An open multicenter clinical phase 1/1b study of MK-0472 as monotherapy and in combination with Pembrolizumab in participants with advanced/metastatic solid tumors (MK-0472-001)
Descrizione riassuntiva dello studio
The study investigates the safety, tolerability, pharmacokinetics, and efficacy of MK-0472 alone and in combination with Pembrolizumab. "Pharmacokinetics" refers to the absorption, metabolism, and elimination of the substance in the body. Approximately 100 patients worldwide are expected to participate in this study. These are the two investigational drugs in the study: - MK-0472: MK-0472 inhibits and blocks the SHP2 protein, which in turn leads to an inhibition of the cell division of tumor cells (in vitro). Initial experiments with MK-0472 in cell culture and animal studies showed positive results. MK-0472 has never been tested in humans. - 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 body's ability to 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)
Intervento studiato
After a thorough eligibility assessment, collection of medical history, and detailed information, the patient will be included in the study. This study has 2 treatment groups with dose escalation of the investigational drug MK-0472:
- Group 1: Participants in this group receive the drug MK-0472. Starting with the lowest dose, it will be slowly increased with the other enrolled patients if the previous dose is deemed safe.
- Group 2: Participants in this group receive the drug MK-0472 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. Once Group 2 is open for recruitment, participants will be assigned to one of the two groups with equal probability.
MK-0472 is a capsule and is taken orally every day. Pembrolizumab is administered intravenously as an infusion solution every 3 weeks. The maximum treatment duration is not defined for MK-0472 and is up to approximately 2 years for Pembrolizumab, as long as safety is ensured and your disease does not progress.
Participants visit the study center approximately 6 times within 6 weeks at the beginning of treatment, then less frequently (about every 3 weeks). During and after the treatment phase, health status will be regularly monitored for any signs of disease progression using imaging studies. After the treatment period, a safety follow-up visit and a monitoring phase will follow. If the investigational medication has not been discontinued due to disease worsening, follow-up appointments at the study center are planned approximately every 12 weeks with imaging methods. In case of disease worsening, participants will be contacted by phone approximately every 12 weeks to inquire about their health status.
During study visits, various measures and examinations may be performed, including: discussion of well-being and current medication, inquiry about daily activities and any limitations, administration/distribution of the investigational medication, imaging procedures such as CT and/or MRIs, X-rays or bone scans, cardiac examinations (electrocardiogram (ECG)), samples of blood, urine, or tissue, physical examination including checking vital signs (pulse, blood pressure, etc.).
(BASEC)
Malattie studiate
Male and female participants with confirmed inoperable, advanced/metastatic solid tumors with known RTK (receptor tyrosine kinase) activation due to certain genetic mutations are being studied, who have received or not tolerated all available treatments that provide clinical benefit. Given the unmet medical need for patients with advanced tumors, new therapeutic agents are needed. Basic research in cell culture and animal models suggests that the SHP2 protein acts as a key mediator between several intracellular oncogene signaling pathways in cancers, such as in the RTK signaling pathway. Given the critical role of SHP2 in tumors, researchers believe that its inhibition could suppress tumor growth and cell division of tumor cells and could have broad therapeutic applications in oncology.
(BASEC)
• Confirmed diagnosis of an inoperable, advanced/metastatic solid tumor with known RTK genetic mutation in which the patient has received or not tolerated all available treatments that are known to provide clinical benefit. • Measurable and evaluable lesion by imaging • Provision of an archived or new tumor tissue sample that has not been irradiated (BASEC)
Criteri di esclusione
• Treatment with a systemic cancer therapy within the last 4 weeks prior to the first dose of the study intervention (2 weeks or less for palliative radiotherapy) • Clinically significant cardiovascular disease • Additional diseases such as hyperparathyroidism, hypercalcemia, or certain diseases of the eyes and gastrointestinal tract (BASEC)
Luogo dello studio
Bellinzona, Ginevra, San Gallo
(BASEC)
Sponsor
Sponsor: Merck Sharp & Dohme LLC, USA Sponsor's Representative in Switzerland: MSD Merck Sharp & Dohme AG, Luzern, Schweiz
(BASEC)
Contatto per ulteriori informazioni sullo studio
Persona di contatto in Svizzera
Klaudia Georgi
+41 58 618 33 88
klaudia.georgi@cluttermsd.comMSD Merck Sharp & Dohme AG, Luzern, Schweiz
(BASEC)
Nome del comitato etico approvante (per studi multicentrici solo il comitato principale)
Commissione d'etica Ticino
(BASEC)
Data di approvazione del comitato etico
22.06.2023
(BASEC)
ID di studio ICTRP
NCT05853367 (ICTRP)
Titolo ufficiale (approvato dal comitato etico)
A Phase 1/1b Open-label, Multicenter Clinical Study of MK-0472 as Monotherapy and Combination Therapy in Participants with Advanced/Metastatic Solid Tumors. (BASEC)
Titolo accademico
A Phase 1/1b Open-label, Multicenter Clinical Study of MK-0472 as Monotherapy and Combination Therapy in Participants With Advanced/Metastatic Solid Tumors. (ICTRP)
Titolo pubblico
Study of MK-0472 in Participants With Advanced/Metastatic Solid Tumors (MK-0472-001) (ICTRP)
Malattie studiate
Metastatic Solid TumorsAdvanced Solid Tumors (ICTRP)
Intervento studiato
Drug: MK-0472Biological: PembrolizumabDrug: MK-1084 (ICTRP)
Tipo di studio
Interventional (ICTRP)
Disegno dello studio
Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)
Criteri di inclusione/esclusione
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
- Has histologically or cytologically confirmed solid tumor by pathology report that
is advanced/metastatic
- Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if
they have received HBV antiviral therapy for at least 4 weeks, and have undetectable
HBV viral load prior to study enrollment
- Participants with history of hepatitis C virus (HCV) infection are eligible if HCV
viral load is undetectable at screening
- Participants with human immunodeficiency virus (HIV) infection must have well
controlled HIV on stable (>4 weeks) antiretroviral therapy (ART)
- Arm 1: Oncogenic receptor tyrosine kinase (RTK) pathway alterations confirmed by a
historical report or local testing (tissue or blood) and have received, or been
intolerant to, all available treatment known to confer clinical benefit
- Arm 2: Tumor types known to be sensitive to anti-programmed cell death 1 protein
(PD-1)/ligand 1 (L1) therapies are eligible. Tumor types permitted include:
melanoma, non-small cell lung cancer (NSCLC) without epidermal growth factor
receptor (EGFR)/anaplastic lymphoma kinase (ALK)/ROS1 mutations, renal cell
carcinoma, urothelial carcinoma, Merkel cell carcinoma, MSI-high CRC, endometrial
cancer, cervical cancer, small cell lung cancer, triple negative breast cancer,
esophageal cancer, gastric cancer, biliary tract cancer, hepatocellular carcinoma,
head and neck squamous cancer, cutaneous squamous cancer, anal squamous cancer, and
mesothelioma
- Arm 3: Has histologically OR blood-based confirmation of Kirsten rat sarcoma viral
oncogene homolog (KRAS) G12C mutation
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
- Has not recovered to common terminology criteria for adverse events (CTCAE) Grade 1
or better from any adverse events that were due to cancer therapeutics administered
more than 4 weeks earlier. Participants receiving ongoing replacement hormone
therapy for endocrine immune-related AEs will not be excluded from participation in
this study
- Has history of a second malignancy, unless potentially curative treatment has been
completed with no evidence of malignancy for 2 years
- History of hyperparathyroidism or hypercalcemia
- Has one or more of the following ophthalmological findings/conditions: a)
Intraocular pressure >21 mm Hg and/or any diagnosis of glaucoma b) Diagnosis of
central serous retinopathy, retinal vein occlusion, or retinal artery occlusion and
c) Diagnosis of retinal degenerative disease
- Has clinically significant cardiovascular disease
- Bullous exfoliative skin disorders of any grade
- Known hypersensitivity to MK-0472, MK-1084, or pembrolizumab, or any of their
excipients
- Received therapy with a proton-pump inhibitor or an H2 histamine blocker receptor
antagonist within 7 days before the first scheduled day of study dosing
- Has discontinued prior therapy with an anti-programmed cell death-1 (PD-1),
anti-programmed death-ligand 1 (PD-L1), or anti-programmed death-ligand 2 (PD-L2)
agent or with an agent directed to another stimulatory or coinhibitory T-cell
receptor due to an adverse event
- Received prior systemic anticancer therapy including investigational agents within 4
weeks before first dose
- Received a live or live-attenuated vaccine within 30 days before the first dose of
study intervention
- Has received an investigational agent or has used an investigational device within 4
weeks prior to study intervention administration
- Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
or any other form of immunosuppressive therapy within 7 days prior to the first dose
of study medication
- Has 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. Participants with previously treated brain metastases may participate
provided they are radiologically stable for at least 4 weeks as confirmed by repeat
imaging performed during the study screening, are clinically stable and have not
required steroid treatment for at least 14 days before the first dose of study
intervention
- Has active autoimmune disease that has required systemic treatment in the past 2
years except replacement therapy
- Has history of pneumonitis/interstitial lung disease that required steroids or has
current pneumonitis/interstitial lung disease
- Has active infection requiring systemic therapy
- Has history of allogeneic tissue/solid organ transplant
- Have not adequately recovered from major surgery or have ongoing surgical
complications (ICTRP)
non disponibile
Endpoint primari e secondari
Number of Participants Who Experience a Dose Limiting Toxicity (DLT) as Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0;Number of Participants Who Experience One or More Adverse Events (AEs);Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) (ICTRP)
Area Under the Concentration Time-curve From Time 0 to the End of the Dosing Period (AUCtau) of MK-0472;Lowest Plasma Concentration (Ctrough) of MK-0472;Maximum Plasma Concentration (Cmax) of MK-0472 (ICTRP)
Data di registrazione
non disponibile
Inclusione del primo partecipante
non disponibile
Sponsor secondari
non disponibile
Contatti aggiuntivi
Medical Director;Toll Free Number, Trialsites@msd.com, 1-888-577-8839, Merck Sharp & Dohme LLC, (ICTRP)
ID secondari
MK-0472-001, 2024-516006-32-00, U1111-1310-1179, 0472-001 (ICTRP)
Risultati-Dati individuali dei partecipanti
non disponibile
Ulteriori informazioni sullo studio
https://clinicaltrials.gov/study/NCT05853367 (ICTRP)
Risultati dello studio
Riepilogo dei risultati
non disponibile
Link ai risultati nel registro primario
non disponibile