This study is a Phase Ib/II open label, single arm, adaptive multi-centre trial of copanlisib
in combination with trastuzumab in pretreated recurrent or metastatic HER2-positive breast
Patients with HER2 positive, metastatic or incurable recurrent breast cancer, following
disease progression during, or after, treatment with at least one systemic treatment regimen
in the metastatic or recurrent setting, will be treated with copanlisib (at 30, 45 or 60 mg
flat dosing IV weekly - depending on the maximum tolerated dose (MTD) determined in the Phase
Ib part of the study) plus trastuzumab (4 mg/kg IV Cycle 1 Day 1 and then 2 mg/kg IV weekly
starting from day 8).
Phase Ib One of three dose levels of copanlisib is assigned at registration according to the
dose escalation scheme.
Phase II The copanlisib dose for the Phase II part of the trial will be based on the MTD
established in the Phase Ib part of the study.
Clinical and laboratory parameters will be assessed to evaluate disease response and toxicity
of study therapy.
Safety assessments will be performed throughout the study.
Efficacy assessments (radiological examination) will be performed on all patients every 8
weeks for the first 24 weeks and every 12 weeks thereafter.
Following baseline cardiac assessment, cardiac safety monitoring will include physical exam
(with New York Heart Association (NYHA) functional classification for patients with diagnosed
congestive heart failure) during each cycle, Multigated acquisition (MUGA) scan or
Echocardiogram (ECHO) and 12 lead Electrocardiogram (ECG) within 7 days of Day 1 of every
third cycle starting at cycle 3 (Cycle 3, Cycle 6, etc.).
Patients are eligible to be included in the study only if they meet all of the following
1. Adult women ≥18 years of age with histologically confirmed, recurrent, or metastatic,
HER2-positive breast cancer.
Eligible recurrent disease is recurrent disease that is considered incurable by the
treating oncologist. Many local only recurrences are treated with curative intent; a
treatment plan with curative intent for a local only recurrence would indicate that
the patient is not eligible for this clinical trial. A local only recurrence must be
considered incurable by the treating oncologist for the patient to be eligible.
2. Documented HER2 overexpression by local laboratory (IHC 3+ or FISH or CISH positive).
3. At least one measurable lesion according to RECIST criteria (Version 1.1). Patients
with bone only disease are not eligible.
4. Patient has received at least one trastuzumab based or TDM1-based treatment regimen in
the setting of metastatic disease or incurable locoregional recurrence. A trastuzumab
based or TDM1-based treatment regimen is considered as any treatment regimen that
includes trastuzumab or TDM1.
Patients must have had at least 1 line of therapy for metastatic and/or incurable
locoregional recurrent disease to be eligible. A patient is eligible regardless of the
period of time from adjuvant therapy so long as she has disease that is progressing
after at least 1 line of trastuzumab-based therapy in the setting of metastatic
disease and/or incurable locoregional recurrence.
5. Disease progression during or following the most recent anticancer therapy.
6. ECOG performance status ≤2.
7. Life expectancy of at least 3 months.
8. Availability of fresh tissue and/or archival tumour tissue at screening.
9. 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 100 days 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: combined (oestrogen and progestogen
containing) hormonal contraception associated with inhibition of ovulation (oral,
intravaginal, transdermal) progestogen only hormonal contraception associated with
inhibition of ovulation (oral, injectable and implantable), intrauterine device (IUD),
intrauterine hormone releasing system (IUS), bilateral tubal occlusion, successfully
vasectomised partner and sexual abstinence. In addition, the use of condoms by
patients or their partners is required unless the woman has had a hysterectomy.
10. Adequate baseline laboratory values collected no more than 14 days before starting
Total bilirubin ≤1.5 x ULN (<3 x ULN for patients with liver involvement). Alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN for
patients with liver involvement from breast cancer).
Lipase ≤1.5 x ULN. Glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 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 evidence of underlying
abnormality in coagulation parameters exists. 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 predose 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. Absolute neutrophil count (ANC) ≥1 x 109/L. For patients
with malignant bone marrow infiltration, ANC count ≥0.75 x 109/L.
Fasting blood glucose <125 mg/dL (≤6.9 mmol/L) if not diabetic or <160 mg/dL (≤8.9
mmol/L) if diabetic
11. Left ventricular ejection fraction (LVEF), above the Institutions lower limit of
normal, as determined by ECHO or MUGA.
12. Patients must have recovered from clinically significant side effects associated with
prior radiotherapy and chemotherapy.
5.1.1 Additional criteria for Phase II:
13. PIK3CA mutation confirmed by central laboratory.
14. Phase Ib subjects (who are confirmed PIK3CA mutation carriers) must have been treated
at the MTD in order to proceed with enrolment/registration to the Phase II study.
Patients who meet any of the following criteria at the time of screening will be excluded
from study registration:
1. Known breast cancer involvement of the brain, unless adequately controlled as
documented by baseline CT Scan (or PET CT/MRI if as per RECIST 1.1) that has not
progressed since previous scans and that does not require corticosteroids for
management of CNS symptoms
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. Uncontrolled
arterial hypertension (systolic blood pressure >160 mmHg or diastolic pressure >90
mmHg despite optimal medical management).
4. Uncontrolled Type I or II diabetes mellitus. Defined as HbA1c >8.5% or a fasting
plasma glucose >8.9 mmol/L as determined during screening laboratory assessments.
5. 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.
6. Non-healing wound, ulcer, or bone fracture.
7. Active, clinically serious infections >CTCAE Grade 2 (CTCAE v4.0).
8. Known history of human immunodeficiency virus (HIV) infection.
9. 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. Patients who test positive for HBsAg or 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.
10. Patients with seizure disorder requiring medication.
11. 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.
12. Proteinuria of CTCAE Grade 3 or higher.
13. History or concurrent condition of interstitial lung disease of any severity, and/or
severely impaired lung function (as judged by the investigator).
14. Concurrent diagnosis of pheochromocytoma.
15. Pregnant or breast feeding patients. Women of childbearing potential must have a serum
pregnancy test performed a maximum of 7 days before start of treatment, and a negative
result must be documented before start of treatment.
16. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior
therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow
17. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in
18. Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results.
19. Any illness or medical conditions that are unstable or could jeopardize the safety of
patients and their compliance in the study.
20. Patients permanently withdrawn from study participation will not be allowed to re
enter the study.
5.2.1 Excluded previous therapies and medications:
21. Treatment with investigational drugs other than PI3K inhibitors less than 28 days
before start of treatment.
22. Ongoing immunosuppressive therapy.
23. Radiotherapy or immunotherapy/chemotherapy less than 4 weeks before start of
24. Myeloid growth factors less than 7 days before start of treatment.
25. Blood or platelet transfusion less than 7 days before start of treatment.
26. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone
or equivalent. Previous corticosteroid therapy must be stopped or reduced to the
allowed dose 7 days before performing the screening CT scan (or PET CT/MRI as per
RECIST 1.1) and again prior to the first study drug administration. If a patient is on
chronic corticosteroid therapy, corticosteroids should be de escalated to the minimum
allowed dose before the screening. Patients may continue to use topical or inhaled
27. History of having received an allogeneic bone marrow or organ transplant.
28. Major surgical procedure or significant traumatic injury (as judged by the
investigator) less than 28 days before start of treatment. This does not include the
study specific biopsy.
29. Antiarrhythmic therapy (beta blockers or digoxin are permitted).
30. Use of strong inhibitors of CYP3A4 is prohibited from Day 14 of Cycle 1 until the
Safety follow up visit.
31. Use of inducers of CYP3A4 is prohibited from Day 14 of Cycle 1 until the Safety follow
Zoledronate or denosumab for patients with bone metastasis is allowed.