| 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] |
| 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) |
|
| 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
- physical function(PF), OG25-Pain and GHS/QoL scores as measured by EORTC as key secondary objective
- efficacy as measured by Objective Response Rate (ORR)
- efficacy as measured by Duration of Response (DOR)
- safety and tolerability of zolbetuximab
- health related quality of life(HRQoL) using the parameters as measured by European Organization for Research and Treatment of Cancer QLQ-C30, QLQ-OG25, Global Pain(GP) and the EuroQOL Five Dimensions Questionnaire 5L(EQ5D-5L) questionnaires
- the pharmacokinetics of zolbetuximab
- the immunogenicity profile of zolbetuximab
- efficacy as measured by Time to Progression(TTP)
- PFS following subsequent anti-cancer treatment(PFS2)
- Disease Control Rate(DCR)
- potential genomic and/or other biomarkers that may correlate with treatment outcome to zolbetuximab and mFOLFOX6
- Health Resource Utilization(HRU) |
|
| 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 (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.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:
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 for 6 months after the final study drug administration.
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.
Disease Specific Criteria:
10.Subject has histologically confirmed diagnosis of Gastric or GE) 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 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 HER2-Negative tumor as determined by local or central testing on a gastric or GE) tumor specimen.(Unique to China: Subject has a known HER2-negative gastric or GEJ tumor)
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 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).
|
|
| E.4 | Principal exclusion criteria |
Prohibited Treatment or Therapies
1.Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GE) 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.Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GE) adenocarcinoma ≤ 14 days prior to randomization and recovered from any related toxicity.
3.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.
4.Subject has received other investigational agents or devices within 28 days prior to randomization.
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 local requirements.)
9.Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.
10.Per investigator judgment, subject has significant gastric bleeding and/or untreated gastric ulcers that exclude the subject from participation.
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. 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.
12.Subject has an active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization.
13.Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.
14.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.E 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).
15.Subject has a history of central nervous system metastases and/or carcinomatous meningitis from gastric/GEJ cancer.
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.
|
|
| 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
-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.
-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 using the additional parameters as measured by EORTC QLQ- C30, QLQ-OG25 plus GP and EQ5D-5L questionnaires
-Pharmacokinetics of zolbetuximab Ctrough
-Immunogenicity of zolbetuximab as measured by the frequency of anti-drug 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.6.1 | 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 |
|
| 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.8.2.3.1 | Comparator description |
| 0.9% Sodium Chloride Injection |
|
| 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 | 8 |
| 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 |
| Chile |
| Colombia |
| Peru |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
|
| 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
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
