TAK-243 for Advanced Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4/5 inhibitors, CYP3A4/5 inducers

Disqualifiers: Uncontrolled illness, Hepatic cirrhosis, Cardiopulmonary disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 21-28 days per cycle

95 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and optimal dose of a new drug, TAK-243, for individuals with advanced or metastatic cancer, including aggressive lymphomas. TAK-243 inhibits an enzyme that aids cancer cell growth. Participants with advanced solid tumors or lymphomas unresponsive to other treatments might be suitable candidates. As a Phase 1 trial, this research aims to understand how TAK-243 functions in people, offering participants the chance to be among the first to receive this new treatment.

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking certain medications, specifically strong inhibitors and inducers of CYP3A4/5, as well as strong inhibitors of BCRP or OATP, 14 days before joining and throughout the study. Herbal medications are also not allowed, except for vitamins. It's important to discuss your current medications with the trial team to ensure there are no interactions with TAK-243.

Is there any evidence suggesting that this trial's treatment is likely to be safe?

Research has shown that TAK-243, a drug aimed at fighting cancer, has produced promising results in early studies. It blocks an enzyme that cancer cells need to grow and survive. This enzyme is more active in cancer cells than in healthy ones, allowing the drug to target tumors more effectively than normal tissues.

In lab studies, TAK-243 slowed tumor growth in various cancer models. However, these findings are primarily from lab settings, so more research is needed to fully understand its effects in humans.

Since this trial is in an early phase, it focuses on finding the best dose and identifying any side effects. While there is some evidence of its potential, TAK-243 is still being tested for safety in people. Participants might experience side effects, but researchers are still studying how common and severe they might be.

Anyone considering joining this trial should talk with healthcare providers to understand the potential risks and benefits based on the available data. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about TAK-243 because it introduces a new approach to treating advanced cancer by targeting the ubiquitin-activating enzyme (UAE), which is crucial for protein degradation in cancer cells. Unlike traditional chemotherapy or targeted therapies that focus on specific proteins or DNA damage, TAK-243 disrupts the protein recycling process in cancer cells, potentially leading to their death. This mechanism is unique and may offer a novel way to tackle cancers that have become resistant to other treatments. Additionally, TAK-243's administration both twice weekly and once weekly allows for flexibility in dosing, which could improve patient compliance and reduce side effects compared to more frequent treatment schedules.

What evidence suggests that TAK-243 might be an effective treatment for advanced cancer?

Research has shown that TAK-243 is a promising new treatment for advanced cancers. This trial will evaluate TAK-243 in two dosing schedules: Arm A, where participants receive TAK-243 twice weekly, and Arm B, where participants receive it once weekly. The drug blocks a specific enzyme that cancer cells need to grow and survive. Early findings suggest that TAK-243 can prevent cancer cells from repairing their DNA, making it harder for them to continue growing. Studies also indicate that it may shrink tumors and improve outcomes for cancer patients. Although still in the early stages of testing, these results offer hope for those with hard-to-treat cancers. ^{1 3 4 6 7}

Who Is on the Research Team?

Sarah Shin, MD

Principal Investigator

National Cancer Institute LAO

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic solid tumors that have worsened after treatment, or lymphoma patients without curative options. Participants must be in relatively good health (ECOG <=2), have measurable disease, and meet specific blood and organ function criteria.

Inclusion Criteria

Platelets ≥ 75,000/mcL

My liver function tests are within acceptable limits, even with liver metastases.

My hemoglobin level is at least 9 g/dL, even if I needed a transfusion to reach this.

Exclusion Criteria

Prolonged rate corrected QT (QTc) interval ≥ 470 m/sec, calculated according to institutional guidelines

Patients who are receiving any other investigational agents

I have not received any live vaccines within 30 days before starting TAK-243, and will not for 100 days after the last dose.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive UAE inhibitor TAK-243 intravenously on a dose-escalation schedule, with Arm A receiving doses on days 1, 4, 8, and 11 of a 21-day cycle, and Arm B receiving doses on days 1, 8, and 15 of a 28-day cycle. Patients also undergo biopsy, CT, MRI, and blood collection throughout the study.

21-28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, including assessment of objective tumor response and pharmacodynamic variables.

Up to 30 days after the last dose of treatment

What Are the Treatments Tested in This Trial?

Interventions

• TAK-243

Trial Overview The study is testing TAK-243's safety and optimal dosage in treating advanced cancers. TAK-243 targets an enzyme more active in cancer cells to stop their growth. The trial includes imaging tests like CT scans, MRIs, echocardiography, biopsies, and biospecimen collection.

How Is the Trial Designed?

Group I: Arm B (once weekly UAE inhibitor TAK-243) Experimental Treatment 6 Interventions

Patients receive UAE inhibitor TAK-243 IV on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on study, and undergo CT, MRI, and collection of blood throughout the study, and may undergo ECHO as clinically indicated on study.

Group II: Arm A (twice weekly UAE inhibitor TAK-243) Experimental Treatment 6 Interventions

Patients receive UAE inhibitor TAK-243 IV on days 1, 4, 8, and 11 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on study, and undergo CT, MRI, and collection of blood throughout the study, and may undergo ECHO as clinically indicated on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

TAK1 is significantly overexpressed in thyroid cancer tissues (78.2%) compared to adjacent normal tissues (14.9%), and its expression is associated with advanced clinical stages and lymph node metastasis, indicating its potential role in cancer progression.

Inhibition of TAK1 using the selective inhibitor 5Z-7-oxozeaenol reduced thyroid cancer cell proliferation and invasion while promoting apoptosis, likely through the suppression of the NF-κB signaling pathway, suggesting that targeting TAK1 could improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of TAK1 expression in thyroid cancer. Lin, P., Niu, W., Peng, C., et al.[2018]

The phase I trial involving 67 patients found that the oral TORC1/2 inhibitor TAK-228, when combined with paclitaxel, showed a safety profile similar to other TORC inhibitors, with common side effects including neutropenia and diarrhea.

TAK-228 demonstrated promising preliminary antitumor activity, with 14 out of 54 evaluable patients achieving either a partial response or stable disease lasting at least 6 months, supporting further research into its use with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. Burris, HA., Kurkjian, CD., Hart, L., et al.[2022]

TAK-117, an investigational PI3Kα-selective inhibitor, demonstrated an acceptable safety profile with intermittent dosing allowing for higher total weekly exposures compared to once-daily dosing, with a maximum tolerated dose (MTD) of 900 mg.

While TAK-117 showed limited single-agent antitumor activity, with some patients achieving stable disease, further studies are recommended to explore its potential in combination therapies for advanced solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies. Juric, D., de Bono, JS., LoRusso, PM., et al.[2019]

LYTAK1, a specific TAK1 inhibitor, effectively inhibits the growth of ovarian cancer cells while sparing normal ovarian epithelial cells, indicating its potential as a targeted therapy.

The mechanism of action involves inducing necrosis in ovarian cancer cells through mitochondrial permeability transition pore (mPTP) opening, and LYTAK1 also shows enhanced efficacy when combined with paclitaxel in vivo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of ovarian cancer cell growth by a novel TAK1 inhibitor LYTAK1. Ying, L., Chunxia, Y., Wei, L.[2015]

TAK-733, a novel MEK inhibitor, showed significant antitumor activity in colorectal cancer (CRC) cell lines and patient-derived tumor explants, particularly in those with BRAF or KRAS/NRAS mutations, indicating its potential as a targeted therapy.

Despite promising preclinical results, the single-agent efficacy of TAK-733 in clinical settings has been limited, highlighting the need for further research to understand resistance mechanisms and develop combination treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts. Lieu, CH., Klauck, PJ., Henthorn, PK., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06223542

Studying TAK-243 in Patients With Advanced Cancer This phase I trial studies the side effects and best dose of ubiquitin-activating enzyme (UAE) inhibitor TAK-243 (TAK-243) in treating patients with a solid ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10949913/

Activity of the Ubiquitin-activating Enzyme Inhibitor TAK- ... However, the prognosis remains poor with a median overall survival of approximately 15 months even in the EDP-M treatment arm (4). Therefore, ...

3. aacrjournals.org aacrjournals.org/mct/article/14/12_Supplement_2/A164/233351/Abstract-A164-The-small-molecule-UAE-inhibitor-TAK

Abstract A164: The small molecule UAE inhibitor TAK-243 ... Abstract A164: The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02045095

A Dose Escalation Study of MLN7243 (TAK-243) in Adult ... Participants must have a histologically confirmed diagnosis of an advanced, metastatic malignant solid tumor and must have failed or exhausted standard ...

5. aacrjournals.org aacrjournals.org/cancerrescommun/article/doi/10.1158/2767-9764.CRC-24-0085/735086/am/Activity-of-the-ubiquitin-activating-enzyme

Activity of the ubiquitin-activating enzyme inhibitor TAK-243 in ... TAK-243 is a promising potential treatment option for ACC, either as monotherapy or in combination with existing therapies or BCL2 inhibitors.

6. selleckchem.com selleckchem.com/products/tak-243-mln243.html

TAK-243 (MLN7243) | E1 Activating inhibitor | Mechanism TAK-243 treatment causes death of cancer cells and, in primary human xenograft studies. TAK-243 demonstrates broad antitumor activity in models of solid and ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S016748892300191X

The ubiquitin-proteasome pathway inhibitor TAK-243 has ... Here, we reveal that TAK-243 has major effects on Ca 2+ handling in a range of cultured mammalian cells (αT3, HeLa and SH-SY5Y).