Phase I Study of Combination of Gedatolisib With Palbociclib and Faslodex in Patients With ER+/HER2- Breast Cancer

Palbociclib (Ibrance®) is an orally active highly selective reversible inhibitor of
cyclin-dependent kinase (CDK) 4 and CDK 6. Faslodex® (Fulvestrant) is a potent anti-estrogen
drug that binds and degrades estrogen receptors (ERs). Interim results from the Phase 3 trial
(Study PALOMA-3) have shown that combination of palbociclib and Faslodex increases
progressive-free survival (PFS) from 3.8 to 9.2 months in patients with metastatic estrogen
receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast
cancer that progressed during or after anti-endocrine therapy (Turner et al. 2015). The
palbociclib/Faslodex combination was found to be well tolerated. Additionally, there is
growing data indicating that this combination can be safely and effectively administered up
front in anti-endocrine therapy-naive patients in the neoadjuvant setting.

Gedatolisib (code name PF-05212384, formerly known as PKI-587) is an intravenous (IV)
adenosine triphosphate (ATP) competitive, highly selective and potent inhibitor of pan-class
I isoform phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3-K) and mammalian target of
rapamycin (mTOR) (Fry et al. 2004). Preclinical and first-in-human studies have shown a
manageable safety profile with predictable toxicity for this class of drugs.

Activation of the PI3-K/Akt/mTOR/p-S6 pathway has been associated with endocrine resistance
in ER+ breast cancer. There is ample evidence that inhibition of this pathway, in combination
with anti-hormonal therapy, increases PFS (Baselga et al. 2012). There is also clinical
evidence that combination therapy targeting all three pathways is feasible, safe and
effective (Sweeney et al. 2014). The advantage of Gedatolisib is its potential to inhibit
signaling through different PI3-K isoforms. Also important is the fact that once a week
administration may be as effective, but less toxic, than chronic oral dosing. If
hyperglycemia is a surrogate for effective PI3-K/Akt/mTOR/p-S6 inhibition, once weekly dosing
of Gedatolisib would appear to accomplish equivalent degrees of hyperglycemia as chronically
oral dosing and with less toxicity.

Preoperative or neoadjuvant systemic chemotherapy, once reserved for patients with locally
advanced breast cancer in whom the goal was to render large breast cancers operable, has
become increasingly common due to the improvement in disease-free survival and overall
survival. Historically, the endpoint of pathological Complete Response (pCR) in neoadjuvant
therapy against ER+/HER2- breast cancer has been of limited value. However, new targeted
agents, with higher response rates, have the potential to use pCR assessment as a strong
clinical endpoint in drug development. Given the systemic response rate in previously treated
Stage 4 breast cancer patients, the expectation will be a similar high rate of pathological
improvement which can lead to greater use of targeted agents in the neoadjuvant setting.

In addition to the potential of better pathological improvement, the advantage of clinical
studies involving neoadjuvant therapy is that they can provide response information in
patients that are treatment-naïve. This type of clinical trial can also be used to assess
cellular and molecular changes with serial biopsies while on neoadjuvant therapy, which can
aid in development of companion tissue and/or imaging biomarkers, and further the development
of preclinical models.

Accordingly, this investigation assesses the safety and efficacy of the combination of
Gedatolisib, palbociclib and faslodex in the neoadjuvant setting in previously untreated
patients with ER+/HER2- breast cancer. Being the first clinical trial using this combination
in neoadjuvant setting, one of the main objectives for the current trial is to determine the
Maximum Tolerated Dose (MTD) of Gedatolisib when used in combination with palbociclib and
faslodex. Subsequent Phase II clinical trials will be conducted to assess the safety and
efficacy of the Gedatolisib/palbociclib/faslodex combination, with the dose of Gedatolisib
being the MTD determined from the current trial.

Inclusion Criteria:

A. Stage I-IV, with primary cancer in place, non-inflammatory invasive breast cancer
confirmed by core needle or incisional biopsy (excisional biopsy is not allowed):

- the disease is ER+ (defined as ER expression >10% of invasive cancer cells according
to immunohistochemical [IHC] staining)

- HER2- (defined as IHC staining of 0 to 1+ or fluorescence in situ hybridization [FISH]
ratio of HER2 gene copy/chromosome 17 of <2.0.)

- the disease is previously untreated for breast cancer, operable and intend to undergo
surgery for her disease (e.g., a mastectomy or lumpectomy) after completion of
neoadjuvant therapy

- the disease must be measurable, defined as clinically or radiographically measureable
target lesion in the breast that is ≥1 cm in diameter

- the disease cannot be axillary disease only (i.e., no identifiable tumor in the breast
that is ≥1 cm on physical exam or radiographic study)

- the disease can be multi-centric or bilateral disease, provided the target lesion
meets the above eligibility criteria

- breast cancer patients with lobular and luminal histology will be included. However,
patients with lobular histology should not be more than a quarter of the total number
of patients in this trial, as the investigational drugs are likely to have greater
activities in patients with luminal histology.

(Note 1: In patients with Stage III disease, imaging studies is performed to rule out overt
metastatic disease. In patients with clinically positive axillae, histologic confirmation
by biopsy or fine-needle aspiration is performed. Patients with clinically negative axillae
can undergo pretreatment sentinel lymph node sampling.) (Note 2: In patients with Stage IV
disease, the disease must be of low burden. Low burden is defined in this study as no more
than one metastatic site in the liver or lung, or up to three metastatic sites in the bone,
regardless of the number of lymph nodes per latest radiographic scan. If a patient is found
to have metastatic disease on scan(s) performed after patient completes study neoadjuvant
therapy, surgery will not be performed and patients will be excluded from this study.)

B. Females ≥18 years of age.

C. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
sterile) must use effective contraceptive methods (such as abstinence, intrauterine device
[IUD], or double barrier device) during the study, and must have a negative serum or urine
pregnancy test within one week prior to treatment initiation.

D.Mentally competent, able to understand and willingness to sign the informed consent form.

E.At least 4 weeks must have elapsed from any prior major surgery or hormonal therapy. The
following procedures are not considered major surgical procedure:

- Obtaining the required research needle biopsies

- Placement of a radiopaque clip to localize a tumor or tumors for subsequent surgical
resection

- Placement of a port for central venous access

- Fine needle aspiration of a prominent or suspicious axillary lymph node

- Needle biopsy of a clinically or radiographically detected lesion to rule out
metastatic diseaseF.Laboratory values ≤2 weeks must be:

- Sampling of sentinel lymph node.

F.Laboratory values ≤2 weeks must be:

- Adequate glycemic balance (hemoglobin A1c or glycated hemoglobin ≤8%; fasting serum
glucose 130 mg/dL, and fasting triglycerides 300 mg/dL).

- Adequate hematology (white blood cell [WBC] 3500 cells/mm3 or 3.5 bil/L; Granulocytes
≥ 1,000/μL; platelet count 100,000 cells/mm3 or 100 bil/L; absolute neutrophil count
[ANC] ≥1500 cells/mm3 or 1.5 bil/L; and hemoglobin (Hgb) ≥9 g/dL or ≥90 g/L).

- Adequate hepatic function (aspartate aminotransferase [AST/SGOT] 3x upper normal limit
[UNL], alanine aminotransferase [ALT/SGPT] 3x UNL (≤5x UNL if liver metastases
present), bilirubin 1.5x UNL).

- Adequate renal function (serum creatinine 1.5 mg/dL or 133 µmol/L).

- Adequate coagulation (International Normalized Ratio [INR] must be <1.5, <2.3 if
patient is on stable, therapeutic doses of warfarin and has no active bleeding or
pathologic condition that is associated with a high risk of bleeding)

Exclusion Criteria

A.Serious medical illness, such as significant cardiac disease (e.g. symptomatic congestive
heart failure, unstable angina pectoris, symptomatic coronary artery disease, myocardial
infarction within the past 6 months, uncontrolled or symptomatic cardiac arrhythmia, or New
York Heart Association Class III or IV), or severe debilitating pulmonary disease, that
would potentially increase patients' risk for toxicity.

B. A marked baseline prolongation of QT/QTc interval (e.g., repeated exhibition of a QTc
interval >470 ms).

C. A history of additional risk factors for torsade de pointes (e.g., clinically
significant heart failure, hypokalemia, family history of Long QT Syndrome).

D. Arterial thrombotic event, stroke, or transient ischemia attack within the past 12
months.

E. Uncontrolled hypertension (systolic blood pressure >160 mm Hg or diastolic blood
pressure >90 mm Hg), or peripheral vascular disease ≥grade 2.

F.Active central nervous system (CNS), epidural tumor or metastasis, or brain metastasis.

G.Any active uncontrolled bleeding, a bleeding diathesis (e.g., active peptic ulcer
disease), or a history of bleeding (e.g., hemoptysis, upper or lower gastrointestinal
bleeding) within the past 6 months.

H.Dyspnea with minimal to moderate exertion. Patients with large and recurrent pleural or
peritoneal effusions requiring frequent drainage (e.g. weekly). Patients with any amount of
clinically significant pericardial effusion.

I.Diabetes of any type, except non-insulin dependent diabetes mellitus .(NIDDM) that is
controlled and with hemoglobin A1c <8%.

J.Evidence of active infection during screening, or serious infection within the past
month.

K.Patients with known HIV infection.

L.Serious or non-healing wound, skin ulcer, or bone fracture.

M.Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the
past 6 months.

N.Neuropathy of grade ≥2.

O.Albumin <2.5 g/dL or <25 g/L.

P.Lactating females.

Q.Any condition or abnormality which may, in the opinion of the investigator, compromise
the safety of patients.

R.Unwilling or unable to follow protocol requirements.

S.Patients receiving any other standard or investigational treatment for their cancer, or
any other investigational agent for any indication within the past 3 weeks prior to
participating in the study.

T.Requirement for immediate palliative treatment of any kind including surgery and
radiation.