E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or
Gastroesophageal Junction (GEJ) Adenocarcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the stomach or of the gastroesophageal junction which cannot be removed by surgery. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001150 |
E.1.2 | Term | Adenocarcinoma gastric |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of zolbetuximab plus capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX (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. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate efficacy as measured by Overall Survival (OS) as a key secondary objective
- To evaluate efficacy as measured by Objective Response Rate (ORR)
- To evaluate efficacy as measured by Duration of Response (DOR)
- To evaluate safety and tolerability of zolbetuximab
- To evaluate health related quality of life (HRQoL) using the parameters as measured by European
Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and QLQ-OG25 plus STO22 Belching subscale, Global Pain (GP) and the EuroQOL Five Dimensions Questionnaire 5L (EQ5D-5L) questionnaires
- To evaluate the pharmacokinetics of zolbetuximab
- To evaluate the immunogenicity profile of zolbetuximab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General Criteria:
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations 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. A 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:
- Not a woman of childbearing potential (WOCBP) as defined in [Appendix 12.3 Contraception Requirements] OR
- WOCBP who agrees to follow the contraceptive guidance as defined in [Appendix 12.3 Contraception Requirements] throughout the treatment period and for 6 months after the final study treatment administration.
4. 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.
5. Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study treatment administration.
6. A male subject with female partner(s) of childbearing potential:
- must agree to use contraception as detailed in [Appendix 12.3 Contraception Requirements] during the treatment period and for 6 months after the final study treatment administration.
7. A male subject must not donate sperm during the treatment period and for 6 months after the final study treatment administration.
8. 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 treatment administration.
9. Subject agrees not to participate in another interventional study while receiving study drug in present study.
Disease Specific Criteria:
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 non-measurable) 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 HER2-negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen.
Physical or Laboratory Findings:
15. Subject has ECOG performance status 0 or 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 case of multiple central laboratory data within this period, the most recent data 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 (ANC) ≥ 1.5x109/L
c. Platelets ≥ 100x109/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 (AST) and alanine aminotransferase (ALT) ≤ 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 (PT/INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
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E.4 | Principal exclusion criteria |
Prohibited Treatment or Therapies:
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 as long as it was completed at least 6 months prior to randomization.
2. Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days prior to randomization and has not recovered from any related toxicity.
3. Subject has received treatment with herbal medications or other treatments that have known antitumor activity within 28 days prior to randomization.
4. Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subject 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 is eligible.
5. Subject has received other investigational agents or devices within 28 days prior to randomization.
Medical History or Concurrent Disease:
6. Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies.
7. Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
8. Subject has prior severe allergic reaction or intolerance to any component of CAPOX.
9. Subject has known dihydropyrimidine dehydrogenase (DPD) deficiency. (NOTE: Screening for DPD deficiency should be conducted per local requirements.)
10. Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.
11. Per investigator judgement, subject has significant gastric bleeding and/or untreated gastric ulcers that exclude the subject from participation.
12. 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 virus (HCV) serology but negative HCV RNA test are eligible.
c. Subjects treated for HCV with undetectable viral load results are eligible.
13. Subject has an active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization.
14. Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.
15. Subject has significant cardiovascular disease, including any of the following:
a. Congestive heart failure (defined as New York Heart Association [NYHA] Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, cerebrovascular accident (CVA), 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 Pointes);
c. 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 (Subjects with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible.)
16. Subject has history of central nervous system (CNS) metastases and/or carcinomatous meningitis from gastric/GEJ cancer.
17. Subject has known peripheral sensory neuropathy > grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality.
18. Subject has had a major surgical procedure ≤ 28 days prior to randomization.
a. Subject without complete recovery from a major surgical procedure ≤ 14 days prior to randomization.
19. Subject has psychiatric illness or social situations that would preclude study compliance, per investigator judgement.
20. Subject has another malignancy for which treatment is required per investigator's clinical judgement.
21. Subject has any concurrent disease, infection, or co-morbid 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is progression free survival (PFS), defined as the time from the date of randomization until the date of radiological progressive disease (PD) per Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1) by independent review committee (IRC) or death from any cause, whichever is earliest. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be performed when the protocol-defined number of PFS events has been observed. |
|
E.5.2 | Secondary end point(s) |
The secondary endpoints are:
- OS, defined as the time from the date of randomization until the date of death from any cause
- ORR, defined as the proportion of subjects who have a best overall response of complete response
(CR) or partial response (PR) as assessed by IRC per RECIST 1.1
- 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
- Safety and tolerability, as measured by AEs, laboratory test results, vital signs, ECGs and ECOG performance status
- HRQoL, as collected via EORTC QLQ-C30, QLQ-OG25 plus STO22 Belching subscale, GP, and EQ5D-5L questionnaires
- Pharmacokinetics of zolbetuximab, Ctrough
- Immunogenicity of zolbetuximab as measured by the frequency of antidrug-antibody (ADA)
positive subjects |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoint analysis will be performed at the protocol defined primary PFS analysis and at the final OS analysis after 100% of the planned death events have been observed. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Austria |
Canada |
China |
Croatia |
Germany |
Greece |
Ireland |
Japan |
Korea, Republic of |
Malaysia |
Netherlands |
Portugal |
Romania |
Spain |
Taiwan |
Thailand |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the last visit or scheduled procedure shown in the Schedule of Assessments for the last study participant in the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 15 |