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: HIV, Uncontrolled diabetes, Hypertension, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of the drug MLN0128 (also known as TAK-228, an experimental treatment) in treating cancers with specific genetic changes called mTOR mutations. The researchers aim to determine if MLN0128 can inhibit cancer cell growth by blocking essential enzymes. This trial suits individuals with these genetic changes who do not have conditions like uncontrolled diabetes, heart issues, or a history of taking similar drugs. Participants will take the drug daily and undergo regular scans and tests to monitor progress. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

Is there any evidence suggesting that MLN0128 (TAK-228) is likely to be safe for humans?

Research has shown that sapanisertib, also known as MLN0128 or TAK-228, has been tested for safety in people with various advanced cancers. In these studies, most patients tolerated sapanisertib well. Common side effects included tiredness, nausea, and diarrhea, but these were usually manageable.

One study found that sapanisertib had a manageable safety profile. While some side effects occurred, they weren't severe enough to make patients stop treatment. These findings suggest that sapanisertib is relatively safe, although it may cause side effects in some individuals. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about MLN0128 (sapanisertib) because it works differently from current cancer treatments. While most existing therapies focus on directly killing cancer cells or blocking hormones, MLN0128 targets a specific pathway called mTOR, which is crucial for cancer cell growth and survival. This unique mechanism can potentially stop the tumor's growth more effectively and with fewer side effects. Additionally, MLN0128 is taken orally, making it a convenient option for patients compared to other treatments that require injections or infusions.

What evidence suggests that MLN0128 (TAK-228) might be an effective treatment for cancer?

Research has shown that sapanisertib, also known as MLN0128 (TAK-228), may help treat certain cancers. It showed early signs of effectiveness against kidney cancer and cancer of the uterus lining. This treatment blocks an enzyme called mTOR, which aids cancer cell growth. Early studies have primarily focused on its safety, with initial results suggesting it might slow some cancers. However, it appears less effective on its own for advanced cancers like relapsed acute lymphoblastic leukemia, a type of blood cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

John L Hays

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for cancer patients with mTOR genetic changes. It's open to those with various cancers, including tumors, multiple myeloma, solid tumors, and lymphoma. Participants must meet specific criteria that will be detailed by the researchers.

Inclusion Criteria

I have never been treated with TORC1/2 inhibitors.

Patients must not have known hypersensitivity to MLN0128 or compounds of similar chemical or biologic composition

Women of childbearing age should avoid becoming pregnant while taking MLN0128 (TAK-228) and must agree to specific contraception methods

Exclusion Criteria

I have had a condition where my lymphocytes were abnormal.

I haven't had cancer in the last 5 years, except for skin cancer.

I have issues absorbing medications due to past GI surgery or disease.

Timeline for a Trial Participant

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

Regular visits for imaging and biopsies

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for 2 years and then every 6 months for 1 year.

3 years

Follow-up visits every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• MLN0128 (TAK-228)

Trial Overview The trial is testing MLN0128 (TAK-228), a drug aimed at stopping cancer growth by inhibiting enzymes necessary for cell growth in patients whose cancer has mTOR mutations.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10891443/

Phase I study of sapanisertib (CB‐228/TAK‐228/MLN0128 ... This Phase 1 dose‐escalation/expansion study assessed safety/ tolerability of sapanisertib in combination with ziv‐aflibercept in advanced solid tumors.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02417701

Sapanisertib in Treating Patients With Stage IV or ... This phase II trial studies how well sapanisertib works in treating patients with lung cancer that is stage IV or has come back (recurrent) and has a ...

3. aacrjournals.org aacrjournals.org/cancerrescommun/article/4/2/378/734232/Phase-I-Study-of-mTORC1-2-Inhibitor-Sapanisertib

Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228 ... The primary endpoint was to evaluate the safety and tolerability of sapanisertib in combination with metformin, to determine MTD and dose- ...

4. nature.com nature.com/articles/s41416-020-01041-x

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK- ... Conclusions. Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10726920/

A phase 2 and pharmacological study of sapanisertib in ... Sapanisertib 3 mg daily was safe for patients with relapsed/refractory acute lymphoblastic leukemia. Its efficacy as single agent is limited.

6. sciencedirect.com sciencedirect.com/science/article/pii/S205970292032336X

Phase I study of the investigational oral mTORC1/2 ... This phase I study (NCT02412722 ; MLN0128-1004) evaluated the safety, tolerability, PK and preliminary efficacy of milled TAK-228 capsule formulation ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38126764/

Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228 ... Conclusions: The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with antitumor ...