| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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.
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| E.1.1.1 | Medical condition in easily understood language |
| Pre-treated recurrent or metastatic HER2-positive breast cancer. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006198 |
| E.1.2 | Term | Breast cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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). |
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| E.2.2 | Secondary objectives of the trial |
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). |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The following sub-studies will be conducted to confirm the secondary objectives for the Phase II study. All sub-studies are incorporated within the main protocol.
Biomarker Assessments (Mandatory)
Predictive values of Exosomes/extracellular vesicles (EV) and circulating tumour cells and DNA for trastuzumab and copanlisib.
Fresh Tumour Tissue Biopsy and Blood Sample Translational sub-study (Optional)
DNA/RNA sequencing and proteomic analysis
Imaging sub-study (Optional)
Value of early on treatment fluorodeoxyglucose (FDG)-PET CT scanning in later response prediction [Sub-Study in Dublin sites only (15 patients from Phase Ib and II)]
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| E.3 | Principal 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 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 ≤ 6.0 mmol/L if not diabetic or ≤ 8.9 mmol/L if diabetic
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.
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| E.4 | Principal 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 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 corticosteroids.
29. History of having received an allogeneic bone marrow or organ transplant.
30. 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.
31. Anti-arrhythmic therapy (beta blockers or digoxin are permitted).
32. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until the Safety follow up visit.
33. Use of inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until the Safety follow up visit.
Zoledronate or denosumab for patients with bone metastasis is allowed.
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| E.5 End points |
| E.5.1 | 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 based on radiological assessment.
Primary Safety Endpoints
Phase Ib
• To determine the incidence of dose limiting toxicity (DLT) of copanlisib in combination with trastuzumab within the 1st cycle at each dose level.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary outcome measure, CBR, is the proportion of patients with clinical benefit as defined in Section 4.3.1. The binomial proportions of patients with clinical benefit will be presented with accompanying CIs calculated using the method of Wilson (without continuity correction). All Phase II patients and Phase Ib patients treated at MTD will be included in this analysis. |
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| E.5.2 | 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). |
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| E.5.2.1 | 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.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| LVLS (Last Visit Last Subject). The end of study is defined as when all enrolled patients have completed treatment and follow-up on the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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