A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared with Placebo Plus mFOLFOX6 as First-line Treatment of Subjects with Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Astellas Pharma Global Development Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Nov 2018 → ongoing

Decision date (initial)

2024-07-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-511365-11-00

EudraCT number

2017-002567-17

ClinicalTrials.gov

NCT03504397

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Efficacy, Others, Safety, Pharmacogenomic, Pharmacoeconomic

To evaluate the efficacy of zolbetuximab plus mFOLFOX6 compared with placebo plus mFOLFOX6 (as first-line treatment) as measured by Progression Free Survival (PFS) in subjects with Claudin (CLDN)18.2 positive, human epidermal growth factor receptor 2 (HER2)–negative locally advanced unresectable or metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma

Secondary objectives 13

1. Evaluate efficacy as measured by Overall Survival(OS) as key secondary objective
2. Evaluate physical function(PF), OG25-Pain and GHS/QoL scores as measured by EORTC as key secondary objective
3. Evaluate efficacy as measured by Objective Response Rate(ORR)
4. Evaluate efficacy as measured by Duration of Response(DOR)
5. Evaluate safety and tolerability of zolbetuximab
6. Evaluate health related quality of life(HRQoL) using additional parameters as measured by EORTC QLQ-C30,QLQ-OG25,Global Pain(GP) and EuroQOL Five Dimensions Questionnaire 5L(EQ5D-5L) questionnaires
7. Evaluate pharmacokinetics of zolbetuximab
8. Evaluate the immunogenicity profile of zolbetuximab
9. Evaluate efficacy as measured by Time to Progression(TTP)
10. Evaluate PFS following subsequent anti-cancer treatment(PFS2)
11. Evaluate Disease Control Rate(DCR)
12. Evaluate potential genomic and/or other biomarkers that may correlate with treatment outcome to zolbetuximab and mFOLFOX6
13. Evaluate Health Resource Utilization(HRU)

Conditions and MedDRA coding

Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Regulatory references

Plan to share IPD

No

IPD plan description

not applicable

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] Authorization for US sites) must be obtained from the subject or legally authorized representative (if applicable) prior to any study-related procedures
2. Subject is considered an adult (e.g., ≥ 18 years of age in the US) according to local regulation at the time of signing the informed consent
3. Subject agrees not to participate in another interventional study while on study treatment
4. Female subject is eligible to participate if she is not pregnant (negative serum pregnancy test at Screening; female subjects with elevated serum beta human chorionic gonadotropin (βhCG) and a demonstrated non-pregnant status through additional testing are eligible) and at least 1 of the following conditions applies: a.Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.3 Contraception Requirements OR b. WOCBP who agrees to follow the contraceptive guidance as defined in Appendix 12.3 Contraception Requirements throughout the treatment period and for 9 months after the final administration of oxaliplatin and 6 months after the final administration of all other study drugs
5. Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study treatment administration
6. Female subject must not donate ova starting at Screening and throughout the study period, and 9 months after the final administration of oxaliplatin and for 6 months after the final administration of all other study drugs
7. A sexually active male subject with female partner(s) who are of childbearing potential must agree to use contraception as detailed in Appendix 12.3 Contraception Requirements during the treatment period and for at least 6 months after the final study drug administration
8. Male subject must not donate sperm starting at Screening and throughout the study period and for 6 months after the final study drug administration
9. 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 for the time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration
10. Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma
11. Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to randomization
12. Subject has radiologically evaluable disease (measurable and/or nonmeasurable disease according to RECIST 1.1), per local assessment, ≤ 28 days prior to randomization. For subjects with only 1 evaluable lesion and prior radiotherapy ≤3 months before randomization, the lesion must either be outside the field of prior radiotherapy or have documented progression following radiation therapy
13. Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing
14. Subject has a known HER2-negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen. (Unique to China: Subject has a known HER2-negative gastric or GEJ tumor)
15. Subject has ECOG performance status 0 to 1
16. Subject has predicted life expectancy ~12 weeks in the opinion of the investigator
17. Subject must meet all of the following criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to randomization. In the case of multiple sample collections within this period, the most recent sample collection with available results should be used to determine eligibility. a.Hemoglobin (Hgb) ≥ 9 g/dL. Subjects requiring transfusions are eligible if they have a post-transfusion Hgb ≥ 9 g/dL. b.Absolute neutrophil count ≥ 1.5 x 109/L c.Platelets ≥ 100 x 109/L d.Albumin ≥ 2.5 g/dL e.Total bilirubin ≤ 1.5 x upper limit of normal (ULN) without liver metastases (or < 3.0 x ULN if liver metastases are present) f.Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present) g.Estimated creatinine clearance ≥ 30 mL/min h.Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)

Exclusion criteria 20

1. Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-adjuvant or adjuvant chemotherapy, immunotherapy or other systemic anticancer therapies, as long as it was completed at least 6 months prior to randomization. Subject may have received treatment with herbal medications that have known antitumor activity > 28 days prior randomization
2. Per investigator judgment, subject has significant gastric bleeding and/or untreated gastric ulcers that exclude the subject from participation
3. Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive HBs Ag) or C infection. NOTE: Screening for these infections should be conducted per local requirements. a.For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test will be performed and if positive, the subject will be excluded. b.Subjects with positive hepatitis C (HCV) serology, but negative HCV RNA test are eligible. c.Subjects treated with HCV with undetectable viral load results are eligible
4. Subject has an active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization
5. Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization
6. Subject has significant cardiovascular disease, including any of the following: a.Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to randomization. b.History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointesc. QTc interval > 450 msec for male subjects: QTc interval > 470 msec for female subjects d.History or family history of congenital long QT syndrome e.Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible)
7. Subject has a history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer
8. Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days prior to randomization and recovered from any related toxicit
9. Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subjects 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 dose of systemic corticosteroids, or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed
10. Subject has received other investigational agents or devices within 28 days prior to randomization
11. Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies
12. Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment
13. Subject has prior severe allergic reaction or intolerance to any component of mFOLFOX6
14. Subject has known dihydropyrimidine dehydrogenase deficiency (DPD). (NOTE: Screening for DPD deficiency should be conducted per local requirements)
15. Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting
16. Subject has known peripheral sensory neuropathy > grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality
17. Subject has had a major surgical procedure 28 days prior to randomization. a.Subject is without complete recovery from a major surgical procedure 14 days prior to randomization
18. Subject has psychiatric illness or social situations that would preclude study compliance, per investigator judgment
19. Subject has another malignancy for which treatment is required per investigator's clinical judgment
20. Subject has any concurrent disease, infection or comorbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data in the opinion of the investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is PFS, which is defined as the time from the date of randomization until the date of radiological PD (per Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 by independent review committee [IRC]) or death from any cause, whichever is earliest

Secondary endpoints 8

1. OS, defined as the time from the date of randomization until the date of death from any cause
2. Time to confirmed deterioration (TTCD) using the PF, OG25-Pain and GHS/QoL scores as measured by EORTC QLQ-C30 and QLQ-OG25. TTCD is defined as time to first confirmed deterioration, i.e., time from randomization to first clinically meaningful deterioration that is confirmed at the next scheduled visit
3. ORR, defined as the proportion of subjects who have a best overall response (BOR) of CR or PR as assessed by IRC per RECIST 1.1
4. DOR, defined as the time from the date of the first response (CR/PR) until the date of PD as assessed by IRC per RECIST 1.1 or date of death from any cause, whichever is earliest
5. Safety and tolerability, as measured by AEs, laboratory test results, vital signs, ECGs and Eastern Cooperative Oncology Group (ECOG) performance status
6. HRQoL using the additional parameters as measured by EORTC QLQC30, QLQ-OG25 plus GP and EQ5D-5L questionnaire
7. Pharmacokinetics of zolbetuximab Ctrough
8. Immunogenicity of zolbetuximab as measured by the frequency of antidrug antibody (ADA) positive subject

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Astellas Pharma Global Development Inc.

Sponsor organisation

Astellas Pharma Global Development Inc.

Address

2375 Waterview Drive

City

Northbrook

Postcode

60062-6111

Country

United States

Scientific contact point

Organisation

Astellas Pharma Global Development Inc.

Contact name

Head of Regulatory Affairs

Public contact point

Organisation

Astellas Pharma Global Development Inc.

Contact name

Head of Regulatory Affairs

Third parties 15

Locations

6 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 37 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications