| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| primary breast cancer |
| primäres Mammakarzinom |
|
| E.1.1.1 | Medical condition in easily understood language |
| breast cancer |
| primäres Brustkrebs |
|
| 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 compare efficacy of pre-operative standard of care treatment with or without a therapeutic cancer vaccine (L-BLP25), measured by Residual Cancer Burden (RCB) at the time of surgery |
|
| E.2.2 | Secondary objectives of the trial |
• to compare the efficacy of pre-operative standard of care treatment with or without a therapeutic cancer vaccine (L-BLP25), when measured by pathological complete remission (pCR, =absence of invasive cancer cells in surgical specimen) at the time of surgery.
• to detect differences in the efficacy between reverse versus conventional sequenced chemotherapy with or without L-BLP25, when measured by RCB.
• to compare safety and tolerability of standard of care pre-operative treatment with or without a therapeutic cancer vaccine (L-BLP25).
• to compare differences in tumor associated lymphocytes and ki67 status along the course of therapy in women who receive standard of care pre-operative treatment with or without L-BLP25
• to evaluate Quality of Life in women treated with our without a therapeutic cancer vaccine (L-BLP25)
• additional sensitivity analyses of subgroups according to pre-defined study populations
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Pre- and postmenopausal female patients with core-biopsied, early primary invasive breast cancer of any clinical and/or radiological tumor stage (except T4d, inflammatory breast cancer) scheduled to receive pre-operative therapy.
• One core from the biopsy will be dedicated to analyses of a validated gene expression array
• Patients must fulfill the following criteria:
-Postmenopausal AND E+++ or [E++ and ki67<14%] AND G 1,2,X AND scheduled for endocrine therapy as standard of care (34 A)
OR
-Triple negative OR E- OR E+ OR [E++ and ki67>14%] OR G3 OR premenopausal status AND scheduled for anthracyclin-taxan-based chemotherapy as institutional standard of care (34 B)
*Note: for ki67 status determination any antibody can be used; scores for determination of E/PR receptor status according to institutional standard
• No distant metastasis (M0) or secondary carcinoma as assessed clinically and radiologically (X-Ray or CT or MRI or PET) within 3 months prior randomization
• Age ≥ 18
• WHO performance status 0 or 1
• No prior chemotherapy, radiotherapy, or endocrine therapy for invasive breast cancer
• Willingness to undergo Sln and/or ALND Procedure (Sentinel/Axillary Lymph node dissection) acc. to institutional standard
• No medical and/or cardiologic contraindication to receive an anthracyclin- and taxan-containing chemotherapy or endocrine therapy regimen
• Adequate Hematologic function (≤ 14 days prior to randomization)
• Adequate Renal function (≤ 14 days of randomization)
• Adequate Hepatic function (≤ 14 days of randomization)
• Adequate cardiac function: Normal cardiac function must be confirmed by LVEF (Echocardiography or MUGA scan) for chemotherapy treatment only. The result must be above 50% or above the lower normal limit of the institution. In addition each of the following criteria must be met:
o NYHA<III
o No uncontrolled angina, arrhythmia, hypertension
o No myocardial infarction over the last 6 months as confirmed by ECG
• Negative pregnancy test (serum or urine) max. 7 days prior to randomization for pre-menopausal patients. In postmenopausal patients, no pregnancy tests must be performed at any time, requested that
a) FSH and estradiol are in postmenopausal range and/or
b) the patient is amenorrhoeic for > 12 months with uterus still in situ and/or
c) the patient is 61 years of age or older.In this situation, the investigator must document why the pregnancy test was not performed.
• In all premenopausal patients adequate conception with non-hormonal methods (e.g. condoms, non-levonorgestrel-releasing intrauterine devices, diaphragms, vasectomized partner, or abstinence) is mandatory during study duration until at least 30 days after the last vaccination of L-BLP25.
• Competent to comprehend, sign, and date an IEC/IRB-approved informed consent form and able to comply with the required treatments, visits and assessments
• Informed consent signed prior to randomization and prior to any study specific procedure (study specific baseline blood sample) |
|
| E.4 | Principal exclusion criteria |
• HER2 overexpression (+++)
• Past or current history of other neoplasms in the last 5 years, except basal cell cancer of the skin, non-melanoma skin cancer and in situ cancer of the cervix
• Any medical condition rendering the patient unfit for standard of care pre-operative therapy (chemotherapy or endocrine therapy in the respective SoC treatment group)
• Concurrent or prior systemic antitumor therapy < 5 years
• Patients scheduled for any chemotherapy other than EC->T or T->EC
• Clinically significant cardiovascular disease (including unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) < 1 year before randomization
• Known autoimmune disease (e.g. rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, Crohn´s disease, multiple sclerosis, ankylosing spondylitis)
• Severely compromised haematopoietic function
• Known immunodeficiency disease (cellular immunodeficiency, hypogammaglobulinaemia, dysgamaglobulinaemia)
• Known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection
• Active infection requiring systemic treatment or any uncontrolled infections < 14 days prior to randomization
• Major surgery, or significant traumatic injury occurring within 4 weeks prior randomization
• Use of i.v. or s.c. immune modulators (Viscum album etc.)
• Pre-treatment with L-BLP25
• Concurrent treatment with another approved or investigational anticancer treatment is not permitted, excluding therapy as permitted in the protocol
• Concurrent participation in another clinical trial with the same endpoints is not permitted
• Pregnancy or breastfeeding
• Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or IMP/NIMP administration, or which, in the judgment of the investigator, would make the patient inappropriate for enrollement into this study
• Known hypersensitivity against taxanes and/or epirubicin and/or cyclophosphamide or aromatase inhibitors in the respective SoC treatment group
• Concurrent treatment with corticosteroids except as use for the prophylactic medication regimen, inhalational use, prevention or treatment of acute hypersensitivity reactions, treatment of nausea / vomiting or chronic treatment (initiated > 6 months prior to study entry) at low dose (< 20 mg methylprednisolone or equivalent) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Histo-pathological response to pre-operative standard of care treatment with or without L-BLP25 therapy when measured by Residual Cancer Burden (RCB0/I versus RCBII/III) at the time of surgery |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Proportion of pathological complete remission (pCR; = absence of invasive cancer cells in surgical specimen)
• Efficacy of reverse versus conventional sequence chemotherapy with or without L-BLP25 as measured by RCB
• Safety and tolerability of vaccination with L-BLP25
• Proportion of patients with lymphocyte-predominant breast cancer as measured by tumor associated lymphocytes (TAL) and changes in TAL, as well as ki67 status under tumor therapy;
• Quality of Life (QoL)
• Subgroup analysis according to pre-defined study populations
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• pCR, lymphocyte-predominant breast cancer, KI-67, RCB: at the time of surgery
• Safety/tolerabilty: after final surgery
• QoL: after the End of Study Visit |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
• tolerability
• Quality of Life
• sensitivity |
|
| 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 |
| with or without IMP (L-BLP25) |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 19 |
| 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 end of trial is defined with database closure. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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