Immunotherapeutic treatment with Pembrolizumab (antibody) in patients with early stage non-small cell lung cancer

• Register: EUCTR
• Last refreshed on: 28 March 2022
• Main ID: EUCTR2015-000575-27-PT
• Date of registration: 05/08/2015
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: Immunotherapeutic treatment with Pembrolizumab (antibody) in patients with early stage non-small cell lung cancer
• Scientific title: A randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy (PEARLS) - PEARLS
• Date of first enrolment: 07/10/2015
• Target sample size: 1180
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-000575-27
• 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

Australia, Austria, Belgium, Canada, Czechia, Denmark, Estonia, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Netherlands, Poland, Portugal, Russian Federation, Slovenia, Spain, Sweden, Switzerland, Turkey, United Kingdom

Contacts

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
- Before patient registration, written informed consent for tumor testing must be given according to ICH/GCP and national/local regulations. For
patients that accept to participate in the translational research, we recommend the informed consent for translational research be signed
before registration step 1;
- Pathological diagnosis of NSCLC confirmed at surgery, any histology is eligible;
- Confirmed UICC v7 stage IB with T = 4 cm, II-IIIA NSCLC after complete surgical resection (lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy) as documented in the pathology report;
- Resection margins proved microscopically free (R0); Resection margins are evaluated at the bronchial, venous and arterial stumps, peribronchial soft tissue, any peripheral margin near the tumor or of
additionally resected tissue;
- A systematic complete mediastinal lymph node dissection or a lobespecific
mediastinal lymph node dissection (Appendix K) is
recommended. At a minimum, the pathology and/or operative report must include the examination of at least two different mediastinal lymph
node (N2) levels, one of which is the subcarinal (level 7) and the second of which is lobe-specific;
- In the uncommon clinical situation where the surgeon thoroughly examines a particular mediastinal lymph node level and does not find any lymph nodes, that mediasintal lymph node level may be counted
among the minimum two required levels. However, the surgeon must clearly document in the operative report or in a separate written statement that the lymph node level was explored and no lymph nodes were present. Normal appearing lymph nodes, if present, must be biopsied or/removed;
- No extracapsular extension of tumor in resected mediastinal (N2) lymph nodes. Extracapsular tumor extension is permitted in resected N1 lymph nodes
- The highest mediastinal node removed can be positive for malignancy
- Carcinoma in situ can be present at bronchial margin
- Availability of tumor sample obtained at surgical resection for PD-L1 Immunohistochemistry (IHC) expression assessment.
- At least 18 years;
- Adjuvant chemotherapy is not mandatory but considered for patients with stage IB (T = 4 cm) and strongly recommended for stage II and IIIA, and will be administered according to national and local guidelines. Patients who received more than 4 cycles of adjuvant therapy are not eligible;
- Patients not receiving adjuvant chemotherapy must be randomized and dosed with pembrolizumab/placebo within 12 weeks of their surgery
date.
- Participants who receive adjuvant chemotherapy must begin adjuvant chemotherapy within 12 weeks of the surgery date. Patients receiving
adjuvant chemotherapy must be randomized and dosed with
pembrolizumab/placebo at least 3 weeks but no more than 12 weeks from the last dose of chemotherapy (Day 1 of last cycle).
- ECOG Performance status 0-1;
- Adequate organ function performed within 10 days of treatment initiation;
- Female patients with childbearing potential must have a negative urine or serum pregnancy test at screening (within 72 hours of first infusion of study medication);
- If of childbearing potential, female patients must be willing to use two adequate barrier methods throughout the study, starting with the screening visit up to 120 days after last infusion of chemotherapeutic and investigational agents as specified in the protocol;
- Male patients with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods thr
Exclusion criteria:
- Evidence of disease at clinical examination and/or baseline radiological assessment on baseline assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination within 8 weeks prior to the randomization date;
- Prior or planned neoadjuvant or adjuvant radiotherapy and/or neoadjuvant chemotherapy for the current malignancy;
- Prior treatment with an anti-PD-1, anti-PD-L1/2, anti- CD137, CTLA-4 modulators or any other immune-modulating agents; patients receiving live vaccine within 30 days prior to the first infusion of study treatment are not eligible;
- Current participation in a interventional clinical trial or treatment with an investigational agent or use of an investigational device within 4 weeks of the first infusion of study treatment;
- Known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive). Known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg results. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay;
- Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 3 days prior to the first infusion of trial treatment;
- History of interstitial lung disease (ILD) OR a history of (noninfectious)
pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis;
- Active autoimmune disease that has required systemic treatment in
past 2 years (i.e. with use of disease modifying agents, corticosteroids
or immunosuppressive drugs). Any replacement therapy (i.e., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement are also allowed
- History of a hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible;Note: prior radiotherapy for another malignancy (breast cancer/lymphoma/germ cell tumors, etc.) is not an exclusion criterion, the same applies for prior anti-cancer systemic chemotherapy;
- Previous allogeneic tissue/solid organ transplant;;
- Active infection requiring therapy;
- Surgery or chemotherapy related toxicity (non-hematological, toxicity resolved to grade 1 (see Appendix D), with the exception of alopecia, fatigue, neuropathy and lack of appetite /nausea);
- Patients with two synchronous primary non-small cell lung cancers.


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

Health Condition(s) or Problem(s) studied

Stage IB (T = 4 cm), II and IIIA NSCLC
MedDRA version: 21.1 Level: PT Classification code 10061873 Term: Non-small cell lung cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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

Intervention(s)

Trade Name: KEYTRUDA 25 mg/mL concentrate for solution for infusion
Pharmaceutical Form: Concentrate for 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-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Secondary Objective: - To prospectively compare DFS as assessed by the investigator in the PD-L1 positive population (TPS=1%);
- To prospectively determine and compare OS in the PD-L1 strong positive and overall population;
- To prospectively determine and compare OS in the PD-L1 positive population;
- To prospectively determine and evaluate the Lung Cancer Specific Survival (LCSS) in the whole population irrespective of PD-L1 status;
- To prospectively assess the safety of pembrolizumab after radical surgery followed by standard adjuvant chemotherapy.

Main Objective: To prospectively investigate whether adjuvant treatment with pembrolizumab after completion of radical surgery (lobectomy/pneumonectomy) with or without standard adjuvant chemotherapy for stage IB (T = 4 cm) -II-IIIA NSCLC patients improves Disease Free Survival (DFS), as assessed locally by the investigator, compared to placebo in the PD-L1 strong positive subgroup (TPS=50%) or overall population.

Note: TNM stage (according to the 7th edition of the TNM classification for lung cancer)

Primary end point(s): 1. DFS in the PD-L1 strong positive sub-group;
2. DFS in the overall population (co-primary endpoint).

Timepoint(s) of evaluation of this end point: 1. Every 12 weeks (± 2 weeks) during the 1st year after randomization, every 6 months for the 2nd and 3rd year, yearly up to the end of the 5th year
2. Every 12 weeks (± 2 weeks) during the 1st year after randomization, every 6 months for the 2nd and 3rd year, yearly up to the end of the 5th year

Secondary Outcome(s)

Secondary end point(s): 1. DFS in the PD-L1 positive population;
2. OS in the overall population;
3. OS in the PD-L1 strong positive subgroup;
4. OS in the PD-L1 positive population;
5. LCSS in the overall population;
6. Toxicity according to CTCAE version 4.03.

Timepoint(s) of evaluation of this end point: 1. Every 12 weeks (± 2 weeks) during the 1st year after randomization, every 6 months for the 2nd and 3rd year, yearly up to the end of the 5th year
2. OS will be measured from the date of randomization until the date of death.
3. OS will be measured from the date of randomization until the date of death.
4. OS will be measured from the date of randomization until the date of death.
5. LCSS will be measured from the date of randomization until the date of death (due to lung cancer specifically)
6. Every 3 weeks during treatment and at 12 weeks after the last treatment

Secondary ID(s)

MK-3475-091-03

2015-000575-27-IE

1416-LCG

Source(s) of Monetary Support

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

Ethics review

Status: Approved
Approval date: 02/10/2015
Contact: