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A Phase 1/2, Study Evaluating the Safety, Tolerability, PK, and Efficacy of AMG 510 in Subjects With Solid Tumors With a Specific KRAS Mutation (CodeBreaK 100)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03600883
Recruitment Status : Recruiting
First Posted : July 26, 2018
Last Update Posted : September 2, 2021
Sponsor:
Information provided by (Responsible Party):
Amgen

Brief Summary:

Evaluate the safety and tolerability of AMG 510 in adult subjects with KRAS p.G12C mutant advanced solid tumors.

Estimate the maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) in adult subjects with KRAS p.G12C mutant advanced solid tumors.


Condition or disease Intervention/treatment Phase
KRAS p.G12C Mutant Advanced Solid Tumors Drug: AMG 510 Drug: Anti PD-1/L1 Drug: Midazolam Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 733 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 510 Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and AMG 510 Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreaK 100)
Actual Study Start Date : August 27, 2018
Estimated Primary Completion Date : January 27, 2026
Estimated Study Completion Date : January 27, 2026

Arm Intervention/treatment
Experimental: Phase 1 Dose Exploration Part 1 monotherapy

Cohorts with food effect and alternative dosing regimens

Enrollment into the dose exploration cohorts may be from any eligible solid tumor type. Dose escalation will begin with 2-4 subjects treated at the lowest planned dose level of 180 mg. If no DLT is observed, dose escalation will continue to the next planned dose cohort

Drug: AMG 510
Characterize the pharmacokinetics (PK) of AMG 510 following administration as an oral Tablet formulation

Experimental: Phase 1 Dose Expansion Part 2 monotherapy
Upon completing the dose exploration part of the study, dose expansion may proceed with 3 groups consisting of subjects with KRAS p.G12C mutant advanced solid tumors. Dose expansion in these 3 groups may be done concurrently
Drug: AMG 510
Characterize the pharmacokinetics (PK) of AMG 510 following administration as an oral Tablet formulation

Experimental: Phase 2 monotherapy
Additional subjects will be enrolled in the dose expansion to confirm the recommended phase 2 dose. Enrollment into phase 2 will be opened after confirmation of the recommended phase 2 dose
Drug: AMG 510
Characterize the pharmacokinetics (PK) of AMG 510 following administration as an oral Tablet formulation

Experimental: Phase 1 combination arm with AMG 510 and anti PD-1/L1
Additional subjects will be enrolled into the combination arm with AMG 510 in combination with an anti (PD-1/L1)
Drug: AMG 510
Characterize the pharmacokinetics (PK) of AMG 510 following administration as an oral Tablet formulation

Drug: Anti PD-1/L1
Administered as an intravenous (IV) infusion

Experimental: Phase 1 monotherapy treatment naive advanced NSCLC
Separate cohort of part 1 dose expansion subjects to evaluate the safety and clinical activity of AMG 510 administered orally once daily in subjects with previously untreated advanced non-small cell lung cancer (NSCLC). Drug-drug interaction will be evaluated in 6 of the subjects enrolled in the treatment naive cohort by adding Midazolam alone on Day -1 and in combination with AMG 510 on Day 15 of Cycle 1, where each cycle is 21 days.
Drug: AMG 510
Characterize the pharmacokinetics (PK) of AMG 510 following administration as an oral Tablet formulation

Drug: Midazolam
Administered as an oral hydrochloride (HCI) syrup

Experimental: Phase 2 monotherapy dose comparison
Subjects with NSCLC will be enrolled in a dose comparison study evaluating safety and efficacy
Drug: AMG 510
Characterize the pharmacokinetics (PK) of AMG 510 following administration as an oral Tablet formulation




Primary Outcome Measures :
  1. Primary: Number of subjects with treatment-emergent adverse events [ Time Frame: 24 Months ]

    Treatment-emergent adverse events will be a primary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC
    • Phase 2 monotherapy dose comparison

  2. Primary: Number of subjects with treatment-related adverse events [ Time Frame: 24 Months ]

    Treatment-related adverse events will be a primary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC

  3. Primary: Number of subjects with grade ≥3 treatment-emergent adverse events [ Time Frame: 24 Months ]

    Grade ≥3 treatment-emergent adverse events will be a primary outcome measure in the following group:

    - Phase 2 monotherapy dose comparison


  4. Primary: Number of subjects with serious adverse events [ Time Frame: 24 Months ]

    Serious adverse events will be a primary outcome measure in the following group:

    - Phase 2 monotherapy dose comparison


  5. Primary: Number of subjects with adverse events of interest [ Time Frame: 24 Months ]

    Adverse events of interest will be a primary outcome measure in the following group:

    - Phase 2 monotherapy dose comparison


  6. Primary: Number of subjects with clinically significant changes in vital signs [ Time Frame: Baseline to 24 Months ]

    Vital signs will be a primary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC

  7. Primary: Number of subjects with clinically significant changes in physical examination results [ Time Frame: Baseline to 24 Months ]

    Physical examinations will be a primary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1

  8. Primary: Number of subjects with clinically significant changes on electrocardiograms (ECGs) [ Time Frame: Baseline to 24 Months ]

    ECGs will be a primary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC

  9. Primary: Number of subjects with clinically significant changes in clinical laboratory values [ Time Frame: Baseline to 24 Months ]

    Abnormal clinical laboratory values will be a primary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC

  10. Primary: Number of subjects with dose-limiting toxicities (DLTs) [ Time Frame: 21 Days ]

    DLTs will be a primary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC

  11. Primary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    ORR will be a primary outcome measure in the following group:

    • Phase 1 monotherapy treatment naïve advanced NSCLC
    • Phase 2 monotherapy
    • Phase 2 monotherapy dose comparison

  12. Primary: Duration of response (DOR) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    DOR will be a primary outcome measure in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  13. Primary: Disease control as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    Disease control will be a primary outcome measure in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  14. Primary: Progression-free survival (PFS) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    PFS will be a primary outcome measure in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  15. Primary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    Duration of SD will be a primary outcome measure in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  16. Primary: Time to response (TTR) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    TTR will be a primary outcome measure in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC



Secondary Outcome Measures :
  1. Secondary: Plasma concentration (Cmax) of AMG 510 [ Time Frame: 24 Months ]

    Cmax will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC
    • Phase 2 monotherapy dose comparison

  2. Secondary: Plasma concentration (Cmax) of midazolam [ Time Frame: 16 Days ]

    Cmax of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  3. Secondary: Time to achieve Cmax (Tmax) of AMG 510 [ Time Frame: 24 Months ]

    Tmax will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC

  4. Secondary: Area under the plasma concentration-time curve (AUC) of AMG 510 [ Time Frame: 24 Months ]

    AUC will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 1 monotherapy treatment naïve advanced NSCLC
    • Phase 2 monotherapy dose comparison

  5. Secondary: Area under the plasma concentration-time curve (AUC) of midazolam [ Time Frame: 16 Days ]

    AUC of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  6. Secondary: Clearance of midazolam from the plasma [ Time Frame: 16 Days ]

    Clearance of midazolam from the plasma will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  7. Secondary: Terminal half-life (t1/2) of midazolam [ Time Frame: 16 Days ]

    t1/2 of midazolam will be a secondary outcome measure for the subgroup of subjects who were administered midazolam in the following group:

    - Phase 1 monotherapy treatment naïve advanced NSCLC


  8. Secondary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    ORR will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1

  9. Secondary: Duration of response (DOR) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    DOR will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 2 monotherapy dose comparison

  10. Secondary: Disease control as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    DOR will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 2 monotherapy dose comparison

  11. Secondary: Progression-free survival (PFS) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    DOR will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 2 monotherapy dose comparison

  12. Secondary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    Duration of SD will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1

  13. Secondary: Depth of response (best percentage change from baseline in lesion sum diameters) as assessed by RECIST 1.1 criteria [ Time Frame: Baseline to 24 Months ]

    Depth of response will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  14. Secondary: Time to response (TTR) as assessed by RECIST 1.1 criteria [ Time Frame: 24 Months ]

    DOR will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 2 monotherapy dose comparison

  15. Secondary: Overall survival (OS) [ Time Frame: 24 Months ]

    OS will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy
    • Phase 2 monotherapy
    • Phase 1 combination arm with AMG 510 and anti PD-1/L1
    • Phase 2 monotherapy dose comparison

  16. Secondary: AMG 510 exposure and QTc interval relationship [ Time Frame: 24 Months ]

    AMG 510 exposure and QTc interval relationship will be a secondary outcome measure for the following groups:

    • Phase 1 Dose Exploration Part 1 monotherapy
    • Phase 1 Dose Expansion Part 2 monotherapy

  17. Secondary: Progression-free survival (PFS) at 6 months [ Time Frame: 6 Months ]

    PFS at 6 months will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy


  18. Secondary: Progression-free survival (PFS) at 12 months [ Time Frame: 12 Months ]

    PFS at 12 months will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy


  19. Secondary: Overall survival (OS) at 12 months [ Time Frame: 12 Months ]

    OS at 12 months will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy


  20. Secondary: Number of subjects with treatment-emergent adverse events [ Time Frame: 24 Months ]

    Treatment-emergent adverse events will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy


  21. Secondary: Number of subjects with grade ≥3 treatment-emergent adverse events [ Time Frame: 24 Months ]

    Grade ≥3 treatment-emergent adverse events will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy


  22. Secondary: Impact of treatment on disease-related symptoms and health related quality of life (HRQOL) as assessed by EORTC QLQ-C30 [ Time Frame: 24 Months ]

    Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  23. Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by disease-specific modules Quality-of-Life Questionnaire Lung Cancer Module (QLQ LC13) [ Time Frame: 24 Months ]

    Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  24. Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by non-small cell lung cancer symptom assessment questionnaire (NSCLC SAQ) for NSCLC [ Time Frame: 24 Months ]

    Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  25. Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Severity (PGIS) [ Time Frame: 24 Months ]

    Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  26. Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Change (PGIC) in cough, dyspnea and chest pain for NSCLC [ Time Frame: 24 Months ]

    Impact of treatment on disease-related symptoms and HRQOL will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  27. Secondary: Treatment-related symptoms and impact on the subject as assessed by EORTC QLQ-C30 [ Time Frame: 24 Months ]

    Treament related symptoms and impact on the subject will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  28. Secondary: Treatment-related symptoms and impact on the subject as assessed by selected questions from the Patient-reported Outcome of the Common Terminology Criteria for Adverse Events (PRO-CTCAE library) [ Time Frame: 24 Months ]

    Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  29. Secondary: Treatment-related symptoms and impact on the subject as assessed by a single item about symptom bother, item GP5 of the Functional Assessment of Cancer Therapy - General (FACT-G) [ Time Frame: 24 Months ]

    Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison


  30. Secondary: Change from baseline in physical function as assessed by EORTC QLQ-C30 [ Time Frame: Baseline to 24 Months ]

    Treatment-related symptoms and impact on the subject will be a secondary outcome measure for the following group:

    - Phase 2 monotherapy dose comparison




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men or women greater than or equal to 18 years old.
  • Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C mutation identified through molecular testing.

Exclusion Criteria

  • Active brain metastases from non-brain tumors.
  • Myocardial infarction within 6 months of study day 1.
  • Gastrointestinal (GI) tract disease causing the inability to take oral medication.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03600883


Contacts
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Contact: Amgen Call Center 866-572-6436 medinfo@amgen.com

Locations
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Sponsors and Collaborators
Amgen
Investigators
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Study Director: MD Amgen
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT03600883    
Other Study ID Numbers: 20170543
First Posted: July 26, 2018    Key Record Dates
Last Update Posted: September 2, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
URL: https://www.amgen.com/datasharing

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Midazolam
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action