| 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 |
| Gastric or Gastroesophageal Junction Adenocarcinoma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
1. To evaluate Progression Free Survival (PFS) per RECIST 1.1 by blinded central radiologists’ review of subjects with PD-L1 positive expression with advanced gastric or GEJ adenocarcinoma who have progressed on one previous line of therapy, when treated with pembrolizumab compared to paclitaxel.
2. To evaluate Overall Survival (OS) of subjects with PD-L1 positive expression with advanced gastric or GEJ adenocarcinoma who have progressed on one previous line of therapy, when treated with pembrolizumab compared to paclitaxel.
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate PFS per RECIST 1.1 by blinded central radiologists’ review of all subjects who have progressed on 1 previous line of therapy..
2. To evaluate OS of all subjects with advanced gastric or GEJ adenocarcinoma who have progressed on one previous line of therapy..
3. To evaluate PFS per RECIST 1.1 by investigator assessment and PFS per irRECIST by blinded central radiologists’ review, among subjects with PD-L1 positive expression and all subjects..
4. To evaluate the Time to Progression (TTP), Overall Response Rate (ORR), and Duration of Response (DOR), per RECIST 1.1 by blinded central radiologists’ review and per RECIST 1.1 by investigator assessment among subjects with PD-L1 positive expression and all subjects..
5. To evaluate the safety and tolerability profile of pembrolizumab in subjects with PD-L1 positive expression and all subjects.
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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) 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 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 histologically or cytologically-confirmed diagnosis of gastric or GEJ adenocarcinoma.
4. Have metastatic disease or locally advanced, unresectable disease.
5. Have measurable disease as defined by RECIST 1.1 as determined by investigator. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
6. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
7. Has experienced documented objective radiographic or clinical disease progression during or after first-line therapy containing any platinum/fluoropyrimidine doublet.
i. To be considered as second-line, the subject needs to have the documentation of disease progression on first-line treatment. The disease progression can be confirmed by CT scan or by clinical evidence (such as cytology report from newly developed ascites and plural effusion).
ii. Any new or worsening malignant effusion (documented by ultrasound) may be confirmed by pathologic criteria (histology and/or cytology) if appropriate.
iii. A subject experiencing clinical disease progression during or within 6 months following the last dose of adjuvant therapy will be eligible for enrollment provided they received a platinum/fluoropyrimidine doublet as required.
iv. To be eligible, the subject is required to have received at least one dose of platinum and fluoropyrimidine therapy.
8. Be willing to provide tissue for PD-L1 biomarker analysis from a newly obtained core, excisional, or endoscopic biopsy and, based on the adequacy of the tissue sample quality for assessment of PD-L1 status, received permission for enrollment from the Core Lab. Repeat samples may be required if adequate tissue is not provided. Formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides.
i. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. No additional anti-cancer treatment should be administered after tumor sample is obtained. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
ii. Collection of an archived tissue sample will also be requested (where available) to support evaluation of the clinical utility of PD-L1 assessment in newly obtained vs. archived tissue samples; however, a subject will not be precluded from participating in the study if an archived tissue sample is not available for collection or is otherwise insufficient for analysis.
iii. The following inclusion criteria is only applicable after the results from the interim futility analysis: If at the time of enrollment, only subjects with PD-L1 positive expression are being enrolled, then subject must have a confirmed PD-L1 positive expression sample per central laboratory evaluation to be eligible for enrollment.
9. Subjects with HER-2/neu negative tumors are eligible. For subjects with HER2/neu positive tumors or have an unknown tumor status, need to match the following:
i. If HER2/neu positive, subject must have documentation of disease progression on treatment containing trastuzumab.
ii. Subjects with unknown status must have their HER2/neu status determined locally.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.
Male subjects should 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.
11. Demonstrate adequate organ function
12. Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
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| E.4 | Principal exclusion criteria |
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
2. Has squamous cell or undifferentiated gastric cancer.
3. Has 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.
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
a. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
7. 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, or in situ cervical cancer that has undergone potentially curative therapy.
8. 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 for at least four weeks prior to the first dose of trial treatment and any 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.
9. Has history or evidence of interstitial lung disease or active non-infectious pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition, 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 120 days after the last dose of trial treatment.
14. Has received prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or if the subject has previously participated in Merck pembrolizumab (MK-3475) clinical trials.
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.
17. Has received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
18. Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
This trial will use progression free survival (PFS) and overall survival (OS) as a dual primary endpoint. The endpoint of OS is the standard for demonstrating superiority of antineoplastic therapy in clinical studies in the area of oncology. Additionally, 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 progression, as this methodology is uniformly 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 assessment of progression.
RECIST 1.1 will also be used by the local site for treatment decisions for both arms of the study. However RECIST 1.1 will be adapted to account for the unique tumor response profile seen with immunotherapies such as pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific immune responses which may be functionally anergic. The response patterns seen with such an approach may extend beyond the typical time course of responses seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor burden or even the appearance of new lesions. Standard RECIST criteria may not provide a complete response assessment of immunotherapeutic agents such as pembrolizumab.
When feasible, subjects within the pembrolizumab arm should not be discontinued until progression is confirmed. This allowance to continue treatment despite initial radiologic progression takes into account the observation that some subjects can have a transient tumor flare in the first few months after the start of immunotherapy, but with subsequent disease response.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response will be assessed throughout the entire 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) |
PFS – RECIST 1.1 by investigator assessment, and irRECIST by blinded central radiologists’ review. Progression-free-survival (PFS) is defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first.
Time to Progression (TTP) – RECIST 1.1 by blinded central radiologists’ review, and RECIST 1.1 by investigator assessment. Time to Progression (TTP) is defined as the time from randomization to the first documented disease progression. If there is no documented disease progression, TTP is censored at last tumor assessment date.
Overall Response Rate (ORR) – RECIST 1.1 by blinded central radiologists’ review, and RECIST 1.1 by investigator assessment. Overall response rate is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR).
Duration of Response (DOR) – RECIST 1.1 by blinded central radiologists’ review, and RECIST 1.1 by investigator assessment
For subjects who demonstrated CR or PR, response duration 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. Response duration for subjects who have not progressed or died at the time of analysis will be censored a t the date of their last tumor assessment.
The primary safety objective of this trial is to characterize the safety and tolerability of pembrolizumab in subjects with metastatic gastric cancer. The primary 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 pembrolizumab compared to paclitaxel 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. Adverse Events (AEs) will be analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Response will be assessed throughout the entire study. The first protocol defined response assessment is scheduled for Week 6, with additional assessments following at 6 week intervals. 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Guatemala |
| Hong Kong |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lithuania |
| Malaysia |
| Mexico |
| New Zealand |
| Norway |
| Philippines |
| Poland |
| Puerto Rico |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
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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 trial 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 | |
| E.8.9.1 | In the Member State concerned days | |
| 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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