An open-label, multicenter phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of MK-1084 as monotherapy and in combination with Pembrolizumab in participants with KRASG12C-mutated advanced solid tumors (MK-1084-001)
Résumé de l'étude
The study examines the safety, tolerability, pharmacokinetics, and effect of MK-1084 alone and in combination with Pembrolizumab. "Pharmacokinetics" refers to the absorption, metabolism, and elimination of the substance in the body. Approximately 185 patients are expected to participate in this study worldwide. These are the two investigational drugs in the study: - MK-1084: MK-1084 contains a chemical active ingredient and specifically inhibits the mutated KRAS-G12C protein. Generally, RAS proteins play a significant role in cell division and differentiation, and when these proteins are overly activated, it can lead to cancer. Initial experiments with MK-1084 in cell culture and animal studies have been promising. MK-1084 has never been tested in humans. Upcoming study data on treatments with chemically similar inhibitors alone or in combination with immunotherapy (similar to Pembrolizumab, see below) are eagerly awaited due to promising preclinical data. - Pembrolizumab: The immune system plays an important role in tumor control. Pembrolizumab is an antibody that can prevent the tumor from inhibiting the immune system and thus enhance its natural fight by binding to a specific receptor (PD1 receptor). Pembrolizumab is already approved in Switzerland and other countries for the treatment of various types of cancer.
(BASEC)
Intervention étudiée
After a thorough eligibility assessment, collection of medical history, and detailed information, the participant will be included in the study. Subsequently, based on the existing disease, the participant will be assigned to one of the following two groups:
Group 1: Advanced solid tumor with known KRAS gene mutation (KRASG12C mutation), who has already received at least one line of therapy
• Receives the drug MK-1084
Group 2: Untreated NSCLC with known KRAS gene mutation (KRASG12C mutation)
• Receives the drugs MK-1084 combined with Pembrolizumab
This study is an open-label study, meaning that both the physician and the participants themselves know which treatment they have been assigned.
The treatment duration is up to five years, as long as safety is ensured and the medication shows efficacy. Participants will visit the study center approximately 42 times during the treatment period. During and after the treatment phase, health status will be regularly monitored for any potential progression of the cancer disease through imaging studies. In case of disease deterioration, participants will visit the study center two additional times for safety follow-up visits. Subsequently, participants will be contacted by phone approximately every 12 weeks.
During study visits, various measures and examinations may take place, including: discussion of health status and current medication, inquiry into daily activities and any related restrictions, administration/distribution of study medication, imaging procedures such as CT and/or MRI scans, eye examinations, cardiac examinations (echocardiogram (ECHO) and/or electrocardiogram (ECG)), samples of blood, urine, or tissue, physical examination including checking vital signs (pulse, blood pressure, etc.).
(BASEC)
Maladie en cours d'investigation
Male and female participants with advanced solid tumors (solid tumors) or untreated non-small cell lung cancer ("Non-Small Cell Lung Cancer" or NSCLC) are being studied. Additionally, a specific mutation of the so-called KRAS gene (KRAS = "Kirsten Rat Sarcoma Viral Oncogene Homolog") must be present, specifically a KRASG12C mutation. The KRAS gene is the most frequently mutated oncogene in human cancers, thus a part of the genetic material that, when altered, can promote uncontrolled tumor growth. Mutations in this particular gene are often associated with resistance to targeted therapies, aggressive disease, and poor prognosis.
(BASEC)
• Confirmed diagnosis of metastatic solid tumor that has already received at least one line of therapy (Group 1) or confirmed diagnosis of untreated NSCLC, which expresses the PD-L1 protein (Group 2). • A confirmed KRASG12C mutation. • Measurable and evaluable lesion by imaging and ability to swallow and retain oral medication. (BASEC)
Critères d'exclusion
• Treatment with chemotherapeutics, radiotherapy, or biological cancer therapy within the last 4 weeks prior to the first dose of the study intervention (2 weeks for palliative radiotherapy) • Active metastasis of the CNS (central nervous system) and/or carcinomatous meningitis (inflammatory reaction due to cancer spread to the meninges) • Major surgery under general anesthesia within the last 2 weeks or minor surgeries under local anesthesia within the last 72 hours prior to the first dose of the study intervention (BASEC)
Lieu de l’étude
Bellinzona, St-Gall
(BASEC)
Sponsor
non disponible
Contact pour plus d'informations sur l'étude
Informations générales
Merck Sharp & Dohme LLC,
1-888-577-8839
klaudia.georgi@cluttermsd.com(ICTRP)
Informations scientifiques
Merck Sharp & Dohme LLC,
1-888-577-8839
klaudia.georgi@cluttermsd.com(ICTRP)
Nom du comité d'éthique approbateur (pour les études multicentriques, uniquement le comité principal)
Ethikkommission Ostschweiz EKOS
(BASEC)
Date d'approbation du comité d'éthique
23.12.2021
(BASEC)
Identifiant de l'essai ICTRP
NCT05067283 (ICTRP)
Titre officiel (approuvé par le comité d'éthique)
non disponible
Titre académique
A Phase 1, Open-label, Multicenter Study to Assess Safety, Tolerability, PK, and Efficacy of MK-1084 as Monotherapy and as Part of Various Combination Therapies in Participants With KRAS G12C Mutant Advanced Solid Tumors (ICTRP)
Titre public
A Study of MK-1084 in KRAS Mutant Advanced Solid Tumors (MK-1084-001) (ICTRP)
Maladie en cours d'investigation
Advanced Solid Tumors (ICTRP)
Intervention étudiée
Drug: MK-1084Biological: PembrolizumabDrug: carboplatinDrug: pemetrexedBiological: cetuximabDrug: oxaliplatinDrug: leucovorinDrug: 5-fluorouracil (ICTRP)
Type d'essai
Interventional (ICTRP)
Plan de l'étude
Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)
Critères d'inclusion/exclusion
Inclusion Criteria:
For all participants:
- Has measurable disease by RECIST 1.1 criteria
- Has adequate organ function
- Male participants agree to protocol-specified contraception requirements including
refraining from donating sperm and using protocol-specified contraceptives unless
confirmed to be azoospermic
- Female participants must not be pregnant or breastfeeding, and must agree to
protocol-specified contraceptive requirements and must have a negative highly
sensitive pregnancy test within 24 hours (for a urine test) or 72 hours (for a serum
test) before the first dose of study intervention
For Arm 1 - Has locally advanced unresectable or metastatic solid-tumor malignancy with
histologically OR blood-based confirmation of KRAS G12C mutation who has received at
least 1 line of therapy for systemic disease
For Arm 2
- Has an untreated metastatic non-small cell lung cancer (NSCLC) with histologically
OR blood-based confirmation of KRAS G12C mutation and histologic confirmation of
programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) =1%
For Arm 3
- Has locally advanced unresectable or metastatic solid-tumor malignancy with
histologically or blood-based confirmation of KRAS G12C mutation who has received at
least 1 line of therapy for systemic disease Expansion Group A: 2L+NSCLC
- Has histologically or cytologically confirmed diagnosis of unresectable or
metastatic NSCLC with histological or blood-based confirmation of KRAS G12C mutation
and submits archival tumor sample
- Previous treatment failure of at least 1 line of systemic therapy Expansion Group B
- Has locally advanced unresectable or metastatic solid-tumor malignancy, excluding
NSCLC or CRC, with histologically or blood- based confirmation of KRAS G12C mutation
who has received at least 1 line of therapy for systemic disease
Arm 4 only - Has an untreated advanced or metastatic nonsquamous NSCLC with
histologically or blood-based confirmation of KRAS G12C mutation
Arm 5 only
- Histologically or cytologically confirmed diagnosis of locally advanced unresectable
or metastatic colorectal adenocarcinoma and with histologically or blood-based
confirmation of KRAS G12C mutation
- Previous treatment failure of one or 2 previous line(s) of systemic therapy
Arm 6 only
- Locally advanced unresectable or metastatic colorectal adenocarcinoma with
histologically or blood-based confirmation of KRAS G12C mutation
Exclusion Criteria:
- Has received chemotherapy, definitive radiation, or biological cancer therapy within
4 weeks (2 weeks for palliative radiation) before first dose of study intervention
- Has a history of second malignancy, unless potentially curative treatment has been
completed with no evidence of malignancy for 5 years
- Has clinically active central nervous system (CNS) metastases and/or carcinomatous
meningitis
- Has an active infection requiring systemic therapy
- Known history of HIV infection or. has a known history of Hepatitis B virus or known
active Hepatitis C virus infection
- Has a history of interstitial lung disease, noninfectious pneumonitis requiring
active steroid therapy, or ongoing pneumonitis
- Has an active autoimmune disease requiring systemic therapy
- Has not fully recovered from any effects of major surgical procedure without
significant detectable infection
- Has one or more of the following ophthalmological findings/conditions: intraocular
pressure >21 mm Hg and/or any diagnosis of glaucoma diagnosis of central serous
retinopathy, retinal vein occlusion, or retinal artery occlusion and/or a diagnosis
of retinal degenerative disease
- Has received live or live-attenuated vaccine within 4 weeks of study start
Arm 4 Only
- Is unable to interrupt aspirin or other nonsteroidal anti-inflammatories (NSAIDs),
other than an aspirin dose =1.3 grams per day, for at least 2 days (5 days for
long-acting agents [for example, piroxicam]) before, during, and for at least 2 days
after administration of pemetrexed.
- Is unable/unwilling to take folic acid, vitamin B12, and dexamethasone (ICTRP)
non disponible
Critères d'évaluation principaux et secondaires
Number of Participants Who Experience a Dose-Limiting Toxicity (DLT);Number of Participants Who Experience an Adverse Event (AE);Number of Participants Who Discontinue Study Treatment Due to an AE (ICTRP)
Objective Response Rate (ORR);Duration of Response (DOR);Mean Plasma Concentration of MK-1084;Maximum Concentration (Cmax) of MK-1084;Time to Maximum Concentration (Tmax) of MK-1084;Minimum Concentration (Cmin) of MK-1084;Area Under the Concentration Time-Curve 0-12 Hours (AUC 0-12) of MK-1084;Area Under the Concentration Time-Curve 0-24 Hours (AUC 0-24) of MK-1084;Half-Life (t1/2) of MK-1084 (ICTRP)
Date d'enregistrement
non disponible
Inclusion du premier participant
non disponible
Sponsors secondaires
non disponible
Contacts supplémentaires
Medical Director;Toll Free Number, Trialsites@msd.com, 1-888-577-8839, Merck Sharp & Dohme LLC, (ICTRP)
ID secondaires
MK-1084-001, jRCT2041220034, 2022-501563-40-00, U1111-1281-2482, 1084-001 (ICTRP)
Résultats-Données individuelles des participants
non disponible
Informations complémentaires sur l'essai
https://clinicaltrials.gov/ct2/show/NCT05067283 (ICTRP)
Résultats de l'essai
Résumé des résultats
non disponible
Lien vers les résultats dans le registre primaire
non disponible