E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neoadjuvant treatment of WT1-positive Stage II or III breast cancer. Patients will receive the WT1-A10 + AS15 ASCI in combination with standard neodjuvant therapy. Patients will be recruited in different cohorts according to the standard neoadjuvant treatment they will receive (aromatase inhibitor, chemotherapy or chemotherapy combined with trastuzumab). |
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E.1.1.1 | Medical condition in easily understood language |
Early breast cancer treated before surgery |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006200 |
E.1.2 | Term | Breast cancer stage II |
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006201 |
E.1.2 | Term | Breast cancer stage III |
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 |
This exploratory Phase I/II study aims to evaluate safety and to achieve a first insight into the immunogenicity and clinical activity of WT1-A10 + AS15 ASCI as neoadjuvant therapy administered with different standard treatments in different cohorts of patients with WT1-positive primary invasive breast cancer. |
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E.2.2 | Secondary objectives of the trial |
There are no secondary objectives. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.The patient is at least 18 years of age at the time the informed consent to screening has been obtained.
2. The patient has proven T1 with lymph node involvement or T2-T4c, any N, M0 primary invasive breast cancer, histologically confirmed by core needle biopsy.
Isolated supraclavicular lymph node involvement is allowed.
3. The patient’s tumor shows WT1 antigen expression, detected by quantitative RT-PCR or any updated technique at the time of sample analysis.
4. The patient has one of the following histologically confirmed breast cancer subtypes:
•Estrogen receptor (ER) and/or progesterone (PgR) positive tumor
•HER2-overexpressing breast cancer
•HER2-negative breast cancer.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of study treatment allocation.
6. Baseline LVEF of equal or more than 50% as measured within six weeks prior to study treatment allocation by echocardiography or MUGA scan.
7. The patient shows normal organ function.
8. A female patient of childbearing potential may be enrolled in the study, if the patient:
•has practiced adequate contraception for 30 days prior to study product administration, and
•has a negative pregnancy test within one week prior to study treatment allocation, and
•has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the study product administration series. |
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E.4 | Principal exclusion criteria |
1. The patient has inflammatory breast cancer, which is defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or peau d'orange without erythema).
2. Diagnosis established by incisional biopsy.
3. Prior and concomitant neoadjuvant anti-breast-cancer treatments such as chemotherapy, immunotherapy / biological response modifiers, endocrine therapy, and radiotherapy, unless authorized specifically by the protocol.
4. The patient is known to be human immunodeficiency virus (HIV)-positive.
5. The patient has symptomatic autoimmune disease such as, but not limited to multiple sclerosis, lupus, and inflammatory bowel disease. Patients with vitiligo are not excluded.
6. The patient is known to have difficult-to-control hypertension, coronary artery disease, arrhythmia requiring treatment, clinically significant valvular disease, cardiomegaly on chest X-ray, ventricular hypertrophy on ECG or previous myocardial infarction or congestive heart failure.
7. The patient has a history of allergic reactions likely to be exacerbated by any component of the investigational product used in the study.
8. The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.
9. The patient has (or has had) previous or concomitant malignancies at other sites, except effectively treated malignancy that is considered by the investigator highly likely to have been cured.
10. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the study procedures.
11. The patient has received any investigational or non-registered product (e.g., drug or vaccine) within 30 days preceding the first dose of study products or planned use during the study period.
12. The patient requires concomitant treatment with any immunosuppressive agents or with systemic corticosteroids prescribed for chronic treatment (more than seven consecutive days).
13. The patient has a significant disorder of coagulation or receives treatment with warfarin derivatives or heparin. Patients receiving individual doses of low molecular weight heparin outside of 24 hours prior to WT1-A10 + AS15 ASCI/placebo administration are eligible. Patients receiving prophylactic antiplatelet medications e.g. low-dose aspirin, and without a clinically-apparent bleeding tendency are eligible. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I segment
Safety: Occurrence of severe toxicities i.e.,
1. A Grade 3 or higher toxicity that is related or possibly related to the combined administration of standard treatment and WT1-A10 + AS15 ASCI/placebo. Grade 3 myalgia, athralgia, headache, fever, rigors/chills and fatigue (including lethargy, malaise and asthenia) should persist for 48 hours despite therapy in order to be considered as a severe toxicity.
2. A decrease in LVEF from baseline with 10 points or more and at <50% that is related or possibly related to the combined administration of standard treatment and WT1-A10 + AS15 ASCI/placebo and that is confirmed by a second LVEF assessment within approximately three weeks.
3. A Grade 2 (i.e., asymptomatic with testing that suggests ischemia; stable angina) or higher cardiac ischemia/infarction that is related or possibly related to the combined administration of standard treatment and WT1-A10 + AS15 ASCI/placebo.
4. A Grade 2 or higher allergic reaction occurring within 24 hours following the WT1-A10 + AS15 ASCI/placebo administration.
5. A Grade 3 or higher blood/bone marrow toxicity that is considered as related or possibly related to the combined administration of standard treatment and WT1-A10 + AS15 ASCI/placebo, i.e.,
•The hemoglobin level < 8.0 g/dL
•The leukocyte count < 2.0 x 10E9/L
•The neutrophil count < 1.0 x 10E9/L
•The platelet count < 50.0 x 10E9/L
Important note: In case of concomitant chemotherapy/trastuzumab (i.e., Cohort B, C, D or E) a Grade 3 or higher blood/bone marrow event will be considered as a severe toxicity only if it is NOT resolved to Grade <= 1 within five weeks post last chemotherapy administration.
6. A decrease in renal function at the time of WT1-A10 + AS15 ASCI/placebo administration that is considered as related or possibly related to the combined administration of standard treatment and WT1-A10 + AS15 ASCI/placebo and evaluated by a calculated creatinine clearance < 40 mL/min.
Immunogenicity: The anti-WT1 humoral response post-WT1-A10 + AS15 ASCI/placebo dose 4, evaluated using a blood sample collected at Visit 5.
Phase II segment
Safety:
-Occurrence of severe toxicities
-Occurrence of adverse events and serious adverse events, including abnormal hematological and biochemical parameters.
-Occurrence of serious adverse events related to study treatment.
Immunogenicity:
-The anti-WT1 humoral response.
Clinical endpoints:
-The pathological response (complete response or partial response) in the breast and axillary nodes at the definitive surgery.
-Disease free survival.
-Overall survival.
The presence of a predictive tumor gene expression profile at baseline, during and post-neoadjuvant treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I:
Severe toxicities: up to 36 months after concluding visit
Immunogenicity: Post study treatment Dose 4, evaluated using a blood sample collected at Visit 5.
Phase II:
Severe toxicities: up to 36 months after concluding visit.
Adverse events and serious adverse events: during the whole study treatment period and ending 30 days after the last study treatment administration.
Serious adverse events related to study treatment: up to 36 months after concluding visit.
Immunogenicity: At treatment start, and at specified time points during treatment depending on the treatment regimen, at concluding visit, and 6 and 12 months after.
Pathological response: at surgery
Overall survival and disease-free survival: from surgery until 6 years after the concluding visit
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.10 | Pharmacogenetic | Yes |
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 |
Immunogenicity, translational research |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 9 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
France |
Germany |
Italy |
Russian Federation |
United Kingdom |
United States |
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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
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Last visit of the last patient participating in the trial. |
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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 | 11 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 28 |
E.8.9.2 | In all countries concerned by the trial years | 11 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 28 |