| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 Positive Metastatic and/or Unresectable Gastric or Gastro Esophageal Junction (GEJ)Adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Gastric 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071114 |
| E.1.2 | Term | Metastatic gastric adenocarcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 compare overall survival (OS) in HER2-positive (defined as IHC 3+ or IHC 2+/ISH+) gastric cancer(GC) and GEJ subjects treated with TDXd vs. Ram + PTX. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare PFS in HER2-positive GC and GEJ adenocarcinoma subjects treated with TDXd or Ram + PTX;
• To evaluate further the clinical efficacy of TDXd and Ram + PTX by objective response rate (ORR based on Investigator assessment;
• To evaluate further the clinical efficacy of TDXd and Ram + PTX by DoR;
• To evaluate further the clinical efficacy of TDXd and Ram + PTX by DCR;
• To evaluate the safety of T-DXd at 6.4 mg/kg dose;
• To evaluate the Pharmacokinetics (PK) of T-DXd;
• To evaluate immunogenicity of TDXd
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Sign and date the Tissue Screening and Main ICFs, prior to the start of any study-specific qualification procedures.
2. Adults (according to local regulation) and able to provide informed consent for study participation.
3. Pathologically documented gastric and GEJ adenocarcinoma that has been previously treated in the metastatic setting (unresectable, locally advanced, or metastatic disease).
4. Progression on or after first-line therapy with a trastuzumab or approved trastuzumab biosimilar-containing regimen.
Note: Prior adjuvant therapy with a trastuzumab-containing regimen can be counted as a line of therapy if the subject progressed on or within 6 months of completing adjuvant therapy.
5. Is willing and able to provide an adequate tumor sample for tissue screening to confirm HER2 status by Central Laboratory. See Section 8.1.2.
6. Centrally confirmed HER2-positive (IHC 3+ or IHC 2+ and evidence of HER2 amplification by ISH) as classified by ASCO-CAP on a tumor biopsy obtained after progression on or after a first-line trastuzumab or approved trastuzumab biosimilar-containing regimen.
7. ECOG PS of 0 or 1 at both Screening and within 3 days prior to randomization.
8. Adequate laboratory parameters as evidenced by all blood counts (refer protocol for details) within 14 days of randomization.
9. Has adequate treatment washout period before randomization/enrollment, as described in the protocol.
10. LVEF ≥50% within 28 days before randomization per echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
11. Recovered from the effects of any prior surgery or radiotherapy.
12. Men and women of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for female subjects and 4 months for male subjects after the last dose of study drug. Methods considered as highly effective methods of contraception are detailed in Section 10.3.4. For Ram + PTX, sites should follow local label or institutional guidelines.
13. Male subjects must not freeze or donate sperm starting at Screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to randomization/enrollment in this study. For Ram + PTX, sites should follow local label or institutional guidelines.
14. Female subjects must not donate, or retrieve for their own use, ova from the time of Screening and throughout the study Treatment Period, and for at least 7 months after the final study drug administration. For Ram + PTX, sites should follow local label or institutional guidelines.
15. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. |
|
| E.4 | Principal exclusion criteria |
1. Use of anticancer therapy after trastuzumab-containing treatment.
2. Medical history of myocardial infarction (MI) within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association [NYHA] Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation before enrollment to rule out MI.
3. Has a QT interval corrected by Fridericia’s formula (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male subjects) based on average of the Screening triplicate12-lead electrocardiogram (ECG).
4. Has a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). Drainage and CART must be at least 2 weeks prior to Screening.
5. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
6. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disease (eg, pulmonary emboli within 3 months of the study randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.).
7. Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented (or a suspicion of) pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the electronic case report form (eCRF) for patients who are included in the study.
8. Prior pneumonectomy.
9. Spinal cord compression or clinically active CNS metastases, defined as untreated and symptomatic or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
a. Subjects with clinically inactive brain metastases may be included in the study.
b. Subjects with brain metastases who were treated and are no longer symptomatic, and subjects who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy (WBRT) and randomization/study enrollment.
10. Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated.
11. History of severe hypersensitivity reactions to either the T-DXd or inactive ingredients in T-DXd.
12. History of severe hypersensitivity reactions to other monoclonal antibodies or any components used in the ramucirumab drug product preparation.
13. Known allergy or hypersensitivity to PTX or any components used in the PTX preparation or other contraindication for taxane therapy such as peripheral neuropathy, Grade 2.
14. Current uncontrolled infection requiring antibiotics, antivirals, or antifungals or an unexplained fever >38.0°C during Screening visits or on the first scheduled day of dosing (at the discretion of the Investigator, subjects with tumor fever may be enrolled), which in the Investigator’s opinion might compromise the subject’s participation in the study or affect the study outcome.
15. Substance abuse or any other medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that may, in the opinion of the Investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
16. Social, familial, or geographical factors that would interfere with study participation or follow-up.
17. Known HIV infection, or active hepatitis B or C infection. Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Subjects should be tested for HIV prior to randomization/enrollment if required by local regulations or IRB/IEC.
18. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy).
19. Prior treatment with an ADC consisting of an exatecan derivative that is a topoisomerase I inhibitor.
20. Pregnant, breastfeeding, or planning to become pregnant.
21. Subjects who, in the opinion of the Investigator, have symptoms or signs suggestive of clinically unacceptable deterioration of the primary disease at the time of Screening or otherwise considered inappropriate for the study by the Investigator.
22. Clinically significant gastrointestinal disorder in the opinion of Investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After at least 237 (70%) OS events are recorded for interim analysis and 339 OS events are recorded for final analysis |
|
| E.5.2 | Secondary end point(s) |
- Progression-Free Survival (PFS)
- Objective Response Rate (ORR)
- Duration of Response (DoS)
- Disease Control Rate (DCR)
- SAEs, TEAEs and other safety parameters
- PK profile
- Immunogenicity (Incidence of ADA and NAb) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS, ORR: At the time of interim analysis and final analysis;
DoR, DCR: At the time of primary analysis;
SAEs, TEAEs and other safety parameters: Continuous monitoring and reported at the time of the primary analysis;
PK Profile and Immunogenicity: At the time of primary analysis |
|
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Immunogenicity, Biomarker Analysis, Health economics and outcomes research (HEOR), Quality of Life (QoL), Patient Reported Outcomes (PROs) |
|
| 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 | No |
| 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Ramucirumab and Paclitaxel |
|
| 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 | 3 |
| 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 |
| Brazil |
| Chile |
| China |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| Singapore |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| Belgium |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Poland |
| Portugal |
| Romania |
| Spain |
| United Kingdom |
| Argentina |
|
| 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
|
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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