KEYMAKER-U01 Umbrella Master Study: Studies of Investigational Agents With Either Pembrolizumab (MK-3475) Alone or With Pembrolizumab PLUS Chemotherapy in Participants With Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-U01/KEYMAKER-U01)

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

KEYMAKER-U01 Master Study: A Phase 2, Umbrella Study With Rolling Arms of Investigational Agents With Either Pembrolizumab in Combination With Chemotherapy or With Pembrolizumab Alone in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04165798
• Other study ID #: 3475-U01
• Secondary ID: MK-3475-U01KEYMA
• Status: Recruiting
• Start date: December 19, 2019
• Est. completion date: February 13, 2032

Study information

• Verified date: April 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study is referred to as the "umbrella master protocol" for pembrolizumab (MK-3475) in the treatment of non-small cell lung cancer (NSCLC). This pembrolizumab NSCLC umbrella master protocol uses a platform design and consists of this master screening study and three substudies. Each substudy will enroll a different population of NSCLC participants.

The goal of this umbrella master protocol is to screen potential participants with NSCLC for enrollment into 1 of 4 substudies. Participants must first enroll in this pembrolizumab master protocol study and undergo screening for NSCLC that will be used to assign them to participation in 1 of 4 pembrolizumab substudies.

Description:

The following 4 pembrolizumab substudies will evaluate the efficacy of different investigational agents in combination with pembrolizumab given in sequence or in combination with pembrolizumab PLUS chemotherapy:

• KEYMAKER-U01 Substudy 1: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents with Pembrolizumab in Combination with Chemotherapy in Treatment-Naïve Patients with Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-01A) - NCT04165070

• KEYMAKER-U01 Substudy 2: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents in Combination with Pembrolizumab in Treatment Naïve Patients with PD-L1 Positive Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-01B) - NCT04165083

• KEYMAKER-U01 Substudy 3: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents in Combination with Pembrolizumab in Patients with Advanced Non-small Cell Lung Cancer (NSCLC) Previously Treated with anti-PD-(L)1 Therapy (MK-3475-01C) - NCT04165096

• KEYMAKER-U01 Substudy 01E: A Phase 2 Umbrella Study With Rolling Arms of Investigational Agents With or Without Chemotherapy in Combination With Pembrolizumab in Treatment of Participants With Newly Diagnosed Resectable Stages II-IIIB (N2) Non-small Cell Lung Cancer (NSCLC) (MK-3475-01E) - NCT number pending

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 735
• Est. completion date: February 13, 2032
• Est. primary completion date: February 13, 2032
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has histologically- or cytologically-confirmed diagnosis of Stage IV squamous or nonsquamous NSCLC

• Participants with nonsquamous NSCLC who are not eligible for an approved targeted therapy

• Is able to to provide archival tumor tissue sample collected either within 5 years or within the interval from completion of last treatment but before entering the screening period or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated obtained within 90 days of treatment initiation

• Has not received prior systemic treatment for their metastatic NSCLC

• Has adequate organ function within 10 days of initiation of study treatment

• Male participants must agree to use contraception and should refrain from donating sperm during the treatment period and:

• Substudy 1: for at least 120 days after the last dose of pembrolizumab and for at least 180 days after the last dose of chemotherapy

• Substudies 2 and 3: for at least 120 days after study treatments

• Substudy 4: for at leasrt 100 days after the last dose of MK-2870 or MK-7684A, and for at least 90 days after the last dose of radiation therapy

• Female participants must not be pregnant or breastfeeding, and at least 1 of the following conditions apply:

1. Not a woman of childbearing potential (WOCBP), OR

2. A WOCBP who agrees to use contraception during the treatment period and:

• Substudy 1: for at least 120 days after the last dose of pembrolizumab and for at least 180 days after the last dose of chemotherapy.

• Substudies 2 and 3: for at least 120 days after study treatment

• Substudy 01E: for at least 120 days after the last dose of pembrolizumab, 190 days after the last dose of MK-2870, 120 days after the last dose of MK-7684A, 120 days after the last dose of vibostolimab, 190 days after the last dose of chemotherapy, and 180 days after the last dose of radiation therapy

• Substudies 1, 2, and 3 only:

• Is able to complete all screening procedures within the 35-day screening window

• Substudies 1 and 2 only:

• Has not received prior systemic treatment for their metastatic NSCLC

• Substudy 2 only:

• Has a programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) =1%

• Substudy 3 only:

• Has progressed on treatment with an anti-PD-(L)1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies

• Has progressive disease during/after platinum doublet chemotherapy

• Substudy 01E only:

• Participant has previously untreated and pathologically confirmed resectable Stage II, IIIA, or IIIB (N2) NSCLC per American Joint Committee on Cancer 8th Edition

• Tumors must be resectable in the judgment of a thoracic surgeon

Exclusion Criteria:

• Has preexisting neuropathy that is moderate in intensity

• Has received a live or live-attenuated vaccine within 30 days before the first dose of study treatment. Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment

• 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 before the first dose of study treatment

• Has an active autoimmune disease that has required systemic treatment in the past 2 years

• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease

• Has an active infection requiring systemic therapy

• Has a known history of HIV infection

• Has a known history of Hepatitis B or known active Hepatitis C virus infection

• Has had an allogenic tissue/solid organ transplant

• Substudies 1, 2, and 3 only:

• Has a diagnosis of small cell lung cancer

• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis

• Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment administration, or New York Heart Association Class III or IV congestive heart failure

• Has had major surgery <3 weeks before the first dose of study treatment

• Is expected to require any other form of antineoplastic therapy while on study

• Has received prior radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study treatment

• Has received any prior immunotherapy and was discontinued from that treatment due to a severe or worse immune-related adverse event (irAE)

• Has had chemotherapy or biological cancer therapy within 4 weeks before the first dose of study treatment or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks before the first dose of study treatment (including participants who had previous immunomodulatory therapy with residual irAEs)

• Previously had a severe hypersensitivity reaction to treatment with monoclonal antibodies (including pembrolizumab) and/or any of their excipients

• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment

• Substudy 1 only:

• Has symptomatic ascites or pleural effusion (if receiving pemetrexed)

• Has a history or current evidence of a gastrointestinal (GI) condition (e.g. inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral medications

• Is getting chemotherapy and has clinically active diverticulitis, intra-abdominal abscess, GI obstruction, or peritoneal carcinomatosis

• Is unable to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs), other than aspirin dose less than or equal to 1.3 gm/day for a 5-day period (8-day period for long acting agents such as peroxicam), for participants who will receive pemetrexed

• Is unable or unwilling to take folic acid or vitamin B12 supplementation, for participants who will receive pemetrexed

• Has a known sensitivity to any component of carboplatin, paclitaxel, pemetrexed or any of their excipients

• Substudies 1 and 2 only:

• Has received prior systemic cytotoxic chemotherapy or other targeted or biological antineoplastic therapy for metastatic disease

• Has received prior therapy with an anti-programmed cell death-1 (PD-1), anti-programmed cell death-ligand 1 (PD-L1), or anti-PD-L2 agent or prior therapy targeting other immunoregulatory receptors or mechanisms

• Substudy 3 only:

• Has received prior therapy targeting other immuno-regulatory receptors or mechanisms, not including anti-PD-(L)1 agents

• Has participated in Substudies 1 or 2

• Substudy 01E only:

• Has one of the following tumor locations/types:

• NSCLC involving the superior sulcus

• Large-cell neuro-endocrine cancer

• Mixed tumors containing small cell and non-small cell elements

• Sarcomatoid tumor

• Documentation by local test report indicating presence of ALK gene rearrangements (ALK status not required and unknown or undetermined ALK status are acceptable)

• Has a known severe hypersensitivity (= Grade 3) to any of the investigational agents and/or any of their excipients, the study chemotherapy agents and/or to any of their excipients, pembrolizumab and/or any of its excipients, and/or to another biologic therapy

• History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing.

• Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease

• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease

• 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 coinhibitory T-cell receptor

• Received prior radiotherapy within 2 weeks of start of study intervention, or radiation related toxicities, requiring corticosteroids

• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years

• Has not adequately recovered from major surgery or has ongoing surgical complications

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung

Intervention

Diagnostic Test:
• Tumor Imaging
Participants will undergo tumor imaging using either a magnetic resonance imaging (MRI) scan or a computed tomography (CT) scan.

Procedure:
• Tumor Tissue Collection
Participants without archival tumor tissue samples will undergo tumor tissue collection for newly obtained tumor tissue.
• Blood Sample Collection
Participants will have blood samples drawn for analysis of: genetics ribonucleic acid (RNA) serum biomarker plasma biomarker circulating tumor DNA (ctDNA)

Locations

Country	Name	City	State
Hungary	Orszagos Koranyi Pulmonologiai Intezet ( Site 0060)	Budapest
Hungary	Petz Aladar Megyei Oktato Korhaz ( Site 0062)	Gyor	Gyor-Moson-Sopron
Hungary	Jász-Nagykun-Szolnok Vármegyei Hetényi Géza Kórház ( Site 0061)	Szolnok	Jasz-Nagykun-Szolnok
Israel	Soroka Medical Center ( Site 0072)	Beer-Sheva
Israel	Rambam Health Care Campus-Oncology ( Site 0076)	Haifa
Israel	Shaare Zedek Medical Center ( Site 0075)	Jerusalem
Israel	Meir Medical Center ( Site 0071)	Kfar-Saba
Israel	Rabin Medical Center ( Site 0074)	Petah Tikva
Israel	Chaim Sheba Medical Center ( Site 0070)	Ramat Gan
Israel	Sourasky Medical Center ( Site 0077)	Tel Aviv
Italy	Azienda Ospedaliera Universitaria Careggi ( Site 0173)	Florence	Firenze
Italy	IRCCS Ospedale San Raffaele ( Site 0171)	Milano
Italy	Policlinico Gemelli di Roma ( Site 0174)	Roma	Lazio
Korea, Republic of	Seoul National University Bundang Hospital ( Site 0081)	Seongnam-si	Kyonggi-do
Korea, Republic of	Samsung Medical Center ( Site 0082)	Seoul
Korea, Republic of	Severance Hospital ( Site 0080)	Seoul
Poland	Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 0150)	Gdansk	Pomorskie
Poland	Szpital Wojewódzki im. Mikoaja Kopernika w Koszalinie-Oddzial Dzienny Chemioterapii ( Site 0152)	Koszalin	Zachodniopomorskie
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Klinika Nowotworow Pluca i Klatki Pier	Warszawa	Mazowieckie
Spain	ICO L Hospitalet ( Site 0090)	Hospitalet de Llobregat	Barcelona
Spain	Hospital Universitario Quiron Madrid ( Site 0091)	Pozuelo de Alarcon	Madrid
United States	MedStar Franklin Square Medical Center ( Site 0033)	Baltimore	Maryland
United States	Dana Farber Cancer Institute ( Site 0002)	Boston	Massachusetts
United States	Massachusetts General Hospital ( Site 0003)	Boston	Massachusetts
United States	Cleveland Clinic ( Site 0006)	Cleveland	Ohio
United States	Ohio State University Comprehensive Cancer Center ( Site 0015)	Columbus	Ohio
United States	City of Hope ( Site 0014)	Duarte	California
United States	Sanford Fargo Medical Center ( Site 0039)	Fargo	North Dakota
United States	Banner MD Anderson Cancer Center ( Site 0001)	Gilbert	Arizona
United States	John Theurer Cancer Center at Hackensack University Medical Center ( Site 0037)	Hackensack	New Jersey
United States	The University of Texas MD Anderson Cancer Center ( Site 0009)	Houston	Texas
United States	Dartmouth Hitchcock Medical Center ( Site 0016)	Lebanon	New Hampshire
United States	University of Kentucky Markey Cancer Center ( Site 0019)	Lexington	Kentucky
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone Health ( Site 0034)	New York	New York
United States	Oncology Hematology West, PC DBA Nebraska Cancer Specialists ( Site 0031)	Omaha	Nebraska
United States	Abramson Cancer Center of the University of Pennsylvania ( Site 0010)	Philadelphia	Pennsylvania
United States	UCSF Medical Center at Mission Bay ( Site 0007)	San Francisco	California
United States	Sanford Cancer Center ( Site 0038)	Sioux Falls	South Dakota
United States	Georgetown University ( Site 0036)	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Hungary,  Israel,  Italy,  Korea, Republic of,  Poland,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Programmed Cell Death-Ligand 1 (PD-L1) Tumor Expression Level: Tumor Proportion Score (TPS) <1% vs. TPS =1%	Participants' tumors will be evaluated for their PD-L1 tumor expression level using archival tumor tissue samples or newly obtained tumor tissue. The percentage of participants who have a Tumor Proportion Score (TPS) <1% vs. a TPS =1% will be presented.	Up to approximately 1 month
Primary	Tumor Histology Status: Squamous Non-small Cell Lung Cancer (NSCLC) vs. Nonsquamous NSCLC	Participants' tumors will be evaluated for their tumor histology status as being either squamous vs. nonsquamous NSCLC using archival or newly obtained tumor tissue samples. The percentage of participants who have squamous vs. nonsquamous NSCLC will be presented.	Up to approximately 1 month

External Links

•   Merck Clinical Trials Information