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be withdrawn by the patient at any time without prejudice to future medical care.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.
