A Phase III, Randomized, Double-blind Trial Comparing Trastuzumab Plus Chemotherapy and Pembrolizumab With Trastuzumab Plus Chemotherapy and Placebo as First-line Treatment in Participants With HER2 Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma (KEYNOTE 811)

Phase 1

• Conditions: HER2 Positive Advanced Gastric or Gastroesophageal Junction Adenocarcinoma; MedDRA version: 21.1Level: LLTClassification code 10071114Term: Metastatic gastric adenocarcinomaSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-000224-34-DE
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-06-22
• Last Update Posted: 26 February 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 732

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:
- 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.
5. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: - Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
- 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 longterm 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.
- 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.
- 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.
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 Resear

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. 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. 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. 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. Kknown 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. 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. 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.
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 sign

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified