AMG 193 + Docetaxel for Advanced Solid Cancers

(MTAP Trial)

Recruiting in Palo Alto (17 mi)

+90 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Amgen

Must not be taking: CYP3A4 inducers, Anticoagulants

Disqualifiers: Brain metastases, Infection, Heart failure, others

No Placebo Group

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}

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

Trial 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 (Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor)
• Docetaxel (Taxane)

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 or lost MTAP expression 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. 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).

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Pennsylvania New York, NY

Center for Oncology and Blood Disorders Houston, TX

Lumi Research Kingwood, TX

University of Virginia Cancer Center Charlottesville, VA

More Trial Locations

Who Is Running the Clinical Trial?

Amgen Lead Sponsor

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] We previously reported CHFR methylation in a subset of colorectal cancer (CRC; ∼30%) with high concordance with microsatellite instability (MSI). We also showed that CHFR methylation predicted for sensitivity to docetaxel, whereas the MSI-high phenotypes were sensitive to gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to gemcitabine and docetaxel. We enrolled a Phase 2 trial of gemcitabine and docetaxel in patients with MSI-high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21-day cycle. A total of 6 patients with CHFR-methylated, MSI-high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred at 10 patients. No RECIST criteria tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression-free survival (PFS) was 1.79 months (95% confidence interval [CI] = 1.28, not available [NA]) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were lymphopenia (67%), leukopenia (33%), and anemia (33%). Although negative, this study establishes a proof-of-concept for the implementation of epigenetic biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of personalized medicine. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CHFR silencing via DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumors. The frequent association of CHFR methylation with microsatellite instability (MSI) suggested a possible combination therapy with gemcitabine, because the MSI phenotype may result in sensitivity to nucleoside analogues. WHAT QUESTION DID THIS STUDY ADDRESS? We hypothesized that metastatic colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to gemcitabine and docetaxel, and have designed this Phase 2 trial in biomarker-selected mCRC to test this prediction. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study enrolled a molecularly defined subgroup of patients with colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive biomarkers for therapeutic agents in defined subsets of patients are warranted.

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] Docetaxel is a clinically well established antimitotic chemotherapy medication. Labeled docetaxel indications are breast cancer, gastric cancer, head and neck cancer, non-small cell lung cancer, and prostate cancer.

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] To evaluate the effects of methylation inhibitor 5-Aza-2'-Deoxycytidine (5-aza-2dc) and docetaxel (DT), alone or in combination, on the proliferation, migration, apoptosis and cell cycles of the human prostate cancer cell line PC3, and to investigate the possible mechanisms of these two drugs acting on prostate cancer in vitro.

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

Docetaxel for patients with paclitaxel-resistant Müllerian carcinoma. [2018] To determine the efficacy and toxicity of docetaxel in patients with müllerian carcinoma resistant to paclitaxel.

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] Phenotypic differences among cancers with the same origin may be associated with chemotherapy response. CHFR silencing associated with DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumor types. However, the use of microsatellite instability (MSI:unstable-MSS:stable) as a predictive marker for therapeutic effect has had conflicting results. We examined these molecular alterations as predictors of chemotherapy sensitivity in colorectal cancer (CRC). Differential sensitivity to docetaxel and gemcitabine was compared to potential predictive biomarkers CHFR methylation and MSI status. Cell lines that were MSI-H/CHFR-methylated, MSS/CHFR-methylated and MSS/CHFR-unmethylated were assessed for in vivo sensitivity of CRC cell line xenografts to docetaxel and/or gemcitabine. We observed increased sensitivity in vitro to gemcitabine in cell lines with MSI and docetaxel in cell lines with CHFR inactivation via DNA methylation. In vivo treatment of human xenografts confirmed differential sensitivity, with the MSI-H/CHFR-methylated line RKO having tumor growth inhibition to each agent, and at least additive tumor growth inhibition with combination therapy. The MSS-CHFR-unmethylated line, CACO2 , was resistant to single and combination therapy, while COLO205, the MSS/CHFR-methylated line, showed tumor growth inhibition with docetaxel, but not gemcitabine, therapy. CHFR methylation in CRC cell lines predicted for sensitivity in vitro and in vivo to docetaxel, while MSI-H cell lines were more sensitive to gemcitabine. These data suggest that a subset of CRC patients would be selectively sensitive to a novel combination of gemcitabine and docetaxel, and are the basis for an ongoing clinical trial of this combination in a biomarker-selected patient population.

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

A preclinical therapeutic schedule optimizing docetaxel plus estramustine administration in prostate cancer. [2018] Androgen-dependent and castration-resistant prostate cancer (PC) is usually sensitive to docetaxel chemotherapy. Nevertheless, docetaxel resistance frequently appears after several cycles of treatment, raising the problem of salvage treatment for docetaxel-resistant PC patients. Although the combination of docetaxel and estramustine prolongs metastasis-free and overall survival of patients with androgen-independent PC, the use of this modality remains limited in elderly patients or patients with several comorbidities, especially vascular disease or gastrointestinal toxicity, because of unacceptable toxicity including venous thrombosis. The aims of this study were therefore (i) to evaluate the in-vivo efficacy of estramustine combined with docetaxel since initial tumor growth and following the appearance of docetaxel resistance in the androgen-dependent human PC xenograft PAC120, and (ii) to evaluate the efficacy of estramustine in six human androgen-independent PC models derived from PAC120. In docetaxel-resistant tumor-bearing mice, estramustine alone induced a TGD2 of 18 days, whereas the combination of docetaxel and estramustine induced a TGD2 of 50 days (P

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

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors. [2018] This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects.

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

AMG 193 Effective in Multiple Tumor Types. [2023] In a phase I trial of the MTA-cooperative PRMT5 inhibitor AMG 193, five of 39 patients with advanced MTAP-deleted solid tumors who had scans following initial treatment experienced partial responses. The responses occurred in five tumor types-esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer.

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

Docetaxel in the management of advanced pancreatic cancer. [2022] The poor outcome of pancreatic cancer with conventional treatment options emphasizes the need for continued research. The benefits of gemcitabine in improving quality of life and survival have been established in patients with advanced pancreatic cancer. Randomized clinical trials studying the addition of a second drug to gemcitabine, either a classic cytotoxic (5-fluorouracil, cisplatin, irinotecan, pemetrexed, oxaliplatin, or exatecan) or targeted agents (ie, the farnesyl transferase inhibitor R115777 or the metalloproteinase inhibitor marimastat) have not resulted in improvement in survival compared with gemcitabine alone. Although limited activity of docetaxel in patients with pancreatic adenocarcinoma has been reported in single-agent studies, attractive efficacy results have been documented with docetaxel in combination with other chemotherapeutic agents for the management of advanced pancreatic cancer. Phase I and II trials of docetaxel in combination with gemcitabine, irinotecan, 5-fluorouracil, or thalidomide, as well as trials of docetaxel and radiotherapy, suggest that docetaxel combinations in pancreatic cancer should be further studied in randomized trials.

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

Potentiation of docetaxel antitumor activity by batimastat against mouse forestomach carcinoma. [2018] Docetaxel is a chemical compound belonging to the taxoid class of anticancer agents. Batimastat (BB-94) is the first matrix metalloproteinase inhibitor entering clinical trials. To improve the treatment of tumors, we studied the combined effects of docetaxel and batimastat on mouse forestomach carcinoma (MFC), and compared them with doxorubicin. In vitro growth curve analysis, MTT assay, and clonogenic assay were used to determine the cytotoxic effect of docetaxel or/and BB-94 on MFC. They showed that docetaxel, but not BB-94, had a significant cytotoxicity and that the effect of docetaxel was not enhanced by BB-94. In an early stage MFC tumor model, an obvious antitumor effect of docetaxel or doxorubicin given iv at maximum tolerated dose (MTD) was observed. Tumor growth inhibition was greater for docetaxel + BB-94 (96.0%) than for doxorubicin + BB-94 (88.0%), docetaxel (89.0%), doxorubicin (68.0%), and BB-94 (33.0%). Docetaxel showed activity against advanced stage MFC tumor in a dose-dependent manner and was more effective at MTD than doxorubicin, with 4/5 regression, 46.5 days tumor growth delay, and 2.8 log10 tumor-cell kill. Our results suggest that docetaxel is an effective new cytotoxic drug against MFC tumor and that BB-94 enhances the antitumor activity of docetaxel in the dose and schedule used.

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

Docetaxel for treatment of solid tumours: a systematic review of clinical data. [2022] Docetaxel is a semisynthetic taxane, a class of anticancer agents that bind to beta tubulin, thereby stabilising microtubules and inducing cell-cycle arrest and apoptosis. Docetaxel was first approved for the treatment of anthracycline-refractory metastatic breast cancer in the mid-1990s. Since then, several randomised trials have reported improved time-to-progression, overall survival, or both in metastatic breast cancer treated with single-agent docetaxel or docetaxel-based combination regimens. Data from two adjuvant trials have shown a survival benefit with the addition of docetaxel to standard anthracycline-based regimens in patients with high-risk early breast cancer. In four randomised studies, docetaxel improved survival in locally advanced or metastatic non-small-cell lung cancer. Moreover, two trials have shown that docetaxel combined with estramustine or corticosteroids improves survival in metastatic androgen-independent prostate cancer. Here, we review major randomised phase III trials with docetaxel in the treatment of solid malignant disease.