| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the stomach and lower esophagous |
|
| 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 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) |
|
| E.2.3 | Trial contains a sub-study | No |
| 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. If the ratio is <2.0 but the HER2 gene copy number is >6 the participant may be considered ISH-positive.
3. Have measurable disease as defined by RECIST 1.1 by scans with IV contrast 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. Male participants are eligible to participate if they agree to the following during the intervention period and for at least:
• 180 days after the last dose of chemotherapy; no male contraception is needed for pembrolizumab and trastuzumab.
• Refrain from donating sperm
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause [Appendix 3]) as detailed below:
o Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study drugs is more stringent than the requirements above, the local label requirements should be followed.
5. A female participant is eligible to participate if she is not pregnant (see Appendix 3 of the Protocol), not breastfeeding, and at least 1 of the following conditions applies:
o Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
o • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low-user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long- term and persistent basis), as described in Appendix 7 during the intervention period and for at least 120 days after the last dose of pembrolizumab, and 150 days after trastuzumab, 180 days after the last dose of chemotherapy, whichever is longest, and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
o A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
o If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• Additional requirements for pregnancy testing during and after study intervention are in Section 8.3.6 and Appendix 3.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
6. The participant (or legally acceptable representative if applicable) provides documented 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. |
English continued:
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. Note: Participants with EF 50 to 54 may still be eligible with discussion with Sponsor AND after consultation with cardiology AND after being medically optimized and
b. QT interval calculated according to the Fridericia method (QTcF) value ≤470 msec
for males and ≤480 msec for females (mean of 3 measurements corrected for heart
rate using Fridericia’s formula).
10. Have provided tumor tissue sample deemed adequate for PD-L1 and MSI 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. |
|
| 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 and there was no evidence of progression within the timeframe.
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). No testing for TB is required unless mandated by local
health authority.
10. Has an active infection requiring systemic therapy.
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 or diuretic drugs within 2 weeks prior to enrollment. If the
participant is receiving diuretic drugs for other reasons, it is acceptable.
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. Participants with a contraindication to standard-of-care
therapy should be excluded, ie:
• Participants with a history of a severe and unexpected reaction to a
fluoropyrimidine-containing treatment
• Participants with severe dyspnea at rest related to advanced disease
stage or oxygen-dependent complications
• Participants presenting with clinically significant dehydration should
avoid a cisplatin-containing regimen.
• Participants with hypokalemia, hypomagnesemia, or hypocalcemia
• Participants with evidence of neutropenia should not be assigned to an
xaliplatin-containing regimen as recommended by the local package
insert.
• Participants with severe leukopenia should not be assigned to a
capecitabine-containing regimen.
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. Removed.
|
English continued:
18. Has active or clinically significant cardiac disease including:
- symptomatic congestive heart failure (CHF)
- history or current evidence of clinically significant cardiac arrhythmia
requiring anti-arrhythmic therapy other than beta blockers or digoxin
and/or conduction abnormality within 6 months prior to start of study treatment except atrial fibrillation and paroxysmal supraventricular tachycardia
- active coronary artery disease
19. Severe hypersensitivity (≥Grade 3) to pembrolizumab, trastuzumab,
study chemotherapy agents and/or to any excipients, murine proteins,
or platinum-containing products
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.
21. Has severe hypersensitivity (≥Grade 3) to pembrolizumab,
trastuzumab, study chemotherapy agents and/or to any excipients,
murine proteins, or platinum-containing products.
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 stimula
inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137)
24. Has received a live or live attenuated vaccine within 30 days prior to the first dose of study treatment. Note: Killed vaccines are allowed.
25. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. |
|
| 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.
|
|
| 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
|
|
| 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 | 6 |
| 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 |
| Guatemala |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| United States |
| France |
| Poland |
| Spain |
| Germany |
| Italy |
| Ireland |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 4 |
Print
