| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 10030155 |
| E.1.2 | Term | Oesophageal carcinoma |
| 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 |
1) To compare OS in subjects with squamous cell carcinoma of the esophagus.
2) To compare OS in subjects with PD-L1 Combined Positive Score (CPS)≥10.
3) To compare OS in all subjects. |
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| E.2.2 | Secondary objectives of the trial |
1) To evaluate the progression free survival (PFS) per RECIST 1.1 assessed by central vendor review in all subjects, when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel, or irinotecan.
2) To evaluate the Objective Response Rate (ORR) per RECIST 1.1 assessed by central vendor review in all subjects, when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel, or irinotecan.
3) To evaluate the PFS and ORR per RECIST 1.1 assessed by central vendor review in subjects with squamous cell carcinoma of the esophagus and subjects with PD-L1 CPS≥10, when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel, or irinotecan.
4) Evaluate the safety and tolerability profile of pembrolizumab in all subjects, when treated with pembrolizumab compared to investigator's choice of paclitaxel, docetaxel, or irinotecan. |
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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 |
Subjects must:
- Be ≥ 18 years of age on the day of signing the informed consent.
- Have histologically or cytologically confirmed diagnosis of adenocarcinoma or squamous cell carcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ.
- Have metastatic disease or locally advanced, unresectable disease. 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.
- Have a life expectancy greater than 3 months.
- Have measurable disease based on RECIST 1.1 as determined by local site investigator/radiology assessment.
- Have an ECOG performance status of 0 or 1.
- Have experienced documented radiographic or clinical disease progression on one previous line of standard therapy. This study will only include second-line subjects. Second-line subjects are defined as those who have progressed during or after receiving at least one dose of standard therapy given in a first line setting.
- Provide either a newly obtained or archival tissue sample for intratumoral immunerelated GEP analysis and PD-L1 by immunohistochemistry analysis. Newly-obtained tissue is preferred. Formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides.
- Demonstrate adequate organ function.
- Negative pregnancy test for females of child bearing potential prior to starting study and male and female subjects of childbearing potential must be willing to use an adequate method of contraception. |
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| E.4 | Principal exclusion criteria |
The subject will be excluded from participating in the trial if the subject:
- Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
- Has an active autoimmune disease that has required systemic treatment in past 2 years.
- 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.
- Has known central nervous system (CNS) metastases and/or carcinomatous meningitis (includes past history or current metastasis).
- Has received prior anti-cancer monoclonal antibody (mAb), chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1. Subjects must have recovered from adverse events due to a previously administered agent to baseline toxicity grade or to grade 1 or less prior to enrollment.
- Has received prior therapy with an 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.
- Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
- Has experienced documented objective radiographic or clinical disease progression during or after receiving more than 1 line of therapy.
- Has a known additional malignancy that progressed or required active treatment within the last 5 years. Exceptions include curatively treated basal cell and squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers and in situ or intramucosal pharyngeal cancer. Has received a live vaccine within 30 days of planned start of pembrolizumab.
- 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.
- Has a known history of Human Immunodeficiency Virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
- Has known history of or is positive for hepatitis B (hepatitis B surface antigen reactive) or known active hepatitis C (hepatitis C virus RNA or hepatitis C antibody is detected). No hepatitis testing is required unless mandated by local health authority.
- Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
- Has an active infection requiring systemic therapy.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- 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.
- Has a known allergy, hypersensitivity, or contraindication to preselected chemotherapy agent (i.e., paclitaxel, docetaxel, or irinotecan) or any components used in their preparation.
- Experienced weight loss > 10% over approximately 2 months prior to first dose of study therapy.
- Has clinically apparent ascites or pleural effusion by physical exam. (Note that small amount of ascites which is only detectable on imaging studies is allowed.) |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Overall Survival (OS) in subjects with squamous cell carcinoma of the Esophagus.
2. Overall Survival (OS) in subjects with PD-L1 CPS≥10
3. Overall Survival (OS) in all subjects. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim efficacy analysis for OS Performed after enrollment is completed, approximately 251 OS events and 385 OS events have been observed among subjects with squamous cell carcinoma of the esophagus and all subjects, respectively, and 8 months after last subject randomized. If there are fewer than 172 OS events among subjects with PD-L1 CPS≥10 at the time, the analysis may be delayed for up to 2 months or when the target number of OS events in subjects with PD-L1 CPS≥10 is reached, whichever occurs first.
Final analysis
After approximately 310 OS events and 473 OS events have been observed among subjects with squamous cell carcinoma of the esophagus and all subjects, respectively, and 16 mo after last subject randomized |
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| E.5.2 | Secondary end point(s) |
1.Progression-free survival (PFS) – RECIST 1.1 by central imaging vendor review in all subjects, defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on central imaging vendor review or death due to any cause, whichever occurs first.
2.Objective Response Rate (ORR) – RECIST 1.1 by central imaging vendor review in all subjects, defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR).
3.Safety and tolerability Endpoints
|
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These end points will be evaluated at end of study. |
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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 | 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Investigator choice of Docetaxel, Paclitaxel, or Irinotecan |
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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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| China |
| Colombia |
| Czechia |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Hong Kong |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| Norway |
| Peru |
| Portugal |
| Russian Federation |
| Singapore |
| Spain |
| Sweden |
| Taiwan |
| Thailand |
| 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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| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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