MLN0128 for Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Proton pump inhibitors, Corticosteroids

Disqualifiers: Uncontrolled hypertension, Diabetes, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: Up to 3 years

49 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II MATCH treatment trial tests how well MLN0128 (TAK-228) works in treating patients with cancer that has certain genetic changes called TSC1 or TSC2 mutations. MLN0128 (TAK-228) may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Will I have to stop taking my current medications?

The trial requires that you stop taking proton pump inhibitors (PPIs) at least 7 days before starting the study drug and avoid them during the trial. You should also not take H2 receptor antagonists within 24 hours of the first dose. If you are on strong CYP1A2 inhibitors or CYP inducers, discuss alternatives with your doctor.

What data supports the effectiveness of the drug MLN0128 (TAK-228) for cancer treatment?

Research shows that MLN0128, a drug that targets specific proteins involved in cancer growth, has been effective in reducing tumor growth in breast cancer models and has shown activity in various solid tumor models. This suggests it may be promising for treating different types of cancer. ^{1 2 3 4 5}

Is MLN0128 (TAK-228) safe for humans?

In a study with patients having certain types of cancer, TAK-228 was generally safe but did cause some side effects like mouth sores, skin rash, tiredness, and low blood cell counts. Most patients experienced at least one side effect, with the most serious being low platelet counts, fatigue, and low white blood cell counts. ^{2 6 7 8 9}

How is the drug MLN0128 different from other cancer treatments?

MLN0128 is unique because it is a dual inhibitor of mTORC1 and mTORC2, which are proteins involved in cell growth and survival, making it potentially more effective than standard treatments that only target one of these proteins. It is taken orally and has shown promise in preclinical models for various cancers, including breast cancer and leukemia, by effectively blocking cancer cell growth and spread. ^{3 5 10 11 12}

Research Team

John L Hays

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for cancer patients with specific genetic changes known as TSC1 or TSC2 mutations. It's open to those with certain types of lymphoma, multiple myeloma, solid tumors, and other cancers. The full eligibility criteria are not provided but would include more detailed health requirements.

Inclusion Criteria

Patients must fulfill all eligibility criteria of MATCH Master Protocol at the time of registration to treatment step (Step 1, 3, 5, 7)

I agree not to donate sperm during and up to 120 days after the study.

My brain cancer has been treated, stable for over a month, and I haven't needed steroids or seizure meds for 4 weeks.

Exclusion Criteria

Patients living outside the US

I have a history of cancer.

Patients known to be HIV-positive

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive sapanisertib (MLN0128 [TAK-228]) orally once daily on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 3 years

Bi-weekly visits for imaging and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up includes imaging and clinical assessments.

3 years

Every 3 months for 2 years, then every 6 months for 1 year

Treatment Details

Interventions

• MLN0128 (TAK-228)

Trial Overview The study is testing the effectiveness of a drug called MLN0128 (TAK-228) in stopping cancer growth by targeting enzymes needed for cell growth. Patients will undergo tests like CT scans, MRIs, biopsies, and biospecimen collection to monitor the treatment's effects.

Participant Groups

Group I: Treatment (sapanisertib [MLN0128 (TAK-228)]) Experimental Treatment 5 Interventions

Patients receive sapanisertib (MLN0128 \[TAK-228\]) PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT or MRI during screening and on study, as well as during follow-up as clinically necessary. Patients also undergo biopsies and blood sample collection on study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a phase I study involving 61 patients with advanced solid tumors, the investigational drug sapanisertib (TAK-228) was found to be well tolerated, with maximum tolerated doses established for different administration schedules, and no significant differences in adverse events across treatment regimens.

TAK-228 demonstrated antitumor activity, particularly when combined with paclitaxel, showing objective response rates of 18% for the combination therapy and 12% for the daily administration, indicating its potential effectiveness in treating certain malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the investigational oral mTORC1/2 inhibitor sapanisertib (TAK-228): tolerability and food effects of a milled formulation in patients with advanced solid tumours. Moore, KN., Bauer, TM., Falchook, GS., et al.[2022]

TAK-228, an oral TORC1/2 inhibitor, was evaluated in a clinical study involving 39 patients with multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia, showing a maximum tolerated dose of 4 mg daily and 9 mg for a 3 days on, 4 days off regimen.

The treatment was associated with significant drug-related toxicities, with 92% of patients experiencing at least one side effect, including common severe effects like thrombocytopenia and fatigue, indicating the need for careful monitoring and further research into combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia. Ghobrial, IM., Siegel, DS., Vij, R., 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

LYTAK1, a novel TAK1 inhibitor, suppresses KRAS mutant colorectal cancer cell growth in vitro and in vivo. [2018]

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

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

3. Netherlands pubmed.ncbi.nlm.nih.gov

Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Phase I study of the investigational oral mTORC1/2 inhibitor sapanisertib (TAK-228): tolerability and food effects of a milled formulation in patients with advanced solid tumours. [2022]

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

Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program. [2022]

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

Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients. [2021]

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

Phase 1 dose-escalation, pharmacokinetic, and cerebrospinal fluid distribution study of TAK-285, an investigational inhibitor of EGFR and HER2. [2021]

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

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia. [2022]

9. 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]

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

A phase II study of the dual mTOR inhibitor MLN0128 in patients with metastatic castration resistant prostate cancer. [2022]

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

Determination of MLN0128, an investigational antineoplastic agent, in human plasma by LC-MS/MS. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. [2023]