A Study of ASP2138 in Adults With Stomach Cancer, Gastroesophageal Junction Cancer, Pancreatic Cancer

Study Overview
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Brief Summary
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Claudin 18.2 protein, or CLDN18.2 is a protein found on cells in the digestive system. It is also found on some tumors. Researchers are looking at ways to attack CLDN18.2 to help control tumors. ASP2138 is thought to bind to 2 targets at the same time: CLDN18.2 and a protein called CD3 found on immune cells, called T-cells. ASP2138 works by binding to both the tumor cell and CD3 which tells the immune system to attack the tumor. ASP2138 is a potential new treatment for people with stomach cancer, gastroesophageal junction cancer, (cancer where the tube that carries food (esophagus) joins the stomach) or pancreatic cancer. Before ASP2138 is available as a treatment, the researchers need to understand how it is processed by and acts upon the body. This information will help to find a suitable dose and to check for potential medical problems from the treatment. Adults 18 years or older with stomach cancer, gastroesophageal junction cancer, or pancreatic cancer can take part. Their cancer is locally advanced unresectable or metastatic. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body. The main aims of the study are to check the safety of ASP2138, how well it is tolerated, and to find a suitable dose of ASP2138 to be used later in this study. This is an open-label study. This means that people in this study and clinic staff will know that people will receive ASP2138. The study will have 2 phases. In phase 1, different small groups of people will receive lower to higher doses of ASP2138. Any medical problems will be recorded at each dose. This is done to find suitable doses of ASP2138 to use later in the study. The first group will receive the lowest dose of ASP2138. A medical expert panel will check the results from this group and decide if the next group can receive a higher dose of ASP2138. The panel will do this for each group until all groups have received ASP2138, or until suitable doses have been selected for later in the study. Doctors will also check how each type of cancer is responding to ASP2138. In phase 1b, other different small groups will receive suitable doses of ASP2138 found from phase 1. This phase will check how each type of cancer responds to ASP2138. The response to ASP2138 is measured using scans and blood tests. Doctors will continue to check all medical problems throughout the study. ASP2138 will be given through a vein in the arm. This is called an infusion. People will receive weekly infusions of ASP2138 in a 14-day (2-week) treatment cycle. People will continue to receive treatment until: their cancer gets worse; they have medical problems they can't tolerate; they ask to stop treatment; the doctors decide that continuing treatment is no longer in that person's best interest; the study is ended by the sponsor. Doctors will check if people had any medical problems from ASP2138. Other checks will include medical examinations, checking the nervous system, blood and urine tests and vital signs. Nervous system checks include checking peoples state of mind, reflexes, balance, movement and muscle strength. Vital signs include medical examinations, body temperature, breathing rate, and blood oxygen levels. Electrocardiograms (ECG) will be done to check the heart rhythm during the study. People will receive ASP2138 in a hospital. They will have blood tests and doctors will check for medical problems. People will also visit the clinic on certain days during their treatment, with extra visits during the first 3 cycles of treatment. People will visit the clinic after treatment has finished. The doctors will check for more medical problems. Other checks will include medical examinations, blood and urine tests, and vital signs. People will also have an ECG. After this, people will visit the clinic for a check-up several times. The number of visits and checks done at each visit will depend on the health of each person and whether they completed their treatment or not.

Official Title
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A Phase 1/1b Study of ASP2138 in Participants With Metastatic or Locally Advanced Unresectable Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma or Metastatic Pancreatic Adenocarcinoma Whose Tumors Have Claudin (CLDN) 18.2 Expression

Conditions
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Gastric Adenocarcinoma, Gastroesophageal Junction (GEJ) Adenocarcinoma, Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: ASP2138


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is considered an adult according to local regulation at the time of signing the informed consent form (ICF). Female participant is not pregnant, confirmed by serum pregnancy test and medical evaluation by interview and at least 1 of the following conditions apply: Not a woman of childbearing potential (WOCBP) WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 6 months after final study intervention administration. Female participant must agree not to breastfeed starting at screening and throughout the study period and for 6 months after the final study intervention administration. Female participant must not donate ova starting at screening and throughout the study period and for 6 months after the final study intervention administration. Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 6 months after the final study intervention administration. Male participant must not donate sperm during the treatment period and for 6 months after the final study intervention administration. Male participant with 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 period and for 6 months after the final study intervention administration. Participant's tumor sample is positive for claudin (CLDN)18.2 expression by central immunohistochemistry (IHC) testing. Participant has radiographically-confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to the first dose of study intervention. Participant has at least 1 measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 28 days prior to the first dose of study intervention. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Participant has QT interval by Fredericia (QTcF) =< 470 msec. Participant agrees not to participate in another interventional study while receiving study treatment in the present study. Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participant has predicted life expectancy >= 12 weeks. Participant must meet all of criteria based on laboratory tests within 7 days prior to the first dose of study drug. In case of multiple laboratory data within this period, the most recent data should be used. If a participant has received a recent blood transfusion, the laboratory tests must be obtained >= 2 weeks after any blood transfusion. Disease Specific Criteria: Gastric/GEJ Cancer Participant has histologically confirmed gastric or gastroesophageal junction (GEJ) adenocarcinoma. Participant with gastric or GEJ adenocarcinoma who has progressed, is intolerant, has refused, or for whom there is no standard approved therapies that impart significant clinical benefit (no limit to the number of prior treatment regimens). Disease Specific Criteria: Pancreatic Cancer Participant has histologically or cytologically confirmed pancreatic adenocarcinoma. Participant with pancreatic adenocarcinoma who has progressed, is intolerant, has refused, or for whom there is no standard approved therapies that impart significant clinical benefit (no limit to the number of prior treatment regimens). Exclusion Criteria: Participant has received other investigational agents, or antineoplastic therapy including immunotherapy or devices concurrently or within 21 days or 5 times the half-life, whichever is shorter, prior to first dose of study intervention administration. Participant has any condition which makes the participant unsuitable for study participation. Participant has known immediate or delayed hypersensitivity or contraindication to any component of study treatment. Participant has had prior severe allergic reaction or intolerance to known ingredients of ASP2138 or other antibodies, including humanized or chimeric antibodies. Participant weighs < 40 kg. Participant has received systemic immunosuppressive therapy, including systemic corticosteroids 14 days prior to first dose of study intervention. Participant using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single daily dose of systemic corticosteroids or receiving systemic corticosteroids as pre-medication for radiologic imaging contrast use are allowed. Participant has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting. Participant has significant gastric bleeding and/or untreated gastric ulcers that exclude the participant from participation. Participant has symptomatic CNS metastases or participant has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Participants with previously treated CNS metastases are eligible, if they are 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. Participant is known to have HIV infection. However, participants with cluster of differentiation (CD4) + T cell counts >= 350 cells/µL and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 6 months are eligible. NOTE: Screening for human immunodeficiency virus (HIV) infection should be conducted per local requirements. Participant is known to have active hepatitis B (positive hepatitis B surface antigen [HBsAg]) or hepatitis C infection. Testing is required for known history of these infections or as mandated by local requirements. NOTE: Screening for these infections should be conducted per local requirements. For participant who is negative for HBsAg, but hepatitis B core antibody (HBc Ab) positive, a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test will be performed and if positive the participant will be excluded. Participant with positive hepatitis C virus (HCV) serology, but negative HCV ribonucleic acid (RNA) test results are eligible. Participant treated for HCV with undetectable viral load results are eligible Participant has had within 6 months prior to first dose of study intervention any of the following: unstable angina, myocardial infarction, ventricular arrhythmia requiring intervention or hospitalization for heart failure. Participant has active infection requiring systemic therapy that has not completely resolved within 7 days prior to the start of study intervention. Participant has active autoimmune disease that has required systemic immunosuppressive treatment within the past 1 month prior to the start of study intervention. Participant has a clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this study or make the participant unsuitable for study participation. Participant has psychiatric illness or social situations that would preclude study compliance. Participant has had a major surgical procedure 28 days before start of study intervention and has not fully recovered. Participant has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ or metastatic pancreatic adenocarcinoma 14 days prior to start of study intervention and has NOT recovered from any related toxicity. Participant has another malignancy for which treatment is required. Participant who has received an CLDN18.2-targeted investigational agent (e.g., zolbetuximab or chimeric antigen receptor CLDN18.2-specific T cells) prior to first dose of study intervention administration is not eligible for dose escalation cohorts. However, a participant who has received an CLDN18.2-targeted investigational agent greater than 28 days or 5 half-lives (whichever is longer) prior to first dose study intervention administration is eligible for dose expansion cohorts only, with the exception of participants who have experienced Grade >= 3 gastrointestinal (GI) toxicity after receiving an CLDN18.2-targeted investigational agent. Participant has a history or complication of interstitial lung disease. China Specific: Participant who has received treatment with herbal medications that have known antitumor activity within 28 days prior to first dose of study treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Phase 1)<br>A dose escalation design will be used to determine the Maximum Tolerated Dose (MTD) and/ or the Recommended Phase 2 Dose (RP2D) regimens to be further evaluated in the Dose Expansion arms. Dose escalation part consists of three parts (Part A, B and C), and up to 80 patients would be enrolled in total. Participants will be assigned to sequentially escalating dose cohorts of ASP2138 in each part. Part B and Part C will be opened sequentially based upon sponsor review of emerging data. | Drug: ASP2138<br>* intravenous<br>|
| Experimental: Dose Expansion (Phase 1b) Gastric/GEJ cancer<br>Participants will receive ASP2138 at the RP2D regimens determined in Dose Escalation arm. | Drug: ASP2138<br>* intravenous<br>|
| Experimental: Dose Expansion (Phase 1b) Pancreatic cancer<br>Participants will receive ASP2138 at the RP2D regimens determined in Dose Escalation arm. | Drug: ASP2138<br>* intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose Limiting Toxicities (DLTs) (Phase 1 Dose Escalation) | A DLT is defined as any of the prespecified Adverse Events (AEs) (graded using National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0, except cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] which are graded using American Society for Transplantation and Cellular Therapy [ASTCT] consensus grading) or laboratory findings that the investigator or sponsor cannot clearly attribute to a cause other than study drug occurring during the DLT evaluation period. | Up to 28 days | 
| Number of participants with Adverse Events (AEs) | An AE is any untoward medical occurrence temporally associated with the use of study intervention, whether or not considered related to the study intervention. 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 study intervention. This includes events related to the comparator and events related to the (study) procedures. | Up to 15 months | 
| Number of participants with serious AEs (SAEs) | An SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or other medically important events. | Up to 15 months | 
| Number of participants with laboratory value abnormalities | Number of participants with potentially clinically significant laboratory values. | Up to 13 months | 
| Number of participants with vital sign abnormalities | Number of participants with potentially clinically significant vital sign values. | Up to 15 months | 
| Number of participants with electrocardiogram (ECG) abnormalities | Number of participants with potentially clinically significant ECG values. | Up to 12 months | 
| Number of participants with physical exam abnormalities | Number of participants with potentially clinically significant physical exam values. | Up to 13 months | 
| Number of participants at each grade of the Eastern Cooperative Oncology Group (ECOG) performance status | The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance. | Up to 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of ASP2138 in serum: Area under the concentration-time curve (AUC) from the time of dosing to the start of the next dosing interval at multiple dose conditions (AUCtau) | AUCtau will be recorded from the PK serum samples collected. | Up to 12 months | 
| PK of ASP2138 in serum: maximum concentration (Cmax) | Cmax will be recorded from the PK serum samples collected. | Up to 12 months | 
| PK of ASP2138 in serum: concentration immediately prior to dosing at multiple dosing (Ctrough) | Ctrough will be recorded from the PK serum samples collected. | Up to 12 motnhs | 
| PK of ASP2138 in serum: time of the maximum concentration (Tmax) | Tmax will be recorded from the PK serum samples collected. | Up to 12 months | 
| Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Phase 1b dose expansion) | ORR is defined as the proportion of participants for each dosing scheme whose best overall response is rated as confirmed complete response (CR) or partial response (PR) per RECIST 1.1. | Up to 21 months | 
| Disease control rate (DCR) per RECIST 1.1 (Phase 1b dose expansion) | DCR is defined as the proportion of participants for each dosing scheme whose best overall response is rated as confirmed CR, PR or stable disease (SD) per RECIST 1.1. | Up to 21 months | 
| Change from baseline in serum carbohydrate antigen 19-9 (CA19-9) (pancreatic only) (Phase 1b dose expansion) | Serum CA19-9 level will be assessed by local laboratory in participants with pancreatic cancer. | up to 21 months | 
| Change from baseline in claudin (CLDN) 18.2 tumor expression level | Comparison of CLDN18.2 expression in baseline versus on-treatment tumor biopsies will be performed. | Up to 6 weeks | 
| Change from baseline in programmed death-ligand 1 (PD-L1) tumor expression level | Comparison of PD-L1 expression in baseline versus on-treatment tumor biopsies will be performed. | Up to 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Claudin (CLDN) 18.2, ASP2138, Pharmacokinetics, Safety, Tolerability