| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Gastroesophageal Adenocarcinoma (GEA) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastroesophageal Adenocarcinoma (GEA) |
|
| 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 | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10082464 |
| E.1.2 | Term | Advanced gastric carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055458 |
| E.1.2 | Term | Esophageal adenocarcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 compare the efficacy of zanidatamab in combination with chemotherapy or in combination with chemotherapy and tislelizumab to the efficacy of trastuzumab in combination with chemotherapy in subjects with unresectable locally advanced, recurrent or metastatic HER2 positive GEA |
|
| E.2.2 | Secondary objectives of the trial |
●To further compare the efficacy of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab to chemotherapy with trastuzumab
●To evaluate the safety and tolerability of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab
●To evaluate the effect of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab on health-related quality of life (HRQoL)
●To evaluate the pharmacokinetics (PK) of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab
●To evaluate the PK of tislelizumab in combination with chemotherapy and zanidatamab
●To evaluate the immunogenicity of zanidatamab in combination with chemotherapy or chemotherapy and tislelizumab
●To evaluate the immunogenicity of tislelizumab in combination with chemotherapy and zanidatamab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histologically confirmed unresectable locally advanced, recurrent or metastatic HER2-positive gastroesophageal adenocarcinoma (adenocarcinomas of the stomach or esophagus, including the gastroesophageal junction), defined as 3+ HER2 expression by IHC or 2+ HER2 expression by IHC with ISHpositivity per central assessment. Subjects with esophageal adenocarcinoma must not be eligible for combined chemoradiotherapy at the time of enrollment.
2.Assessable (measurable or non-measurable) disease as defined by RECIST 1.1.
3.Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, assessed within 3 days prior to randomization
4.Adequate organ function
5.Left ventricular ejection fraction (LVEF) ≥ 50% as determined by either echocardiogram or multiple gated acquisition scan (MUGA)
|
|
| E.4 | Principal exclusion criteria |
1.Prior treatment with a HER2-targeted agent, with the exception of subjects who received HER2-targeted treatment for breast cancer > 5 years prior to initial diagnosis of GEA.
2.Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2 or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
3. Prior treatment with systemic antineoplastic therapy or intraperitoneal chemotherapy for unrespectable locally advanced, recurrent or metastatic GEA.
4.Untreated central nervous system (CNS) metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks prior to randomization. Stable, treated brain metastases are allowed (defined as subjects who are completely off steroids and anticonvulsants and are neurologically stable with no evidence of radiographic progression for at least 4 weeks prior to randomization).
5.Known history of or ongoing leptomeningeal disease (LMD).
6.Known additional malignancy that is not considered cured or that has required treatment within the past 3 years.
7.Known active hepatitis
8.Any history of human immunodeficiency virus (HIV) infection
9.Known SARS-CoV-2 infection; subjects with prior infection that has resolved per local institutions’ requirements and screening guidance are eligible
10.Clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic congestive heart failure (CHF).
11.QTc Fridericia (QTcF) > 470 ms.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
●Progression-free survival (PFS) by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), assessed by blinded independent central review (BICR)
●Overall survival (OS)
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary PFS analysis will be performed once the target event count has been reached for each comparison. This is estimated to occur 7 months after the last subject is randomized. At this time, interim analyses of OS will be performed.
The primary analyses of OS will be performed once the target event count has been reached for each comparison. It is estimated that this will occur approximately 20 months after the last subject is randomized. |
|
| E.5.2 | Secondary end point(s) |
●Confirmed objective response rate (ORR) by RECIST 1.1, assessed by BICR
●Duration of response (DOR) by RECIST 1.1, assessed by BICR
●PFS by RECIST 1.1, per investigator assessment
●Confirmed ORR by RECIST 1.1, per investigator assessment
●DOR by RECIST 1.1, per investigator assessment
●Frequency, type, severity, seriousness, and relatedness of adverse events (AEs)
●Frequency and severity of clinical laboratory abnormalities
●Change from baseline in health economics and outcomes research / patient-reported outcomes (HEOR/PRO) parameters
●Serum concentration and PK parameters for zanidatamab
●Serum concentrations for tislelizumab
●Frequency, duration, and time of onset of anti zanidatamab antibodies and neutralizing antibodies, if applicable
●Frequency, duration, and time of onset of anti tislelizumab antibodies and neutralizing antibodies, if applicable
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary PFS analysis will be performed once the target event count has been reached for each comparison. This is estimated to occur 7 months after the last subject is randomized. At this time, interim analyses of OS will be performed.
The primary analyses of OS will be performed once the target event count has been reached for each comparison. It is estimated that this will occur approximately 20 months after the last subject is randomized. |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 143 |
| 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 |
| Chile |
| Guatemala |
| Ukraine |
| Brazil |
| Canada |
| Georgia |
| India |
| Mexico |
| Serbia |
| South Africa |
| Turkey |
| United Kingdom |
| Belgium |
| Estonia |
| France |
| Germany |
| Greece |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| 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
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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