| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Gastric or Gastroesophageal Junction Adenocarcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030137 |
| E.1.2 | Term | Oesophageal adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
In subjects with advanced gastric or GEJ adenocarcinoma treated with pembrolizumab monotherapy or a combination of pembrolizumab with chemotherapy versus chemotherapy alone, as first-line treatment in subjects with PD-L1 expression.
Objective 1: Evaluate Progression Free Survival (PFS) per RECIST 1.1 as assessed by blinded central radiologists’ review in subjects with PD-L1 Combined Positive Score (CPS) ≥ 1.
Objective 2: Evaluate overall survival (OS).
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| E.2.2 | Secondary objectives of the trial |
(1) Objective: Evaluate Overall Response Rate (ORR), and Duration of Response (DOR), per RECIST 1.1 as assessed by central radiologists in subjects with PD-L1 CPS ≥ 1.
(2) Objective: Evaluate Progression Free Survival (PFS) per RECIST 1.1 as assessed by blinded central radiologists' review in subjects treated with Pembrolizumab.
(3) Objective: Evaluate the safety and tolerability profile.
(4) Objective: Evaluate changes in health-related quality-of-life assessments from baseline using the EORTC QLQ-C30 and the EORTC QLQ-STO22
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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 |
| Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be ≥ 18 years of age on day of signing informed consent (or acceptable age according to local regulations, whichever is older).
3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale within 10 days prior to the first dose of trial treatment.
4. Have histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.
5. Be HER2/neu negative and PD-L1 positive.
6. Have measurable disease as defined by RECIST 1.1 as determined by investigator assessment. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
7. Have provided tumor tissue sample deemed adequate for PD-L1 biomarker analysis.
a. Notification of eligibility must be received prior to randomization.
b. Additional samples may be required if adequate tissue is not provided.
8. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
9. Female subjects of childbearing potential must be willing to use an adequate method of contraception, for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
10. Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Demonstrate adequate organ function. All screening labs should be performed within 10 days of treatment initiation.
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| E.4 | Principal exclusion criteria |
1. Has squamous cell or undifferentiated gastric cancer.
2. Has had previous therapy for locally advanced, unresectable or metastatic gastric/GEJ cancer. Subjects may have received prior neoadjuvant or adjuvant therapy as long as it was completed at least 6 months prior to randomization.
3. 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.
4. Has had radiotherapy within 14 days of randomization. Subjects who received radiotherapy >14 days prior to randomization must have completely recovered from any radiotherapy related AEs/toxicities.
5. Has a known additional malignancy that is progressing or requires active treatment. 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.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging at least four weeks prior to the first dose of trial treatment and neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
7. Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
8. 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 to the first dose of trial drug.
9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition (e.g. known deficiency of the enzyme dihydropyrimidine dehydrogenase [DPD]), therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13. 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.
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
17. Is currently participating in and receiving study therapy or has participated in a trial of an investigational agent o has used an investigational device within 4 weeks prior to the first dose of trial treatment.
18. Has received a live vaccine within 30 days prior to the first dose of trial drug.
Note: Examples of live vaccines include, but are not limited to the following: measles, mumps, rubella, varicella / zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Endpoints
This trial (MK3475-062) will use a dual endpoint of OS and PFS. PFS is an acceptable scientific endpoint for a randomized Phase III trial to demonstrate superiority of a new antineoplastic therapy. RECIST 1.1 will be used to determine the dates of progression as this methodology is accepted by regulatory authorities. Because the treatment assignment is unblinded for pembrolizumab monotherapy, images will be read by central radiologists blinded to treatment assignment to minimize bias in the response.
RECIST 1.1 as assessed by the central vendor will be used as the primary PFS efficacy endpoint. Standard RECIST 1.1 will be used by the local site for treatment decisions until verification of PD by the central imaging vendor. Following verification of PD by central vendor, treatment decision may be made by the adaptation of RECIST 1.1, termed immune-related RECIST (irRECIST )
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response will be assessed throughout the study. The first protocol defined response assessment is scheduled for Week 6, with additional assessments following at 6 week intervals. |
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| E.5.2 | Secondary end point(s) |
Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of pembrolizumab monotherapy and in combination therapy in subjects with gastric or GEJ adenocarcinoma. The safety analysis will be based on subjects who experienced toxicities as defined by CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received study treatments, including serious adverse events (SAEs) and events of clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant medications administered will be recorded. AEs will be analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.
Furthermore, specific immune-related adverse events (irAEs) will be collected and designated as immune-related ECIs. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety will be assessed at all study visits conducted either in person or by phone. |
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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 | No |
| 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 | 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Partial blind: MK3475 monotherapy open label.MK3475/PBO double blind in combi treatment arms |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 61 |
| 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 |
| Colombia |
| Guatemala |
| Hong Kong |
| Japan |
| Korea, Democratic People's Republic of |
| Mexico |
| New Zealand |
| Puerto Rico |
| Russian Federation |
| South Africa |
| Taiwan |
| United States |
| Austria |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Latvia |
| Lithuania |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
| Czechia |
| Argentina |
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| 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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| The overall trial ends when the last subject completes the last study-related phone-call or visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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