First-line Esophageal Carcinoma Study with Chemo vs. Chemo + Pembrolizumab

• Register: EUCTR
• Last refreshed on: 21 August 2017
• Main ID: EUCTR2017-000958-19-ES
• Date of registration: 17/05/2017
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: First-line Esophageal Carcinoma Study with Chemo vs. Chemo + Pembrolizumab
• Scientific title: A Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Pembrolizumab (MK-3475) in Combination with Cisplatin and 5-Fluorouracil versus Placebo in Combination with Cisplatin and 5-Fluorouracil as First-Line Treatment in Subjects with Advanced/Metastatic Esophageal Carcinoma (KEYNOTE-590) - First-line Esophageal Carcinoma Study with Chemo vs. Chemo + Pembrolizumab
• Date of first enrolment: 07/07/2017
• Target sample size: 700
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000958-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Brazil, Canada, Chile, China, France, Germany, Guatemala, Hong Kong, Japan, Korea, Republic of, Malaysia, Russian Federation, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

Contacts

• Name: Investigación Clínica
• Affiliation: Merck Sharp & Dohme de España S.A.

• Name: Investigación Clínica
• Affiliation: Merck Sharp & Dohme de España S.A.

Key inclusion & exclusion criteria

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 intratumoral immune-related GEP analysis and 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)Central laboratory confirmation of tumor tissue sample adequacy is required 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 the central laboratory prior to subject being enrolled. b)For subjects from whom newly obtained samples cannot be obtained (e.g., 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 immune-related GEP assessment and 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 therapy
9.Male subjects of childbearing potential must agree to use an adequate method of contraception as ou
Exclusion criteria:
1.Has locally advanced esophageal carcinoma that is resectable or potentially curable with radiation therapy (as determined by local investigator)
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 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 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, or in situ breast cancer that has undergone potentially curative therapy
5.Has known active central nervous system 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 4 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 confirmed by repeat imaging, and have not required steroids for at least 14 days before the first dose of trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
6.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) is not considered a form of systemic treatment and is allowed. Brief (i.e., < 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
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 (e.g., known deficiency of the enzyme dihydropyrimidine dehydrogenase), 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 trial treatment
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) cli

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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
MedDRA version: 20.0 Level: LLT Classification code 10015366 Term: Esophageal carcinoma System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: Cisplatin Accord 1 mg/mL
Product Name: Cisplatin
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: CISPLATIN
CAS Number: 15663-27-1
Other descriptive name: CISPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Trade Name: Fluorouracil
Product Name: Fluorouracil
Pharmaceutical Form: Solution for injection
INN or Proposed INN: FLUOROURACIL
CAS Number: 51-21-8
Other descriptive name: FLUOROURACIL
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Secondary Objective: 1.Evaluate ORR per RECIST 1.1, as determined by blinded independent central review, between treatment arms in all subjects
2.Evaluate ORR per RECIST 1.1, as determined by blinded independent central review, between treatment arms in subjects whose tumors are GEP biomarker-positive
3.Evaluate PFS per irRECIST, as determined by blinded independent central review, between treatment arms in all subjects and in subjects whose tumors are GEP biomarker-positive
4.Evaluate duration of response (DOR) per RECIST 1.1, as determined by blinded independent central review, between treatment arms in all subjects and in subjects whose tumors are GEP biomarker-positive
5.Evaluate the safety and tolerability profile

Please refer to the protocol for the complete list

Main Objective: 1. To compare progression-free survival (PFS) per RECIST 1.1, as determined by blinded independent central review, between treatment arms in all subjects
2.To compare PFS per RECIST 1.1, as determined by blinded independent central review, between treatment arms in subjects whose tumors are GEP biomarker-positive
3.To compare overall survival (OS) between treatment arms in all subjects
4.To compare OS between treatment arms in subjects whose tumors are GEP biomarker-positive

Timepoint(s) of evaluation of this end point: Main Progression-free survival (PFS) and interim overall survival (OS) at IA (~31 months after trial starts)
OS at final analysis (~40 months after trial starts)

Primary end point(s): 1.Progression-free survival (PFS) based o n RECIST 1.1 as assessed by blinded independent central review in all subjects
2. PFS based o n RECIST 1.1 as assessed by blinded independent central review in subjects whose tumors are GEP biomarker-positive
3. Overall survival (OS) in all subjects
4. OS in subjects whose tumors are GEP biomarker-positive

Secondary Outcome(s)

Secondary end point(s): 1.Objective response rate (ORR) based on RECIST 1.1 as assessed by blinded independent central review in all subjects
2. ORR based on RECIST 1.1 as assessed by blinded independent central review in subjects whose tumors are GEP biomarker-positive

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

Secondary ID(s)

2017-000958-19-DE

MK-3475-590

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc