|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
|E.1.1.1||Medical condition in easily understood language ||
|Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
|E.1.1.2||Therapeutic area ||Diseases [C] - Cancer [C04]
|E.1.2 Medical condition or disease under investigation
|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)
|E.1.3||Condition being studied is a rare disease || Yes
|E.2 Objective of the trial
|E.2.1||Main objective of the trial ||
|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
|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) QLQ-C30, QLQ-OG25, 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
- To evaluate efficacy as measured by Time to Progression (TTP)
- To evaluate PFS following subsequent anti-cancer treatment (PFS2)
- To evaluate Disease Control Rate (DCR)
- To evaluate potential genomic and/or other biomarkers that may correlate with treatment outcome to zolbetuximab and mFOLFOX6
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
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 studyrelated
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.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
- WOCBP who agrees to follow the contraceptive guidance as defined in
Appendix 12.3 Contraception Requirements throughout the treatment
period and for at least 6 months after the final study drug
5.Female subject must agree not to breastfeed starting at Screening and
throughout the study period, and for 6 months after the final study
6.Female subject must not donate ova starting at Screening and
throughout the study period, and for 6 months after the final study drug
7.A sexually active male subject with female partner(s) who are of
childbearig 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
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.
Disease Specific Criteria:
10.Subject has histologically confirmed diagnosis of Gastric or GEJ
11.Subject has radiologically confirmed locally advanced unresectable or
metastatic disease within 28 days prior to the first dose of study
12.Subject has measurable disease according to RECIST 1.1 within 28
days prior to the first dose
of study treatment. For subjects with only 1 measurable lesion and prior
radiotherapy, the lesion must be outside the field of prior radiotherapy
or must 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 to 1.
16.Subject has predicted life expectancy 12 weeks in the opinion of the
17.Subject must meet all of the following criteria based on the centrally
analyzed laboratory tests 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 to determine eligibility.
a.Hemoglobin (Hgb) ≥ 9 g/dl. NOTE: Subject must not have received any
growth factor or blood transfusions within 14 days prior to the
hematology values obtained at screening. Subjects requiring
transfusions to meet eligibility criteria are not eligible.
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)
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)
|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 the
first dose of study treatment. Subject may have received treatment with
herbal medications that have known antitumor activity > 28 days prior
to first dose of study treatment.
2.Subject has received radiotherapy for locally advanced unresectable or
metastatic gastric or GEJ adenocarcinoma unless the radiotherapy was
completed > 28 days prior to start of study treatment. Subject who
received palliative radiotherapy to peripheral bone metastases 14 days
prior to start of study treatment and has recovered from all acute
toxicities is allowed.
3.Subject has received systemic immunosuppressive therapy, including
systemic corticosteroids within 14 days prior to first dose of study
treatment. 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) or a single dose of
systemic corticosteroids are allowed.
4.Subject has received other investigational agents or devices within 28
days prior to first dose of study treatment.
Medical History or Concurrent Disease
5.Subject has prior severe allergic reaction or intolerance to known
ingredients of zolbetuximab or other monoclonal antibodies, including
humanized or chimeric antibodies.
6.Subject has known immediate or delayed hypersensitivity, intolerance
or contraindication to any component of study treatment.
7.Subject has prior severe allergic reaction or intolerance to any
component of mFOLFOX6.
8.Subject has known dihydropyrimidine dehydrogenase deficiency
(DPD). (NOTE: Screening for DPD deficiency should be conducted per
9.Subject has gastric outlet syndrome or persistent/recurrent vomiting.
10.Subject with recent gastric bleeding or symptomatic subjects with
proven gastric ulcers that would exclude the subject from participation
per investigator judgment.
11.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. 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. Subjects with positive serology but
negative HCV RNA test results are eligible.
12.Subject has an active autoimmune disease that has required systemic
treatment within the past 2 years.
13.Subject has active infection requiring systemic therapy that has not
completely resolved within 14 days prior to start of study treatment.
14.Subject has significant cardiovascular disease, including any of the
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 administration of first dose
of study drug.
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
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 first dose of
study drugs are eligible)
15.Subject has known active central nervous system metastases and/or
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 the
start of study treatment.
a.Subject is without complete recovery from a major survival procedure
≤14 days prior to the first dose of study treatment.
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.
|E.5 End points
|E.5.1||Primary end point(s)||
|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.
|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 have 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 (BOR) of CR or 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, electrocardiograms (ECGs) and Eastern Cooperative Oncology
Group (ECOG) performance status
-HRQoL, as collected via EORTC QLQ-C30, QLQ-OG25, GP and EQ5D-5L
-Pharmacokinetics of zolbetuximab Ctrough
-Immunogenicity of zolbetuximab as measured by the frequency of antidrug
antibody (ADA) positive subjects.
|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.
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| No
|E.6.13.1||Other scope of the trial description||
|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.188.8.131.52||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.8.1.3||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.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
|E.8.2.4||Number of treatment arms in the trial||2
The trial involves single site in the Member State concerned
|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||12
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||60
|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||
|Korea, Republic of
|E.8.7||Trial has a data monitoring committee|| Yes
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of study in all participating countries is defined as the last subject's last visit, or last contact.
|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||6
|E.8.9.1||In the Member State concerned days||8
|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||8
|E.8.9.2||In all countries concerned by the trial days||14