TAK-228 and TAK-117 Followed by Cisplatin and Nab Paclitaxel for Metastatic Triple Negative Breast Cancer

Seventy to eighty percent of breast cancers have a gene expression profile which is
characterized by homologous recombination deficiency (HRD) and high proliferation. HRD leads
to errors in DNA pathway [non -homologous end joining (NHEJ)] that repair DNA-breaks, a
process required for metastatic triple negative breast cancer (TNBC) survival. The hypothesis
of this pilot trial is that administration of the oral combination of TAK-228 and TAK-117
(PIKTOR) will inhibit NHEJ in metastatic TNBC, leading at the time of disease progression to
metastases that are HR-deficient and sensitive to cisplatin plus nab paclitaxel therapy.

Inclusion Criteria:

1. Female patients 18 years or older.

2. Have a diagnosis of metastatic TNBC previously treated with standard anthracycline,
cyclophosphamide, and taxane chemotherapy, unless there was a contraindication to
doxorubicin, in which case prior treatment with this agent is not required.

3. Have not received more than 3 prior chemotherapy regimens for metastatic disease.
Prior platinum and/or taxane therapy in the adjuvant or metastatic setting is
permitted.

4. Androgen receptor-negative (less than 10% positive nuclei) on standard IHC performed
at the local pathology laboratory.

5. Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or hepatic
metastatic disease that is amenable to core needle biopsy.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See Appendix I)

7. 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, agree to practice 1 effective methods 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 [eg, USPI, SmPC, etc,]) 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 [eg, 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.)

8. Screening clinical laboratory values as specified below:

1. Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x
10^9; platelet count ≥ 100 x 10^9; 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/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);

3. Renal: creatinine clearance ≥60 mL/min based either on Cockroft-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

9. Ability to swallow oral medications.

10. Must be able to fast for glucose monitoring throughout PIKTOR treatment.

11. 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 ≥2 months before the first dose of study
drug.

3. No hemorrhage after treatment

4. Off-treatment with dexamethasone for 3 weeks before administration of the first
dose of PIKTOR

5. No ongoing requirement for dexamethasone or anti-epileptic drugs

12. 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.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the
study:

1. Leptomeningeal disease that is symptomatic or cytology-proven.

2. 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.

3. Known human immunodeficiency virus infection.

4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C
infection.

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
study drug

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

10. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI
disease, or for an unknown reason that may alter the absorption of PIKTOR. 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
revascularization procedures

2. Ischemic cerebrovascular event, including transient ischemic attack and artery
revascularization procedures

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 f. Pulmonary
embolism

12. Significant active cardiovascular or pulmonary disease including:

1. Uncontrolled hypertension (ie, systolic blood pressure >180 mm Hg, diastolic
blood pressure > 100 mm Hg). Use of anti-hypertensive agents to control
hypertension before Cycle1 Day 1 is allowed.

2. Pulmonary hypertension

3. Need for supplemental oxygen

4. Significant valvular disease; severe regurgitation or stenosis by imaging
independent of symptom control with medical intervention, or history of valve
replacement

5. Medically significant (symptomatic) bradycardia

6. History of arrhythmia requiring an implantable cardiac defibrillator

7. Baseline prolongation of the rate-corrected QT interval (QTc) (eg, 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
are met.

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 (See Appendix IV).

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