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

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ClinicalTrials.gov Identifier: NCT03017833
Recruitment Status : Recruiting
First Posted : January 11, 2017
Last Update Posted : January 2, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief 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). Sapanisertib and metformin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm Recurrent Malignant Solid Neoplasm Refractory Neoplasm Other: Laboratory Biomarker Analysis Drug: Metformin Other: Pharmacological Study Drug: Sapanisertib Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of TAK-228 (MLN0128) in Combination With Metformin in Patients With Advanced Cancers
Actual Study Start Date : March 12, 2018
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : March 31, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (metformin, sapanisertib)
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.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Metformin
Given PO
Other Name: N,N-dimethylbiguanide

Other: Pharmacological Study
Ancillary studies

Drug: Sapanisertib
Given PO
Other Names:
  • INK-128
  • INK128
  • MLN-0128
  • MLN0128
  • TAK-228




Primary Outcome Measures :
  1. Incidence of serious adverse events [ Time Frame: Up to 4 years ]
    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.

  2. Clinical and laboratory values [ Time Frame: Up to 4 years ]
    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.

  3. Vital sign measurements [ Time Frame: Up to 4 years ]
    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.

  4. GI symptoms [ Time Frame: Up to 4 years ]
    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.

  5. Incidence of neurotoxicity [ Time Frame: Up to 4 years ]
    Descriptive statistics will be provided on the grade and type of toxicity by dose level.


Secondary Outcome Measures :
  1. Incidence and grade of adverse events [ Time Frame: Up to 4 years ]
    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.

  2. Incidence of dose limiting toxicities [ Time Frame: Up to 4 years ]
    Descriptive statistics will be provided on the grade and type of toxicity by dose level.

  3. Death during study [ Time Frame: Up to 4 years ]
    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.

  4. Withdrawals from study due to adverse events [ Time Frame: Up to 4 years ]
    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.

  5. Change in treatment regimen due to adverse events [ Time Frame: Up to 4 years ]
    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.

  6. Establishment of recommended phase 2 dosage [ Time Frame: Up to 42 days ]
    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.

  7. Best tumor responses by dose level [ Time Frame: Up to 4 years ]
    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.

  8. Progression free survival by dose level [ Time Frame: Up to 4 years ]
    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.

  9. Overall survival by dose level [ Time Frame: Up to 4 years ]
    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.

  10. The peak plasma concentration (Cmax) [ Time Frame: Up to 4 years ]
    Will be determined by observation of the data.

  11. The area under the plasma concentration-time curve (AUC) [ Time Frame: Up to 4 years ]
    The AUC from 0 to 24 hours postdose (AUC0-24) will be calculated using the linear trapezoidal.

  12. Elimination half-life (t1/2) [ Time Frame: Up to 4 years ]
    Will be calculated by 0.693/k



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03017833


Contacts
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Contact: Vivek Vivek 713-563-1930 vsubbiah@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Vivek Subbiah    713-563-1930      
Principal Investigator: Vivek Subbiah         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Vivek Subbiah M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03017833    
Other Study ID Numbers: 2014-0186
NCI-2017-00150 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2014-0186 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2017    Key Record Dates
Last Update Posted: January 2, 2020
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs