| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with primary breast cancer (now in neoadjuvant or adjuvant setting). |
| Patienten mit primärem Brustkrebs in neoadjuvanter oder adjuvanter Situation. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with primary breast cancer |
| Patienten mit primärem Brustkrebs |
|
| 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 | 10006192 |
| E.1.2 | Term | Breast cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 the invasive disease-free survival (IDFS) after neo- / adjuvant chemotherapy with EnPC or dtEC-dtD in patients with early node-positive or high-risk node-negative breast cancer. |
| Vergleich des invasiv-krankheitsfreien Überlebens (IDFS) nach neo-/ adjuvanter Chemotherapie mit EnPC oder dtEC-dtD bei Patientinnen mit primärem nodal-positivem oder Hochrisiko-nodal-negativem Brustkrebs. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare overall survival (OS) between arms.
• To compare distant disease-free survival (DDFS) between arms.
• To compare locoregional relapse-free survival (LRRFS) between arms.
• To compare local relapse-free survival (LRFS) between arms.
• To compare regional relapse-free survival (RRFS) between arms.
• To compare brain metastasis free survival (overall and in the subgroup of TNBC and HER2 positive separately) between arms.
• To evaluate the compliance in arms.
• To compare the safety between arms (including time to resolve neuropathy to grade 1).
• To measure the side effects of taxanes.
• To compare treatment effects by intrinsic subtypes; and by Ki-67 between arms.
• To compare treatment effects by pN0/1, pN2 or pN3 in the adjuvant cohort.
• To compare treatment effects by nodal status c/p N0/1, c/p N2; c/p N3 in the overall cohort.
• To compare the pCR rates per arm in patients treated with neoadj. therapy.
Further secondary objectives are noted in the protocol. |
• Vergleich des Gesamtüberlebens (OS) zwischen den beiden Armen.
• Vergleich des Fernmetastasen-freien Überlebens (DDFS) zwischen den beiden Armen.
• Vergleich des lokoregionär-rückfallfreien Überlebens (LRRFS) zwischen den beiden Armen.
• Vergleich des lokal-rückfallfreien Überlebens (LRFS) zwischen den beiden Armen.
• Vergleich des regionär-rückfallfreien Überlebens (RRFS) zwischen den beiden Armen.
• Vergleich des Hirnmetastasen-freien Überlebens (insgesamt und in den Subgruppen TNBC und HER2-positiv).
• Auswertung der Compliance in den beiden Armen.
• Vergleich der Sicherheit zwischen den beiden Armen (einschließlich der Zeit des Ausheilens einer Neuropathie auf Grad 1).
• Auswertung der Nebenwirkungen der Taxan-Behandlung.
• Vergleich des Behandlungserfolgs in den Subgruppen sowie nach Ki-67 zwischen den beiden Armen.
• Vergleich des Behandlungserfolges in den adjuvanten Subgruppen pN0/1, pN2 bzw. pN3.
Further secondary objectives are noted in the protocol. |
|
| 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 |
1) Substudy biology of lymph node metastases
• To identify biomarkers in primary tumors that are associated with an increased rate of lymph node metastases.
• To explore the role of tumor cell proliferation in lymph nodes compared to primary tumors and the association of tumor cell proliferation in lymph nodes with prognosis.
• To examine the association of the presence of immune cells in the primary tumor with lymph node metastases.
• To examine differences in tumor cell properties in lymph node metastases in patients with and without distant recurrence.
2) Substudy on SNP
Primary objective: To associate the germline genotype of the patient with the treatment response in both randomization arms.
Secondary objective: To associate the germline genotype of the patient with the long term prognosis of the patients in both randomization arms. To associate the germline genotype of the patient with the molecular profile of the tumors.
3) Substudy on ovarian function
Primary objective:
To evaluate the rate of premature ovarian failure in each treatment arm 2 years after end of chemotherapy defined as no regular menstruation and FSH > 15mIE/mL and E2 < 30 (50pg/mL).
Secondary objectives:
• To evaluate the rate of menstruation prior to chemotherapy, at End of Treatment (EOT), and 6 months after EOT, 12 months after EOT, 18 months after EOT and 24 months after EOT.
• To evaluate FSH, E2, AMH prior to chemotherapy, at End of Treatment (EOT), and 6 months after EOT, 12 months after EOT, 18 months after EOT and 24 months after EOT.
• To evaluate the follicle count prior to chemotherapy, at End of Treatment (EOT), and 6 months after EOT, 12 months after EOT, 18 months after EOT and 24 months after EOT.
• To assess the menopausal symptom score prior to chemotherapy, at End of Treatment (EOT), and 6 months after EOT, 12 months after EOT, 18 months after EOT and 24 months after EOT.
• To correlate clinical outcome (DFS and OS) with the rate of amenorrhea.
4) Substudy on subcutaneous trastuzumab:
Co-primary objectives:
• To compare patient preference for i.v. injection versus s.c. injection of trastuzumab for patients receiving injections into the thigh versus the abdominal wall.
• To assess the pharmacokinetic profile of s.c. injection of trastuzumab into the thigh versus the abdominal wall
Secondary objectives:
• Safety and tolerability according to administration site.
• Validation of factors potentially influencing patient preference of s.c. trastuzumab as detected in the PrefHer study (MO22982). |
|
| E.3 | Principal inclusion criteria |
1. Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
2. Histologically confirmed unilateral or bilateral primary carcinoma of the breast.
3. Age at diagnosis at least 18 years, female, and biologically not older than 65 years (but in any case not older than 70 years).
4. In case of adjuvant therapy: Adequate surgical treatment with histological complete resection (R0) of the invasive breast tumor. Choice of axilla surgery is up to the participating site.
5. Centrally confirmed ER/PgR/HER2 and Ki-67 status detected on surgical removed tissue (for adjuvant patients) or from core biopsy (for neoadjuvant patients). ER/PR positive is defined as ≥ 1% stained cells and HER2 positive is defined as IHC 3+ in > 10% immunoreactive cells or FISH (or equivalent test) ratio ≥ 2.0. Formalin-fixed, paraffin-embedded (FFPE) breast tissue has to be sent to the Institute of Pathology at the Charité Berlin prior to randomization.
6. High risk breast cancer as defined as:
• HER2 positive or triple-negative tumors irrespective of nodal status or
• Luminal B-like tumors (ER and/or PgR positive, HER2 negative, Ki-67 > 20%) with involved lymph nodes or
• 4 or more involved lymph nodes.
7. Complete staging work-up within 3 months prior to randomization. All patients must have performed bilateral mammography, breast ultrasound, breast MRT (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRT and bone scan. In case of positive bone scan, bone X-ray (or CT or MRT) is mandatory. Other tests may be performed as clinically indicated.
8. Karnofsky Performance status index ≥ 80%.
9. Estimated life expectancy of at least 10 years irrespective of the diagnosis of breast cancer.
10. Confirmed normal cardiac function by ECG and cardiac ultrasound (LVEF or shortening fraction) within 2 weeks prior to randomization. LVEF must be above 55%.
11. Laboratory requirements:
Hematology
• Absolute neutrophil count (ANC) ≥ 2.0 x 109/L and
• Platelets ≥ 100 x 109/L and
• Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L).
Hepatic function
• Total bilirubin ≤ 1.5x above upper normal limits (UNL) and
• ASAT (SGOT) and ALAT (SGPT) ≤ 1.5x UNL and
• Alkaline phosphatase ≤ 2.5x UNL.
Renal function
• Creatinine ≤ 1.25 UNL,
• Creatinine Clearance > 30mL/min (if creatinine is above UNL, according to Cockroft-Gault).
12. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
13. Complete baseline documentation must be submitted via MedCODES and approved by GBG Forschungs GmbH.
14. Patients must be available and compliant for central diagnostics, treatment and follow-up. |
1. Schriftliche Einwilligungserklärung für alle Studienmaßnahmen vor dem Beginn der studienspezifischen Maßnahmen (gemäß lokaler regulatorischer Erfordernisse).
2. Histologisch bestätigter unilateraler oder bilateraler primärer Brustkrebs.
3. Weiblich und Alter bei Diagnose mindestens 18 Jahre und biologisch nicht älter als 65 Jahre (aber nicht älter als 70 Jahre).
4. Bei adjuvanten Patientinnen: Adäquate operative Behandlung mit histologisch kompletter Resektion (R0) des invasiven Brustkrebses. Die Wahl der Axilla-Operation obliegt dem Zentrum.
5. Zentrale Bestimmung von ER, PgR und HER2-Rezeptor sowie des Ki-67 Status am OP-Resektat (bei adjuvanten Patientinnen) bzw. an der Stanzbiopsie (bei neoadjuvanten Patientinnen). ER/PgR-positiv ist definiert als ≥ 1% gefärbte Zellen und HER2-positiv ist definiert als IHC 3+ mit einem validierten Test in > 10% der immunreaktiven Zellen oder FISH (bzw. Äquivalent)-Ratio ≥ 2,0. Formalin-fixiertes und in Paraffin eingebettetes (FFPE)-Brustgewebe muss vor der Randomisation an die GAIN-2 Zentralpathologie (Charité Berlin) gesendet werden.
6. Hochrisiko-Brustkrebs ist definiert als:
• HER2-positiver oder triple-negativer Tumor unabhängig vom Nodalstatus oder
• Luminal B-Tumor (ER und/oder PgR-positiv, HER2-negativ, Ki-67 > 20%) mit befallenen Lymphknoten oder
• mindestens 4 befallene Lymphknoten.
7. Komplette Staging-Untersuchungen innerhalb von 3 Monaten vor der Randomisation. Für alle Patientinnen müssen bilaterale Mammographie, Brustultraschall, Brust-MRT (optional), Röntgen-Thorax (PA und lateral), Ultraschall des Abdomens oder CT-Scan oder MRT und Knochenscan (falls ≥ 3 Lymphknoten befallen sind oder falls symptomatisch) durchgeführt werden. Im Falle eines positiven Knochenscans ist eine Röntgenaufnahme der Knochen (oder ein CT bzw. MRT) obligat.
Falls klinisch indiziert, können weitere Untersuchungen durchgeführt werden.
8. Karnofsky-Index ≥ 80%.
9. Voraussichtliche Lebenserwartung von mindestens 10 Jahren unab¬hängig von der Brustkrebsdiagnose.
10. Normale Herzfunktion muss durch EKG und Herz-Ultraschall (LVEF oder Shortening Fraction) innerhalb von zwei Wochen vor Randomisation bestätigt werden (LVEF > 55%).
11. Laborwerte:
Hämatologie
• Absolute Neutrophilen-Anzahl (ANC) ≥ 2,0 x 109/l und
• Blutplättchen ≥ 100 x 109/l und
• Hämoglobin ≥ 10 g/dl (≥ 6,2 mmol/l).
Leberfunktion
• Gesamt-Bilirubin ≤ 1,5x UNL und
• ASAT (SGOT) und ALAT (SGPT) ≤ 1,5x UNL und
• Alkalische Phosphatase ≤ 2,5x UNL.
Nierenfunktion
• Kreatinin ≤ 1,25x obere Normgrenze (UNL),
• Kreatinin-Clearance > 30 ml/min (falls Kreatinin gemäß Cockroft-Gault über dem UNL ist).
12. Negativer Schwangerschaftstest (Urin oder Serum) innerhalb von 14 Tagen vor Randomisation bei allen Frauen im gebärfähigen Alter.
13. Die komplett dokumentierte Baseline muss via MedCODES erfolgt und von der GBG Forschungs GmbH akzeptiert sein.
14. Die Patientinnen müssen sich zur zentralen Diagnostik, zur Behandlung und zur Teilnahme an der GBG-Patientinnenselbstauskunft bereit erklärt haben. |
|
| E.4 | Principal exclusion criteria |
1. Patients with Luminal A-like tumors (ER and or PgR positive, HER2 negative and Ki-67 ≤ 20%) and
• if neoadjuvant: < cN2 or < pN2(sn).
• if adjuvant: < 4 involved lymph nodes.
2. Non-operable breast cancer.
3. In case of adjuvant therapy: time since axillary dissection or SLNB > 3 months (optimal < 1 month).
4. Previous and already (neoadjuvant or adjuvant) treated invasive breast carcinoma.
5. Previous malignant disease being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
6. Known or suspected congestive heart failure (> NYHA I) and/or coronary heart disease, angina pectoris requiring anti-anginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP > 160/90mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
7. Evidence for infection including wound infections, HIV, hepatitis.
8. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
9. Pre-existing motor or sensory neuropathy of a severity ≥ grade 1 by NCI-CTCAE version 4.0.
10. Other severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study.
11. Previous or concurrent treatment with:
• concurrent chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (≤ 10mg methylprednisolone or equivalent) except inhalative corticoids.
• concurrent sex hormones. Prior treatment must be stopped before study entry.
• concurrent treatment with any investigational, not marketed drug within 30 days prior to study entry.
• previous or concurrent anti-cancer therapy for any reason.
12. Absolute contraindications for the use of corticosteroids.
13. Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
14. Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol. |
1. Patientinnen mit Luminal A-Tumoren (ER und/oder PgR-positiv, HER2-negativ und Ki-67 ≤ 20%) und
• bei neoadjuvanten Patientinnen: cN2 oder pN2(sn),
• bei adjuvanten Patientinnen: weniger als 4 befallene Lymphknoten.
2. Nicht operabler Brustkrebs.
3. Bei adjuvanten Patientinnen: Zustand nach axillärer Dissektion oder SLNB > 3 Monate (optimal < 1 Monat).
4. Vorheriger und bereits (neoadjuvant oder adjuvant) behandelter invasiver Brustkrebs.
5. Frühere Krebserkrankung mit einem krankheitsfreien Intervall von weniger als 5 Jahren (ausgenommen CIS der Cervix und nicht-melanomatöses Karzinom der Haut).
6. Bekannte oder vermutete kongestive Herzinsuffizienz (> NYHA I) und/oder koronare Herzerkrankung, Angina pectoris mit Notwendigkeit einer antianginösen Medikation, Z.n. Herzinfarkt, Hinweis auf einen transmuralen Infarkt im EKG, unkontrollierter oder unzureichend kontrollierter Bluthochdruck (z.B. > 160 / 90 mm Hg unter Behandlung mit zwei Blutdrucksenkern), Arrhythmien, die eine dauerhafte Therapie verlangen, und klinisch signifikante Herzklappenerkrankung.
7. Infektion (inklusive Wundinfektion, HIV und Hepatitis).
8. Signifikante neurologische oder psychiatrische Erkrankung inklusive einer Psychose, einer Demenz oder einer Epilepsie, die das Verstehen der Einwilligung oder die Einwilligung in die Studienteilnahme verhindern würde.
9. Bereits existierende motorische oder sensorische Neuropathie Grad ≥ 1 nach NCI-CTCAE Kriterien (Version 4).
10. Weitere schwere oder relevante Begleiterkrankungen, die einer Gabe zytotoxischer Präparate oder einer Studienteilnahme verhindern würden.
11. Vorherige oder
• gleichzeitige Langzeitbehandlung mit Kortikosteroiden, es sei denn mit Beginn > 6 Monaten vor Studieneintritt und in geringer Dosierung (≤ 10 mg Methylprednisolon oder Äquivalent). Inhalative Gluco-corticoide sind erlaubt.
• gleichzeitige Hormonbehandlung. Gabe muss vor Studieneintritt beendet werden.
• gleichzeitige Behandlung mit einer nicht-zugelassenen Prüfsubstanz oder in den letzten 30 Tagen vor Studieneintritt.
• frühere oder gleichzeitige Antikrebstherapie.
12. Absolute Kontraindikation für Kortikosteroide.
13. Schwangere oder stillende Patientinnen. Patientinnen im gebärfähigen Alter müssen eine adäquate nicht-hormonelle Kontrazeption (Barrieremethode, intrauterine Methode, Sterilisierung) während der Studientherapie anwenden.
14. Bekannte Überempfindlichkeit gegen eine der in dieser Studie verwendeten Medikamente. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Invasive Disease Free Survival (DDFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A time driven final efficacy analysis will be performed 45 months after end of accrual. At that time it is expected that 797 events have occurred. |
|
| E.5.2 | Secondary end point(s) |
LRRFS, RRFS, LRFS, IDFS and OS are defined as the time period between randomization and first event and will be analyzed after the end of the study by referring to data from GBG patient’s registry.
Curves will be estimated using the Kaplan-Meier method, based on the ITT population, and compared with a two-sided log-rank test. Univariate and multivariate Cox-proportional hazards model will be used to adjust hazard ratios for stratification factor and the above defined covariates and pCR
Tolerability and Safety: Descriptive statistics for the 2 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped. The reason for termination includes aspects of efficacy (e.g. termination due to tumor progression), safety (e.g. termination due to adverse events) and compliance (e.g. termination due to patient's withdrawal of consent). Reasons for premature termination will be categorized according to the main reason and will be presented in frequency tables. Safety by toxicity grades is defined by the NCI-CTCAE v4.0. The quality of life will be assessed using EORTC QLC-C30 and FACT-Taxane.
Translational research: Exploratory analyses will be performed to identify possible relationships between biomarkers and survival. Patients with missing biomarker data will not be included in the respective analysis.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
A time driven final efficacy analysis will be performed 45 months after end of accrual. At that time it is expected that 797 events have occurred.
Two safety interim analyses are planned after 200 and 900 patients have completed chemotherapy
There is no timepoint for the evaluation of the translational research. |
|
| 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 | Yes |
| 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) | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| dosisdicht nebenwirkungsangepaßt dtEC-dtD |
| dose dense tailored dtEC-dtD |
|
| 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 | 130 |
| 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
|
| End of trial is after the last cycle of chemotherapy (or last dose of subcutaneous trastuzumab for patient in this substudy only) |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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