reaction (IRRs) (Initial Treatment) [ Time Frame: Up to a maximum of 52 weeks ]
   IRRs are considered AEs of special interest. In the event a participant is diagnosed with an IRR, then it should be reported as an AE.
7. Safety and tolerability assessed by infusion-related reaction (IRRs) (Retreatment) [ Time Frame: Up to a maximum of 52 weeks ]
   IRRs are considered AEs of special interest. In the event a participant is diagnosed with an IRR, then it should be reported as an AE.
8. Safety and tolerability assessed by Serious Adverse Events (SAEs) (Initial Treatment) [ Time Frame: Up to a maximum of 60 weeks ]
   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 (except for planned procedures as allowed per study) or leads to prolongation of hospitalization (except if prolongation of planned hospitalization is not caused by an AE). Hospitalization for treatment/observation/examination caused by AE is to be considered as serious; and other medically important events.
9. Safety and tolerability assessed by Serious Adverse Events (SAEs) (Retreatment) [ Time Frame: Up to a maximum of 60 weeks ]
   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 (except for planned procedures as allowed per study) or leads to prolongation of hospitalization (except if prolongation of planned hospitalization is not caused by an AE). Hospitalization for treatment/observation/examination caused by AE is to be considered as serious; and other medically important events.
10. Number of participants with laboratory value abnormalities and/or adverse events (Initial Treatment) [ Time Frame: Up to a maximum of 52 weeks ]
    Number of participants with potentially clinically significant laboratory values.
11. Number of participants with laboratory value abnormalities and/or adverse events (Retreatment) [ Time Frame: Up to a maximum of 52 weeks ]
    Number of participants with potentially clinically significant laboratory values.
12. Safety assessed by 12- lead electrocardiogram (ECG) (Initial Treatment) [ Time Frame: Up to a maximum of 48 weeks ]
    ECGs should be obtained after the participant has rested quietly and is awake in a fully supine position (or semi-recumbent, if supine is not tolerated) for 10 minutes before the first ECG from a triplicate or single ECG. For ECGs done in triplicate, there should be at least 2 minutes between each ECG. Any abnormal ECGs including those that worsen from baseline, that is considered to be clinically significant and not related to underlying disease, is to be reported as an (S)AE.
13. Safety assessed by 12- lead electrocardiogram (ECG) (Retreatment) [ Time Frame: Up to a maximum of 48 weeks ]
    ECGs should be obtained after the participant has rested quietly and is awake in a fully supine position (or semi-recumbent, if supine is not tolerated) for 10 minutes before the first ECG from a triplicate or single ECG. For ECGs done in triplicate, there should be at least 2 minutes between each ECG. Any abnormal ECGs including those that worsen from baseline, that is considered to be clinically significant and not related to underlying disease, is to be reported as an (S)AE.
14. Number of participants with vital signs abnormalities and/or adverse events (Initial Treatment) [ Time Frame: Up to a maximum of 60 weeks ]
    Number of participants with potentially clinically significant vital sign values.
15. Number of participants with vital signs abnormalities and/or adverse events (Retreatment) [ Time Frame: Up to a maximum of 60 weeks ]
    Number of participants with potentially clinically significant vital sign values.
16. Number of participants with Physical Exam abnormalities and/or adverse events (Initial Treatment) [ Time Frame: Up to a maximum of 48 weeks ]
    Number of participants with potentially clinically significant physical exam values.
17. Number of participants with Physical Exam abnormalities and/or adverse events (Retreatment) [ Time Frame: Up to a maximum of 48 weeks ]
    Number of participants with potentially clinically significant physical exam values.
18. Safety assessed by Eastern Cooperative Oncology Group Performance Status (ECOG PS) (Initial Treatment) [ Time Frame: Up to a maximum of 52 weeks ]

    The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 4 (completely disabled).

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

19. Safety assessed by Eastern Cooperative Oncology Group Performance Status (ECOG PS) (Retreatment) [ Time Frame: Up to a maximum of 52 weeks ]

    The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 4 (completely disabled).

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

20. Pharmacokinetics (PK) of ASP1948 in serum: AUClast [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Area under the concentration time curve from the time of dosing to the last measurable concentration (AUClast) will be derived from the pharmacokinetic (PK) serum samples collected.
21. Pharmacokinetics (PK) of ASP1948 in serum: AUCinf [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Area under the concentration time curve from the time of dosing extrapolated to time infinity (AUCinf) will be derived from the pharmacokinetic (PK) serum samples collected.
22. Pharmacokinetics (PK) of ASP1948 in serum: AUCinf %extrap [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Percentage of AUCinf due to extrapolation from time of the last measurable concentration to time infinity (AUCinf %extrap) will be derived from the pharmacokinetic (PK) serum samples collected.
23. Pharmacokinetics (PK) of ASP1948 in serum: AUCtau [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Area under the concentration-time curve from the time of dosing to the start of next dosing interval (AUCtau) will be derived from the pharmacokinetic (PK) serum samples collected.
24. Pharmacokinetics (PK) of ASP1948 in serum: Cmax [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Maximum concentration (Cmax) will be derived from the pharmacokinetic (PK) serum samples collected.
25. Pharmacokinetics (PK) of ASP1948 in serum: Ctrough [ Time Frame: Up to a maximum of 48 weeks for each treatment period ]
    Initial and retreatment. Concentration immediately prior to dosing at multiple dosing (Ctrough) will be derived from the pharmacokinetic (PK) serum samples collected.
26. Pharmacokinetics (PK) of ASP1948 in serum: tmax [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Time of the maximum concentration (tmax) will be derived from the pharmacokinetic (PK) serum samples collected.
27. Pharmacokinetics (PK) of ASP1948 in serum: t1/2 [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Terminal elimination half-life (t1/2) will be derived from the pharmacokinetic (PK) serum samples collected.
28. Pharmacokinetics (PK) of ASP1948 in serum: tlast [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Time of last measurable concentration (tlast) will be derived from the pharmacokinetic (PK) serum samples collected.
29. Pharmacokinetics (PK) of ASP1948 in serum: CL [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Total clearance after intravenous dosing (CL) will be derived from the pharmacokinetic (PK) serum samples collected.
30. Pharmacokinetics (PK) of ASP1948 in serum: V [ Time Frame: Up to a maximum of 22 weeks in initial treatment period of dose escalation ]
    Initial dose escalation treatment only. Volume of distribution after intravenous dosing (V) will be derived from the pharmacokinetic (PK) serum samples collected.

Secondary Outcome Measures :

1. Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) V1.1 and modified RECIST 1.1 for immune-based therapeutics (iRECIST) (Initial Treatment) [ Time Frame: Up to a maximum of 88 weeks ]
   ORR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed complete response (CR) or partial response (PR).
2. Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) V1.1 and modified RECIST 1.1 for immune-based therapeutics (iRECIST) (Retreatment) [ Time Frame: Up to a maximum of 88 weeks ]
   ORR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed complete response (CR) or partial response (PR).
3. Duration of Response (DOR) per RECIST V1.1 and iRECIST (Initial Treatment) [ Time Frame: Up to a maximum of 88 weeks ]
   DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.
4. Duration of Response (DOR) per RECIST V1.1 and iRECIST (Retreatment) [ Time Frame: Up to a maximum of 88 weeks ]
   DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.
5. Persistence of response after discontinuation per RECIST V1.1 and iRECIST (Initial Treatment) [ Time Frame: Up to a maximum of 88 weeks ]
   Persistence of response is defined as the time from the date of treatment discontinuation to the date of radiographical progression or date of censoring.
6. Persistence of response after discontinuation per RECIST V1.1 and iRECIST (Retreatment) [ Time Frame: Up to a maximum of 88 weeks ]
   Persistence of response is defined as the time from the date of treatment discontinuation to the date of radiographical progression or date of censoring.
7. Disease Control Rate (DCR) per RECIST V1.1 and iRECIST (Initial Treatment) [ Time Frame: Up to a maximum of 88 weeks ]
   DCR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed CR, PR or stable disease (SD).
8. Disease Control Rate (DCR) per RECIST V1.1 and iRECIST (Retreatment) [ Time Frame: Up to a maximum of 88 weeks ]
   DCR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed CR, PR or stable disease (SD).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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, 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 • o 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.

Contacts and Locations

Locations

United States, Connecticut

Yale Center for Clinical Investigation

New Haven, Connecticut, United States, 06520-8028

United States, Kentucky

Norton Cancer Institute

Louisville, Kentucky, United States, 40202

United States, Maryland

Cancer Center at Greater Baltimore Medical

Baltimore, Maryland, United States, 21153

United States, Michigan

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States, 48109

United States, Missouri

Washington University

Saint Louis, Missouri, United States, 63110

United States, Nebraska

Oncology Hematology West P.C. dba Nebraska Cancer Specialists

Omaha, Nebraska, United States, 68310

United States, Nevada

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States, 89169

United States, New York

Icahn School of Medicine at Mount Sinai

New York, New York, United States, 10029

United States, Oklahoma

University of Oklahoma

Oklahoma City, Oklahoma, United States, 73104

United States, Pennsylvania

UPMC- Hillman Cancer Center

Pittsburgh, Pennsylvania, United States, 15232

United States, South Carolina

University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Tennessee

Sarah Cannon Research Institute - SCRI

Nashville, Tennessee, United States, 37203

Henry-Joyce Cancer Center

Nashville, Tennessee, United States, 37232

United States, Texas

Mary Crowley Cancer Research Center

Dallas, Texas, United States, 75230

South Texas Accelerated Research Therapeutics

San Antonio, Texas, United States, 78229

United States, Virginia

Virginia Cancer Care Specialist, PC

Fairfax, Virginia, United States, 22031

United States, Washington

University of Washington-Seattle Cancer Care Alliance

Seattle, Washington, United States, 98109

Canada

Site CA15002

Edmonton, Canada

Site CA15004

Montreal, Canada

Italy

Site IT39008

Milano, Italy

Site IT39006

Modena, Italy

Japan

Site JP81002

Chiba, Japan

Site JP81001

Tokyo, Japan

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, Korea, Republic of

Portugal

Site PT35104

Porto, Portugal

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, Spain

Taiwan

Site TW88601

Taipei, Taiwan

Site TW88602

Taipei, Taiwan

United Kingdom

Site GB44006

Manchester, United Kingdom

Sponsors and Collaborators

Astellas Pharma Global Development, Inc.

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor; Astellas Pharma Global Development, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bao R, Surriga O, Olson DJ, Allred JB, Strand CA, Zha Y, Carll T, Labadie BW, Bastos BR, Butler M, Hogg D, Musi E, Ambrosini G, Munster P, Schwartz GK, Luke JJ. Transcriptional analysis of metastatic uveal melanoma survival nominates NRP1 as a therapeutic target. Melanoma Res. 2021 Feb 1;31(1):27-37. doi: 10.1097/CMR.0000000000000701.

• Responsible Party: Astellas Pharma Global Development, Inc.
• ClinicalTrials.gov Identifier: NCT03565445
• Other Study ID Numbers: 1948-CL-0101; 2018-003873-82 ( EudraCT Number ); KEYNOTE KN-A87 ( Other Identifier: Merck ); jRCT2031200341 ( Registry Identifier: Japan Registry for Clinical Trials (jRCT) )
• First Posted: June 21, 2018
• Last Update Posted: April 28, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• URL: https://www.clinicalstudydatarequest.com/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):

NSCLC; Tumors; squamous cell carcinoma of the head and neck (SCCHN); Oncology; breast cancer; ASP1948; mCRPC; ovarian cancer; Locally advanced or metastatic solid tumor malignancies; pancreatic cancer; Advanced solid tumors

Additional relevant MeSH terms:

Neoplasms; Pembrolizumab; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action