A Phase I/Ib Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 410 Alone and in Combination With Other Agents in Participants With KRAS Altered Advanced or Metastatic Solid Tumors

Study Identifier:
20240031
CT.gov Identifier:
NCT07094113
EudraCT Identifier:
N/A
EU Trial (CTIS) Number:
N/A
Study Contact Information:
N/A
Recruiting

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Study 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.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
  • Solid Tumor
    • Phase
    The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
    I
    Sex
    Female & Male
    Age
    18+ years
    Study Drug
    N/A
    Study Status
    Indicates the current recruitment status or the expanded access status
    Recruiting

    Requirements information
    Inclusion criteria
    • Sign an informed consent form, including complying with the informed consent form (ICF) and the requirements and limitations in this research protocol.
    • Age ≥ 18 years (or ≥ legal age of adulthood if the legal Age of adulthood in your country/region is greater than 18 years).
    • Participants must have pathologically confirmed locally advanced or metastatic malignant tumors and any missense mutation in the KRAS gene, excluding KRAS G12R and Q61R mutations. The mutation must be detectable in tumor tissue or plasma and documented in the participant's medical record. Participants with KRAS wild-type gene amplification may be enrolled upon providing analytically validated KRAS WT amplification test results and with the consent of the investigator and Amgen medical monitor. Participants must not have a standard treatment option or must have actively refused such treatment. a. For all NSCLC participants: Participants carrying gene alterations in driver genes other than KRAS (e.g., EGFR or NTRK) for which a targeted therapy has been approved will be excluded.
    • Study patients who are able to swallow and retain the PO administered orally and who are willing to record their daily adherence to the investigational drug in a dosing log or electronic log are eligible to receive the treatment.
    • The Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1.
    • According to researchers, the minimum life expectancy is more than 3 months.
    • Patients had a measurable disease as defined by RECIST v1.1 (Review of Treatment Efficacy Criteria for Solid Tumors), determined by researchers at the research center.
    • Organ function is good.
    • Prior to enrollment, electrolyte levels should be within the normal range (calcium, magnesium, phosphorus, and potassium, according to local laboratory definitions). Electrolyte abnormalities must be corrected before administration.
    • Archived (formalin-fixed, paraffin-embedded [FFPE]) tumor tissue collected within 5 years prior to screening (see the laboratory manual for details). If no archived tumor tissue is available, participants may be admitted by performing a tumor biopsy prior to AMG 410 administration (day 1 of cycle 1). If there is insufficient archived tissue and a biopsy cannot be safely performed, participants may also be admitted to the study upon agreement between the investigator and the Amgen medical monitor.
    • 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
    • Untreated symptomatic central nervous system (CNS) or subdural metastases, regardless of size, or asymptomatic brain metastases > 2 cm (per lesion). Note: For treated CNS metastases, participants are permitted to enroll if imaging and neurological examinations show stability for ≥ 14 days and no steroid use (> 10 mg Prednisone equivalent) is required for at least 7 days prior to the administration of the first dose of study treatment.
    • Uncontrollable pleural effusion and/or ascites (defined as requiring frequent drainage procedures more than once a month).
    • A history of allergic or hypersensitivity reactions to similar products (e.g., drugs with similar chemical structures or other monoclonal antibodies) or any excipients.
    • History of other malignant tumors within the past 5 years.
    • Participants with active systemic infection or symptoms indicating an acute and/or uncontrollable infection, and who require IV antibiotics within 7 days prior to the first dose of study treatment, are eligible for enrollment. Note: Participants with simple urinary tract infections and uncomplicated bacterial pharyngitis are permitted enrollment if they respond to aggressive treatment.
    • A history of arterial or venous thrombosis (e.g., stroke, transient ischemic attack, pulmonary embolism, or deep vein thrombosis); for arterial thrombosis, it must have occurred within 12 months prior to the first dose of study treatment; for venous thrombosis, it must have occurred within 6 months prior to the first dose of study treatment.
    • Lung function tests: a. History of grade 2 or higher (non-infectious) interstitial lung disease (ILD)/lung inflammation within the past 5 years. b. Imaging findings at screening showing any evidence of ILD/lung inflammation. c. Requirement of any oxygen therapy due to underlying lung disease within the past 3 months.
    • Cardiac function: a. Evidence of clinically significant pericardial effusion. b. Mean QRS duration > 110 ms at screening assessment. c. Mean QTcF interval > 450 ms at screening ECG assessment. d. History of myocardial infarction and/or symptomatic congestive heart failure (New York Heart Association functional class II), left ventricular (LV) hypertrophy, and left ventricular wall thickness ≥ 14 mm within the past year. e. Recent history of coronary revascularization or other interventions to treat coronary artery insufficiency (including pharmacological therapy within the past year). Patients with stable cardiac conditions after treatment and who have received stable pharmacological therapy for 6 months may be considered for enrollment with cardiologist approval. f. Known Wolf-Parkinson-White syndrome or a genetic syndrome that increases the risk of sudden cardiac death, such as long QT syndrome, short QT syndrome, hereditary hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or catecholamine-sensitive polymorphic ventricular tachycardia. g. History of atrial fibrillation or atrial flutter requiring continuous medication, including anticoagulation therapy, or a history of sustained ventricular tachycardia, cardiac arrest, ventricular fibrillation, or polymorphic ventricular tachycardia. h. Current significant conduction system abnormalities, including Brugda syndrome, complete heart block, a need for a permanent pacemaker, or second- or third-degree conduction block. i. Left ventricular ejection fraction (LVEF) < 50% within 4 weeks prior to C1D1, based on echocardiography or multi-gated acquisition (MUGA) scan results. j. Medically uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg), based on the average of 3 measurements.
    • Gastrointestinal diseases that prevent oral medication, malabsorption syndrome, intravenous nutrition, and uncontrollable inflammatory gastrointestinal diseases (such as Crohn's disease and ulcerative colitis) may be present.
    • Live vaccines and live attenuated vaccines are prohibited within 28 days prior to the administration of the first dose of study treatment.
    • Has a history of solid organ transplantation.
    • Previously treated with a direct KRAS G12C inhibitor or any other KRAS or RAS-targeting inhibitor (except in Part 2b).
    • Participants who have received antitumor therapy (chemotherapy, antibody therapy, molecularly targeted therapy, hormone therapy, or investigational drug) within 28 days prior to the administration of the first dose of study treatment are eligible for enrollment, unless the antitumor therapy has a 5-fold half-life of less than 28 days (in which case, participants with a prior treatment washout time of < 28 days may be allowed to enroll in this study after consultation with an Amgen medical monitor).
    • 14. Currently infected with any of the following viruses or have a history of infection with any of the following viruses: a. Human Immunodeficiency Virus (HIV) infection: Participants infected with HIV and receiving antiretroviral therapy with undetectable viral load are permitted to enroll in this study, but are required to be monitored for viral reactivation regularly throughout the study treatment period in accordance with local or institutional guidelines. b. Active Hepatitis C infection (participants with detectable Hepatitis C antibody [HCV Ab] and Hepatitis C virus [HCV] RNA viral load above the limit of quantitation): Participants with HCV Ab and HCV RNA viral load below the limit of quantitation (HCV RNA negative), regardless of prior treatment, are permitted to enroll in this study. c. Active hepatitis B infection (HBsAg positive) and hepatitis B virus (HBV) DNA viral load above the limit of quantitation (HBV DNA positive): Participants who have recovered from hepatitis B infection (defined as HBsAg negative and HBV core antibody positive, followed by HBV DNA viral load below the limit of quantitation [HBV DNA negative]) are eligible for enrollment in this study, but are required to be monitored for viral reactivation regularly throughout the study treatment period according to local or institutional guidelines, and to be assessed for the need for HBV prophylaxis. d. Active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, excepted: Negative SARS-CoV-2 RNA test by real-time polymerase chain reaction (RT-PCR) within 72 hours prior to the first dose of AMG 410; and no COVID-19 symptoms within 7 days prior to the first dose of AMG 410 (calculated from the date of positive test in asymptomatic participants).
    • The patient is using a drug known to prolong the QRS interval (a significant sodium channel blocker).
    • The patient is using a drug known to prolong the QTc interval.
    • The use of a known cytochrome P450 (CYP) 3A4 sensitive substrate (narrow therapeutic window) within 14 days prior to Day 1 of the study or within 5 half-lives of the drug or its major active metabolite (whichever is longer) without review and approval by the Principal investigator and Amgen Medical Monitor.
    • Use of known potent CYP3A4 inducers (including herbal supplements such as St. John's wort) or potent CYP3A4 inhibitors (including grapefruit juice) within 14 days prior to Day 1 of the study or within 5 half-lives of the drug or its major active metabolite (whichever is longer) without review and approval by the Principal investigator and Amgen Medical Monitor.
    • The use of known P-gp-sensitive substrates or breast cancer resistance protein (BCRP) substrates (with narrow therapeutic window) or clinical P-gp inhibitors (verapamil, Lapatinib, or ranolazine) within 14 days prior to Day 1 of the study or within 5 half-lives of the drug or its major active metabolite (whichever is longer) without review and approval by the Principal investigator and Amgen Medical Monitor.
    • The use of a proton pump inhibitor (PPI) or histamine-2 receptor antagonist (H2RA) within 7 days prior to Day 1 of the study or within 5 half-lives of the drug or its major active metabolite (whichever is longer) without review and approval by the Principal investigator and Amgen Medical Monitor.
    • 20
    • :
    • twenty one The toxicity caused by previous antitumor therapy (including radiotherapy) has not improved to at least Grade 1 of the Common Adverse Event Evaluation Criteria (CTCAE) version 5.0, except for hair loss or stable and well-controlled toxicity.
    • 21
    • :
    • twenty two The patient had received therapeutic or palliative radiotherapy within 2 weeks prior to the administration of the first dose of the study treatment.
    • 22
    • :
    • twenty three The patient had undergone major surgery within 28 days prior to receiving the first dose of the study treatment.
    • 23
    • :
    • twenty four Participants of fertility potential did not wish to use the contraceptive method prescribed in the study protocol during treatment and for an additional 6 months after the last dose of AMG 410, Pembrolizumab, or panitumumab.
    • Currently pregnant (confirmed by a positive pregnancy test), breastfeeding, or planning to become pregnant, donate eggs, or breastfeed during the trial and within an additional 6 months after the last dose of AMG 410, Pembrolizumab, or panitumumab.
    • Participants whose partners had fertility potential were unwilling to abstain from sexual intercourse (avoid heterosexual intercourse) or use contraception for an additional 3 months during treatment and after the last dose of AMG 410, Pembrolizumab, or panitumumab.
    • Participants who were designated male at birth, whose partners were pregnant, and who were unwilling to abstain from sex or use condoms for an additional 3 months during treatment and after the last dose of AMG 410, Pembrolizumab, or panitumumab.
    • Participants who do not wish to avoid sperm donation during treatment and for an additional 3 months after the last dose of AMG 410, Pembrolizumab, or panitumumab.
    • Based on the judgment of the individual and the researcher, participants may not be able to complete all the procedures, limitations, and requirements required by the research protocol.
    • The participant has had or currently has any other clinically significant disorder, condition, or disease that the researcher believes would pose a risk to the participant's safety.
    • Participants who experienced any immune-related toxicity exceeding CTCAE v5.0 grade 2 in previous treatments were not eligible to participate in this study, except for those with fully supplemented thyroid dysfunction.
    • Participants who are currently on anticoagulation therapy, have consented to a fresh biopsy, and are unable to safely discontinue anticoagulation therapy.
    • Within 14 days prior to Study 1 or within 5 half-lives of the relevant drug or its major active metabolite (whichever is longer), use of a known organic anion transporter 3 (OAT3) clinical substrate with a narrow therapeutic index (such as Methotrexate and Ciprofloxacin[with a potential risk of QTc interval prolongation]) without review and approval by the Principal investigator and Amgen Medical Monitor.
    • 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.

    Clinical Study Information for Healthcare Providers

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    Study Locations

    Location
    Investigator
    Status
    Condition(s) Treated at Site
    Location
    START Madrid, Spain (FJD)
    Madrid, Spain, 28040
    Investigator
    Status
    Recruiting
    Condition(s) Treated at Site
    Solid Tumor