<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03017833</url>
  </required_header>
  <id_info>
    <org_study_id>2014-0186</org_study_id>
    <secondary_id>NCI-2017-00150</secondary_id>
    <secondary_id>2014-0186</secondary_id>
    <secondary_id>P30CA016672</secondary_id>
    <nct_id>NCT03017833</nct_id>
  </id_info>
  <brief_title>Sapanisertib and Metformin in Treating Patients With Advanced or Metastatic Relapsed or Refractory Cancers</brief_title>
  <official_title>Phase I Study of TAK-228 (MLN0128) in Combination With Metformin in Patients With Advanced Cancers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>M.D. Anderson Cancer Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and best dose of sapanisertib and metformin in&#xD;
      treating patients with cancers that have spread to other parts of the body&#xD;
      (advanced/metastatic), have come back (recurrent), or do not respond to treatment&#xD;
      (refractory). Sapanisertib and metformin may stop the growth of tumor cells by blocking some&#xD;
      of the enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the safety and tolerability and to determine maximum tolerated dose (MTD) of&#xD;
      the combination of sapanisertib (TAK-228) with metformin in patients with advanced cancers&#xD;
      refractory to standard therapy.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the clinical tumor response of this combination. II. To characterize the&#xD;
      pharmacokinetic (PK) profile of metformin and TAK-228.&#xD;
&#xD;
      OUTLINE: This is a dose escalation study.&#xD;
&#xD;
      Patients receive metformin orally (PO) 1-3 times daily on days 1-42 and sapanisertib PO daily&#xD;
      on days 15-42 of cycle 1. Patients then receive metformin PO daily and sapanisertib PO daily&#xD;
      on days 1-28 of cycle 2 and beyond. Cycles repeat every 28 days in the absence of disease&#xD;
      progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up within 30 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 12, 2018</start_date>
  <completion_date type="Actual">December 21, 2022</completion_date>
  <primary_completion_date type="Actual">December 21, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of serious adverse events</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical and laboratory values</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vital sign measurements</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>GI symptoms</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of neurotoxicity</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Descriptive statistics will be provided on the grade and type of toxicity by dose level.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence and grade of adverse events</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of dose limiting toxicities</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Descriptive statistics will be provided on the grade and type of toxicity by dose level.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death during study</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Withdrawals from study due to adverse events</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in treatment regimen due to adverse events</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Establishment of recommended phase 2 dosage</measure>
    <time_frame>Up to 42 days</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best tumor responses by dose level</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival by dose level</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival by dose level</measure>
    <time_frame>Up to 4 years</time_frame>
    <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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The peak plasma concentration (Cmax)</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be determined by observation of the data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The area under the plasma concentration-time curve (AUC)</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>The AUC from 0 to 24 hours postdose (AUC0-24) will be calculated using the linear trapezoidal.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Elimination half-life (t1/2)</measure>
    <time_frame>Up to 4 years</time_frame>
    <description>Will be calculated by 0.693/k</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">31</enrollment>
  <condition>Advanced Malignant Solid Neoplasm</condition>
  <condition>Metastatic Malignant Solid Neoplasm</condition>
  <condition>Recurrent Malignant Solid Neoplasm</condition>
  <condition>Refractory Neoplasm</condition>
  <arm_group>
    <arm_group_label>Treatment (metformin, sapanisertib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients 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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (metformin, sapanisertib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (metformin, sapanisertib)</arm_group_label>
    <other_name>N,N-dimethylbiguanide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Pharmacological Study</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (metformin, sapanisertib)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sapanisertib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (metformin, sapanisertib)</arm_group_label>
    <other_name>INK-128</other_name>
    <other_name>INK128</other_name>
    <other_name>MLN-0128</other_name>
    <other_name>MLN0128</other_name>
    <other_name>TAK-228</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion:&#xD;
&#xD;
          1. Male or female patients 18 years or older.&#xD;
&#xD;
          2. Voluntary written consent must be given before performance of any study related&#xD;
             procedure not part of standard medical care, with the understanding that consent may&#xD;
             be withdrawn by the patient at any time without prejudice to future medical care.&#xD;
&#xD;
          3. Female patients who: Are postmenopausal for at least 1 year before the screening&#xD;
             visit, OR Are surgically sterile, OR If they are of childbearing potential, agree to&#xD;
             practice 1 highly effective method of contraception and one additional effective&#xD;
             (barrier) method at the same time, from the time of signing the informed consent&#xD;
             through 90 days (or longer as mandated by local labeling [eg USPI, SmPC, etc] after&#xD;
             the last dose of study drug, or Agree to practice true abstinence, when this is in&#xD;
             line with the preferred and usual lifestyle of the patient (Periodic abstinence [e.g,&#xD;
             calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides&#xD;
             only, and lactational amenorrhea are not acceptable methods of contraception. Female&#xD;
             and male condoms should not be used together.) MUST have a negative serum or urine&#xD;
             pregnancy test within 7 days of initiating protocol treatment unless prior&#xD;
             hysterectomy or menopause (defined as 12 consecutive months without menstrual&#xD;
             activity).&#xD;
&#xD;
          4. CONTINUED FROM #3: Patients should not become pregnant or breastfeed while on this&#xD;
             study. The effects of TAK-228 and metformin on the developing human fetus are unknown.&#xD;
             Should a woman become pregnant or suspect she is pregnant, she should inform her&#xD;
             treatment physician immediately. Male patients, even if surgically sterilized (ie,&#xD;
             status post-vasectomy), who: Agree to practice highly effective barrier contraception&#xD;
             during the entire study treatment period and through 120 days after the last dose of&#xD;
             study drug, or Agree to practice true abstinence, when this is in line with the&#xD;
             preferred and usual lifestyle of the patient, as described in #3 above. Agree not to&#xD;
             donate sperm during the course of this study or within 120 days after receiving their&#xD;
             last dose of study drug.&#xD;
&#xD;
          5. Patients must have a diagnosis of advanced or metastatic malignancy that is refractory&#xD;
             to standard therapies, who have relapsed after standard therapy, or whose cancers have&#xD;
             no standard therapy that induces a CR rate of at least 10% or improves survival by at&#xD;
             least three months.&#xD;
&#xD;
          6. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance&#xD;
             status &lt;/= 1.&#xD;
&#xD;
          7. Adequate organ function, as specified below, within 7 days before the first dose of&#xD;
             study drug: a) Bone marrow reserve consistent with: absolute neutrophil count (ANC)&#xD;
             &gt;/= 1.5 x 10^9/L; platelet count &gt;/= 100 x 10^9/L; hemoglobin &gt;/= 9 g/dL without&#xD;
             transfusion within 1 week preceding study drug administration; b) Hepatic: total&#xD;
             bilirubin &lt;/= 1.5 x upper limit of normal (ULN), transaminases (aspartate&#xD;
             aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine&#xD;
             aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) &lt;/= 2.5 x ULN (&lt;/= 5 x&#xD;
             ULN if liver metastases are present); c) Renal: creatinine clearance &gt;/=50 mL/min&#xD;
             based either on Cockroft-Gault estimate or based on urine collection (12 or 24 hour);&#xD;
             d) Metabolic: fasting serum glucose (&lt;/= 130 mg/dL) and fasting triglycerides &lt;/= 300&#xD;
             mg/dL.&#xD;
&#xD;
          8. Ability to swallow oral medications.&#xD;
&#xD;
          9. Patients with diabetes are allowed and may be on antidiabetic treatment other than&#xD;
             Metformin. The diabetes must be under control within normal range (HbA1C &lt;/=7%).&#xD;
&#xD;
         10. Patients must be at least 5 half-lives beyond previous treatment with metformin and&#xD;
             currently not taking metformin.&#xD;
&#xD;
         11. Patients must be &gt;/= 4 weeks beyond previous treatment of any chemotherapy, other&#xD;
             investigational therapy, hormonal, biological, targeted agents or radiotherapy, and&#xD;
             must have recovered to &lt;/= grade 1 or previous baseline for each toxicity. Exception:&#xD;
             Patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks&#xD;
             before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not&#xD;
             included in the radiotherapy field. Patients who have received non-chemotherapeutic&#xD;
             biological agents will need to wait at least 5 half-lives or 4 weeks, whichever is&#xD;
             shorter, from the last day of treatment of non-chemotherapeutic biological agents.&#xD;
&#xD;
         12. Patients must have evaluable or measurable disease by RECIST 1.1 criteria. These&#xD;
             measurements will be done by the Quantitative Imaging Analysis Core (QIAC) group.&#xD;
&#xD;
        Exclusion:&#xD;
&#xD;
          1. Female patients who are both lactating and breastfeeding or have a positive serum&#xD;
             pregnancy test during the screening period or a positive urine pregnancy test on Day 1&#xD;
             before first dose of study drug.&#xD;
&#xD;
          2. Any serious medical or psychiatric illness that could, in the investigator's opinion,&#xD;
             potentially interfere with the completion of treatment according to this protocol.&#xD;
&#xD;
          3. Participation in other clinical trials, including those with other investigational&#xD;
             agents not included in this trial, within 5 half lives of those investigational agents&#xD;
             before the start of this trial and throughout the duration of this trial.&#xD;
&#xD;
          4. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI&#xD;
             disease, or for an unknown reason that may alter the absorption of TAK-228. In&#xD;
             addition, patients with enteric stomata are also excluded.&#xD;
&#xD;
          5. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) &gt; 7%;&#xD;
             patients with a history of transient glucose intolerance due to corticosteroid&#xD;
             administration may be enrolled in this study if all other inclusion/exclusion criteria&#xD;
             are met.&#xD;
&#xD;
          6. History of any of the following within the last 6 months prior to study entry:&#xD;
             Ischemic myocardial event, including angina requiring therapy and artery&#xD;
             revascularization procedures; Ischemic cerebrovascular event, including TIA and artery&#xD;
             revascularization procedures; Requirement for inotropic support (excluding digoxin) or&#xD;
             serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation,&#xD;
             ventricular fibrillation or ventricular tachycardia); Placement of a pacemaker for&#xD;
             control of rhythm; New York Heart Association (NYHA) Class III or IV heart failure;&#xD;
             Pulmonary embolism.&#xD;
&#xD;
          7. Significant active cardiovascular or pulmonary disease at the time of study entry,&#xD;
             including: Uncontrolled high blood pressure (i.e., systolic blood pressure &gt;150mm Hg,&#xD;
             diastolic blood pressure &gt; 90 mm Hg). Use of anti-hypertensive agents to control&#xD;
             hypertension before Cycle1 Day 1 is allowed.; Pulmonary hypertension; Uncontrolled&#xD;
             asthma or O2 saturation &lt; 90% by ABG (Arterial Blood Gas) analysis or pulse oximetry&#xD;
             on room air; Significant valvular disease; severe regurgitation or stenosis by imaging&#xD;
             independent of symptom control with medical intervention, or history of valve&#xD;
             replacement; Medically significant (symptomatic) bradycardia; History of arrhythmia&#xD;
             requiring an implantable cardiac defibrillator; Baseline prolongation of the&#xD;
             rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval &gt; 480&#xD;
             milliseconds, or history of congenital long QT syndrome, or torsades de pointes).&#xD;
&#xD;
          8. Previous treatment with dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1&#xD;
             inhibitors&#xD;
&#xD;
          9. Patients receiving corticosteroids (either IV or oral steroids, excluding inhalers or&#xD;
             low-dose hormone replacement therapy) within 1 week before administration of the first&#xD;
             dose of study drug.&#xD;
&#xD;
         10. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,&#xD;
             active central nervous system disease, active infection, or any other condition that&#xD;
             could compromise participation of the patient in the study.&#xD;
&#xD;
         11. Patients with major surgery within 30 days prior to entering the study.&#xD;
&#xD;
         12. History of hypersensitivity to TAK-228 or metformin.&#xD;
&#xD;
         13. Patients who have a history of brain metastasis are eligible for the study provided&#xD;
             that all the following criteria are met: A. Brain metastases which have been treated&#xD;
             B. No evidence of disease progression for &gt;/= 3 months before the first dose of study&#xD;
             drug. C. No hemorrhage after treatment D. Off-treatment with dexamethasone for 4 weeks&#xD;
             before administration of the first dose of TAK-228 E. No ongoing requirement for&#xD;
             dexamethasone or anti-epileptic drugs&#xD;
&#xD;
         14. Known human immunodeficiency virus infection.&#xD;
&#xD;
         15. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C&#xD;
             infection.&#xD;
&#xD;
         16. Diagnosed or treated for another malignancy within 2 years before administration of&#xD;
             the first dose of study drug, or previously diagnosed with another malignancy and have&#xD;
             any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma&#xD;
             in situ of any type are not excluded if they have undergone complete resection.&#xD;
&#xD;
         17. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within&#xD;
             7 days before receiving the first dose of study drug.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vivek Subbiah</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>University of Texas MD Anderson Cancer Center Website</description>
  </link>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>January 9, 2017</study_first_submitted>
  <study_first_submitted_qc>January 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <last_update_submitted>December 21, 2022</last_update_submitted>
  <last_update_submitted_qc>December 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03017833
org study id: 2014-0186
secondary id: NCI-2017-00150
secondary id: 2014-0186
secondary id: P30CA016672
nct id: NCT03017833
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of serious adverse events
time frame: Up to 4 years
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: Clinical and laboratory values
time frame: Up to 4 years
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: Vital sign measurements
time frame: Up to 4 years
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: GI symptoms
time frame: Up to 4 years
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: Incidence of neurotoxicity
time frame: Up to 4 years
description: Descriptive statistics will be provided on the grade and type of toxicity by dose level.
measure: Incidence and grade of adverse events
time frame: Up to 4 years
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
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
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
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
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
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
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
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
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
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
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
description: Will be calculated by 0.693/k
arm group label: Treatment (metformin, sapanisertib)
arm group type: Experimental
description: Patients 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.
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (metformin, sapanisertib)
intervention type: Drug
intervention name: Metformin
description: Given PO
arm group label: Treatment (metformin, sapanisertib)
other name: N,N-dimethylbiguanide
intervention type: Other
intervention name: Pharmacological Study
description: Ancillary studies
arm group label: Treatment (metformin, sapanisertib)
intervention type: Drug
intervention name: Sapanisertib
description: Given PO
arm group label: Treatment (metformin, sapanisertib)
other name: INK-128
other name: INK128
other name: MLN-0128
other name: MLN0128
other name: TAK-228
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Vivek Subbiah
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
country: United States
url: http://www.mdanderson.org
description: University of Texas MD Anderson Cancer Center Website
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Metformin