Copanlisib in Combination With T-DM1 in Pretreated Unresectable Locally Advanced or Metastatic HER2-positive Breast Cancer

Inclusion Criteria:

1. Written informed consent must be provided before any study-specific tests or procedures are performed.
2. Adult women ≥ 18 years of age.
3. Histologically confirmed HER2-positive breast cancer:

   * Documented HER2 overexpression by local laboratory defined as a score of 3+ by IHC or a ratio of ≥ 2.0 by ISH.
   * HER2-positive on diagnostic breast biopsy or surgical breast resection sample or metastatic disease site biopsy.
4. Patient with unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination.
5. Patient has received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.
6. At least one measurable lesion according to RECIST criteria (Version 1.1). Patients with bone only disease are eligible if lesion(s) can be accurately assessed by CT/MRI according to RECIST (Version 1.1).
7. ECOG performance status ≤ 2.
8. Life expectancy of at least 3 months.
9. Availability of fresh tissue and/or archival tumour tissue at screening.
10. Women of childbearing potential must agree to use a highly effective method of contraception when sexually active. This applies from signing of the informed consent form until at least 7 months after the last study drug administration. The investigator or a designated associate is required to advise the patient how to achieve an adequate birth control. Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include:

    i. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).

    ii. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable).

    iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v. Bilateral tubal occlusion. vi. Successfully vasectomised partner. vii. Sexual abstinence.

    Postmenopausal women defined as follows:
    * Woman 60 years of age or older, OR
    * Woman younger than 60 years of age with spontaneous cessation of menses for at least 12 consecutive months prior to registration, OR
    * Prior bilateral oophorectomy, OR
    * Woman younger than 60 years of age who have had a prior hysterectomy (without bilateral oophorectomy) AND who have an FSH level in the postmenopausal range (or \>34.4 IU/L if institutional range is not available).
11. Adequate baseline laboratory values collected no more than 14 days before starting study treatment:

    * Total bilirubin ≤ 1.5 x ULN (\< 3 x ULN for patients with metastatic disease in the liver)
    * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver involvement by breast cancer).
    * Lipase ≤ 1.5 x ULN.
    * Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula. If not on target, this evaluation may be repeated once after at least 24 hours either according to the MDRD abbreviated formula or by 24 hour sampling. If the later result is within acceptable range, it may be used to fulfil the inclusion criteria instead.
    * International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior underlying coagulopathy disorder. Close monitoring of these patients (Day 15 of Cycle 1 and Day 1 of each cycle) will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
    * Platelet count ≥ 75 x 109/L. For patients with breast cancer bone marrow infiltration, platelet count ≥ 50 x 109/L.
    * Haemoglobin (Hb) ≥ 8 g/dL.
    * Fasting blood glucose ≤6.0 mmol/L if not diabetic or ≤8.9 mmol/L if diabetic.
    * Absolute neutrophil count (ANC) ≥ 1 x 109/L. For patients with malignant bone marrow infiltration, ANC count ≥ 0.75 x 109/L.
12. Left ventricular ejection fraction (LVEF), at or above the Institutions lower limit of normal, as determined by ECHO or MUGA.
13. Patients must have recovered from clinically significant side effects associated with prior radiotherapy and chemotherapy with the exception of fatigue or neuropathy.

Exclusion Criteria:

1. Known breast cancer involvement of the brain, unless adequately controlled based on the clinical judgement of the treating physician.
2. Congestive heart failure \> New York Heart Association (NYHA) class II.
3. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before registration.
4. Uncontrolled arterial hypertension despite optimal medical management (per investigator's opinion).
5. Uncontrolled Type I or II diabetes mellitus. Defined as HbA1c \> 8.5% as determined during screening laboratory assessments.
6. 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 registration.
7. Non-healing wound, ulcer, or bone fracture.
8. Active, clinically serious infections \> Grade 2 (CTCAE v5.0).
9. Known history of human immunodeficiency virus (HIV) infection.
10. 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 laboratory panel Patients who test positive for Hepatitis B surface Antigen (HBsAg) or Hepatitis B core Antigen (HBcAb) will be eligible if they are negative for HBV-DNA; patients who test positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
11. Patients with CMV PCR positive.
12. Patients with seizure disorder requiring medication.
13. Patients with evidence or history of bleeding diathesis. Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study treatment.
14. Proteinuria of Grade 3 or higher (CTCAE v5.0). Patient will be excluded if \> 2+ on urinalysis (unless 24 hr collection shows 24 hour urinary protein \< 3.5g/24hrs).
15. History or concurrent condition of interstitial lung disease of any severity, and/or severely impaired lung functions (as judged by the investigator).
16. Concurrent diagnosis of pheochromocytoma.
17. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum or urine pregnancy test within 7 days of first dose, and a negative result must be documented before start of treatment.
18. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow parameters.
19. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation.
20. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
21. Any illness or medical conditions that are unstable or could jeopardise the safety of patients and their compliance in the study.
22. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.