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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of a new treatment, MLN0128 (TAK-228), for individuals with cancer who have specific genetic changes known as TSC1 or TSC2 mutations. The treatment aims to halt cancer growth by blocking enzymes essential for cancer cell proliferation. Suitable candidates for this trial have cancer with TSC1 or TSC2 mutations, no recent heart issues, and are not currently using certain medications, such as proton pump inhibitors. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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) generally maintains a manageable safety profile. Patients in earlier studies tolerated the treatment, and the side effects were considered manageable. For example, one study showed early signs of effectiveness against certain cancers, and patients generally tolerated sapanisertib well when combined with other drugs. Another study confirmed that patients could handle the drug, even when taken with treatments like metformin. While side effects occurred, they were usually not severe.

This is a Phase 2 trial, indicating that the treatment has already passed initial safety tests, suggesting it is reasonably safe for further testing. However, as with any clinical trial, risks or side effects may still exist that are not yet fully understood. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about sapanisertib (MLN0128) because it offers a novel approach to treating cancer by targeting a specific pathway known as mTOR, which is crucial for cancer cell growth and survival. Unlike many traditional treatments that may focus on broad cell-killing strategies, sapanisertib specifically inhibits mTOR, potentially offering a more targeted attack on cancer cells with fewer side effects. Additionally, it is administered orally, which could provide a more convenient option compared to intravenous chemotherapy. This unique mechanism and delivery method could make it a promising option for patients who have not responded well to existing treatments.

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

Research has shown that MLN0128, also known as sapanisertib, might help stop cancer growth by blocking certain enzymes that cancer cells need. In earlier studies, this treatment demonstrated early signs of shrinking tumors in some cancers, such as kidney and endometrial cancer. However, it proved less effective when used alone for other cancers, like relapsed acute lymphoblastic leukemia. The treatment has generally been safe, with manageable side effects. Overall, MLN0128 appears promising, especially for cancers with specific genetic changes. Participants in this trial will receive sapanisertib (MLN0128) as the investigational treatment. ^{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 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 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

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

What Are the Treatments Tested in This Trial?

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.

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-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]

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]

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 ...