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Soft-tissue SarcomaPhase 2NCT02987959

Study of TAK-228 (MLN0128) in Soft Tissue Sarcomas

A Phase 2 study testing TAK-228 in people with Soft-tissue Sarcoma, run by Fox Chase Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is an open-label phase II study of TAK-228 for patients ≥ 18 years of age with complex genomic sarcomas exhibiting Phosphoinositide-3 Kinase (PI3K) pathway dysregulation. Patients must have surgically unresectable or metastatic disease that is refractory to at least one prior line of therapy (not including… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Soft-tissue Sarcoma
What is being tested?
TAK-228
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
6 participants
Where
1 siteUnited States
Study dates
21 Feb 2017to 24 Jul 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • This trial has two step inclusion criteria.
  • Step 1 Inclusion Criteria
  • Male or female patients 18 years or older.
  • Patients must have a diagnosis of a locally advanced or metastatic sarcoma that is progressing. The following subtypes (considered genomically complex) will be eligible: leiomyosarcoma (well differentiated or poorly differentiated), undifferentiated pleomorphic sarcoma, myxofibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, malignant peripheral nerve sheath tumor, angiosarcoma or extraskeletal osteosarcoma. Other potentially genomically complex Soft Tissue Sarcomas (STS) subtypes may be included on a case-by-case basis after discussion with the principal investigator.
  • Measurable disease by RECIST 1.1 criteria (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field), described in detail in section 15.
  • Progression of disease by radiographic imaging (10% increase in size by RECIST v1.1 within 6 months of registration) or presence of new lesions.
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  • Must have received at least 1 prior systemic therapy for advanced disease (does not include adjuvant/neoadjuvant therapy in a curative setting).
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
  • Adequate contraception as follows:
  • For women:
  • Postmenopausal for at least 1 year before the screening visit, OR Surgically sterile, OR If they are of childbearing potential, agree to practice 1 effective method of contraception, and 1 additional (barrier) method, at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling [eg. United Surgical Partners Internationals (USPI), Summary of Product Characteristics (SmPC), etc;]) after the last dose of study drug OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence [e.g, calendar, ovulation, symptothermal, postovulation methods] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
  • Highly effective methods:
  • Intra-uterine devices (IUD) Hormonal (birth control pills/oral contraceptives, injectable contraceptives, contraceptive patches, or contraceptive implants)
  • Other effective Methods:
  • Latex Condoms Diaphragm with spermicide; Cervical cap;Sponge
  • For men, even if surgically sterilized (ie, status post-vasectomy), they must:
  • Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (Periodic abstinence [e.g, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
  • Agree not to donate sperm during the course of this study or 120 days after receiving their last dose of study drug
  • Screening clinical laboratory values as specified below:
  • Bone marrow reserve consistent with: i. absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L; ii. platelet count ≥ 100 x 10(9)/L; iii. hemoglobin ≥ 9 g/dL without transfusion within 1 week preceding study drug administration b) Hepatic: i. total bilirubin ≤ 1.5 x upper limit of normal (ULN), ii. transaminases (Aspartate aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT) and Alanine aminotransferase/Serum Glutamic Pyruvic Transaminase (ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present); c) Renal: creatinine clearance ≥ 50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour); d) Metabolic: i. Glycosylated hemoglobin (HbA1c) ≤ 7.0%, ii. fasting serum glucose ≤ 130 mg/dL iii. fasting triglycerides ≤ 300 mg/dL
  • Ability to swallow oral medications.
  • Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  • Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:
  • Brain metastases which have been treated
  • No evidence of disease progression for ≥ 3 months or hemorrhage after treatment
  • Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228
  • No ongoing requirement for dexamethasone or anti-epileptic drugs
  • Step 2 Inclusion Criteria: Must be met after meeting step1inclusion and exclusion criteria.
  • 1. Tumor must have dysregulation of the PI3K/AKT/mTOR pathway. For the purposes of this study, patients must have either PTEN protein or genomic loss, or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA)/ Phosphatase and tensin homolog (PTEN) mutation. Patients must be willing to provide sufficient archival tissue. If this is not available fresh tumor for biopsy is required. In the event that a patient has had tumor analyzed for PTEN/PIK3CA status through commercial means, their eligibility and need for additional tissue will be determined on a case by case basis by the principle investigator.

Who cannot join

  • Step 1 Exclusion Criteria
  • Any clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.
  • Known human immunodeficiency virus infection.
  • Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  • Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
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  • Breast feeding or pregnant.
  • Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, patients with enteric stomata are also excluded.
  • Treatment with any investigational products, radiation therapy, surgery, tumor embolization, chemotherapy or immunotherapy within 21 days before the first dose of the study drug. For biologic or hormonal therapy treatment within 14 days or five half-lives of a drug (whichever is longer) before the first dose of study drug.
  • History of any of the following within the last 6 months before administration of the first dose of the drug:
  • Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
  • Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
  • Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)
  • Placement of a pacemaker for control of rhythm
  • New York Heart Association (NYHA) Class III or IV heart failure
  • Pulmonary embolism
  • Significant active cardiovascular or pulmonary disease including:
  • Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, diastolic blood pressure >95 mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle1 Day 1 is allowed.
  • Pulmonary hypertension
  • Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or pulse oximetry on room air
  • Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement
  • Medically significant (symptomatic) bradycardia
  • History of arrhythmia requiring an implantable cardiac defibrillator
  • Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval >480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes)
  • Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >7% ; patients with a history of transient glucose intolerance due to corticosteroid administration or gestational diabetes may be enrolled in this study if all other inclusion/exclusion criteria are met.
  • Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19 or CYP2C9 within 1 week preceding the first dose of study drug.
  • Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug.
  • Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fox Chase Cancer Center

    Philadelphia, Pennsylvania, 19111

Other trials in United States

About this study

Official title: Phase II Study of TAK-228 (MLN0128) in Soft Tissue Sarcomas With Dysregulation of the mTOR Pathway

This is an open-label phase II study of TAK-228 for patients ≥ 18 years of age with complex genomic sarcomas exhibiting Phosphoinositide-3 Kinase (PI3K) pathway dysregulation. Patients must have surgically unresectable or metastatic disease that is refractory to at least one prior line of therapy (not including neoadjuvant or adjuvant therapy in a curative setting). Patients disease must also have evidence of progression prior to enrollment. The purpose of this study is to determine the antitumor activity in this group of patients. Patients must meet all eligibility criteria as detailed in section 10. A total of up to 33 patients will be included in the study. Patients will undergo screening evaluations to determine eligibility within 28 days of the first dose. All patients will be required to submit baseline tumor samples for analysis. Patients who have had their tumors tested commercially for PI3K/ AKT/mechanistic Target of Rapamycin (mTOR) alterations will be assessed on a case by case basis for eligibility and for determination as to whether additional tissue is required.

TAK-228 will be administered orally at 3 mg daily for a 21 day cycle. Clinical and laboratory assessments will be made on day 1 of each cycle. Disease will be assessed by comparing unidimensional tumor measurements on pre and peritreatment imaging (CT or MRI) after weeks 6, 12, 18 and every 12 weeks thereafter. Response will be assessed according to RECIST 1.1. Therapy will continue until disease progression or unacceptable toxicity or withdrawal of consent.

Being tested
TAK-228
Keywords
TAK-228, MLN0128, mTOR
Medical subject headings
Sarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TAK-228Drug

    Also called MLN0128

    TAK-228 is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128) targets 2 distinct mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).

Study groups in NCT02987959
Study groupRoleWhat they receive
TAK-228 treatmentExperimentalPatients with complex genomic sarcomas exhibiting PI3K pathway dysregulation will be treated with TAK-228
Receives: Drug: TAK-228

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. The Progression Free Survival Rate With TAK-228 in Sarcoma Patients With PI3K/AKT/mTOR Pathway Dysregulation

    Progression free rate will be determined by determining the number of patients with complete response, partial response and stable disease

    Measured: 12 weeks post-treatment

Secondary outcomes (4)

  1. The Rate of Toxicity of TAK-228 in This Patient Population as Per Common Terminology Criteria for Adverse Events (CTCAE)v4.03 Criteria.

    Toxicity will be assessed by calculating number of participants experiencing adverse events as per CTCAEv4.03 criteria

    Measured: 1 year

  2. The Objective Response Rate (ORR) of TAK-228 in This Patient Population.

    Objective response rate will be defined as patients with complete response and partial response. As per RECIST v1.1 guidelines, complete response is defined as the disappearance of all measurable lesions, and partial response is defined as >=30% decrease in sum of diameters of target lesions compared to the baseline sum of diameters.

    Measured: upto 4 years

  3. Progression Free Survival in This Patient Population.

    Progression Free Survival, defined as the time from initiation of treatment until disease progression will be calculated.

    Measured: upto 4 years

  4. Overall Survival Rate in This Patient Population

    Overall Survival, defined as the time from initiation of treatment until death from any cause will be calculated.

    Measured: upto 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Dec 2016 (estimated)
  2. Study start21 Feb 2017
  3. Primary completion30 Jan 2019
  4. Study completion24 Jul 2020

Why it stopped: Closed to accrual due to Funding Sponsor withdrawing support due to low accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
6 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02987959
Sponsor's protocol ID
SAR-081
Status last verified
Sep 2022
First submitted
2 Dec 2016
Last updated
14 Oct 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing TAK-228 in people with Soft-tissue Sarcoma, run by Fox Chase Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 29 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 14 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Progression Free Survival Rate With TAK-228 in Sarcoma Patients With PI3K/AKT/mTOR Pathway Dysregulation (time frame: 12 weeks post-treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02987959.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Oct 2022.

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