Sponsor: Amgen (industry)
Phase: 2
Start date: Dec. 26, 2024
Planned enrollment: 200
Last updated in HealthScout: Apr 2025
AMG 193, also known as AM-9747, is an investigational drug developed to target cancers with deletions in the methylthioadenosine phosphorylase (MTAP) gene. Approximately 10% to 15% of solid tumors exhibit MTAP deletions, making them susceptible to therapies that exploit this specific genetic vulnerability.
AMG 193 functions as an MTA-cooperative inhibitor of protein arginine methyltransferase 5 (PRMT5). In MTAP-deleted cells, the accumulation of methylthioadenosine (MTA) enhances the binding of AMG 193 to PRMT5, leading to selective inhibition of PRMT5 activity. This inhibition disrupts essential cellular processes such as DNA damage repair and RNA splicing, ultimately inducing synthetic lethality in MTAP-deficient tumor cells while sparing normal tissues.
In a phase 1 clinical trial involving patients with advanced MTAP-deleted solid tumors, AMG 193 demonstrated promising antitumor activity. Among 42 efficacy-evaluable patients treated at active doses (800 mg once daily, 1200 mg once daily, or 600 mg twice daily), the objective response rate was 21.4%, with responses observed across multiple tumor types, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma, and biliary tract cancer. The median duration of response was 8.3 months, and the median duration of disease control was 9.2 months. Notably, reductions in circulating tumor DNA correlated with clinical responses, suggesting that AMG 193 effectively targets MTAP-deleted tumors.
AMG 193 was generally well-tolerated in the phase 1 study. The most common treatment-related adverse events were nausea (48.8%), fatigue (31.3%), and vomiting (30.0%). Dose-limiting toxicities included nausea, vomiting, fatigue, hypersensitivity reactions, and hypokalemia, primarily occurring at doses of 240 mg or higher. Importantly, no clinically significant myelosuppression was observed, indicating a favorable safety profile.
Last updated: Apr 2025
Last updated: Apr 2025
Goal: The trial aims to evaluate the efficacy, safety, tolerability, and pharmacokinetics of two dose levels of AMG 193 in patients with MTAP-deleted advanced non-small cell lung cancer. The primary focus is on measuring the objective response according to RECIST 1.1 criteria, alongside several secondary outcomes.
Patients: The trial involves individuals diagnosed with advanced non-small cell lung cancer with MTAP deletions who have previously undergone and progressed after at least one systemic therapy for advanced disease. Eligible participants include those with resectable or unresectable conditions and those with treated or small untreated brain metastases.
Design: The study follows a randomized, two-part structure encompassing a dose evaluation followed by a dose expansion phase. A total of 200 participants will be enrolled and assigned to receive differing doses of AMG 193.
Treatments: AMG 193, an investigational drug and first-in-class oral PRMT5 inhibitor, is being evaluated. It operates on a synthetic lethal principle, selectively targeting MTA-cooperative PRMT5 in MTAP-deleted cells while sparing normal ones. Previous phase 1 trials demonstrated a 21.4% objective response rate in MTAP-deleted solid tumors, with the maximum tolerated dose at 1200 mg once daily. AMG 193 has shown promising initial results, particularly in lung, pancreatic, and biliary tract cancers.
Outcomes: The trial measures several outcomes, including the objective response rate assessed by both investigator and blinded independent central review, progression-free survival, duration of response, and overall survival over a 35-month timeframe. Additionally, pharmacokinetic parameters like maximum concentration (Cmax) and area under the curve (AUC) and quality of life assessments will be evaluated.
Burden on patient: The burden on patients may be moderate to high due to the requirement for frequent visits for pharmacokinetic blood draws, particularly in the initial cycles of treatment, alongside regular imaging assessments to evaluate tumor response. Additionally, patients need to comply with the dosing regimen and possible management of adverse effects, hence requiring consistent healthcare visits and coordination.
Inclusion Criteria:
* Histologically or cytologically confirmed metastatic or unresectable locally advanced MTAP-deleted (Homozygous deletion of MTAP in the tumor tissue) non-small cell lung cancer
* Participants will have received and progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for locally advanced and unresectable or metastatic disease.
* Either an archival tissue sample or an archival block must be available.
* Life expectancy of greater than 3 months, in the opinion of the investigator.
* Participants who have had brain metastases and have been appropriately treated with radiation therapy or surgery ending at least 14 days before study day 1 are eligible.
* Participants with untreated asymptomatic brain metastases smaller or equal to 2 cm in size (per lesion if more than one) and not requiring corticosteroid treatment are eligible.
Exclusion Criteria:
Disease Related
• Tumors harboring the following mutations amenable to targeted therapies: epidermal growth factor receptor (EGFR), ALK receptor tyrosine kinase (ALK), ROS proto-oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), MET proto-oncogene (MET), B-Raf proto-oncogene (BRAF), RET proto-oncogene (RET), Human epidermal growth factor receptor 2 (HER2), KRAS proto-oncogene (KRAS).
Other Medical Conditions
* Major surgery within 28 days of study day 1.
* Untreated symptomatic central nervous system (CNS) metastatic disease regardless of size or asymptomatic brain metastases greater than 2 cm per lesion.
St Leonards, New South Wales, 2065, Australia
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Waratah, New South Wales, 2298, Australia
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South Brisbane, Queensland, 4101, Australia
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Salvador, Bahia, 40170-110, Brazil
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Natal, Rio Grande Do Norte, 59062-000, Brazil
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Sao Paulo, São Paulo, 01509-900, Brazil
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Barretos, São Paulo, 14784-400, Brazil
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Montreal, Quebec, H4A 3J1, Canada
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Fuzhou, Fujian, 350028, China
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Zhengzhou, Henan, 450052, China
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Zhengzhou, Henan, 450001, China
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Wuhan, Hubei, 430022, China
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Jinan, Shandong, 250013, China
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Shanghai, Shanghai, 200123, China
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Chengdu, Sichuan, 610041, China
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Beijing, 101149, China
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Hong Kong, Hong Kong
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Shatin, New Territories, Hong Kong
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Nagoya-shi, Aichi, 464-8681, Japan
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Kashiwa-shi, Chiba, 277-8577, Japan
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Sunto-gun, Shizuoka, 411-8777, Japan
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Chuo-ku, Tokyo, 104-0045, Japan
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Koto-ku, Tokyo, 135-8550, Japan
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Wakayama-shi, Wakayama, 641-8510, Japan
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Suwon-si Gyeonggi-do, 16499, Korea, Republic of
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Seongnam-si, Gyeonggi-do, 13496, Korea, Republic of
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Seoul, 03722, Korea, Republic of
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Suwon-si, Gyeonggi-do, 16247, Korea, Republic of
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Singapore, 119074, Singapore
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Singapore, 168583, Singapore
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Taichung, 40705, Taiwan
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Taipei, 10002, Taiwan
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Tainan, 70403, Taiwan
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Duarte, California, 91010, United States
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Los Angeles, California, 90095, United States
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Los Angeles, California, 90067, United States
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Los Angeles, California, 90048, United States
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Duarte, California, 91010, United States
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Norwich, Connecticut, 06360, United States
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Washington, District of Columbia, 20007, United States
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Baton Rouge, Louisiana, 70808, United States
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Ann Arbor, Michigan, 48106, United States
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Grand Rapids, Michigan, 49503, United States
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Nashville, Tennessee, 37203, United States
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Nashville, Tennessee, 37203, United States
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Irving, Texas, 75063, United States
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Dallas, Texas, 75230, United States
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Austin, Texas, 78745, United States
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Dallas, Texas, 75246, United States
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Tyler, Texas, 75702, United States
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Fairfax, Virginia, 22031, United States
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