What is the mechanism of action of this treatment?

Targeted therapies for solid tumors, such as AMG 193, work by specifically inhibiting molecules involved in cancer cell growth and survival. AMG 193 targets PRMT5 in MTAP-null solid tumors, disrupting the cancer cells' ability to proliferate. This targeted approach is significant for patients as it aims to maximize treatment efficacy while minimizing damage to healthy cells, leading to potentially better outcomes and fewer side effects compared to traditional chemotherapy.

What side effects are associated with this type of intervention?

Targeted therapies for solid tumors, such as PRMT5 inhibitors like AMG 193, commonly cause side effects including fatigue, nausea, diarrhea, skin rashes, and liver toxicity. When combined with chemotherapy agents like docetaxel, additional side effects may include myelosuppression, neuropathy, and increased risk of infections. The severity and frequency of these side effects can vary based on the specific drug and patient characteristics.

What prior FDA approvals exist?

The FDA has approved several targeted therapies for the treatment of solid tumors. For instance, enasidenib is approved for relapsed or refractory acute myeloid leukemia with an IDH2 mutation. Gemtuzumab ozogamicin, an immunoconjugate targeting CD33, is used for AML. In the context of solid tumors, targeted therapies like AMG 193, which inhibits PRMT5 in MTAP-null tumors, are being studied. These therapies often involve specific inhibitors that target genetic mutations or protein expressions within the tumor cells, similar to how AMG 193 is being evaluated for its efficacy and safety in combination with docetaxel for advanced MTAP-null solid tumors.

What other types of research exist?

Promising novel alternatives to AMG 193 for solid tumors include: 1) Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, which has shown encouraging efficacy in advanced epithelial cancers. 2) Glembatumumab vedotin (GV), targeting gpNMB, which has been evaluated in triple-negative breast cancer. 3) Antibody-linked small unilamellar vesicles (SUVs) containing methotrexate (MTX), which have demonstrated increased binding and potential anticancer activity in melanoma models.

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Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor

AMG 193 + Docetaxel for Advanced Solid Cancers (MTAP Trial)

Phase 1 & 2

Recruiting

Research Sponsored by Amgen

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Able to swallow and retain orally administered study treatment and willing to record daily adherence to investigational product

Histologically confirmed metastatic or locally advanced solid tumor not amenable to curative treatment with surgery and/or radiation

Must not have

Major surgery

Active infection

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to approximately 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests AMG 193 in adults with advanced cancers. The drug aims to specifically attack these cancer cells.

Who is the study for?

Adults over 18 with advanced solid tumors that can't be cured by surgery or radiation, specifically those without the MTAP gene. Participants must be able to take oral medication and have a life expectancy of at least 12 weeks. They should not have had certain prior treatments, active infections, heart issues, or other recent cancer therapies.

What is being tested?

The trial is testing AMG 193 alone and combined with docetaxel in adults with MTAP-null solid tumors. It aims to find the safest dose for future studies (Parts 1 & 2) and measure how well the tumor responds to AMG 193 (Part 3).

What are the potential side effects?

Potential side effects may include reactions related to immune system activation, such as inflammation in various organs; typical chemotherapy-related effects like nausea, fatigue, hair loss; and possible blood disorders due to bone marrow suppression.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can take pills and am willing to track my medication use.

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My cancer has spread and cannot be cured with surgery or radiation.

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My blood clotting levels are within a normal range.

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My cancer lacks certain genes (CDKN2A or MTAP) or the MTAP protein.

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My lungs are working well.

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I am fully active or can carry out light work.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have had major surgery recently.

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I currently have an infection.

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I have had a blood clot in an artery before.

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I do not have spinal cord compression, untreated brain metastases, or leptomeningeal disease.

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I have had cancer other than my current diagnosis in the last 2 years.

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I have had a heart attack or symptoms of heart failure.

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I have been diagnosed with Congenital Short QT Syndrome.

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I have had radiation to less than 25% of my bone marrow.

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I have not been treated with MAT2A or PRMT5 inhibitors before.

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I have a lung condition that affects the tissue and space around the air sacs.

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I am currently using blood thinners for a clotting issue.

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I am a woman able to have children but unwilling to use specified birth control methods.

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I have had issues like bowel blockage or serious gut infections.

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I have had a solid organ transplant.

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I have lingering side effects from previous cancer treatments.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to approximately 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to approximately 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to approximately 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Parts 1 and 2: Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)

Secondary study objectives

Part 3 Only: Number of Participants Who Experience TEAE

Side effects data

From 2014 Phase 4 trial • 32 Patients • NCT01301729

59%

Leukopenia

56%

Neutropenia

34%

Hypoaesthesia

31%

Agranulocytosis

22%

Alopecia

22%

Asthenia

19%

Pyrexia

16%

Nail disorder

16%

Oedema peripheral

16%

Diarrhoea

16%

Hypophagia

13%

Alanine aminotransferase increased

13%

Neurotoxicity

13%

Cough

13%

Vomting

Musculoskeletal pain

Headache

Aspartate aminotransferase increased

Chest discomfort

Rash

Pigmentation disorder

Nausea

Bone marrow failure

Anaemia

Transaminases increased

Insomnia

Constipation

Mouth ulceration

Nasopharyngitis

Paronychia

Flushing

Face oedema

Thrombocytopenia

Infection

Upper respiratory tract infection

Completed suicide

Cataract

100%

80%

60%

40%

20%

Study treatment Arm

Trastuzumab

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

14Treatment groups

Experimental Treatment

Group I: Part 3: AMG 193 Phase 2Experimental Treatment1 Intervention

Participants with MTAP-null solid tumors will receive AMG 193.

Group II: Part 2b, Phase 1: AMG 193 + Docetaxel Dose ExpansionExperimental Treatment2 Interventions

Participants with MTAP-null NSCLC will receive the identified MTD/RP2D of AMG 193 + docetaxel.

Group III: Part 2a, Phase 1: AMG 193 Dose Exploration + DocetaxelExperimental Treatment2 Interventions

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.

Group IV: Part 1m, Phase 1: AMG 193 Monotherapy Dose ExpansionExperimental Treatment1 Intervention

Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null glioma.

Group V: Part 1l, Phase 1: AMG 193 Monotherapy Dose ExpansionExperimental Treatment1 Intervention

Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null esophageal/gastric cancer.

Group VI: Part 1k, Phase 1: AMG 193 Food Effect Substudy (US Sites Only)Experimental Treatment1 Intervention

Participants will receive AMG 193 once on a fasted state and once after eating a standardized high-fat, high calorie meal.

Group VII: Part 1j, Phase 1: AMG 193 DSPS Substudy (US Sites Only)Experimental Treatment2 Interventions

Participants will receive doses of AMG 193 and comparator AMG 193 test tables at different times in a fasted state.

Group VIII: Part 1i, Phase 1: AMG 193 Dose OptimizationExperimental Treatment1 Intervention

Participants will receive a randomized dose optimization evaluation of AMG 193.

Group IX: Part 1h, Phase 1: AMG 193 Monotherapy Dose ExpansionExperimental Treatment1 Intervention

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).

Group X: Part 1g, Phase 1: AMG 193 Monotherapy Dose ExpansionExperimental Treatment1 Intervention

Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null pancreatic adenocarcinoma

Group XI: Part 1f, Phase 1: AMG 193 Monotherapy Dose ExpansionExperimental Treatment1 Intervention

Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null head and neck squamous cell carcinoma (HNSCC)

Group XII: Part 1e, Phase 1: AMG 193 Monotherapy Dose ExpansionExperimental Treatment1 Intervention

Participants will receive the identified selected dose/MTD of AMG 193 in the following cohort: MTAP-null BTC.

Group XIII: Part 1c, Phase 1: AMG 193 Monotherapy Dose ExpansionExperimental Treatment1 Intervention

Participants will receive the identified MTD/RP2D of AMG 193 in the following cohort: MTAP-null or lost MTAP expression NSCLC.

Group XIV: Part 1a, Phase 1: AMG 193 Monotherapy Dose ExplorationExperimental Treatment2 Interventions

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 AMG 193 at a selected dose and a dose of a comparator AMG 193 table(s).

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Docetaxel

1995

Completed Phase 4

~6550

0 / 22Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Targeted therapies for solid tumors, such as AMG 193, work by specifically inhibiting molecules involved in cancer cell growth and survival. AMG 193 targets PRMT5 in MTAP-null solid tumors, disrupting the cancer cells' ability to proliferate. This targeted approach is significant for patients as it aims to maximize treatment efficacy while minimizing damage to healthy cells, leading to potentially better outcomes and fewer side effects compared to traditional chemotherapy.

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