A Study to Assess the Antitumor Activity, Safety, Pharmacokinetics and Biomarkers of Zolbetuximab (IMAB362) in Participants with Claudin (CLDN) 18.2 Positive, Metastatic or Advanced Unresectable Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma and Locoregional Gastric or GEJ Adenocarcinoma

JRCT ID: jRCT2080225325

Registered date:20/08/2020

Basic Information

• Recruitment status: recruiting
• Health condition(s) or Problem(s) studied: Metastatic or locally advanced unresectable gastric adenocarcinoma and esophagogastric junction (GEJ) adenocarcinoma
• Date of first enrollment: 09/09/2020
• Target sample size: 143
• Countries of recruitment: France,Italy,Japan,South Korea,Taiwan,United States of America
• Study type: Interventional

Intervention(s)

Investigational material (s)
Generic name etc : Zolbetuximab (General Recombination)
INN of investigational material:zolbetuximab
Investigational material: medicine: therapeutic category code: 429 Other tumor
Dosage and administration for investigational material: Will be administered as a minimum 2-hour intravenous (IV) infusion every 2 or 3 weeks.

Generic name etc : Pembrolizumab (General Recombination)
INN of investigational material: pembrolizumab
Investigational material: medicine: therapeutic category code: 429 Other tumor
Dosage and administration for investigational material: In Cohort 3, will be administered at intravenously over 30 minutes on day 1 of every 21-day cycle.

Generic name etc : Oxaliplatin
INN of investigational material: oxaliplatin
Investigational material: medicine: therapeutic category code: 429 Other tumor
Dosage and administration for investigational material: In cohorts 2, 4A, and 4B, will be administered at intravenously over 2 hours on day 1, 15 and 29 in a 42-day cycle (4 cycles). In cohort 5, will be administered intravenously over 2 hours on day 2 of cycles 1 and 5, day 1 or day 2 of cycles 2 to 4 and cycles 6 to 8.
(Combination therapy as mFOLFOX6)

Generic name etc : Leucovorin
INN of investigational material: leucovorin
Investigational material: medicine: therapeutic category code: 429 Other tumor
Dosage and administration for investigational material: In cohorts 2, 4A, and 4B, will be administered at intravenously over 2 hours every 2 weeks. In cohort 5, will be administered intravenously over 2 hours on day 2 of cycles 1 and 5, day 1 or day 2 of cycles 2 to 4 and cycles 6 to 8.
(Combination therapy as mFOLFOX6)

Generic name etc : Folinic acid
INN of investigational material: folinic acid
Investigational material: medicine: therapeutic category code: 392 Antidotes
Dosage and administration for investigational material: In cohorts 2, 4A/4B, will be administered as a 2-hour intravenous infusion. In cohort 5, will be administered as intravenous infusion over 2 hours on day 2 of cycles 1 and 5, day 1 or day 2 of cycles 2 to 4 and cycles 6 to 8.
(Combination therapy as mFOLFOX6)

Generic name etc : Fluorofuracil/5-FU
INN of investigational material: fluorofuracil
Investigational material: medicine: therapeutic category code: 429 Other tumor
Dosage and administration for investigational material: In cohorts 2, 4A, and 4B, will be administered at intravenous bolus over 5 to 15 minutes every 2 weeks, followed by a continuous intravenous infusion over 46 to 48 hours. In cohort 5, will be administered as intravenous infusion over 24 hours on day 2 of cycles 1 and 5, day 1 or day 2 of cycles 2 to 4 and cycles 6 to 8.
(Combination therapy as mFOLFOX6)

Generic name etc : Nivolumab (General Recombination)
INN of investigational material: nivolumab
Investigational material: medicine: therapeutic category code: 429 Other tumor
Dosage and administration for investigational material: In cohort 4A/4B, will be administered at intravenously according to institutional guidelines.

Generic name etc : Docetaxel
INN of investigational material: docetaxel
Investigational material: medicine: therapeutic category code: 424 Antineoplastic preparations extracted from plants
Dosage and administration for investigational material: In cohort 5, will be administered as a intravenous infusion over 1 hour on day 2 of cycles 1 and 5, day 1 or day 2 of cycles 2 to 4 and cycles 6 to 8.

Outcome(s)

• Primary Outcome: - Objective Response Rate (ORR) of zolbetuximab as a single agent as assessed by an independent central reader

Secondary Outcome

- Pharmacokinetics of zolbetuximab as a single agent, in combination with 5 fluorouracil (5-FU), leucovorin or folinic acid and oxaliplatin (mFOLFOX6), in combination with pembrolizumab, in combination with mFOLFOX6 and nivolumab and in combination with fluorouracil, leucovorin or folinic acid, oxaliplatin and docetaxel (FLOT)
- Pharmacokinetics of oxaliplatin and 5-FU in combination with zolbetuximab
- Safety and tolerability of zolbetuximab as a single agent, in combination with mFOLFOX6 (with or without nivolumab), in combination with pembrolizumab, and in combination with FLOT
- Immunogenicity of zolbetuximab as a single agent, in combination with mFOLFOX6 (with or without nivolumab), in combination with pembrolizumab, and in combination with FLOT
- Health-related quality of life (HRQoL)
- ORR of zolbetuximab in combination with pembrolizumab and in combination with mFOLFOX6 as assessed by an independent central reader
- ORR of zolbetuximab as a single agent and in combination with mFOLFOX6 (with or without nivolumab) based on investigator assessment
- Disease control rate (DCR), duration of response (DOR) and progression free survival (PFS) of zolbetuximab as a single agent and in combination with mFOLFOX6 based on independent central reader assessment
- DCR, DOR and PFS of zolbetuximab as a single agent and in combination with mFOLFOX6 (with or without nivolumab) based on investigator assessment
- Overall survival (OS) of zolbetuximab as a single agent, in combination with mFOLFOX6 and nivolumab, and in combination with FLOT
- Safety and tolerability of zolbetuximab + FLOT (Cohort 5) include the following additional assessments:
o Surgical complications
o Surgical mortality as defined by death within 30 days of surgery
o Percentage of subjects able to complete preoperative chemotherapy
o Perioperative mortality and morbidity at 30 days and 90 days post last dose
o Percentage of subjects able to start postoperative chemotherapy
o Percentage of subjects able to complete postoperative chemotherapy

- Cohort 5: Antitumor activity of zolbetuximab and FLOT as measured by radiological response (restaging) and pathological response ypTNM (pCR)
- Cohort 5: Disease-free survival (DFS)
- Cohort 5: Minimal residual disease and disease recurrence as measured by circulating tumor DNA (ctDNA)

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Female subject eligible to participate if she is not pregnant and at least one of the following conditions applies:
a. Not a woman of child-bearing potential (WOCBP) OR
b. WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study drugs.
2. Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration.
3. Female subject must agree not to donate ova starting at screening and throughout the study period, and for 9 months after the final oxaliplatin administration and 6 months after the final administration of all other study drugs.
4. A sexually active male subject with a female partner(s) who is of child-bearing potential must agree to use contraception during the treatment period and for at least 6 months after the final study drug administration.
5. Male subject must agree not to donate sperm starting at screening and throughout the study period, and for 6 months after the final study drug administration.
6. 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 period and for 6 months after the final study drug administration.
7. Subject has histologically confirmed gastric or GEJ adenocarcinoma.
8. Cohorts 1-4: Subject has radiographically-confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to the first dose of study treatment.
9. Subjects tumor is positive for CLDN18.2 expression demonstrating moderate to strong membranous staining as determined by central IHC testing.
10. Subject agrees to not participate in another interventional study while on treatment.
11. Subject has Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
12. Subject has predicted life expectancy >= 12 weeks.
13. Subject must meet all of the following criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to the first dose of study treatment. In case of multiple central laboratory data within this period, the most recent data should be used.
- Hemoglobin (Hgb) >= 9 g/dL (transfusion is allowed, but post-transfusion Hgb [24 hours or later following transfusion] must be >= 9 g/dL)
Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
Platelets >= 100 x 10^9/L
Albumin >= 2.5 g/dL
Total bilirubin <= 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 x upper limit of normal (ULN) in subjects without liver metastases ( <= 5 x ULN if liver metastases are present)
Cohorts 1-4: Estimated creatinine clearance >= 30 mL/min
Cohort 5: Serum creatinine <=1.5 x ULN, or estimated creatinine clearance >= 50 mL/min for subjects with serum creatinine levels > 1.5 x ULN
Prothrombin time/international normalized ratio and partial thromboplastin time <= 1.5 x ULN (except for subjects receiving anticoagulation therapy)

Specific to Cohort 1A:
1. Subject has measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 28 days prior to the first dose of study treatment per investigator assessment. For subjects with only 1 evaluable lesion and prior radiotherapy <= 3 months before enrollment, the lesion must either be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
2. Subject has disease progression on or after at least 2 prior regimens for their advanced disease, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy and all associated side effects have resolved to grade 1 or less.
3. Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment.
4. Subject must be an appropriate candidate for a tumor biopsy and is amenable to undergo a tumor biopsy during the screening period (if applicable) and treatment period as indicated in the Schedule of Assessments.

Specific to Cohort 2:
1. Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment per investigator assessment. For subjects with only 1 evaluable lesion and prior radiotherapy <= 3 months before enrollment, the lesion must either be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
2. Subject has not received prior systemic anti-cancer therapy for their advanced disease (subject may have received neoadjuvant and/or fluorouracil-containing adjuvant chemotherapy as long as it has been completed >= 6 months before the first dose of study treatment).
3. Subject has a gastric or GEJ tumor that is HER2-negative as determined by local or central testing.
4. Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment.
5. Subject must be an appropriate candidate for a tumor biopsy and is amenable to undergo a tumor biopsy during the screening period (if applicable) and treatment period as indicated in the Schedule of Assessments.

Specific to Cohort 3A:
1. Subject has radiologically evaluable disease (measurable and/or non-measurable) according to RECIST 1.1, per local assessment, <= 28 days prior to the first dose of study treatment. For subjects with only 1 evaluable lesion and prior radiotherapy <= 3 months before enrollment, the lesion must either be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
2. Subject has disease progression on or after at least 2 prior regimens for their advanced disease, including fluoropyrimidine and platinum-containing chemotherapy, and if appropriate, HER2/neu-targeted therapy.
3. Subject has not received prior checkpoint inhibitor therapy.

Specific to Cohort 4A and 4B:
1. Subject has radiologically evaluable disease.
2. Subject has not received prior systemic anti-cancer therapy for their advanced disease.
3. Subject has a gastric or GEJ tumor that is HER2-negative as determined by local or central testing.
4. Subject has not received prior checkpoint inhibitor therapy.

Specific to Cohort 4B Only:
1. Subject must have an additional available tumor specimen collected within 3 months prior to the first dose of study treatment.
2. Subject must be an appropriate candidate for a tumor biopsy and is amenable to undergo a tumor biopsy during the screening period (if applicable) and treatment period.

Specific to Cohort 5 Only:
1. Subject has new histologically confirmed primary gastric or GEJ adenocarcinoma that is amenable to curative resection.
2. Subject has locoregional, resectable gastric or GEJ adenocarcinoma. GEJ may include type I-III Siewert classification. Clinical stage will be determined by endoscopic ultrasound (EUS) and/or CT or MRI. Diagnostic laparoscopy may be used as per
institutional guidelines and clinical practices.
3. Subject meets one of the following criteria of locoregional disease by clinical TNM staging:
- GEJ: cT2,N0 (high risk-lesions: >= 3 cm, poorly differentiated), cT1b-cT2,N+ or cT3-cT4a,Any N.
- Gastric: T2 to T4a, and/or N1-3,M0.
4. Subject's tumor expresses CLDN18.2 in >= 75% of tumor cells demonstrating moderate to
strong membranous staining as determined by central IHC testing

Exclude criteria

1. Subject has had prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies.
2. Subject has known immediate or delayed hypersensitivity or contraindication to any component of study treatment.
3. Subject has received other investigational agents or devices concurrently or within 28 days prior to first dose of study treatment.
4. Subject has received systemic immunosuppressive therapy, including systemic corticosteroids 14 days prior to first dose of study treatment.
5. Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent recurrent vomiting.
6. Subject has significant gastric bleeding and/or untreated gastric ulcers that would preclude the subject from participation.
7. Subject has history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer.
8. Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive hepatitis B surface antigen [HBsAg]) or hepatitis C infection.
9. Subject has had within 6 months prior to first dose of study treatment any of the following: unstable angina, myocardial infarction, ventricular arrhythmia requiring intervention or hospitalization for heart failure.
10. Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to the start of study treatment.
11. Subject has active autoimmune disease that has required systemic treatment within the past 3 months prior to the start of study treatment.
12. Subject has a clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this study or make the subject unsuitable for study participation.
13. Subject has psychiatric illness or social situations that would preclude study compliance.
14. Subject has had a major surgical procedure <= 28 days before start of study treatment.
15. Subject is without complete recovery from a major surgical procedure <= 14 days before start of study treatment
16. Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma <= 14 days (Cohorts 1 and 3A) and <= 28 days (Cohorts 2 and 4A or 4B) prior to start of study treatment and has NOT recovered from any related toxicity.
17. Subject has another malignancy, for which treatment is required.
18. Cohort 2, 4, and 5 Only, subject has any of the following:
o Prior severe allergic reaction or intolerance to any component of mFOLFOX6 or FLOT chemotherapeutics in this study
o Known dihydropyrimidine dehydrogenase deficiency (DPD).
o Known peripheral neuropathy > Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the subject ineligible).
o Sinusoidal obstruction syndrome, formerly known as veno-occlusive disease, if present, should be stable or improving.
o History of clinically significant ventricular arrhythmias.
o QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects.
o History or family history of congenital long QT syndrome.
o Cardiac arrhythmias requiring anti-arrhythmic medications (Subjects with rate controlled atrial fibrillation for > 1 month prior to first dose of study treatment are eligible).
19. Cohorts 3A, 4A and 4B Only, subject has any of the following:
o Ongoing or previous autoimmune disease or interstitial lung disease, active diverticulitis or gastrointestinal ulcerative disease, or solid organ or stem cell transplant (for Cohort 4) or other uncontrolled or clinically significant medical disorders.
o 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.
o Known history of serious hypersensitivity reaction to a known ingredient of pembrolizumab or nivolumab.
o Cohort 4B Only: Subject has microsatellite instability-high or mismatch repair deficient tumors.
20. Cohort 5 Only, subject has either of the following:
o Subject cannot undergo curative resection per the investigator's judgment
o Subject meets the following criterion of locoregional disease by clinical TNM staging: cT1N0.

Related Information

• Primary Sponsor: Astellas Pharma Global Development, Inc.
• Secondary ID(s): NCT03505320,2017-002566-50,JapicCTI-205421