Neoadjuvant Her2-targeted Therapy and Immunotherapy With Pembrolizumab

A phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of
neoadjuvant trastuzumab, pertuzumab and weekly paclitaxel (THP) as compared to neoadjuvant
trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel (THP-K), or neoadjuvant
trastuzumab, pembrolizumab and weekly paclitaxel (TH-K) in chemo naive patients with invasive
human epidermal growth factor receptor 2 (HER2) positive breast cancer whose primary tumors
are > 2 cm and/or clinically lymph node positive.

Patients will be randomized to either Arm A: THP (trastuzumab, pertuzumab and weekly
paclitaxel), Arm B: THP-K (trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel) or
Arm C: TH-K (trastuzumab, pembrolizumab and weekly paclitaxel). Patients will be stratified
according to hormone receptor status and lymph node status. All patients will be treated
weekly every three weeks for four cycles (only paclitaxel will be administered weekly) and
then undergo breast surgery. Arm A patients will be regarded as the reference group.

Inclusion Criteria:

- Male/female patients with histologically confirmed invasive HER2-positive (by American
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines)
unilateral breast cancer

- Have previously untreated non-metastaic (M0), cT2-4N0 or cT1-4N1-3 (biopsies of
clinically suspicious lymph nodes to confirm nodal status is encouraged).

- Multifocal/centric disease is permitted if all suspicious foci have been biopsied and
are consistent with HER2-positive (by ASCO/CAP guidelines) invasive breast cancer

- Be a male or female subject 18 years of age on the day of signing informed consent

Male Participants:

- A male participant must agree to use a contraception as detailed in Appendix C of this
protocol during the treatment period and for at least 6 months after the last dose of
study treatment and refrain from donating sperm during this period.

Female Participants:

- A female participant is eligible to participate if she is not pregnant (see Appendix
C), not breastfeeding, and at least one of the following conditions applies: a.) Not a
woman of childbearing potential (WOCBP) as defined in Appendix C OR b.) A WOCBP who
agrees to follow the contraceptive guidance in Appendix C during the treatment period
and for at least 6 months after the last dose of study treatment.

- Have provided archival tumor tissue sample or newly obtained core or excisional biopsy
of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE)
tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
archived tissue.

Note: If submitting unstained cut slides, newly cut slides should be submitted to the
testing laboratory within 14 days from the date slides are cut.

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Evaluation of ECOG is to be performed within 7 days prior to the date of
allocation/randomization.

- Have adequate organ function as defined by the following parameters. Specimens must be
collected within 10 days prior to the start of study treatment.

- Absolute neutrophil count (ANC) ≥1500/µL

- Platelets ≥100 000/µL

- Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La

- Renal Creatinine (≤1.5 × ULN OR) OR Measured or calculated(b) creatinine clearance
(≥30 mL/min for participant with creatinine levels) (GFR can also be used in place of
creatinine or CrCl) (>1.5 × institutional ULN)

- Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total
bilirubin levels >1.5 × ULN aspartate aminotransferase (AST, SGOT) and alanine
aminotransferase (ALT, SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver
metastases)

- Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated
partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended
use of anticoagulants

- Cardiac Echocardiogram or MUGA (multigated radionuclide angiography) Baseline LVEF ≥
55%

Exclusion Criteria:

- A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization
(see Appendix C). If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.

Note: in the event that 72 hours have elapsed between the screening pregnancy test and the
first dose of study treatment, another pregnancy test (urine or serum) must be performed
and must be negative in order for subject to start receiving study medication.

- Has received prior therapy with an anti-PD-1 (programmed death protein 1), anti-PD-L1
(Programmed death-ligand 1), or anti PD L2 (Programmed death-ligand 2) agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX 40, CD137).

- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to randomization.

Note: If participant received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting study treatment.

- Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis.

- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment.

Note: Participants who have entered the follow-up phase of an investigational study may
participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.

- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.

- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years. Note: Participants with basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma,
cervical cancer in situ) that have undergone potentially curative therapy are not
excluded.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

- Has an active infection requiring systemic therapy.

- Has a known history of Human Immunodeficiency Virus (HIV).

- Has a known active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or Hepatitis C virus (i.d. HCV RNA [qualitative] is detected) infection.

- Has a known history of active TB (Bacillus Tuberculosis).

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.

- Has significant cardiovascular disease, such as:

- History of myocardial infarction, acute coronary syndrome or coronary
angioplasty/stenting/bypass grafting within the last 6 months

- Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or
history of CHF NYHA class III or IV

- Angina pectoris requiring anti-anginal medication, uncontrolled arrhythmias, or
uncontrolled hypertension (systolic blood pressure > 180mmHg and/or diastolic
blood pressure > 100mmHg).