MK-3475-U01 - 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)

Studio Clinico

Patologia: Neoplasie del polmone

Osservazionale-Sperimentale: Osservazionale

Monocentrico-Multicentrico: Multicentrico

Randomizzato: Sì

Fase di studio: II

Richiesta mandatoria di tessuto: Sì

Linee di trattamento: Non applicabile

Criteri di inclusione: 

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

Criteri di esclusione: 

- 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. 

Trattamento sperimentale: 

DIAGNOSTIC TEST: Tumor Imaging
PROCEDURE: Tumor Tissue Collection
PROCEDURE: Blood Sample Collection

Trattamento di controllo: 

NA

Centri partecipanti

Nord Italia

Centro Italia

Informazioni Generali

Protocollo

Numero di iscrizione a registro: NCT04165798

Data di inserimento: 13.05.2022

Promotore

Merck Sharp & Dohme LLC

CRO

/

Principal Investigator ITALIA

Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma

Riferimento: Prof. Emilio Bria

Telefono: 0630154953

Email: emilio.bria@policlinicogemelli.it

Localita: Roma