Phase 3 1L Study of Pembrolizumab ± Ipilimumab in NSCLC

• Register: EUCTR
• Last refreshed on: 18 March 2020
• Main ID: EUCTR2016-004364-20-HU
• Date of registration: 14/09/2017
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp.,a subsidiary of Merck & Co.,Inc.
• Public title: Phase 3 1L Study of Pembrolizumab ± Ipilimumab in NSCLC
• Scientific title: A Phase 3, Randomized, Double-Blind Study of Pembrolizumab plus Ipilimumab vs Pembrolizumab plus Placebo in Previously Untreated, Stage IV, Metastatic Non-small Cell Lung Cancer Subjects Whose Tumors are PD-L1 Positive (TPS = 50%) (KEYNOTE-598) - Phase 3 1L Study of Pembrolizumab ± Ipilimumab in NSCLC
• Date of first enrolment: 31/10/2017
• Target sample size: 568
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004364-20
• 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, Colombia, France, Germany, Hungary, Ireland, Italy, Korea, Republic of, Latvia, Mexico, New Zealand, Peru, Poland, South Africa, Spain, Taiwan, Thailand, Turkey, Ukraine, United Kingdom, United States

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/assent for future biomedical research (FBR); however, the subject may participate in the main trial without participating in FBR.
2. Be at least 18 years of age on the day of signing informed consent.
3. Have a histologically or cytologically confirmed diagnosis of Stage IV metastatic NSCLC (AJCC version 8).
4. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesion.
5. Have a life expectancy of at least 3 months.
6. Have an ECOG Performance Status of 0 or 1.
7. Have adequate organ function as indicated in the protocol. Specimens must be collected within 10 days prior to the start of trial treatment.
8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Tumor demonstrates PD-L1 expression in =50% of tumor cells (TPS =50%) as assessed by IHC as determined by an FDA-approved test (22C3 Pharm IHC PharmDx [Dako] assay) at a central laboratoryFormalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
9. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
10. A female subject is eligible to participate if she is not pregnant (see Section 12.5), not breastfeeding, and at least one of the following conditions applies: (1) is not considered to be a woman of childbearing potential (WOCBP) as described in Section 12.5 or (2) isa WOCBP who
agrees to follow the contraceptive guidance in Section 12.5 during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study treatment(s) (MK and or any active comparator/combination).
11. A male subject must agree to use contraception as detailed in Section 12.5 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 311
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 257

Exclusion criteria:
1. Has received prior systemic chemotherapy/other targeted or biological antineoplastic therapy treatment for their Stage IV metastatic NSCLC.
2. Tumor harbors an EGFR-sensitizing (activating) mutation or an ALK translocation.
3. Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of trial treatment.
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
5. Has received prior radiotherapy within 2 weeks of start of trial treatment or received lung radiation therapy of >30 Gy within 6 months of the first dose of trial treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=2 weeks of radiotherapy) to non-CNS disease.
6. The subject’s NSCLC can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation.
7. Tumor specimen is not evaluable for PD-L1 expression.
8. Is receiving systemic steroid therapy =7 days prior to the first dose of trial treatment or receiving any other form of immunosuppressive medication.
a) Corticosteroid use on study after Cycle 1 for management of AEs, SAEs, and events of clinical interest (ECIs), as a pre-medication for IV contrast allergies/reactions or if considered necessary for a subject’s welfare, is allowed.
b) Subjects who receive daily steroid replacement therapy serve as an exception to this rule. Daily prednisone at doses of 5 to 7.5 mg (or hydrocortisone equivalent doses) is an example of replacement therapy.
c) Subjects who use inhaled steroids for the control of asthma serve as an exception to this rule.
9. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
10. Has known untreated-CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (i.e., 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.
11. 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, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial drug.
13. Has a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
14. Has had an allogeneic tissue/solid organ transplant.
15. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox),

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

Health Condition(s) or Problem(s) studied

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

Metastatic programmed cell deathligand 1 (PD-L1) positive (TPS =50%) non-small cell lung cancer (NSCLC)
MedDRA version: 21.1 Level: PT Classification code 10029522 Term: Non-small cell lung cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: Pembrolizumab
Product Code: MK-3475
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: YERVOY
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: IPILIMUMAB
Other descriptive name: IPILIMUMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: 1. To compare the overall survival (OS) in subjects treated with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo.
2. To compare the progression-free survival (PFS) per RECIST 1.1 based on blinded independent central review (BICR) in subjects treated with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo.

Timepoint(s) of evaluation of this end point: IA1 (~34 months); IA2 (~48 months); IA3 (~62 months)

Primary end point(s): 1. Overall survival (OS)
2. Progression-free survival (PFS) per RECIST 1.1 based on BICR

Secondary Objective: 1. To compare the confirmed objective response rate (ORR) per RECIST 1.1 based on BICR in subjects treated with pembrolizumab plus ipilimumab versus pembrolizumab plus placebo.
2. To evaluate the duration of response (DOR) per RECIST 1.1 (based on BICR) in subjects treated with pembrolizumab plus ipilimumab and pembrolizumab plus placebo.
3. To compare time to true deterioration (TTD) in the composite endpoint of cough (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and Lung Cancer Module 13 [EORTC QLQ-LC13] Q1), pain in chest (EORTC QLQ LC13 Q10), and shortness of breath (EORTC QLQ-C30 Q8) in subjects treated with pembrolizumab plus ipilimumab and pembrolizumab plus placebo.
4. To evaluate the safety and tolerability profile of pembrolizumab plus ipilimumab in subjects treated with pembrolizumab plus ipilimumab.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: IA1 (~34 months)

Secondary end point(s): - Objective response rate (ORR) per RECIST 1.1 based on BICR
- Duration of response (DOR)
- Safety and tolerability
- Time to true deterioration (TTD) in PRO composite endpoint

Secondary ID(s)

2016-004364-20-IE

MK3475-598

NCT03302234

Source(s) of Monetary Support

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

Ethics review

Status: Approved
Approval date: 11/10/2017
Contact: