E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2 Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the stomach and lower esophagous |
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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 | LLT |
E.1.2 | Classification code | 10071114 |
E.1.2 | Term | Metastatic gastric adenocarcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 compare PFS between treatment groups
To compare overall survival (OS) between treatment groups. |
|
E.2.2 | Secondary objectives of the trial |
To compare Objective Response Rate (ORR) between treatment groups.
To estimate Duration of Response (DOR), per RECIST 1.1 as assessed by BICR for each treatment group.
To assess the safety and tolerability of pembrolizumab in combination with trastuzumab plus chemotherapy by proportion of adverse events (AEs) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Future Biomedical Research |
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E.3 | Principal inclusion criteria |
1. Male/female participants who are at least 18 years of age on the day of signing the informed consent with histologically or cytologically confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic HER2 positive
gastric or GEJ adenocarcinoma.
2. Be HER2-positive defined as either IHC 3+ or IHC 2+ in combination with ISH+ (or FISH), as assessed by central review on primary or metastatic tumor. ISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of
signals for CEP17.
3. Have measurable disease as defined by RECIST 1.1 as determined by the site investigator. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
Note: The exact same image acquisition and processing parameters should be used throughout the study.
4. A male participant must agree to use an adequate method of contraception as outlined in Appendix 3 of the Protocol, for the course of the study through 180 days after the last dose of all study treatments.
5. A female participant is eligible to participate if she is not pregnant (see Appendix 3 of the Protocol), not breastfeeding, and at least one of the following conditions applies:
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 180 days after the last dose of study treatment.
6. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. The participant may also provide consent for Future Biomedical Research. However the participant may participate in the main study without participating in Future Biomedical Research.
7. Have a performance status of 0 or 1 on the ECOG Performance Scale within 3 days prior to the first dose of trial treatment.
8. Have a life expectancy of greater than 6 months.
9. Participants must have a 12-lead electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed by the investigator or other qualified person to evaluate cardiac function prior to enrollment in the study.
Adequate cardiac function will be assessed by:
a) Left ventricular ejection fraction (LVEF) ≥ 55% as determined by MUGA scan or ECHO; and
b) QT interval calculated according to the Fridericia method (QTcF) value ≤480 msec (mean of 3 measurements corrected for heart rate using Fridericia’s formula).
10. Have provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis. The PD-L1 result must be determined as positive or negative.
11. Have adequate organ function as defined in the Table 2 in the Protocol. Specimens must be collected within 10 days prior to the start of study treatment. |
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E.4 | Principal exclusion criteria |
1. Has had previous therapy for locally advanced unresectable or metastatic gastric/GEJ cancer. Participants may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization without progression.
2. Has had major surgery, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of study treatment.
3. Has had radiotherapy within 14 days of randomization. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
4. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
5. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, ie, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
6. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug.
8. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
9. Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis).
11. Has poorly controlled diarrhea (eg, watery stool, uncontrollable bowel movement with drugs, Grade ≥ 2 and number of defecations, ≥ 5/day).
12. Accumulation of pleural, ascitic, or pericardial fluid requiring drainage within 2 weeks prior to enrollment.
13. Has a history or current evidence of any condition (eg, known deficiency of the enzyme dihydropyrimidine dehydrogenase, hearing impairment, etc.), therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant’s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
14. Has peripheral neuropathy > Grade 1.
15. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.
16. A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization or treatment allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment.
18. Has symptomatic congestive heart failure (CHF) (ie, New York Heart Association > Class II or higher), history or current evidence of clinically significant cardiac arrhythmia requiring anti-arrhythmic therapy other than beta blockers or digoxin and/or conduction abnormality ≤6 months prior to start of study treatment except atrial fibrillation and paroxysmal supraventricular tachycardia, active coronary artery disease, unstable angina (anginal symptoms at rest), new-onset angina within 3 months before randomization, or myocardial infarction ≥6 months before randomization.
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). No testing for HIV is required unless mandated by local health authority.
20. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
21. Has severe hypersensitivity (≥Grade 3) to any pembrolizumab excipients.
22. Has had an allogeneic tissue/solid organ transplant.
23. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137)
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E.5 End points |
E.5.1 | Primary end point(s) |
(FPS) The time from randomization to the first documented disease
progression or death due to any cause, whichever occurs first
(OS) The time from randomization to death due to any cause |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary end points are Progression-free Survival (PFS) and Overall survival (OS).
-IA2:
Timing: to be performed after ~ 542 PFS events have occurred AND ~ 9 months after last participant randomized.
Primary purpose: efficacy analysis for PFS and OS.
-IA3:
Timing: to be performed when at least 18 months after the last participant has been randomized AND at least 606 PFS events have been observed. This is the final PFS analysis.
Primary purpose: efficacy analysis for PFS and OS.
- Final analysis:
Timing: to be performed when at least 28 months after the last participant has been randomized AND at least ~551 deaths have occurred.
Primary purpose: efficacy analysis for OS.
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|
E.5.2 | Secondary end point(s) |
Objective Response: Complete response (CR) or partial response (PR)
DOR: For participants who demonstrate CR or PR, DOR is defined as the time
from first documented evidence of CR or PR until disease progression or death
due to any cause, whichever occurs first.
- Adverse events
- Discontinuation of study treatment due to AEs |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy Objective Response.
- IA1:
Timing: to be performed when ~ 260 participants have been followed up for ~ 8.5 months.
Primary purpose: efficacy and futility analysis for ORR
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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 | 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 | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 85 |
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 |
Australia |
Brazil |
Chile |
China |
France |
Germany |
Guatemala |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
New Zealand |
Poland |
Russian Federation |
Spain |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 5 |
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 | 5 |
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 |