HER2 positive metastatic or recurrent breast cancer, following disease progression during, or after, treatment with at least one treatment regimen in the metastatic or recurrent setting. MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10006198 Term: Breast cancer recurrent System Organ Class: 10029104 -
Conditions
Interventions
Product Name: Copanlisib
Product Code: BAY 80-6946
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: Copanlisib
Other descriptive name: BAY 80-6946 (AS DIHYDROC
Sponsors
Cancer Trials Ireland CLG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Adult women = 18 years of age with histologically confirmed, recurrent, or metastatic, HER2-positive breast cancer. 2. Histologically confirmed HER2-positive breast cancer: o Documented HER2 overexpression by local laboratory (IHC 3+ or FISH or CISH positive). o IHC 3+ or FISH/CISH positive on diagnostic breast biopsy or surgical breast resection sample or metastatic disease site biopsy. 3. Recurrent incurable or metastatic breast cancer. 4. 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. A t least one measurable lesion according to RECIST criteria (Version 1.1). Patients with bone only disease are not eligible. 5. 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. 6. Disease progression during or following at least 1 prior trastuzumab-based or trastuzumab emtansine (T-DM1) based treatment regimen in the setting of metastatic disease or incurable locoregional recurrence. 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 100 days after the last study drug administration. Please refer to protocol for full details. 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 from breast cancer). - 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 th
Exclusion criteria
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 > CTCAE Grade 2 (CTCAE v4.0). 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 (HBsAg, HBsAb,…). 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. 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 v4.0). 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 function (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 performed a maximum of 7 days before start of treatment, 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 jeopardize 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. Excluded previous therapies and medications: 23. Treatment with investigational drugs other than PI3K inhibitors less than 28 days before start of treatment. 24. Ongoing immunosuppressive therapy. 25. Radiotherapy of a target lesion or immuno-/chemotherapy less than 4 weeks (28 days) before start of treatment. 26. Myeloid growth factors less than 7 days before start of treatment. 27. Blood or platelet transfusion less than 7 days before start of treatment. 28. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednis
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib 1. To determine the Maximum Tolerated Dose (MTD), for copanlisib in combination with trastuzumab in patients with histologically confirmed HER2-positive breast cancer that are metastatic or incurable recurrent, following disease progression during, or after, treatment with at least one systemic treatment regimen in the metastatic or recurrent setting. Phase II 1. To evaluate the anti-tumour efficacy of copanlisib in combination with trastuzumab in terms of Clinical Benefit Rate (CBR) in patients with PIK3CA wild type and mutated, histologically confirmed HER2-positive breast cancer that are metastatic or incurable recurrent, following disease progression during, or after, treatment with at least one systemic treatment regimen in the metastatic or recurrent setting (Phase II plus patients with PIK3CA wild type and mutated HER2-positive breast cancer treated at MTD in Phase Ib).;Secondary Objective: Phase Ib 1. To evaluate the safety and tolerability of this regimen. Phase II 1. To evaluate other efficacy measures in patients with PIK3CA wild type and mutated HER2 positive breast cancer treated with this regimen (Phase II plus patients with PIK3CA wild type and mutated HER2 positive breast cancer subsets treated at MTD in Phase Ib). 2. To evaluate the safety and tolerability of this regimen. 3. To assess the incidence of cardiotoxicity in patients treated with this regimen. 4. To examine for predictive biomarkers in tumour tissue and blood. 5. To examine molecular tumour adaptation to clinical trial therapy. 6. To determine if early response on PET-CT predicts later outcome (patients from selected sites).;Primary end point(s): Primary Efficacy Endpoints (Phase II plus patients treated at MTD in Phase Ib) The primary efficacy endpoint of this study is: Clinical Benefit Rate (CBR). Clinical Benefit is defined as complete response (CR) or partial response (PR) at any time-point on the study; or stable disease (SD) lasting at least 24 weeks ba | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints (Phase II patients plus patients treated at MTD in Phase Ib) The secondary efficacy endpoints of this study are: Evaluation of the following parameters in patients treated with this regimen: • Overall Survival (OS). • Progression-Free Survival (PFS) assessed according to RECIST criteria version 1.1. • Time to Treatment Failure (TTF) is defined as time from registration to discontinuation of therapy or add-on of new anti-cancer therapy for any reason (including death, progression and toxicity). • Confirmed tumour response rate as assessed by RECIST criteria version 1.1. • Duration of response (DR) as assessed by RECIST criteria version 1.1. Secondary Safety Endpoints Phase Ib/II • To evaluate the safety and tolerability of this regimen as measured by incidence of adverse events reported and toxicity evaluation as per the NCI Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Phase II • To assess the incidence of cardiotoxicity in patients treated with this regimen. Cardiac safety monitoring will include physical exam, (with NYHA functional classification for patients with diagnosed congestive heart failure) at each cycle, and MUGA scan or ECHO and 12 lead ECG at baseline and every 8 weeks (+/- 1 week). ;Timepoint(s) of evaluation of this end point: All secondary outcome measures will be analysed for Phase II patients and Phase Ib patients treated at MTD. The time to event endpoints are progression-free survival (PFS) and overall survival (OS). PFS is defined as time from registration to disease progression or death from any cause, censored at date last known to be progression-free for those who have not progressed or died. OS is defined as the time from registration to date of death from any cause or censored at date last known alive for those who have not died. | — |
Countries
Ireland
Contacts
Public ContactHead of Operations&ClinicalPrograms
Cancer Trials Ireland CLG
Outcome results
None listed