A Phase III Study of Pembrolizumab in Subjects with Gastric Cancer

• Register: EUCTR
• Last refreshed on: 12 July 2021
• Main ID: EUCTR2014-005241-45-IE
• Date of registration: 05/03/2015
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: A Phase III Study of Pembrolizumab in Subjects with Gastric Cancer
• Scientific title: A Phase III, Randomized, Open-label Clinical Trial of Pembrolizumab (MK-3475) versus Paclitaxel in Subjects with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma who Progressed after First-Line Therapy with Platinum and Fluoropyrimidine - Pembrolizumab (MK-3475) vs Paclitaxel in 2L Subjects with Advanced Gastric Adenocarcinoma
• Date of first enrolment: 29/05/2015
• Target sample size: 720
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-005241-45
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: paclitaxel 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, Belgium, Brazil, Canada, Chile, Colombia, Denmark, Estonia, Finland, Germany, Guatemala, Hong Kong, Ireland, Israel, Italy, Japan, Korea, Republic of, Malaysia, Mexico, New Zealand, Norway, Philippines, Poland, Puerto Rico, Russian Federation, Singapore, South Africa, Spain, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Carlos Mayo
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck Co., Inc

• Name: Carlos Mayo
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck Co., Inc

Key inclusion & exclusion criteria

Inclusion criteria:
1. Be willing and able to provide written informed consent/assent. The subject may also provide consent for FBR. However, the subject may participate in the main trial without participating in FBR.
2. Be = 18 years of age on day of signing informed consent
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 the 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 ECOG Performance Scale.
7. Has experienced documented objective radiographic or clinical disease progression during or after first-line therapy containing any platinum/fluoropyrimidine doublet.
a. 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).
b. Any new or worsening malignant effusion (documented by ultrasound) may be confirmed by pathologic criteria (histology and/or cytology) if appropriate.
c. A subject experiencing clinical disease progression during or within 6 months following the last dose of adjuvant or neo-adjuvant therapy will be eligible for enrollment provided they received a platinum/fluoropyrimidine doublet as required.
d. 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 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. Newly obtained biopsy specimens are preferred to archived samples and formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides. As of 20 March 2016, subjects must be PD-L1 positive to be enrolled.
9. Subjects with HER-2/neu - tumors are eligible. For subjects with HER2/neu positive tumors or have an unknown tumor status, need to match the following:
a. If HER2/neu+ , subject must have documentation of disease progression on treatment containing trastuzumab.
b. Subjects with unknown status must have their HER2/neu status determined locally. If HER2/neu -, the subject will be eligible. If HER2/neu +, the subject must have documentation of disease progression on treatment containing trastuzumab.
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 treatment for the pembrolizumab arm and through 180 days after the last dose of study treatment for
the paclitaxel arm .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 treatment for the pembrolizumab arm and through 180 days after the last dose of study
treatment for the paclitaxel arm.
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
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 < 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. Replacement therapy 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 < 7 days prior to the first dose of trial treatment
5. Has had a prior anti-cancer mAb < 4 weeks prior to Day 1 or has not recovered (i.e., = Grade 1 or at baseline) from AEs due to agents administered > 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy < 2 weeks prior to Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from AEs due to a previously administered agent.
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 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 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, 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 study treatment for the pembrolizumab arm and through 180 days after the last dose of study treatment for the paclitaxel arm.
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 HIV (HIV 1/2 antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or C.
17. Has received a live vaccine within 30 days of planned start of study therapy.
18. Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy.



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

Health Condition(s) or Problem(s) studied

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

Gastric or Gastroesophageal Junction Adenocarcinoma
MedDRA version: 20.0 Level: PT Classification code 10001150 Term: Adenocarcinoma gastric System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: MK-3475; SCH900475
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Other descriptive name: Anti-PD-1 monoclonal antibody
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: Paclitaxel-Actavis 6 mg/mL Concentrate For Solution For Infusion
Product Name: Paclitaxel
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: PACLITAXEL
CAS Number: 33069-62-4
Other descriptive name: Abraxane, Taxol
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Trade Name: Paclitaxel-Amneal 6mg/ml Concentrate For Solution For Infusion
Product Name: Paclitaxel
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: PACLITAXEL
CAS Number: 33069-62-4
Other descriptive name: Abraxane, Taxol
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 6-

Primary Outcome(s)

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. The Sponsor may request survival status to be assessed at additional time points during the course of the study (not to exceed approximately 12 weeks).

Main Objective: 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.

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.

Secondary Objective: 1. Of all subjects with advanced gastric or GEJ adenocarcinoma who have progressed on 1 previous line of therapy, when treated with pembrolizumab compared to paclitaxel, to evaluate: a. PFS per RECIST 1.1 by blinded central radiologists’ review b. OS
2) Among subjects with PD-L1 positive expression and all subjects, when treated with pembrolizumab compared to paclitaxel, to evaluate:
a) PFS per RECIST 1.1 by investigator assessment and PFS per irRECIST by blinded central radiologists’ review
b) Time to Progression (TTP), Overall Response Rate (ORR), and Duration of Response (DOR), per RECIST 1.1 by blinded central radiologists’ review/ by investigator assessment
3) Evaluate the safety and tolerability profile of pembrolizumab in subjects with PD-L1 positive expression and all subjects compared to paclitaxel.

Secondary Outcome(s)

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.

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. The Sponsor may request survival status to be assessed at additional time points during the course of the study (not to exceed approximately 12 weeks). Safety will be assessed at all study visits conducted either in person or by phone.

Secondary ID(s)

MK3475-061

061

2014-005241-45-FI

Source(s) of Monetary Support

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

Ethics review

Status: Approved
Approval date: 29/05/2015
Contact: