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)

• ClinicalTrials.gov Identifier: NCT05094336
• Recruitment Status: Recruiting
• First Posted: October 26, 2021
• Last Update Posted: May 25, 2023
• Sponsor: Amgen
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: October 14, 2021
• First Posted Date: October 26, 2021
• Last Update Posted Date: May 25, 2023
• Actual Study Start Date: February 1, 2022
• Estimated Primary Completion Date: August 27, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 14, 2021)

• Parts 1 and 2: Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) [ Time Frame: 28 days ]
• 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
• Part 3: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 21, 2022)

• 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) ]
• 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) ]
• 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) ]
• 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) ]
• 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) ]
• 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) ]
• Parts 1 and 2: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Disease Control Rate (DCR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Duration of Response (DoR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Time to Response (TTR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Duration of Stable Disease (SD) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Progression-Free Survival (PFS) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
• Part 3 Only: 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
• Part 1a and 1b United States DSPS Group 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) ]
• Part 1a and 1b United States DSPS Group 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) ]
• Part 1a and 1b United States DSPS Group 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) ]
• Part 1a and 1b United States DSPS Group 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) ]
• Part 1a and 1b United States DSPS Group 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) ]
• Part 1a and 1b United States DSPS Group 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) ]

Original Secondary Outcome Measures (submitted: October 14, 2021)

• 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) ]
• 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) ]
• 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) ]
• 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) ]
• 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) ]
• 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) ]
• Parts 1 and 2: Objective Response Rate (ORR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Disease Control Rate (DCR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Duration of Response (DoR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Time to Response (TTR) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Duration of Stable Disease (SD) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Progression-Free Survival (PFS) [ Time Frame: Up to approximately 2 years ]
• Parts 1, 2 and 3: Overall Survival (OS) [ Time Frame: Up to approximately 2 years ]
• Part 3 Only: 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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

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 non-small cell lung cancer (NSCLC), after prior treatment with chemotherapy and/or a programmed death-1/ligand 1 (PD-1/L1) inhibitor.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced MTAP-null Solid Tumors

Intervention

• Drug: AMG 193
  AMG 193: Orally via tablet
  Other Name: MTA Cooperative PRMT5 inhibitor
• Drug: Docetaxel
  Docetaxel: Intravenous infusion
• Drug: Comparator AMG 193 Test Tablet
  Comparator AMG 193 test tablet: Orally via tablet. Only participants in the DSPS group of the Part 1a and 1b, Phase 1: AMG 193 Monotherapy Dose Exploration arm will receive comparator AMG 193 test tablet.

Study Arms

• Experimental: Part 1a and 1b, 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 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.

  Interventions:

  • Drug: AMG 193
  • Drug: 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 squamous NSCLC.

  Intervention: Drug: AMG 193
• 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.
  Interventions:

  • Drug: AMG 193
  • Drug: Docetaxel
• 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.
  Interventions:

  • Drug: AMG 193
  • Drug: Docetaxel
• Experimental: Part 3: AMG 193 Phase 2
  Participants with MTAP-null NSCLC will receive AMG 193.
  Intervention: Drug: AMG 193
• Experimental: Part 1d, Phase 1: AMG 193 Monotherapy Dose Expansion

  Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort:

  MTAP-null adenocarcinoma NSCLC

  Intervention: Drug: AMG 193
• Experimental: Part 1e, Phase 1: AMG 193 Monotherapy Dose Expansion

  Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort:

  MTAP-null BTC

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

  Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort:

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

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

  Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort:

  MTAP-null pancreatic adenocarcinoma

  Intervention: Drug: AMG 193
• Experimental: Part 1h, Phase 1: AMG 193 Monotherapy Dose Expansion

  Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort:

  MTAP-null solid tumor other than squamous or adenocarcinoma NSCLC, BTC, HNSCC, pancreatic adenocarcinoma, primary brain tumor, and lymphoma.

  Intervention: Drug: AMG 193

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 10, 2023): 386
• Original Estimated Enrollment (submitted: October 14, 2021): 340
• Estimated Study Completion Date: April 28, 2028
• Estimated Primary Completion Date: August 27, 2025 (Final data collection date for primary outcome measure)

Eligibility 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 and 1b only) and/or methylthioadenosine phosphorylase (MTAP) (null) in the tumor tissue or blood (Parts 1a to 1h, Parts 2a and 2b) or lost MTAP expression in the tumor tissue (Parts 1a to 1h, 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 Parts 1a and 1b backfill: 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.

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Australia, Austria, Belgium, Canada, France, Germany, Hong Kong, Japan, Switzerland, Taiwan, United States

Administrative Information

• NCT Number: NCT05094336
• Other Study ID Numbers: 20210023
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: 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

• Current Responsible Party: Amgen
• Original Responsible Party: Same as current
• Current Study Sponsor: Amgen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: May 2023