This is an open-label, cohort study to determine the feasibility and tolerability of the
combination of TAK-228 and TAK-117 given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel
on days 1, 8, and 15 for one 28-day cycle in patients with advanced solid tumors.
The goal of this study is to determine a tolerated dose of the combination of TAK-228,
TAK-117 and paclitaxel. To do this, investigators will estimate the maximum tolerated dose
that is defined as the dose level at which less than one-third of patients will experience a
dose-limiting toxicity. A traditional dose escalation design will be used, beginning with the
lowest dose level and escalating to the maximum allowable dose level as specified in the
protocol. Three patients will be treated one at a time at a given dose level. A maximum of 5
dosing levels results in a maximum sample size of n=30 subjects. Adverse events will be
defined using the Common Toxicity Criteria v. 4.0. dose-limiting toxicity is defined as:
- Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except for the
- Grade 3 hyperglycemia lasting ≤14 days (all patients should receive optimal
antiglycemic treatment, including insulin, as clinically indicated).
- Grade 3 rash lasting ≤3 days (all patients should receive topical steroid
treatment, oral antihistamines, and oral steroids, if necessary).
- Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all
patients should receive optimal antiemetic and/or antidiarrheal prophylaxis and/or
- Grade 4 neutropenia lasting >7 days in the absence of growth factor support.
- Grade 4 neutropenia of any duration accompanied by fever ≥38.5°C and/or systemic
- Any other ≥Grade 4 hematologic toxicity.
- Inability to administer at least 75% of planned doses of TAK-228 within Cycle 1, due to
study drug-related toxicity.
- Any clinically significant occurrence that the investigator and sponsor agree would
place patients at an undue safety risk.
Patients experiencing any grade 3 or more hematologic toxicity attributed to the treatment
will hold all therapy until resolution of the toxicity to grade 2 or less. If toxicity
persists, the patients will be removed from the study. Upon resolution of the toxicity, the
patient will restart treatment at the original dose at the discretion of the investigators.
One of the following outcomes will determine the treatment of subsequent patients:
- If none of the three patients experiences a dose-limiting toxicity, the next group of
patients will be entered in the next higher dose cohort. All patients within a cohort
must have completed at least once cycle (28 days) prior to initiation of the next cohort
- If one of the three patients experiences a dose-limiting toxicity, three more patients
will be accrued at the current dose level. Subsequently, if only one of the six patients
treated at this level experiences a dose-limiting toxicity, the dose will be escalated
to the next higher dose in the next group of patients. If two or more of the six
patients experiences a dose-limiting toxicity, the maximum tolerated dose has been
exceeded and is defined as the previous dose at which no more than 1/3 experienced a
- If at least two of the three experience a dose-limiting toxicity, the maximum tolerated
dose has been exceeded and is defined as the previous dose at which no more than 1/3
experienced a dose-limiting toxicity.
If the lowest allowable dose level exceeds the maximum tolerated dose, the study will be
terminated and the combination will not be deemed safe for use in this population.
Additionally, the highest dose level will not be exceeded, even if no dose-limiting
toxicities are experienced at that dose.
The adverse events overall and by individual adverse events categories will be summarized.
Serious adverse events will be summarized in a similar manner. These summaries will be
performed overall and for each dose cohort. Investigators will summarize all events as well
as the highest grade for a given subject. Investigators will summarize the number of subjects
that exhibit a dose-limiting toxicity at each dose cohort and describe the dose-limiting
toxicity for each subject, if applicable.
1. Male or female patients 18 years or older.
2. Patients must have a diagnosis of an advanced solid tumor malignancy
3. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status of 0-2
4. Female patients who:
1. Are postmenopausal for at least 1 year before the screening visit, OR
2. Are surgically sterile, OR
3. If they are of childbearing potential must have a negative pregnancy test and
agree to practice one effective method of pregnancy prevention 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) after the last dose of study drug, OR
4. 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,
sympto- thermal and post ovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together.)
5. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
1. 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
2. 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,
sympto- thermal and post ovulation methods for the female partner], withdrawal,
spermicides only, and lactational amenorrhea are not acceptable methods of
contraception. Female and male condoms should not be used together.)
3. Agree not to donate sperm during the course of this study or within 120 days
after receiving their last dose of study drug
6. Screening clinical laboratory values as specified below:
1. Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥1.5 x
109/L; platelet count ≥100 x 109/L; hemoglobin ≥9 g/dL without transfusion within
1 week preceding study drug administration
2. Hepatic: total bilirubin ≤1.5 x upper limit of normal (ULN), transaminases
(aspartate aminotransferase (AST) /serum glutamic oxaloacetic transaminase (SGOT)
and alanine aminotransferase (ALT) /serum glutamic pyruvic transaminase (SGPT)
≤2.5 x ULN (≤5 x ULN if liver metastases are present);
3. Renal: creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate
or based on urine collection (12 or 24 hour);
4. Metabolic: Glycosylated hemoglobin (HbA1c) <7.0%, fasting serum glucose (≤ 130
mg/dL) and fasting triglycerides ≤300 mg/dL
7. Ability to swallow oral medications.
8. Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that the patient
may withdraw consent at any time without prejudice to future medical care.
9. Patients who have a history of brain metastasis are eligible for the study provided
that all the following criteria are met:
1. Brain metastases which have been treated
2. No evidence of disease progression for ≥3 months before the first dose of study
3. No hemorrhage after treatment
4. Off-treatment with dexamethasone for 4 weeks before administration of the first
dose of TAK-228
5. No ongoing requirement for dexamethasone or anti-epileptic drugs
1. Active central nervous system (CNS) metastasis.
2. Other clinically significant co-morbidities, in the opinion of the investigators, such
as uncontrolled pulmonary disease, active central nervous system disease, active
infection, or any other condition that could compromise the patient's participation in
3. Known human immunodeficiency virus infection.
4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C
5. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.
6. 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 non-melanoma skin cancer or carcinoma
in situ of any type are not excluded if they have undergone complete resection.
7. Breast feeding or pregnant.
8. Treatment with any investigational products within 30 days before the first dose of
9. Previous treatment with phosphoinositide 3-kinase (PI3K), AKT, dual phosphoinositide
3-kinase (PI3K) / mechanistic target of rapamycin (mTOR) inhibitors, TORC1/2
inhibitors (prior treatment with everolimus is allowed).
10. 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.
11. History of any of the following within the last 6 months before administration of the
first dose of the drug:
1. Ischemic myocardial event, including angina requiring therapy and artery
2. Ischemic cerebrovascular event, including transient ischemic attack and artery
3. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular
fibrillation or ventricular tachycardia)
4. Placement of a pacemaker for control of rhythm
5. New York Heart Association (NYHA) Class III or IV heart failure
6. Pulmonary embolism
12. Significant active cardiovascular or pulmonary disease including:
1. Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, diastolic
blood pressure >95 mm Hg). Use of anti-hypertensive agents to control
hypertension before Cycle1 Day 1 is allowed.
2. Pulmonary hypertension
3. Uncontrolled asthma or O2 saturation <90% by arterial blood gas analysis or pulse
oximetry on room air
4. Significant valvular disease; severe regurgitation or stenosis by imaging
independent of symptom control with medical intervention, or history of valve
5. Medically significant (symptomatic) bradycardia
6. History of arrhythmia requiring an implantable cardiac defibrillator
7. 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)
13. 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
14. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19
or CYP2C19 within 1 week preceding the first dose of study drug.
15. Patients receiving systemic 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.
16. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a proton
pump inhibitor (PPI) within 7 days before receiving the first dose of study drug