Clinical Trials /

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

NCT03017833

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Sapanisertib and Metformin in Treating Patients With Advanced or Metastatic Relapsed or Refractory Cancers
  • Official Title: Phase I Study of TAK-228 (MLN0128) in Combination With Metformin in Patients With Advanced Cancers

Clinical Trial IDs

  • ORG STUDY ID: 2014-0186
  • SECONDARY ID: NCI-2017-00150
  • SECONDARY ID: 2014-0186
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03017833

Conditions

  • Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Recurrent Malignant Solid Neoplasm
  • Refractory Neoplasm

Interventions

DrugSynonymsArms
MetforminN,N-dimethylbiguanideTreatment (metformin, sapanisertib)
SapanisertibINK-128, INK128, MLN-0128, MLN0128, TAK-228Treatment (metformin, sapanisertib)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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:

      I. 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.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Metformin
  • Sapanisertib

Eligibility Criteria

        Inclusion:

          1. Male or female patients 18 years or older.

          2. 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.

          3. 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).

          4. 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.

          5. 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.

          6. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
             status </= 1.

          7. 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.

          8. Ability to swallow oral medications.

          9. 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%).

         10. Patients must be at least 5 half-lives beyond previous treatment with metformin and
             currently not taking metformin.

         11. 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.

         12. 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.

        Exclusion:

          1. 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.

          2. Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of treatment according to this protocol.

          3. 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.

          4. 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.

          5. 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.

          6. 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.

          7. 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).

          8. Previous treatment with dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1
             inhibitors

          9. 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.

         10. 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.

         11. Patients with major surgery within 30 days prior to entering the study.

         12. History of hypersensitivity to TAK-228 or metformin.

         13. 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

         14. Known human immunodeficiency virus infection.

         15. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C
             infection.

         16. 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.

         17. 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of serious adverse events
Time Frame:Up to 4 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence and grade of adverse events
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:Incidence of dose limiting toxicities
Time Frame:Up to 4 years
Safety Issue:
Description:Descriptive statistics will be provided on the grade and type of toxicity by dose level.
Measure:Death during study
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:Withdrawals from study due to adverse events
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:Change in treatment regimen due to adverse events
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:Establishment of recommended phase 2 dosage
Time Frame:Up to 42 days
Safety Issue:
Description: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.
Measure:Best tumor responses by dose level
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:Progression free survival by dose level
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:Overall survival by dose level
Time Frame:Up to 4 years
Safety Issue:
Description: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.
Measure:The peak plasma concentration (Cmax)
Time Frame:Up to 4 years
Safety Issue:
Description:Will be determined by observation of the data.
Measure:The area under the plasma concentration-time curve (AUC)
Time Frame:Up to 4 years
Safety Issue:
Description:The AUC from 0 to 24 hours postdose (AUC0-24) will be calculated using the linear trapezoidal.
Measure:Elimination half-life (t1/2)
Time Frame:Up to 4 years
Safety Issue:
Description:Will be calculated by 0.693/k

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated