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Advanced Malignant Solid NeoplasmPhase 1NCT03017833

Sapanisertib and Metformin in Treating Patients With Advanced or Metastatic Relapsed or Refractory Cancers

A Phase 1 study testing Laboratory Biomarker Analysis, Metformin and Pharmacological Study in people with Advanced Malignant Solid Neoplasm and Metastatic Malignant Solid Neoplasm, run by M.D. Anderson Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase I trial studies the side effects and best dose of sapanisertib and metformin in treating patients with cancers that have spread to other parts of the body (advanced/metastatic), have come back (recurrent), or do not respond to treatment (refractory). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis, Metformin and Pharmacological Study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
1 siteUnited States
Study dates
12 Mar 2018to 21 Dec 2022
Phase
Phase 1
Are there results?
None posted in the registry

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

  • Male or female patients 18 years or older.
  • 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
  • Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to practice 1 highly effective method of contraception and one additional effective (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 USPI, 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], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) MUST have a negative serum or urine pregnancy test within 7 days of initiating protocol treatment unless prior hysterectomy or menopause (defined as 12 consecutive months without menstrual activity).
  • CONTINUED FROM #3: Patients should not become pregnant or breastfeed while on this study. The effects of TAK-228 and metformin on the developing human fetus are unknown. Should a woman become pregnant or suspect she is pregnant, she should inform her treatment physician immediately. Male patients, even if surgically sterilized (ie, status post-vasectomy), who: 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, as described in #3 above. Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug.
  • Patients must have a diagnosis of advanced or metastatic malignancy that is refractory to standard therapies, who have relapsed after standard therapy, or whose cancers have no standard therapy that induces a CR rate of at least 10% or improves survival by at least three months.
  • Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status </= 1.
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  • Adequate organ function, as specified below, within 7 days before the first dose of study drug: a) Bone marrow reserve consistent with: absolute neutrophil count (ANC) >/= 1.5 x 10^9/L; platelet count >/= 100 x 10^9/L; hemoglobin >/= 9 g/dL without transfusion within 1 week preceding study drug administration; b) Hepatic: total bilirubin </= 1.5 x upper limit of normal (ULN), 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 Cockroft-Gault estimate or based on urine collection (12 or 24 hour); d) Metabolic: fasting serum glucose (</= 130 mg/dL) and fasting triglycerides </= 300 mg/dL.
  • Ability to swallow oral medications.
  • Patients with diabetes are allowed and may be on antidiabetic treatment other than Metformin. The diabetes must be under control within normal range (HbA1C </=7%).
  • Patients must be at least 5 half-lives beyond previous treatment with metformin and currently not taking metformin.
  • Patients must be >/= 4 weeks beyond previous treatment of any chemotherapy, other investigational therapy, hormonal, biological, targeted agents or radiotherapy, and must have recovered to </= grade 1 or previous baseline for each toxicity. Exception: Patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field. Patients who have received non-chemotherapeutic biological agents will need to wait at least 5 half-lives or 4 weeks, whichever is shorter, from the last day of treatment of non-chemotherapeutic biological agents.
  • Patients must have evaluable or measurable disease by RECIST 1.1 criteria. These measurements will be done by the Quantitative Imaging Analysis Core (QIAC) group.

Who cannot join

  • Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug.
  • Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  • Participation in other clinical trials, including those with other investigational agents not included in this trial, within 5 half lives of those investigational agents before the start of this trial and throughout the duration of this trial.
  • 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.
  • Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met.
  • History of any of the following within the last 6 months prior to study entry: Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures; Ischemic cerebrovascular event, including TIA 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.
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  • Significant active cardiovascular or pulmonary disease at the time of study entry, including: Uncontrolled high blood pressure (i.e., systolic blood pressure >150mm Hg, diastolic blood pressure > 90 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 ABG (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).
  • Previous treatment with dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors
  • Patients receiving 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.
  • Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study.
  • Patients with major surgery within 30 days prior to entering the study.
  • History of hypersensitivity to TAK-228 or metformin.
  • Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met: A. Brain metastases which have been treated B. No evidence of disease progression for >/= 3 months before the first dose of study drug. C. No hemorrhage after treatment D. Off-treatment with dexamethasone for 4 weeks before administration of the first dose of TAK-228 E. No ongoing requirement for dexamethasone or anti-epileptic drugs
  • Known human immunodeficiency virus infection.
  • Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
  • 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.
  • 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

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Phase I Study of TAK-228 (MLN0128) in Combination With Metformin in Patients With Advanced Cancers

This phase I trial studies the side effects and best dose of sapanisertib and metformin in treating patients with cancers that have spread to other parts of the body (advanced/metastatic), have come back (recurrent), or do not respond to treatment (refractory). Sapanisertib and metformin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To evaluate the safety and tolerability and to determine maximum tolerated dose (MTD) of the combination of sapanisertib (TAK-228) with metformin in patients with advanced cancers refractory to standard therapy.

SECONDARY OBJECTIVES:

  1. To assess the clinical tumor response of this combination. II. To characterize the pharmacokinetic (PK) profile of metformin and TAK-228.

OUTLINE: This is a dose escalation study.

Patients receive metformin orally (PO) 1-3 times daily on days 1-42 and sapanisertib PO daily on days 15-42 of cycle 1. Patients then receive metformin PO daily and sapanisertib PO daily on days 1-28 of cycle 2 and beyond. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days.

Being tested
Laboratory Biomarker Analysis, Metformin, Pharmacological Study, Sapanisertib
Medical subject headings
Neoplasm Metastasis, Neoplasms

What participants receive

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

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • MetforminDrug

    Also called N,N-dimethylbiguanide

    Given PO

  • Pharmacological StudyOther

    Ancillary studies

  • SapanisertibDrug

    Also called INK-128, INK128, MLN-0128, MLN0128

    Given PO

Study groups in NCT03017833
Study groupRoleWhat they receive
Treatment (metformin, sapanisertib)ExperimentalPatients receive metformin PO 1-3 times daily on days 1-42 and sapanisertib PO daily on days 15-42 of cycle 1. Patients then receive metformin PO daily and sapanisertib PO daily on days 1-28 of cycle 2 and beyond. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Other: Laboratory Biomarker Analysis; Drug: Metformin; Other: Pharmacological Study; Drug: Sapanisertib

What is being measured

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

  1. Incidence of serious adverse events

    Assessed by Common Terminology Criteria for Adverse Events version 4.0. Descriptive statistics will be provided on the grade and type of toxicity by dose level.

    Measured: Up to 4 years

  2. Clinical and laboratory values

    Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  3. Vital sign measurements

    Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  4. GI symptoms

    Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  5. Incidence of neurotoxicity

    Descriptive statistics will be provided on the grade and type of toxicity by dose level.

    Measured: Up to 4 years

Secondary outcomes (12)

  1. Incidence and grade of adverse events

    Assessed by Common Terminology Criteria for Adverse Events version 4.0. Descriptive statistics will be provided on the grade and type of toxicity by dose level.

    Measured: Up to 4 years

  2. Incidence of dose limiting toxicities

    Descriptive statistics will be provided on the grade and type of toxicity by dose level.

    Measured: Up to 4 years

  3. Death during study

    Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  4. Withdrawals from study due to adverse events

    Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  5. Change in treatment regimen due to adverse events

    Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  6. Establishment of recommended phase 2 dosage

    Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 42 days

  7. Best tumor responses by dose level

    Will be measured according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  8. Progression free survival by dose level

    Will be measured according to RECIST version 1.1. Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  9. Overall survival by dose level

    Will be measured according to RECIST version 1.1. Wilcoxon's Signed-Rank Test and Fisher's exact test will be used. A mixed model accounting for patient effects will be used to analyze longitudinal data (including biomarker data) over time.

    Measured: Up to 4 years

  10. The peak plasma concentration (Cmax)

    Will be determined by observation of the data.

    Measured: Up to 4 years

  11. The area under the plasma concentration-time curve (AUC)

    The AUC from 0 to 24 hours postdose (AUC0-24) will be calculated using the linear trapezoidal.

    Measured: Up to 4 years

  12. Elimination half-life (t1/2)

    Will be calculated by 0.693/k

    Measured: Up to 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 posted11 Jan 2017 (estimated)
  2. Study start12 Mar 2018
  3. Primary completion21 Dec 2022
  4. Study completion21 Dec 2022

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 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03017833
Sponsor's protocol ID
2014-0186
Other IDs
NCI-2017-00150, 2014-0186, P30CA016672
Status last verified
Oct 2023
First submitted
9 Jan 2017
Last updated
4 Oct 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Subbiah V, Coleman N, Piha-Paul SA, Tsimberidou AM, Janku F, Rodon J, Pant S, Dumbrava EEI, Fu S, Hong DS, Zhang S, Sun M, Jiang Y, Roszik J, Song J, Yuan Y, Meric-Bernstam F, Naing A. Phase I Study of mTORC1/2 Inhibitor Sapanisertib (CB-228/TAK-228) in Combination with Metformin in Patients with mTOR/AKT/PI3K Pathway Alterations and Advanced Solid Malignancies. Cancer Res Commun. 2024 Feb 12;4(2):378-387. doi: 10.1158/2767-9764.CRC-22-0260.

    PubMed 38126764

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Laboratory Biomarker Analysis, Metformin and Pharmacological Study in people with Advanced Malignant Solid Neoplasm and Metastatic Malignant Solid Neoplasm, run by M.D. Anderson 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 12 inclusion and 17 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: finished, as of the sponsor's last update on 4 Oct 2023. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Incidence of serious adverse events (time frame: Up to 4 years). The study lists 5 primary outcomes in all. 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 NCT03017833, which also lists 1 linked publication.

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 4 Oct 2023.

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