| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First-line treatment of subjects with locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the esophagogastric junction |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of esophagus or junction between esophagus and stomach |
|
| 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 | LLT |
| E.1.2 | Classification code | 10015366 |
| E.1.2 | Term | Esophageal carcinoma |
| 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 |
1. To compare OS between treatment arms in subjects with esophageal squamous cell carcinoma (ESCC) whose tumors are PD-L1 biomarker positive (CPS ≥10).
2. To compare OS between treatment arms in subjects with ESCC.
3. To compare OS between treatment arms in subjects whose tumors are PDL1 biomarker-positive (CPS ≥10).
4. To compare OS between treatment arms in all subjects.
5. To compare PFS per RECIST 1.1, as determined by Investigator, in subjects with ESCC.
6. To compare PFS per RECIST 1.1, as determined by Investigator, between treatment arms in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10).
7. To compare PFS per RECIST 1.1, as determined by Investigator, between treatment arms in all subjects. |
|
| E.2.2 | Secondary objectives of the trial |
1. Evaluate ORR per RECIST 1.1, as determined by Investigator, between treatment arms in all subjects.
2. Evaluate ORR per RECIST 1.1, as determined by Investigator, between treatment arms in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10), in subjects with ESCC, and in subjects whose tumors are PD L1 biomarker-positive (CPS ≥10).
3. Evaluate duration of response (DOR) per RECIST 1.1, as determined by Investigator, between treatment arms in all subjects and in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10), in subjects with ESCC, and in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10).
4. Evaluate the safety and tolerability profile.
5. To evaluate changes from baseline in health-related quality of life using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC Quality Of Life Questionnaire Oesophageal Module (QLQ-OES18) in all subjects and in subjects whose tumors |
|
| E.2.3 | Trial contains a sub-study | No |
| 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/or 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 for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the trial without participating in Future Biomedical Research
2.Be ≥ 18 years of age on the day of signing informed consent
3.Have histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ. a)Subjects with direct invasion into adjacent organs such as the aorta or trachea (T4b disease) should be closely evaluated for bleeding risk prior to enrollment and a Sponsor consultation before enrollment is required. b)Subjects with Siewert type 1 adenocarcinoma of the EGJ with known human epidermal growth factor receptor-2/neu (HER-2/neu)-positive tumors are not eligible. If HER-2/neu status is unknown, site should follow local standards for HER-2/neu testing
4.Have measurable disease per RECIST 1.1 as determined by the local site investigator/radiology assessment. A lesion(s) situated in a previously irradiated area can be considered a target lesion(s) if progression has been demonstrated and the lesion(s) is considered measurable per RECIST 1.1 criteria
5.Have an ECOG performance status of 0 to 1
6.Provide either a newly obtained or archival tissue sample for PD-L1 by immunohistochemistry analysis. Newly obtained tissue is preferred. Formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides. Repeat samples will be required if none of the samples submitted (archival or newly obtained) is adequate. For purposes of this study, newly obtained tissue refers to tissue that was collected between the last line of therapy and the first dose of study medication.
a)Tumor samples that meet the minimum acceptance criteria (as defined in the Procedures Manual) must be submitted to the PD-L1 testing lab prior to subject randomization in the study. If multiple tumor samples are submitted, at least one of the samples must be confirmed to be adequate by a pathologist (either local or from testing laboratory) prior to subject being enrolled.
b)For subjects from whom newly obtained samples cannot be obtained (eg, inaccessible or subject safety concern), an archival specimen may be submitted. c)If newly obtained tissue is provided and an archival tissue sample is available, it should also be provided to support evaluation of the clinical utility of PD-L1 analysis by immunohistochemistry in newly obtained vs. archival tissue samples. However, a subject will not be excluded from participating in the study if he/she has provided newly obtained tissue and an archival tissue sample is not available or is otherwise insufficient for analysis.
7. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. If first dose is given > 72 hours post randomization, pregnancy test should be repeated within 72 hours of first dose
8.Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the course of the study through 120 days after the last dose of study medication and up to 180 days after last dose of cisplatin.
9.Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 5.7.2 – Contraception, starting with the first dose of study medication and up to 180 days after last dose of cisplatin and refrain from donating sperm during this period.
10.Have adequate organ function as defined in the protocol. Specimens must be collected within 14 days prior to the start of study treatment. |
|
| E.4 | Principal exclusion criteria |
1.Has locally advanced esophageal carcinoma that is resectable or potentially curable with radiation therapy
2.Has had previous therapy for advanced/metastatic adenocarcinoma or squamous cell cancer of the esophagus or advanced/metastatic Siewert type 1 adenocarcinoma of the EGJ. Subjects may have received prior neoadjuvant or adjuvant therapy if conditions match the ones described in the protocol.
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 a known additional malignancy that is progressing or requires active treatment. Exceptions include early-stage cancers (carcinoma in situ or Stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, in situ breast cancer that has undergone potentially curative therapy, and in situ or intramucosal pharyngeal cancer.
5.Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects 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 trial 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) is not considered a form of systemic treatment and is allowed. Brief (ie, < 7 days) use of systemic corticosteroids is allowed when use is considered standard of care by investigator
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 to the first dose of trial treatment, or has a history of organ transplant, including allogeneic stem cell transplant.
8.Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
9.Has an active infection requiring systemic therapy
10.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 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
11.Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
12.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 study medication and up to 180 days after last dose of cisplatin.
13.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (i.e., CTLA-4, OX-40, CD137) or has previously participated in a pembrolizumab (MK-3475) clinical trial
14.Has severe hypersensitivity (≥ Grade 3) to any study treatment (pembrolizumab, cisplatin, or 5-FU) and/or any of its excipients
15.Has a known history of active tuberculosis (TB; Mycobacterium tuberculosis).
16.Has a known history of human immunodeficiency virus (HIV) infection. Testing is required only if mandated by local health authority
17.Has known history of or is positive for hepatitis B (hepatitis B surface antigen reactive) or hepatitis C (hepatitis C virus RNA or hepatitis C antibody is detected). Testing is required only if mandated by local health authority
18.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 trial treatment
19.Has received a live vaccine within 30 days prior to the first dose of trial drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
20. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Progression-free survival (PFS) based on RECIST 1.1 as assessed by Investigator in all subjects
2. PFS based on RECIST 1.1 as assessed by Investigator in subjects whose tumors are PD-L1 biomarker-positive (CPS ≥10)
3. Overall survival (OS) in all subjects
4. OS in subjects whose tumors are PD-L1 biomarker-positive |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Main Progression-free survival (PFS) and interim overall survival (OS) at IA (~34 months after trial starts)
OS at final analysis (~40 months after trial starts)
Final analysis: ~46 months after first subject randomized. |
|
| E.5.2 | Secondary end point(s) |
1.Objective response rate (ORR) based on RECIST 1.1 as assessed by Investigator in all subjects
2. ORR based on RECIST 1.1 as assessed by Investigator in subjects whose tumors are PD-L1 biomarker-positive
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Objective response rate (ORR), duration of response (DOR), Quality of Life, PD-L1 biomarker, and Safety at end of study |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Costa Rica |
| Denmark |
| France |
| Germany |
| Guatemala |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Malaysia |
| Peru |
| Romania |
| Russian Federation |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 23 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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