Summary

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 CLDN18.2 and a protein on a type of immune
cell called a T-cell. This "tells" the immune system to attack the tumor. ASP2138 is a
potential treatment for people with stomach cancer, gastroesophageal junction cancer (GEJ
cancer) or pancreatic cancer. GEJ is where the tube that carries food (esophagus) joins
the stomach. Before ASP2138 is available as a treatment, the researchers need to
understand how it is processed by and acts upon the body. In this study, ASP2138 will
either be given by itself, or given together with standard treatments for gastric, GEJ
and pancreatic cancer. Pembrolizumab and mFOLFOX6, and ramucirumab and paclitaxel are
standard treatments for gastric and GEJ cancer. mFOLFIRINOX is a standard treatment for
pancreatic cancer. This information will help find a suitable dose of ASP2138 given by
itself and together with the standard cancer treatments and to check for potential
medical problems from the treatments.

The main aims of the study are:

- To check the safety of ASP2138 and how well people can tolerate medical problems
during the study.

- To find a suitable dose of ASP2138 to be used later in the study.

- These are done for ASP2138 given by itself and when given together with the standard
cancer treatments.

Adults 18 years or older with stomach cancer, GEJ 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. There
should also be the CLDN18.2 marker in a tumor sample. People cannot take part if they
need to take medicines to suppress their immune system, have blockages or bleeding in
their gut, have specific uncontrollable cancers, have specific infections, have a
condition such as hemophagocytic lymphohistiocytosis (HLH) which is when the body
over-reacts to a "trigger" such as infection, or have a specific heart condition ("New
York Heart Association Class III or IV").

Phase 1: Lower to higher doses of ASP2138

- ASP2138 is either given through a vein (intravenous infusion) or just under the skin
(subcutaneous injection).

- Different small groups are given lower to higher doses of ASAP2138.

- ASP2138 is either given by itself, or given with 1 of 3 standard treatments:

- Pembrolizumab and mFOLFOX6 (first treatment for gastric GEJ cancer)

- Ramacirumab and paclitaxel (Second treatment for gastric or GEJ cancer)

- ASP2138 with mFOLFIRINOX (first treatment for pancreatic cancer)

Phase 1b: doses of ASP2138 worked out from Phase 1

- ASP2138 is either given through a vein or just under the skin. This depends on the
findings from Phase 1.

- People with gastric cancer, GEJ cancer or pancreatic cancer are given doses of
ASP2138, worked out from Phase 1.

- This includes doses of ASP2138 given by itself and ASP2138 given with the standard
cancer treatments.

- The standard cancer treatments given depends on the type of cancer they have.

End of treatment visit: This is 7 days after final dose of study treatment or if the
study doctor decides to stop the person's treatment.

People who have locally advanced unresectable pancreatic cancer will not receive ASP2138
by itself.

Eligibility

1. Participant is considered an adult according to local regulation at the time of signing the informed consent form (ICF).
2. Female participant is not pregnant, confirmed by serum pregnancy test and medical evaluation by interview and at least 1 of the following conditions apply:
3. Not a woman of childbearing potential (WOCBP)
4. WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 6 months after final study intervention administration.
5. 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.
6. Female participant must not donate ova starting at screening and throughout the study period and for 6 months after the final study intervention administration.
7. 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.
8. Male participant must not donate sperm during the treatment period and for 6 months after the final study intervention administration.
9. 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.
10. Participant's tumor sample is positive for claudin (CLDN)18.2 expression by central immunohistochemistry (IHC) testing.
11. Participant has radiographically-confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to the first dose of study intervention.
12. 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.
13. Participant has QT interval by Fredericia (QTcF) =< 470 msec.
14. Participant agrees not to participate in another interventional study while receiving study Intervention in the present study.
15. Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
16. - Participant has predicted life expectancy >= 12 weeks.
17. Participant must meet all of criteria based on laboratory tests within 7 days prior to the first dose of study Intervention. 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 >= 1 week after any blood transfusion. Monotherapy Disease specific Criteria: Gastric/GEJ Cancer
18. Participant has histologically confirmed metastatic, locally advanced unresectable gastric/gastroesophageal junction (GEJ) adenocarcinoma.
19. Escalation: Participant with gastric/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).
20. Unique to South Korea: Participant with gastric/GEJ adenocarcinoma who has refused standard approved therapies is not allowed.
21. Expansion: Participant with gastric/GEJ adenocarcinoma must have received no more than 3 prior lines of systemic chemotherapy treatment.
22. Unique to EU: Expansion: Participant with gastric/GEJ adenocarcinoma must have received at least first-line standard therapies in the metastatic setting, must have received ramucirumab treatment if eligible and where ramucirumab is available, and no more than 3 prior lines of systemic chemotherapy treatment. Monotherapy Disease specific Criteria: Pancreatic Cancer
23. Participant has histologically or cytologically confirmed metastatic pancreatic adenocarcinoma.
24. Escalation: 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).
25. Unique to South Korea: Participant with pancreatic adenocarcinoma who has refused standard approved therapies is not allowed.
26. Expansion: Participants with pancreatic adenocarcinoma must have received no more than 2 prior lines of systemic chemotherapy treatment. Note: Participants with locally advanced unresectable pancreatic adenocarcinoma will not be admitted in monotherapy arms.
27. Unique to EU: Participant with pancreatic adenocarcinoma must have received at least first-line standard therapies in the metastatic setting and no more than 2 prior lines of systemic chemotherapy treatment. For all participants in combination therapy administration:
28. If a participant has received a recent blood transfusion, the laboratory tests must be obtained = 1 week after any blood transfusion. Combination Therapy Disease-specific Inclusion Criteria: ASP2138 in Combination with Pembrolizumab and mFOLFOX6 as First-line Therapy in Gastric/GEJ Cancer
29. Participant has histologically confirmed diagnosis of gastric/GEJ adenocarcinoma.
30. Participant has metastatic or locally advanced unresectable gastric/GEJ adenocarcinoma.
31. Participant with gastric/GEJ adenocarcinoma has progressed and must not have been previously treated for metastatic disease with either chemotherapy or prior checkpoint inhibitor therapy.
32. Participant has a human epidermal growth factor receptor 2 (HER2)-negative tumor per local testing.
33. For combination therapy with oxaliplatin, follow contraception guidelines from time of informed consent through at least 9 months after final study intervention. (Unique to South Korea: For combination therapy with oxaliplatin, follow contraception guidelines from time of informed consent through at least 15 months after final study intervention for women and 12 months after final study intervention for men). Unique to EU:
34. Participant must have a PD-L1 CPS = 1. Combination Therapy Disease Specific Inclusion Criteria: ASP2138 in Combination with Ramucirumab and Paclitaxel as Second-line Therapy in Gastric/GEJ Cancer
35. Participant has histologically confirmed diagnosis of gastric/GEJ adenocarcinoma.
36. Participant has metastatic or locally advanced unresectable gastric/GEJ adenocarcinoma.
37. Participant with gastric/GEJ adenocarcinoma must have previously received 1 line of systemic chemotherapy treatment (i.e., documented objective radiological or clinical disease progression after first line platinum and fluoropyrimidine treatment in the metastatic setting or disease progression during or within 4 months of the last dose of perioperative treatment. Combination Therapy Disease-specific Inclusion Criteria: ASP2138 in Combination with mFOLFIRINOX as First-line Therapy in Pancreatic Cancer
38. Participant has histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma.
39. Participant has confirmed metastatic or locally advanced unresectable pancreatic adenocarcinoma.
40. Participant has pancreatic adenocarcinoma, has progressed and must not have received prior systemic anticancer therapy for their advanced disease.
41. For combination therapy with oxaliplatin, follow contraception guidelines from time of informed consent through at least 9 months after final study intervention. (Unique to South Korea: For combination therapy with oxaliplatin, follow contraception guidelines from time of informed consent through at least 15 months after final study intervention for women and 12 months after final study intervention for men).

Treatment Sites in Georgia