| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive, adenocarcinoma of the breast (except inflammatory breast cancer, T4d) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| To evaluate the cardiac toxicity of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab in comparison to the standard therapy, i.e. trastuzumab abd docetaxel. |
|
| E.2.2 | Secondary objectives of the trial |
• Assessment of the rate of pathological complete response at the time of final surgery;
• Assessment of the rate of total pathological complete response (ytpCR) at the time of final surgery
• Assessment of the rate of overall clinical response rate (cORR), at the time of final surgery
• Assessment of safety
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, age ≥ 18 years.
2. Pathologically confirmed invasive primary breast adenocarcinoma (except inflammatory breast cancer, T4d) scheduled for taxan containing neoadjuvant systemic treatment with or without palpable lymph nodes.
3. Documented HER2 protein overexpression as determined by immunohistochemistry (IHC) 3+ or by demonstrated HER2/c-erbB2 gene amplification according to fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) of the primary tumor by a local laboratory.
4. LVEF ≥ 55% measured by echocardiography within 4 weeks before randomization.
5. ECOG Performance Status ≤ 1
6. Able and willing to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
7. Written informed consent, indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrollment. |
|
| E.4 | Principal exclusion criteria |
Current Treatment
1. Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.
2. Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) excluding inhaled steroids.
3. Chronic daily treatment with aspirin and aspirin analogs (>325 mg/day) or clopidogrel (> 75 mg / day).
4. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of the study treatment.
5. Current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
Laboratory
6. Inadequate bone marrow function: absolute neutrophil count (ANC) < 1.5 x 109/L, platelet count < 100 x 109/L or hemoglobin (Hb) < 9 g/dL.
7. Inadequate liver function: serum (total) bilirubin > upper limit of normal (ULN), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN, AST or ALT > 1.5 x ULN concurrent with serum alkaline phosphatase > 2.5 ULN.
8. Inadequate renal function: Serum creatinine > 177 µmol/L or 2.0 mg/dL. If urine dipstick for proteinuria is ≥ 2+ at baseline, the patient must undergo 24-hour urine collection and demonstrate ≤ 1 g of protein/24 hr
9. Patients not receiving anticoagulant medication who have activated partial thromboplastin time (aPTT) > 1.5 x ULN within 7 days prior to Day1 of the cycle 1.
Concomitant Conditions
10. Other malignancy within the last 5 years before randomization except for curatively treated carcinoma in situ of the cervix or non-melanomatous skin cancer
11. Evidence of distance metastasis judged clinically and at least by chest-X-ray, liver-sonography and bone scan.If there is any clinical suspicion of brain metastasis, a computerized tomography (CT) scan or magnetic resonance imaging (MRI) of the brain must be conducted within 4 weeks prior to randomization.
12. Serious concurrent disease which could affect compliance with the protocol or interpretation of results, including, but not limited to:
• Active infection requiring IV antibiotics.
• Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg).
• Clinically significant history of cardiovascular disease as indicated by: cerebrovascular accident or stroke; myocardial infarction; unstable angina; New York Heart Association (NYHA) (see Appendix 4) Grade II or greater congestive heart failure (CHF); cardiac arrhythmia requiring medication; clinically significant valvular heart disease.
• Dyspnea at rest necessitating supportive oxygen therapy or with significant pleural effusions.
• Poorly controlled diabetes mellitus.
• History or evidence upon physical/neurological examination of CNS disease unrelated to cancer (e.g. uncontrolled seizures) unless adequately treated with standard medical therapy.
• History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• History of abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months of randomization.
• Serious non-healing wound, peptic ulcer, or bone fracture.
• Clinically significant malabsorption syndrome, ulcerative colitis, disease affecting GI function, resection of the stomach or small bowel, or inability to take oral medication.
• Uncorrected hypokalemia or hypomagnesemia.
• Organ allografts requiring immunosuppressive therapy.
13. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect patient compliance with study routines, or place the patient at high risk from treatment related complications.
14. Known hypersensitivity to any of the study drugs or excipients.
15. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies.
Other
16. Pregnant, lactating females or women of childbearing potential without a negative pregnancy test – urine or serum, within 7 days prior to DAY1/cycle1, irrespective of the method of contraception used, including tubal ligation
17. Fertile males or females of childbearing potential (<12 years since last menstruation) unwilling or unable to use effective non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly, or surgical sterilization).
18. Patients not accessible for treatment or follow-up. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary study endpoint is cardiac toxicity of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD plus/minus bevacizumab using a composite endpoint appearing between day 1 of cycle 1 and day 28±3 days after the day of final surgery.
This composite endpoint of cardiac toxicity is defined as the appearance of either
• symptomatic left ventricular dysfunction NYHA grade II, III, or, IV
or
• asymptomatic left ventricular dysfunction defined as a decrease of the left ventricular ejection fraction (as measured by echocardiography) of ≥ 15%-points as compared to base-line with a measured value still above the lower limit of normal (55%)
or
asymptomatic left ventricular dysfunction defined as a decrease of the left ventricular ejection fraction (as measured by echocardiography) of ≥ 10%-points as compared to base-line with a measured value below the lower limit of normal (55%)
or
• the appearance of significant arrhythmias requiring medical treatment or invasive diagnostic measures
LVEF measurements (by echocardiography (biplane Simpson's method) or multiple gated nuclear angiography (MUGA) and an electrocardiogram will be done
• at screening,
• within 3 days before each treatment cycle (cycle 1 - 6),
• within 5 days before final breast surgery,
• and 28 ±3 days after final surgery,
• or whenever clinically indicated during the conduct of study treatment until 28 + 3 days after final surgery.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| between day 1 of cycle 1 and day 28 after the day of final surgery |
|
| E.5.2 | Secondary end point(s) |
Assessments of:
• Pathological complete response (ypCR), defined as absence of invasive tumor at final surgery;
• Total pathological complete response (ytpCR), defined as absence of invasive tumor and tumor cells in the breast and the axillar lymphnodes (ypT0 or yDCIS and ypN=0)
• Overall clinical response rate (cORR), defined as the percentage of patients with either a complete clinical response (cCR) or a partial clinical response (cPR) but no ypCR.
• Safety of the combination trastuzumab and docetaxel with bevacizumab and trastuzumab, docetaxel, and NPLD
plus/minus bevacizumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at time of final surgery (up to 22 weeks) |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Herceptin+Docetaxel+/- Avastin will be compared to Herceptin+Docetaxel+NPLD+/- Avastin |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 11 |
| 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 | Yes |
| 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
|
| The study will end 28 ± 3 days days after the last enrolled patient has undergone final surgery. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
