Copanlisib, Letrozole, and Palbociclib in Treating Patients With Hormone Receptor Positive HER2 Negative Stage I-IV Breast Cancer

PRIMARY OBJECTIVES:

I. Assess the safety, tolerability and to estimate the maximum tolerated dose (MTD) in a
metastatic setting of the following combination: copanlisib + palbociclib + letrozole. (Phase
Ib) II. Compare the biological activity of letrozole in combination with palbociclib,
letrozole in combination with palbociclib and copanlisib, and letrozole in combination with
copanlisib by assessing the percentage change from the baseline value in Ki67 expression
after 2 weeks of therapy in non-metastatic breast cancer. (Phase II)

SECONDARY OBJECTIVES:

I. Evaluate the pathologic complete response (pCR) defined as absence of invasive cancer in
the breast and sampled regional lymph nodes.

II. Evaluate the clinical objective response Response Evaluation Criteria in Solid Tumors
(RECIST) criteria 1.1.

III. Assess safety and tolerability. IV. Evaluate the pharmacokinetics of copanlisib when
given in combination with letrozole, and palbociclib.

V. Measure the gene expression and/or biomarker changes that may be correlated with or
predict biological, clinical, and pathologic response.

OUTLINE: This is a dose-escalation study of copanlisib.

PHASE Ib: Patients with metastatic breast cancer receive copanlisib intravenously (IV) over 1
hour on days 1, 8, and 15, palbociclib orally (PO) once daily (QD) on days 1-21, and
letrozole PO continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses
in the absence of disease progression or unacceptable toxicity.

PHASE II: After determination of MTD, subsequent non-metastatic breast cancer patients are
randomized to 1 of 3 arms:

ARM A: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO
continuously on days 1-28. Treatment repeats every 28 days for up to 4 courses in the absence
of disease progression, or unacceptable toxicity.

ARM B: Patients receive copanlisib (MTD) IV over 1 hour on days 1, 8, and 15, palbociclib PO
QD on days 1-21, and letrozole PO continuously on days 1-28. Treatment repeats every 28 days
for up to 4 courses in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive palbociclib PO QD for days 1-14 of course 1 and letrozole PO
continuously on days 1-14. Patients then undergo biopsy. Patients then receive copanlisib
(MTD) IV over 1 hour on days 1, 8, and 15 and letrozole PO continuously on days 1-28.
Treatment with copanlisib and letrozole repeats every 28 days for up to 3.5 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month.

Inclusion Criteria:

- Post-menopausal (if female) defined as: 1) prior bilateral oophorectomy, 2) age 60 or
over, or 3) < 60 years and amenorrheic for at least 12 months with
follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per
institutional parameters); use of luteinizing hormone-releasing hormone (LHRH)
agonists to induce chemical ovarian ablation will not be allowed for this study

- Tumor is hormone receptor (HR)+ (estrogen receptor and/or progesterone receptor
positive with at least 10% expression of either receptor by local immunohistochemical
staining) and HER2 negative based on local assessment

- FOR PHASE Ib PORTION OF THE STUDY:

- Locally advanced/non-operable or metastatic breast cancer that has not been previously
treated in the metastatic setting with systemic therapy (i.e. first line treatment)

- Measurable disease per RECIST 1.1

- FOR PHASE II PORTION OF THE STUDY:

- Clinical stage I (breast tumor >= 1.0 cm in diameter), stage II or stage III breast
cancer (according to the American Joint Committee on Cancer [AJCC] Staging Manual, 7th
Edition, 2010); multifocal disease is allowed if confined to 1 breast, as long as one
tumor is at least 1 cm and meets all of the other inclusion criteria

- Breast cancer suitable for mandatory baseline core biopsy

- No prior systemic therapy or radiotherapy for currently-diagnosed invasive or
noninvasive breast cancer

- FOR ALL PHASES (Ib AND II):

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Platelets > 100 x 10^9/L

- Hemoglobin >= 8 g/dL (phase Ib) or >= 10 g/dL (for phase II portion)

- For phase Ib portion only: patients may receive erythrocyte transfusions to
achieve this hemoglobin level at the discretion of the investigator; however,
initial study drug treatment must not begin earlier than the day of the
erythrocyte transfusion

- Bilirubin =< 1.5 times the upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 times ULN

- Subjects with Gilbert's syndrome, confirmed by genotyping or Invader UGTIA1 molecular
assay prior to study entry, must have total bilirubin < 3.0 times ULN

- Serum creatinine =< 1.5 times ULN

- Lipase =< 1.5 x ULN

- International normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x ULN

- Left ventricular ejection fraction (LVEF) >= 50%

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Exclusion Criteria:

- FOR PHASE Ib ONLY:

- Early stage (curable) breast cancer

- FOR PHASE II ONLY:

- Metastatic breast cancer (local spread to axillary or internal mammary lymph nodes is
permitted)

- Prior systemic therapy for invasive or non-invasive (DCIS) breast cancer

- Prior radiotherapy to the ipsilateral chest wall or breast for any malignancy

- Bilateral invasive breast cancer

- FOR ALL PHASES (Ib AND II): Inflammatory breast cancer

- FOR ALL PHASES (Ib AND II): Concurrent therapy with any other non-protocol anti-cancer
therapy

- FOR ALL PHASES (Ib AND II): History of any other malignancy within the past 5 years,
with the exception of non-melanoma skin cancer or carcinoma-in-situ of the cervix

- FOR ALL PHASES (Ib AND II): Concurrent diagnosis of pheochromocytoma

- FOR ALL PHASES (Ib AND II): Current therapy with raloxifene, tamoxifen, aromatase
inhibitor, or other selective estrogen receptor modulator (SERM), either for
osteoporosis or prevention of breast cancer; subjects must have discontinued therapies
for at least 28 days prior to first baseline biopsy

- FOR ALL PHASES (Ib AND II): Concurrent treatment with postmenopausal hormone
replacement therapy; prior treatment must be stopped for at least 28 days prior to
first baseline biopsy

- FOR ALL PHASES (Ib AND II): Type I diabetes or patients on insulin therapy are not
allowed; uncontrolled type II diabetes not allowed (glycosylated hemoglobin [HbA1c] >
7.5)

- FOR ALL PHASES (Ib AND II): Proteinuria of >= Common Terminology Criteria for Adverse
Events (CTCAE) grade 3 as estimated by urine protein : creatinine ratio > 3.5 on a
random urine sample

- FOR ALL PHASES (Ib AND II): Uncontrolled arterial hypertension despite optimal medical
management

- FOR ALL PHASES (Ib AND II): Hepatitis B (HBV) or hepatitis C (HCV); all patients must
be screened for HBV and HCV up to 28 days prior to study drug start using the routine
hepatitis virus laboratorial panel

- FOR ALL PHASES (Ib AND II): Known history of human immunodeficiency virus (HIV)
infection

- FOR ALL PHASES (Ib AND II): Uncontrolled infection; active, clinically serious
infections (> CTCAE grade 2)

- FOR ALL PHASES (Ib AND II): History of significant cardiac disease:

- Congestive heart failure > New York Heart Association (NYHA) class 2

- Unstable angina (angina symptoms at rest), new-onset angina (begun within the
last 3 months)

- Myocardial infarction less than 6 months before start of test drug

- Anti-arrhythmic therapy (beta blockers or digoxin are permitted)

- FOR ALL PHASES (Ib AND II): Arterial or venous thrombotic or embolic events such as
cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis
or pulmonary embolism within 3 months before the start of study medication

- FOR ALL PHASES (Ib AND II): Participants receiving anticoagulation therapy are not
allowed

- FOR ALL PHASES (Ib AND II): Patients with evidence or history of bleeding diathesis;
any hemorrhage or bleeding event >= CTCAE grade 3 within 4 weeks of start of study
medication

- FOR ALL PHASES (Ib AND II): Blood or platelet transfusion within 7 days prior to
treatment start

- FOR ALL PHASES (Ib AND II): Non-healing wound or ulcer

- FOR ALL PHASES (Ib AND II): History of, or current autoimmune disease

- FOR ALL PHASES (Ib AND II): Major surgical procedure or significant traumatic injury
(as judged by the investigator) within 28 days before start of study medication, open
biopsy within 7 days before start of study medication

- FOR ALL PHASES (Ib AND II): Patients with seizure disorder requiring medication

- FOR ALL PHASES (Ib AND II): Known hypersensitivity to any of the study drugs, study
drug classes, or excipients in the formulation

- FOR ALL PHASES (Ib AND II): Systemic continuous corticosteroid therapy at a daily dose
higher than 15 mg prednisone or equivalent is not allowed; patients may be using
topical or inhaled corticosteroids; previous corticosteroid therapy must be stopped or
reduced to the allowed dose at least 7 days prior to the first study drug
administration; if a patient is on chronic corticosteroid therapy, corticosteroids
should be de-escalated to the maximum allowed dose after the patient has signed the
consent document

- FOR ALL PHASES (Ib AND II): History of having received an allogeneic bone marrow or
organ transplant

- FOR ALL PHASES (Ib AND II): Chronic oxygen therapy