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AMG 193, Methylthioadenosine (MTA) Cooperative Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor, Alone and in Combination With Docetaxel in Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors (MTAP)

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ClinicalTrials.gov Identifier: NCT05094336
Recruitment Status : Recruiting
First Posted : October 26, 2021
Last Update Posted : January 11, 2024
Sponsor:
Information provided by (Responsible Party):
Amgen

Brief Summary:

The primary objective of Parts 1 and 2 of this study is to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 193 alone and in combination with docetaxel in adult participants with metastatic or locally advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.

The primary objective of Part 3 of this study is to evaluate the objective response rate (ORR) of AMG 193 in adult participants with metastatic or locally advanced MTAP-null solid tumors.


Condition or disease Intervention/treatment Phase
Advanced MTAP-null Solid Tumors Drug: AMG 193 Drug: Docetaxel Drug: Comparator AMG 193 Test Tablet Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 527 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/1b/2 Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of AMG 193 Alone and in Combination With Docetaxel in Subjects With Advanced MTAP-null Solid Tumors
Actual Study Start Date : February 1, 2022
Estimated Primary Completion Date : February 27, 2026
Estimated Study Completion Date : February 27, 2028

Resource links provided by the National Library of Medicine

Drug Information available for: Docetaxel

Arm Intervention/treatment
Experimental: Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration

Participants with MTAP-null solid tumors will receive escalating doses of AMG 193 to estimate the MTD and/or the RP2D.

A group of these participants in the United States (US) will have the option to take part in a Drug Substance Particle Size (DSPS) assessment. These participants will receive escalating doses of AMG 193 and a dose of a comparator AMG 193 test tablet.

Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Drug: Comparator AMG 193 Test Tablet
Comparator AMG 193 test tablet: Orally via tablet. Only participants in the DSPS group of the Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration, and Part 1j, Phase 1 arms will receive comparator AMG 193 test tablet.

Experimental: Part 1c, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort: MTAP-null or lost MTAP expression NSCLC.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Experimental: Part 2a, Phase 1: AMG 193 Dose Exploration + Docetaxel
Participants with MTAP-null NSCLC will receive escalating doses of AMG 193 + a fixed dose of docetaxel to estimate the MTD/RP2D of the combination.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Drug: Docetaxel
Docetaxel: Intravenous infusion

Experimental: Part 2b, Phase 1: AMG 193 + Docetaxel Dose Expansion
Participants with MTAP-null NSCLC will receive the identified MTD/RP2D of AMG 193 + docetaxel.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Drug: Docetaxel
Docetaxel: Intravenous infusion

Experimental: Part 3: AMG 193 Phase 2
Participants with MTAP-null solid tumors will receive AMG 193.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Experimental: Part 1e, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null BTC.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Experimental: Part 1f, Phase 1: AMG 193 Monotherapy Dose Expansion

Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort:

MTAP-null head and neck squamous cell carcinoma (HNSCC)

Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Experimental: Part 1g, Phase 1: AMG 193 Monotherapy Dose Expansion

Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort:

MTAP-null pancreatic adenocarcinoma

Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Experimental: Part 1h, Phase 1: AMG 193 Monotherapy Dose Expansion
Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null or lost MTAP expression solid tumors (other than lymphoma or primary brain tumor).
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Experimental: Part 1i, Phase 1: AMG 193 Dose Optimization
Participants will receive a randomized dose optimization evaluation of AMG 193.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Experimental: Part 1j, Phase 1: AMG 193 DSPS Substudy (US Sites Only)
Participants will receive doses of AMG 193 and comparator AMG 193 test tables at different times in a fasted state.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor

Drug: Comparator AMG 193 Test Tablet
Comparator AMG 193 test tablet: Orally via tablet. Only participants in the DSPS group of the Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration, and Part 1j, Phase 1 arms will receive comparator AMG 193 test tablet.

Experimental: Part 1k, Phase 1: AMG 193 Food Effect Substudy (US Sites Only)
Participants will receive AMG 193 once on a fasted state and once after eating a standardized high-fat, high calorie meal.
Drug: AMG 193
AMG 193: Orally via tablet
Other Name: MTA Cooperative PRMT5 inhibitor




Primary Outcome Measures :
  1. Parts 1 and 2: Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) [ Time Frame: 28 days ]
  2. Parts 1 and 2: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE) [ Time Frame: Up to approximately 2 years ]

    Adverse events (AEs) are defined as any untoward medical occurrence in clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are any event that occurs after the participant has received study treatment. Any clinically significant changes in vital signs, electrocardiograms (ECGs) and clinical laboratory tests will be recorded as TEAEs.

    Serious AEs (SAEs) are defined as any event that meets at least 1 of the following serious criteria:

    • Results in death (fatal)
    • Requires in-patient hospitalization or prolongation of existing hospitalization
    • Results in persistent or significant disability/incapacity
    • Is a congenital anomaly/birth defect
    • Other medically important serious event

  3. Part 3: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]

Secondary Outcome Measures :
  1. Parts 1 and 2: Maximal Plasma Concentration (Cmax) of AMG 193 [ Time Frame: Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Part 1 Cycle = 28 days, Part 2 Cycle =21 days) ]
  2. Parts 1 and 2: Time to Achieve Maximal Plasma Concentration (Tmax) of AMG 193 [ Time Frame: Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Part 1 Cycle = 28 days, Part 2 Cycle =21 days) ]
  3. Parts 1 and 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of AMG 193 [ Time Frame: Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Part 1 Cycle = 28 days, Part 2 Cycle =21 days) ]
  4. Part 2 Only: Maximal Plasma Concentration (Cmax) of Docetaxel [ Time Frame: Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days) ]
  5. Part 2 Only: Time to Achieve Maximal Plasma Concentration (Tmax) of Docetaxel [ Time Frame: Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days) ]
  6. Part 2 Only: Area Under the Plasma Concentration Versus Time Curve (AUC) of Docetaxel [ Time Frame: Cycle 1 Day 1 to Pre-Dose Cycle 5 Day 1 (Cycle =21 days) ]
  7. Parts 1 and 2: ORR [ Time Frame: Up to approximately 2 years ]
  8. Parts 1, 2 and 3: Disease Control Rate (DCR) [ Time Frame: Up to approximately 2 years ]
  9. Parts 1, 2 and 3: Duration of Response (DoR) [ Time Frame: Up to approximately 2 years ]
  10. Parts 1, 2 and 3: Time to Response (TTR) [ Time Frame: Up to approximately 2 years ]
  11. Parts 1, 2 and 3: Duration of Stable Disease (SD) [ Time Frame: Up to approximately 2 years ]
  12. Parts 1, 2 and 3: Progression-Free Survival (PFS) [ Time Frame: Up to approximately 2 years ]
  13. Parts 1, 2 and 3: Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
  14. Part 3 Only: Number of Participants Who Experience TEAE [ Time Frame: Up to approximately 2 years ]

    AEs are defined as any untoward medical occurrence in clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are any event that occurs after the participant has received study treatment. Any clinically significant changes in vital signs, ECGs and clinical laboratory tests will be recorded as TEAEs.

    SAEs are defined as any event that meets at least 1 of the following serious criteria:

    • Results in death (fatal)
    • Requires in-patient hospitalization or prolongation of existing hospitalization
    • Results in persistent or significant disability/incapacity
    • Is a congenital anomaly/birth defect
    • Other medically important serious event

  15. Part 1a Only: Maximal Plasma Concentration (Cmax) of AMG 193 [ Time Frame: Cycle 2 Day 1 to pre-dose on Cycle 2 Day 2 (Cycle = 28 days) ]
  16. Part 1a Only: Time to Achieve Maximal Plasma Concentration (Tmax) of AMG 193 [ Time Frame: Cycle 2 Day 1 to pre-dose on Cycle 2 Day 2 (Cycle = 28 days) ]
  17. Part 1a Only: Area Under the Plasma Concentration Versus Time Curve (AUC) of AMG 193 [ Time Frame: Cycle 2 Day 1 to pre-dose on Cycle 2 Day 2 (Cycle = 28 days) ]
  18. Part 1a Only: Maximal Plasma Concentration (Cmax) of Comparator AMG 193 Test Tablet [ Time Frame: Cycle 2 Day 2 to pre-dose on Cycle 2 Day 3 (Cycle = 28 days) ]
  19. Part 1a Only: Time to Achieve Maximal Plasma Concentration (Tmax) of Comparator AMG 193 Test Tablet [ Time Frame: Cycle 2 Day 2 to pre-dose on Cycle 2 Day 3 (Cycle = 28 days) ]
  20. Part 1a Only: Area Under the Plasma Concentration Versus Time Curve (AUC) of Comparator AMG 193 Test Tablet [ Time Frame: Cycle 2 Day 2 to pre-dose on Cycle 2 Day 3 (Cycle = 28 days) ]
  21. Part 1k Only: Cmax of AMG 193 during fasted state [ Time Frame: Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days) ]
  22. Part 1k Only: Tmax of AMG 193 during fasted state [ Time Frame: Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days) ]
  23. Part 1k Only: AUC of AMG 193 during fasted state [ Time Frame: Cycle 2 day 1 pre-dose up to 24 hours post-dose (Cycle = 28 days) ]
  24. Part 1k Only: Cmax of AMG 193 during fed state [ Time Frame: Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days) ]
  25. Part 1k Only: Tmax of AMG 193 during fed state [ Time Frame: Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days) ]
  26. Part 1k Only: AUC of AMG 193 during fed state [ Time Frame: Cycle 2 day 2 pre-dose up to 24 hours post-dose (Cycle = 28 days) ]


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:

  • Participant has provided informed consent/assent before initiation of any study specific activities/procedures.
  • Age ≥ 18 years.
  • Evidence of homozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) (null) (Parts 1a, 1j, 1k, and 2a only) and/or methylthioadenosine phosphorylase (MTAP) (null) in the tumor tissue or blood (Parts 1a to 1k, Parts 2a and 2b) or lost MTAP expression in the tumor tissue (Parts 1a to 1k, Parts 2a and 2b).
  • Histologically confirmed metastatic or locally advanced solid tumor not amenable to curative treatment with surgery and/or radiation.
  • Able to swallow and retain orally (PO) administered study treatment and willing to record daily adherence to investigational product.
  • Disease measurable as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).

Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

  • Adequate hematopoietic function per local laboratory
  • Adequate renal function per local laboratory
  • Adequate glucose control per local laboratory (Part 1 only)
  • Adequate liver function per local laboratory
  • Adequate coagulation parameters
  • Adequate pulmonary function
  • Adequate cardiac function
  • Minimum life expectancy of 12 weeks as per investigator judgement.
  • A total of 25 slides of archived tumor tissue (formalin-fixed, paraffin-embedded [FFPE] sample collected within 5 years) or an archival block must be available.
  • For Part 1f (MTAP-null or lost MTAP expression HNSCC): Must be willing to undergo tumor biopsy.
  • For Part 1a: Must be willing to undergo tumor biopsy, before start of treatment (archival sample acceptable if obtained with 6 months of enrollment and subject has not received any other treatment since sample was obtained) and while on treatment.
  • Part 1i: Enrollment criteria for Part 1i are to match the criteria of the expansion arm from which the indication was selected.
  • For DSPS study (Part 1j): Must be willing to participate in DSPS substudy (US sites only).

Food Effect Substudy (Part 1k): Specific Inclusion Criteria

  • Subject able and willing to eat a standardized high-fat, high-caloric meal
  • Subject able and willing to fast for ≥ 6 hours

Exclusion Criteria:

  • Spinal cord compression or untreated brain metastases or leptomeningeal disease.
  • History of other malignancy within the past 2 years
  • Any evidence of current interstitial lung disease
  • Active infection
  • Evidence of active severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection.
  • History of arterial thrombosis
  • Myocardial infarction and/or symptomatic congestive heart failure.
  • Gastrointestinal tract disease
  • History of bowel obstruction, abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
  • History of solid organ transplant.
  • Diagnosis of Congenital Short QT Syndrome.
  • Major surgery
  • Anti-tumor therapy within 28 days of study day 1, unless anti-tumor therapy is a therapy with 5 times the half-life being shorter than 28 days
  • Prior treatment with an methionine adenosyltransferase 2α (MAT2A) inhibitor or a protein arginine methyltransferase 5 (PRMT5) inhibitor.
  • Prior treatment with docetaxel (Part 2 only)
  • Prior irradiation to 25% of the bone marrow.
  • Therapeutic or palliative radiation therapy within 2 weeks of study day 1.
  • Live vaccine therapy within 4 weeks before study drug administration.
  • Use of therapeutic anti-coagulation for treatment of active thromboembolic events.
  • Use of prescription medications that are known strong inducers of cytochrome P450 3A4 (CYP3A4) within 14 days or 5 half-lives (whichever is longer) before study day 1
  • Unresolved toxicity from prior anti-cancer therapy
  • Currently receiving treatment in another investigational device or drug study
  • Known positive test for Human Immunodeficiency Virus (HIV).
  • Positive hepatitis B surface antigen
  • positive hepatitis C virus ribonucleic acid (RNA) by polymerase chain reaction (PCR)
  • Female participants of childbearing potential unwilling to use protocol specified method of contraception

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): NCT05094336


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:
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT05094336    
Other Study ID Numbers: 20210023
First Posted: October 26, 2021    Key Record Dates
Last Update Posted: January 11, 2024
Last Verified: January 2024
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: http://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
Keywords provided by Amgen:
Metastatic MTAP-null solid tumors
Advanced MTAP-null solid tumors
Non-small cell lung cancer
Biliary Tract Cancer (BTC)
Head and neck squamous cell carcinoma
Pancreatic adenocarcinoma
Additional relevant MeSH terms:
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Neoplasms
Docetaxel
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action