KRAS Altered Advanced or Metastatic Solid Tumors
Conditions
Keywords
Non-small cell lung cancer, NSCLC, Colorectal cancer, CRC, Pancreatic ductal adenocarcinoma, PDAC, AMG 410
Brief summary
The purpose of this first-in-human study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AMG 410 when administered alone or in combination with other agents in participants with advanced or metastatic solid tumors harboring KRAS alterations. This is a dose-escalation study in which participants will be assigned to multiple dose levels (DLs) of AMG 410, either as monotherapy or in combination with other agents, followed by expansion cohorts. The goal is to determine the Maximum Tolerated Dose (MTD)-the highest dose with acceptable safety and manageable side effects-or the Recommended Phase 2 Dose (RP2D) of AMG 410 in adult participants with KRAS-altered advanced or metastatic solid tumors.
Detailed description
This is a multicenter, multinational, open-label Phase 1/1b study designed to evaluate the safety, tolerability, PK, PD, and preliminary antitumor activity of AMG 410 in adult participants with advanced or metastatic solid tumors characterized by KRAS alterations. The study will begin with a dose-escalation phase, during which AMG 410 will be administered orally, either as monotherapy or in combination with other agents. Dose escalation will follow a model-based approach to identify the MTD or RP2D. Following dose escalation, additional expansion cohorts may be enrolled at selected dose levels to further characterize the safety profile, PK/PD relationships, and preliminary efficacy in specific tumor types or molecular subgroups. Participants will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria. The maximum duration of AMG 410 administration in this study is 3 years.
Interventions
DRUGAMG 410
Administered as an oral tablet.
DRUGPembrolizumab
Administered as an intravenous (IV) infusion.
DRUGPanitumumab
Administered as an IV infusion.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years (or \> legal age within the country if it is older than 18 years). 2. Pathologically documented, locally-advanced or metastatic malignancy with any missense mutation in the KRAS gene or evidence of KRAS amplification using an analytically validated KRASWT amplification assay. 3. Participants must have no standard of care treatment options or have actively refused such therapy. 4. Able to swallow and retain per oral administered study treatment. 5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 6. Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), as determined by the site investigator. 7. Adequate organ function. 8. Archival (formalin-fixed, paraffin-embedded \[FFPE\]) tumor tissue or block collected within 5 years before screening must be available. Participants without archived tumor tissue may undergo tumor biopsy before AMG 410 dosing (Day1).
Exclusion criteria
1. Untreated symptomatic central nervous system or leptomeningeal metastases. 2. Uncontrolled pleural effusion and/or ascites. 3. History of other malignancy within the past 5 years. 4. Active systemic infection or symptoms that indicate an acute and/or uncontrolled infection requiring IV antibiotics within 7days prior to the first dose of study treatment. 5. History of arterial or venous thrombosis (eg, stroke, transient ischemic attack, pulmonary embolism, or deep vein thrombosis). 6. Live and live-attenuated vaccines are prohibited within 28 days prior to the first dose of study treatment. 7. History of solid organ transplant. 8. Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy, hormonal therapy, or investigational agent) within 28 days of first dose of study treatment. 9. Presence or history of any of the following viral infections: HIV, Hepatitis C, Hepatitis B, and active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 10. Toxicities from prior anti-tumor therapy (including radiotherapy) not having improved to at least Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1. 11. Therapeutic or palliative radiation therapy within 2 weeks of first dose of study treatment. 12. Major surgery within 28 days of first dose of study treatment. 13. History or evidence of any other clinically significant disorder, condition, or disease that, in the opinion of the investigator, would pose a risk to participant safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Dose Limiting Toxicities (DLTs) | Up to 28 days | — |
| Number of Participants with Treatment Emergent Adverse Events (TEAEs) | Up to approximately 3 years | Clinically significant changes in safety assessments (vital signs, electrocardiograms \[ECGs\], and clinical laboratory tests) are to be reported as adverse events. |
| Number of Participants with Serious Adverse Events (SAEs) | Up to approximately 3 years | Clinically significant changes in safety assessments (vital signs, ECGs, and clinical laboratory tests) are to be reported as adverse events. |
Secondary
| Measure | Time frame |
|---|---|
| Maximum Concentration (Cmax) of AMG 410 | Up to 85 days |
| Time to Reach Cmax (Tmax) of AMG 410 | Up to 85 days |
| Area Under the Concentration-time Curve (AUC) Over the Dosing Interval of AMG 410 | Up to 85 days |
| Confirmed Objective Response (OR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Up to approximately 3 years |
| Clinical Benefit per RECIST v1.1 | Up to approximately 3 years |
| Duration of Response (DoR) per RECIST v1.1 | Up to approximately 3 years |
| Time to Response (TTR) per RECIST v1.1 | Up to approximately 3 years |
| Progression-free Survival (PFS) per RECIST v1.1 | Up to approximately 3 years |
| Overall Survival (OS) | Up to approximately 3 years |
| Food Effect Substudy Cohort: Cmax of AMG 410 in the Fed and/or Fasted State | Up to 24 days |
| Food Effect Substudy Cohort: Tmax of AMG 410 in the Fed and/or Fasted State | Up to 24 days |
| Food Effect Substudy Cohort: AUC Over the Dosing Interval of AMG 410 in the Fed and/or Fasted State | Up to 24 days |
| Change From Baseline in Tumor Phosphorylated Extracellular Signal Regulated Kinase (pERK) | Baseline up to approximately 3 years |
Countries
Australia, Belgium, Canada, China, Denmark, France, Germany, Italy, Japan, Netherlands, South Korea, Spain, United Kingdom, United States
Contacts
CONTACTAmgen Call Center
STUDY_DIRECTORMD
Amgen
Outcome results
None listed