AMG 193 + Docetaxel for Advanced Solid Cancers

(MTAP Trial)

Recruiting at 90 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Amgen

Must not be taking: CYP3A4 inducers, Anticoagulants

Disqualifiers: Brain metastases, Infection, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 2 years

649 Participants Needed

Trial Summary

What is the purpose of this trial?

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

Will I have to stop taking my current medications?

The trial requires that you stop taking any prescription medications that are strong inducers of cytochrome P450 3A4 (CYP3A4) at least 14 days or 5 half-lives before starting the study. Additionally, you must not have received anti-tumor therapy within 28 days of the study start date.

What data supports the effectiveness of the drug combination AMG 193 and Docetaxel for treating advanced solid cancers?

Docetaxel has shown effectiveness in treating various cancers like breast, gastric, and prostate cancer. Additionally, research suggests that certain genetic markers in colorectal cancer may predict sensitivity to docetaxel, indicating potential effectiveness in specific patient groups. ^{1 2 3 4 5}

What safety data exists for AMG 193 and Docetaxel in humans?

Docetaxel, a chemotherapy drug, is known to cause side effects like venous thrombosis (blood clots in veins) and gastrointestinal toxicity (stomach and intestine issues), especially in older patients or those with other health problems. In a study of AMG 193, some patients with advanced solid tumors experienced partial responses, but specific safety data for AMG 193 is not detailed. ^{2 4 6 7 8}

What makes the drug combination of AMG 193 and Docetaxel unique for treating advanced solid cancers?

The combination of AMG 193, a PRMT5 inhibitor, and Docetaxel, a well-established chemotherapy drug, is unique because it targets cancer cells through different mechanisms, potentially enhancing the overall antitumor effect. This approach is novel as it combines a targeted therapy with a traditional chemotherapy agent, which may improve treatment outcomes for patients with advanced solid cancers. ^{2 5 9 10 11}

Research Team

MD

Principal Investigator

Amgen

Eligibility Criteria

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.

Inclusion Criteria

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

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

My liver is working well according to recent tests.

Exclusion Criteria

Known positive test for Human Immunodeficiency Virus (HIV)

I have previously been treated with docetaxel.

Evidence of active severe acute respiratory syndrome coronavirus 2 (SARS-COV2) infection

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AMG 193 alone or in combination with docetaxel to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D)

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AMG 193
• Docetaxel

Trial Overview 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).

Participant Groups

Group I: Part 3: AMG 193 Phase 2 Experimental Treatment 1 Intervention

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

Group II: Part 2b, Phase 1: AMG 193 + Docetaxel Dose Expansion Experimental Treatment 2 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 + Docetaxel Experimental Treatment 2 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 Expansion Experimental Treatment 1 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 Expansion Experimental Treatment 1 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 Treatment 1 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 Treatment 2 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 Optimization Experimental Treatment 1 Intervention

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

Group IX: Part 1h, Phase 1: AMG 193 Monotherapy Dose Expansion Experimental Treatment 1 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 Expansion Experimental Treatment 1 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 Expansion Experimental Treatment 1 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 Expansion Experimental Treatment 1 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 Expansion Experimental Treatment 1 Intervention

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

Group XIV: Part 1a, Phase 1: AMG 193 Monotherapy Dose Exploration Experimental Treatment 2 Interventions

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

Who Is Running the Clinical Trial?

Amgen

Lead Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Findings from Research

The Phase 2 trial involving 6 patients with CHFR-methylated, MSI-high colorectal cancer tested the combination of gemcitabine and docetaxel, but no tumor responses were observed, indicating limited efficacy in this specific patient group.

Despite the lack of significant results, the study highlights the potential for using epigenetic biomarkers like CHFR methylation and MSI to guide personalized treatment strategies in colorectal cancer, suggesting a need for further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 2 trial of gemcitabine and docetaxel in patients with metastatic colorectal adenocarcinoma with methylated checkpoint with forkhead and ring finger domain promoter and/or microsatellite instability phenotype. Baretti, M., Karunasena, E., Zahurak, M., et al.[2022]

In a Phase IV study involving 411 Iranian cancer patients, docetaxel (Alvotere) demonstrated an acceptable safety profile, with alopecia being the most common adverse event reported in 41.12% of patients.

The study found that 22.38% of patients experienced severe adverse events (grade 3 or 4), with a notable difference in skin disorders between genders, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Post-Marketing Surveillance Study to Evaluate the Safety Profile of AlvotereⓇ (Docetaxel) in Iranian Patients Diagnosed with Different Types of Cancers Receiving Chemotherapy. Shahi, F., Vafaeezadeh, F., Ansarinejad, N., et al.[2022]

The combination of the methylation inhibitor 5-Aza-2'-Deoxycytidine (5-aza-2dc) and docetaxel (DT) significantly enhances the inhibition of prostate cancer cell proliferation, migration, and invasiveness in the PC3 cell line, with the most pronounced effects observed in the combination treatment group.

Both drugs, especially when used together, effectively induce apoptosis in PC3 cells and alter the cell cycle by reducing the number of cells in the G0/G1 phase and increasing those in the G2/M phase, indicating a potential mechanism for their combined therapeutic action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Inhibitory effect of 5-aza-2'-deoxycytidine combined with docetaxel on prostate cancer PC3 cells in vitro]. Yi, XM., Gong, J., Dong, J., et al.[2018]

Docetaxel shows efficacy in treating müllerian carcinoma in patients who are resistant to paclitaxel, with an overall response rate of 23% and a median survival time of 44 weeks based on a study of 32 patients.

Patients who had a longer interval without taxane treatment (median of 73 weeks) were more likely to respond to docetaxel, indicating that timing may play a crucial role in treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel for patients with paclitaxel-resistant Müllerian carcinoma. Verschraegen, CF., Sittisomwong, T., Kudelka, AP., et al.[2018]

In colorectal cancer, CHFR methylation and microsatellite instability (MSI) status can predict sensitivity to chemotherapy, with MSI-H cell lines showing increased sensitivity to gemcitabine and CHFR-methylated lines responding better to docetaxel.

In vivo studies confirmed that specific colorectal cancer cell lines with these molecular alterations responded differently to treatments, suggesting that a tailored combination of gemcitabine and docetaxel could benefit certain patients, leading to an ongoing clinical trial for biomarker-selected individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CHFR silencing or microsatellite instability is associated with increased antitumor activity of docetaxel or gemcitabine in colorectal cancer. Pelosof, L., Yerram, SR., Ahuja, N., et al.[2022]

In a study involving human prostate cancer models, the combination of estramustine and docetaxel significantly prolonged tumor growth delay (TGD) in docetaxel-resistant tumors, achieving a TGD of 50 days compared to 18 days with estramustine alone.

Despite the efficacy of the combination treatment, its use may be limited in elderly patients or those with comorbidities due to the risk of serious side effects, such as venous thrombosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A preclinical therapeutic schedule optimizing docetaxel plus estramustine administration in prostate cancer. Dahmani, A., de Plater, L., Guyader, C., et al.[2018]

The combination of docetaxel and cisplatin was found to be feasible and manageable at maximum-tolerated doses of docetaxel 100 mg/m2 and cisplatin 75 mg/m2, with a high median relative dose-intensity allowing for 81% of cycles to be administered at full dose.

Common side effects included severe leukocytopenia and granulocytopenia, but these were short-lasting and dose-dependent, while non-hematologic toxicities were generally mild to moderate, indicating a manageable safety profile for this chemotherapy regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors. Pronk, LC., Schellens, JH., Planting, AS., et al.[2018]

In a phase I trial involving 39 patients with advanced solid tumors lacking the MTAP gene, the PRMT5 inhibitor AMG 193 showed promising results, with five patients experiencing partial responses.

These partial responses were observed across various tumor types, including esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancers, indicating the potential efficacy of AMG 193 in treating these specific cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AMG 193 Effective in Multiple Tumor Types. [2023]

Gemcitabine has been established as an effective treatment for improving quality of life and survival in patients with advanced pancreatic cancer, but adding other drugs has not shown improved survival outcomes.

Docetaxel, while showing limited activity as a single agent, has demonstrated promising efficacy when combined with other chemotherapeutic agents, suggesting that further randomized trials are warranted to explore these combinations in treating advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel in the management of advanced pancreatic cancer. Lopes, G., Rocha Lima, CM.[2022]

Docetaxel is a highly effective cytotoxic agent against mouse forestomach carcinoma (MFC), showing significant tumor growth inhibition and superior efficacy compared to doxorubicin in a dose-dependent manner.

The combination of docetaxel and batimastat (BB-94) resulted in greater tumor growth inhibition (96.0%) than either drug alone, indicating that BB-94 enhances the antitumor activity of docetaxel when used together.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potentiation of docetaxel antitumor activity by batimastat against mouse forestomach carcinoma. Gu, B., Wu, D., Li, M., et al.[2018]

Docetaxel, a semisynthetic taxane, effectively stabilizes microtubules to induce cell-cycle arrest and apoptosis, showing improved survival rates in various cancers, including metastatic breast cancer and non-small-cell lung cancer.

Randomized trials have demonstrated that adding docetaxel to standard treatments enhances survival outcomes in high-risk early breast cancer and metastatic prostate cancer, highlighting its efficacy across multiple solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel for treatment of solid tumours: a systematic review of clinical data. Montero, A., Fossella, F., Hortobagyi, G., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

A phase 2 trial of gemcitabine and docetaxel in patients with metastatic colorectal adenocarcinoma with methylated checkpoint with forkhead and ring finger domain promoter and/or microsatellite instability phenotype. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

A Post-Marketing Surveillance Study to Evaluate the Safety Profile of AlvotereⓇ (Docetaxel) in Iranian Patients Diagnosed with Different Types of Cancers Receiving Chemotherapy. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Inhibitory effect of 5-aza-2'-deoxycytidine combined with docetaxel on prostate cancer PC3 cells in vitro]. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Docetaxel for patients with paclitaxel-resistant Müllerian carcinoma. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

CHFR silencing or microsatellite instability is associated with increased antitumor activity of docetaxel or gemcitabine in colorectal cancer. [2022]

6. England pubmed.ncbi.nlm.nih.gov

A preclinical therapeutic schedule optimizing docetaxel plus estramustine administration in prostate cancer. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

AMG 193 Effective in Multiple Tumor Types. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Docetaxel in the management of advanced pancreatic cancer. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Potentiation of docetaxel antitumor activity by batimastat against mouse forestomach carcinoma. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Docetaxel for treatment of solid tumours: a systematic review of clinical data. [2022]