TAK228 With Carbo and Taxol in Advanced Malignancies

Study Groups:

If participant is found to be eligible to take part in this study, participant will be
assigned to a dose level of TAK-228, carboplatin, and paclitaxel based on when participant
joins this study. Up to 6 dose levels of TAK-228, carboplatin, and paclitaxel will be tested.
Up to 6 participants will be enrolled at each dose level. The first group of participants
will receive the lowest dose level. Each new group will receive higher doses than the group
before it, if no intolerable side effects were seen. This will continue until the highest
tolerable dose of the combination of TAK-228, carboplatin, and paclitaxel is found.

After the highest tolerable doses are found, up to an additional 14 participants will be
enrolled to receive the carboplatin, paclitaxel, and TAK-228 at the highest tolerable doses.

Study Drug Administration:

Each cycle is 21 days.

Participant will take TAK-228 by mouth at about the same time each day on Days 2-4, 9-11, and
16-18 of Cycles 1-6. Participant will take TAK-228 on Day 1 of Cycles 7 and beyond.

Participant should swallow the dose whole with a full cup of water (about 8 ounces) on an
empty stomach. Participant should not eat or drink anything for 2 hours before and 1 hour
after participant's TAK-228 dose. Participant should take it at home except on the days when
participant has a study visit.

If participant misses a dose of TAK-228, and it has been less than 12 hours since
participant's scheduled dose, participant can take the dose as soon as participant remembers.
If more than 12 hours has passed since missing a dose at the normal time, participant should
not take the dose. Participant should wait and take participant's next dose as scheduled.

Participant will be asked to keep a study drug diary and document when participant takes
participant's doses. Participant should bring this diary with participant to all clinic
visits.

Participant will receive carboplatin by vein over about 60 minutes on Day 1 of Cycles 1-6.

Participant will receive paclitaxel by vein over about 3 hours on Days 1, 8, and 15 of Cycles
1-6.

Participant may be given standard drugs to help decrease the risk of side effects.
Participant may ask the study staff for information about how the drugs are given and their
risks.

Length of Study Participation:

Participant may continue taking carboplatin and paclitaxel for up to 6 cycles. Participant
may continue taking TAK-228 for as long as the doctor thinks it is in participant's best
interest. Participant will no longer be able to take the study drugs if the disease gets
worse, if intolerable side effects occur, or if participant is unable to follow study
directions.

Participation on the study will be over when participant has completed the follow-up visit.

Study Visits:

At every study visit, participant will be asked about participant's health, any other drugs
participant is taking, and if participant has had any side effects. Participant must fast for
at least 8 hours before each visit.

On Day 1 of every cycle:

- Participant will have a physical exam.

- Blood (about 1 tablespoon) and urine will be collected for routine tests. Part of this
blood sample will be used to check participant's glucose levels.

- Participant will have an EKG (Cycle 1 only). After Cycle 1, participant will have this
performed whenever the doctor thinks it is needed.

- On Day 1 of Cycle 1 and then every 3 cycles after that (Cycle 4, 7, 10, and so on) blood
(about 1 teaspoon) will be drawn for tumor marker testing.

- If participant can become pregnant, urine will be collected for a pregnancy test. If the
test is positive, blood (about 1 teaspoon) will be drawn to confirm participant is
pregnant.

On Day 8 and 15 of Cycles 1-6:

- Participant will have a physical exam.

- Blood (about 2-3 teaspoons) will be drawn for routine tests and to check participant's
glucose levels.

Every 2 cycles, participant will have a CT and/or MRI scan to check the status of the
disease. If the study doctor thinks it is needed, they will be performed more often.

At-Home Glucose Monitoring:

Participant will be asked to monitor participant's glucose levels at home. The study staff
will give participant a glucose monitor (called a glucometer) and teach participant how and
when to use it. Participant will continue to monitor participant's glucose levels at home
until participant's end-of-study visit. Participant will bring the glucometer with
participant to each study visit so the study staff can collect the results of the testing.

The study team will tell participant what an abnormal level is and when to contact the study
doctor/study staff.

Participant will need to return the glucometer to the study staff at the end of the study.

End-of-Study Visits:

On the last day that participant receives study drugs and again about 30 days after
participant's last dose of study drugs:

- Participant will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests, to check participant's
glucose levels, and to test for diabetes.

- Urine will be collected for routine tests.

- Participant will have a CT and/or MRI scan to check the status of the disease.

- On the last day participant takes the study drugs, participant will have an EKG and
ECHO.

- On the last day participant takes the study drugs, blood (about 1 teaspoon) will be
drawn for tumor marker testing.

- If participant can become pregnant, urine will be collected for a pregnancy test. If the
test is positive, blood (about 1 teaspoon) will be drawn to confirm participant is
pregnant.

If participant has side effects at the end-of-study visit and the doctor thinks it is needed,
participant will continue to come into the clinic to have the above tests/procedures repeated
until the side effects go away.

Inclusion Criteria:

1. Male or female patients 18 years or older.

2. Patients must have a diagnosis of a solid tumor malignancy and is refractory to
standard therapies who have relapsed after standard therapy, or whose cancers have no
standard therapy.

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

4. 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 effective method of contraception and 1 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 [e.g., 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.)

5. Continued from Inclusion Criteria # 4: Male patients, even if surgically sterilized
(i.e., 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. (Periodic abstinence [e.g.,
calendar, ovulation, symptothermal, postovulation 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.) 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: 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 transaminases (aspartate aminotransferase/serum glutamic oxaloacetic
transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic
transaminase-ALT/SGPT) Renal: creatinine clearance >/=50 mL/min based either on Cockcroft-Gault estimate or
based on urine collection (12 or 24 hour); d) Metabolic: Glycosylated hemoglobin
(HbA1c)<7%, fasting serum glucose ( 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 consent may
be withdrawn by the patient 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: 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.

10. Patients must have evaluable or measurable disease by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 criteria.

11. Patients must be 4 weeks beyond previous treatment of any chemotherapy or
radiotherapy, and must have recovered to 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.

Exclusion Criteria:

1. Carboplatin or Paclitaxel exposure within past 6 months

2. Central nervous system (CNS) metastasis.

3. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,
active central nervous system disease, active infection, or any other condition that
could compromise the patient's participation in the study.

4. Known history of human immunodeficiency virus infection.

5. Known history of hepatitis B surface antigen-positive, or known or suspected active
hepatitis C infection.

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

7. 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.

8. Breast feeding or pregnant.

9. Treatment with any investigational products within 4 weeks before the first dose of
study drug.

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

11. 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.

12. History of any of the following within the last 6 months before administration of the
first dose of the drug: a) Ischemic myocardial event, including angina requiring
therapy and artery revascularization procedures b) Ischemic cerebrovascular event,
including transient ischemic attack and artery revascularization procedures c)
Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or
ventricular tachycardia) d) Placement of a pacemaker for control of rhythm e) New York
Heart Association (NYHA) Class III or IV heart failure f) Pulmonary embolism.

13. Significant active cardiovascular or pulmonary disease including: a) Uncontrolled
hypertension (i.e., systolic blood pressure >150 mm Hg, diastolic blood pressure > 90
mm Hg). Use of anti-hypertensive agents to control hypertension before Cycle1 Day 1 is
allowed. b) Pulmonary hypertension c) Uncontrolled asthma or O2 saturation < 90% by
arterial blood gas analysis or pulse oximetry on room air d) Significant valvular
disease; severe regurgitation or stenosis by imaging independent of symptom control
with medical intervention, or history of valve replacement e) Medically significant
(symptomatic) bradycardia f) History of arrhythmia requiring an implantable cardiac
defibrillator g) 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).

14. 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.

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 PPI within
7 days before receiving the first dose of study drug.

17. Patients with hypersensitivity or other allergic reaction to platinum chemotherapy.

18. Patients with hypersensitivity or other allergic reaction to taxanes.