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

Trial Summary

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.

What makes the drug TAK-243 unique for treating advanced cancer?

TAK-243 (MLN7243) is unique because it targets a specific pathway involved in cancer cell survival, which may offer a new approach for treating advanced cancers where standard treatments are limited or ineffective. ^{1 2 3 4 5}

What is the purpose of this trial?

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 tumor that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic) and in patients with lymphoma. TAK-243 is a drug that binds to and inhibits the ubiquitin-activating enzyme, an enzyme that is more active on cancer cells than healthy cells, inhibiting tumor cell proliferation and survival.

Research Team

Sarah Shin, MD

Principal Investigator

National Cancer Institute LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

1. United States 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. [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

Inhibition of ovarian cancer cell growth by a novel TAK1 inhibitor LYTAK1. [2015]

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

Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts. [2022]

4. Germany 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. [2022]

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

The role of TAK1 expression in thyroid cancer. [2018]