| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with HER2-positive and hormone-receptor positive metastatic breast cancer |
| Patienten mit HER2-positivem und hormonrezeptorpositivem, metastasierendem Brustkrebs |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with metastatic breast cancer, whose cancer cells have HER2 and hormone receptor proteins on their surface |
|
| 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 |
Primary objective (before amendment)
Assessment of safety of dual HER2-targeted ther. with Herceptin® (trastuzumab) and Perjeta® (pertuzumab) + endocrine ther. compared to dual HER2-targeted ther. with Herceptin® (trastuzumab) and Perjeta® (pertuzumab) + chemother. in patients with HER2-pos., hormone-receptor pos. metastatic breast cancer. Safety: Proportion of patients experiencing any AE (as defined by the modified AE score) during treatment period.
New primary objective
Assessment of tolerability of dual HER2-targeted ther. with Herceptin® and Perjeta® + Kisquali® and standard endocrine ther. compared to dual HER2-targeted ther. with Herceptin® and Perjeta® + chemother. (followed by endocrine therapy + ribociclib in combination with trastuzumab and pertuzumab as maintenance ther.) in patients with HER2-pos., hormone-receptor pos. metastatic breast cancer. Tolerability: Proportion of patients experiencing any AE as defined by the modified AE score during treatment period. |
Primärer Studienendpunkt (vor Amendment)
Evaluation Verträglichkeit der dualen HER2-gerichteten Ther. (Trastuzumab + Pertuzumab) in Komb. mit einer endokrinen Ther. vs der dualen HER2-gerichteten Ther. in Komb. mit einer Chemother. bei Pat. mit HER2-pos., hormonrezeptorpos. metastasiertem Brustkrebs. Sicherheit/Verträglichkeit: Anteil an Pat. mit UEs (AEs) während des Behandlungszeitraums (Definition nach dem modifizierten „AE score“).
Neuer primärer Studienendpunkt
Vergleich der Verträglichkeit der dualen HER2-gerichteten Therapie (Trastuzumab plus Pertuzumab) in Kombination mit Ribociclib und endokriner Therapie versus der dualen HER2-gerichteten Therapie in Kombination mit einer Chemotherapie (gefolgt von einer Erhaltungstherapie mit Trastuzumab und Pertuzumab plus Ribociclib und endokrine Therapie). Sicherheit/Verträglichkeit: Anzahl an UEs (AEs) während des Behandlungszeitraums. |
|
| E.2.2 | Secondary objectives of the trial |
-Tolerability (proportion of pat. with any AE as def. by the mod. AE score during treatment period) of dual HER2-targ. ther. with Herceptin®and Perjeta® + endocrine ther. compared to + chemother. for:
--> pat. randomized before add. of ribociclib
--> pat. randomized before or after the add. of ribociclib
-primary anal. will be repeated as secondary explorative anal. with specific mod. AE score for the ribociclib cohort
-quality-adjusted survival (Q-TWiST method) + comp. between both treatment arms (TA)
-Comp. efficacy of both TA (overall resp. rate, disease cont. r., prog.-free surv., overall surv.) acc. to RECIST v1.1
-incidence of CNS metast. (by CT or MRI according to RECIST v1.1)
-eval. of EORTC QLQ-C30 + EORTC QLQ-BR23 questionnaires
-presence and number of CTCs in peripheral blood + value of CTCs (therapy success)
-endocrine responsiveness score (ERS) of CTCs + value of ERS (therapy success)
-toxicity of both TA
- safety of the study treatments (all grades, all events) |
-Vergleich Verträglichkeit (Anzahl UEs, mod. "AE score") duale HER2-gerichtete Ther. (Trastuzumab + Pertuzumab) + endokrine Ther. vs + Chemotherapie
--> bei Pat. die vor Amend1 in die Studie eingeschlossen wurden
--> bei allen in die Studie eingeschlossenen Pat.
-Primäre Analyse für Ribociclibkohorte (mod. "AE score" beinhaltet zus. Übelkeit, Erbrechen, Durchfall und Stomatitis ab Grad 2)
-quality-adjusted survival (Q-TWiST-Methode), Vergleich der Behandlungsarmen (BA)
-Unterschiede der BA (Allgemeinen Ansprechrate, klin. Erfolgsrate,Progressionsfreies Überleben, Gesamtüberleben) entspr. RECIST v1.1
-Inzidenz ZNS-Metastasen(mittels CT oder MRT nach RECIST Version 1.1)
-Auswert. EORTC QLQ-C30 und EORTC QLQ-BR23 Fragebögen
-Vorkommen und Anzahl der CTCs im peripheren Blut (Therapieansprechen)
-endocrine responsiveness score ERS der CTCs(Therapieansprechen)
-Toxizitätsanalyse und Vergleich der Toxizität beider BA
-Sicherheit und Verträglichkeit der Studienmedikation |
|
| 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 |
Translational research
Within the DETECT V/CHEVENDO trial, prevalence and number of CTCs in the peripheral blood will be determined parallel to tumor evaluation at baseline (i.e. before the start of treatment), 6 weeks after randomization, and after the 12-month study treatment period or at the time of progression, whatever comes first (if possible in correlation with Re-Staging, e.g. CT-Scan).
In addition to the quantitative assessment of CTCs, the expression of the markers estrogen receptor (ER) and HER2 on isolated CTCs will be determined using the CellSearch® system (as described by Paoletti et al. 2011). Based on the level of expression for these markers and the proportion of CTCs showing such marker expression, an endocrine responsiveness score (ERS) will be calculated and its predictive value for assessing therapy efficacy will be determined. The generation of an ERS is based on the idea that high expression levels of ER are predictive of responsiveness to endocrine therapy, while high HER2- expression levels are indicative of resistance to endocrine therapy. The aim of this project is to create an ERS that allows to predict the responsiveness of patients with hormone-receptor positive and HER2-positive metastatic breast cancer to a combined endocrine and HER2-targeted therapy. |
|
| E.3 | Principal inclusion criteria |
Patients will be included in the study only if they meet all the following criteria:
-Signed, written informed consent in study participation
-The primary tumor and/or biopsies from metastatic sites or locoregional recurrences have been confirmed as HER2-positive (FISH-positive or IHC 3+) and hormone receptor positive breast cancer by histopathology according to local testing
-Metastatic breast cancer or locally advanced BC, which cannot be treated by surgery or radiotherapy only
-Pre- and postmenopausal women are allowed
-No more than two prior chemotherapies for metastatic disease
-No more than two prior anti-HER2 therapies for metastatic disease
-Pertuzumab retreatment is allowed if prior adjuvant /neoadjuvant pertuzumab treatment was finished 12 months before
-At least one measurable lesion assessable using standard techniques by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)
-Tumor evaluation according to RECIST version 1.1 has been performed within 4 weeks before randomization based on local assessment
-Age ≥ 18 years
-Standard 12-lead ECG values assessed by the local laboratory:
--QTcF interval at screening < 450 msec (using Fridericia’s correction)
--Resting heart rate 50-90 bpm
-Left ventricular cardiac ejection fraction (LVEF) ≥ 50% at baseline (as measured by echocardiogram)
-ECOG Score ≤ 2
-Adequate organ function within 14 days before randomization, evidenced by the following laboratory results below:
--absolute neutrophil count ≥ 1500 cells/μL,
--platelet count ≥ 100000 cells/μL,
--hemoglobin ≥ 9 g/dL,
--ALT (SGPT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
--AST (SGOT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
--bilirubin ≤ 1.5 × ULN (with the exception of Gilbert’s syndrome)
--creatinine ≤ 2.0 mg/dl or 177μmol/L
--INR ≤ 1,5
-Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplemets before the first dose of study medication:
--Sodium
--Potassium
--Total calcium
-In case of patients of child bearing potential:
Negative serum pregnancy test at baseline (within 7 days prior to randomization) and agreement to remain abstinent (if it is in line with the preferred and usual lifestyle) or use single or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study treatment. |
Patientinnen können nur eingeschlossen werden, wenn alle der folgenden Kriterien erfüllt werden:
-Schriftliches Einverständnis zur Studienteilnahme
-Bestimmung des HER2-Status des primären Mammakarzinoms und/oder einer Metastase mit HER2-Positivität der Gewebsproben, d.h. Immunhistochmie 3+ oder Fluoreszenz in situ Hybridisierung (FISH) positiv sowie histopathologisch bestätigter Hormonrezeptorpositivität
-Metastasiertes Mammakarzinom, das einer Operation oder Strahlentherapie alleine nicht zugänglich ist
-Nicht mehr als 2 vorrangegangenen Chemotherapielinien in der metastasierten Situation
-Prä- oder postmenapausaler Status
-Mindestens eine nach RECIST auswertbare metastatische Läsion, entsprechend den RECIST Leitlinien Version 1.1., basierend auf lokaler Beuerteilung.
-Tumorevaluation nach RECIST Version 1.1 innerhalb von 4 Wochen vor Studienrandomisierung
-Alter ≥ 18 Jahre
-12-Kanal-EKG:
--QTcF Interval bei der Einschlussvisite < 450 msec
--Ruheherzfrequenz 50-90 s/min
-Echokardiografischer Nachweis einer linksventrikulären Ejaktionsfraktion (LVEF) ≥ 50% zu Studienbeginn
-ECOG Score ≤ 2
-Adäquate Knochenmarksreserve und Organfunktion 14 Tage vor dem Zeitpunkt der Rekrutierung, durch folgende Laborparameter bestätigt:
--Absolute Neutrophile ≥ 1500/μL
--Thrombozyten ≥ 100000/μL,
--Hämoglobin ≥ 9 g/dL
--ALT (SGPT) ≤ 2.0 × ULN (≤ 3.0 × ULN bei Lebermetastasierung)
--AST (SGOT) ≤ 2.0 × ULN (≤ 3.0 × ULN bei Lebermetastasierung)
--Bilirubin (gesamt) ≤ 1.5 × ULN (Ausnahme Gilbert’s Syndrom)
--Kreatinin ≤ 2.0 mg/dl oder 177μmol/L
--INR ≤ 1,5
-Unauffällige Laborwerte für: Natrium, Kalium, Kalzium (Ribociclib-Therapie)
-Bei Patientinnen im gebärfähigen Alter gilt: Negativer Schwangerschaftstest innerhalb von 7 Tagen vor Randomisierung und sichere Kontrazeption (d.h. einfache oder kombinierte nicht-hormonelle Kontrazeption mit einer Versagerquote < 1% oder komplette sexuelle Abstinenz) während der Behandlungsdauer bis einschließlich 7 Monate nach Einnahmeende der Studienmedikation. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study for any of the following reasons:
-History of hypersensitivity reactions attributed to trastuzumab, pertuzumab, ribociclib or to other components of drug formulation
-Mandatory need for cytostatic treatment at time of study entry based on clinical judgment and national/international treatment guidelines
-Known CNS metastases
-Any concurrent severe, uncontrolled systemic disease, social or psychiatric condition that might interfere with the planned treatment and with the patient’s adherence to the protocol
-Progression on prior Pertuzumab therapy
-Treatment with Pertuzumab within the last 12 months
-Prior treatment with any mTOR- or CDK4/6-inhibitor
-Treatment with any other investigational agents during trial
-Known hypersensitivity to lecithin (soya) or peanuts
-Life expectancy < 6 months
-Patients with pre-existing grade ≥2 peripheral neuropathy are excluded from taxane-based chemotherapy
-History of serious cardiac disease, including but not confined to:
--history of documented heart failure or systolic dysfunction (LVEF < 50%)
--high-risk uncontrolled arrhythmias i.e., atrial tachycardia with a heart rate ≥100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block) - angina pectoris requiring anti-anginal medication
--clinically significant valvular heart disease
--evidence of transmural infarction on ECG - poorly controlled hypertension (e.g., systolic >180 mm Hg or diastolic >100 mm Hg)
--any other cardiac condition, which in the opinion of the treating physician would make this protocol unreasonably hazardous for the patient
-Dyspnea at rest or other diseases that require continuous oxygen therapy
-Patients with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications
-Patients with known infection with HIV, hepatitis B virus, or hepatitis C virus
-Male patients
-Pregnant, lactating or women of childbearing potential without a negative pregnancy test (serum) within 7 days prior to randomization, irrespective of the method of contraception used
-Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent
-Participation in another clinical study within the 30 days before registration
-Legal incapacity or limited legal capacity |
Patientinnen können nicht in die Studie eingeschlossen werden, wenn einer der folgenden Punkte zutrifft:
-Anamnestisch bekannte Überempfindlichkeit gegenüber Trastuzumab, Pertuzumab oder Ribociclib oder chemisch verwandten Bestandteilen bzw. weiteren Bestandteilen der Medikation
-Vortherapie mit mTOR- oder CDK4/6-Inhibotoren.
-Zwingende Indikation zur Durchführung einer Chemotherapie
-Polyneuropathie (PNP) ≥ 2 für Taxantherapie
-ZNS Metastasen
-Vorliegen von Erkrankungen oder besonderen sozialen oder psychiatrischen Bedingung, die die adäquate Einschätzung oder Evaluation der Studiendaten gefährden oder die Einhaltung des Studienprotokolls stören oder nach Ansicht des behandelnden Arztes zu einer unverhältnismäßigen Gefährdung der Patientin bei Studienteilnahme führen würde
-Progress unter Pertuzumab Therapie
-Behandlung mit Pertuzumab innerhalb der letzten 12 Monate
-Behandlung mit anderen Prüfsubstanzen während der Studie
-Unverträglichkeit gegen Soyalecithin und Erdnüsse
-Lebenserwartung < 6 Monate
-Manifeste kardiale Vorerkrankungen, einschließlich:
--Symptomatische Herzinsuffizenz oder LVEF < 50 %
--Therapiebedürftige oder klinisch relevante Arrhythmien, z.B. Vorhoftachykardien mit einem Ruhepuls ≥100/min, relevante ventrikuläre Arrhythmien (ventrikuläre Tachykardie), höhergradiger AV-Block (2° AV-Block Typ 2 [Mobitz 2] oder 3° AV-Block)
--behandlungsbedürftige Angina Pectoris
--klinisch relevante Herzklappenerkrankungen
--Nachweis einer transmuralen Infarzierung im EKG
--schlecht kontrollierte art. Hypertonie (z.B. systolisch >180 mm Hg oder diastolisch >100 mm Hg)
--jede andere kardiale Begleiterkrankung, die nach Ansicht des behandelnden Arztes zu einer unverhältnismäßigen Gefährdung der Patientin bei Studienteilnahme führen würde
-Ruhedyspnoe oder andere Erkrankungen, die eine kontinuierliche Sauerstofftherapie erfordern
-Schlecht eingestellter Diabetes mellitus oder Nachweis einer klinisch relevanten diabetischen Vaskulopathie
-Bekannte HIV-, Hepatitis B- oder Hepatitis C-Erkrankung
-Männlicher Patient
-Schwangerschaft oder Stillzeit sowie gebärfähige Patientinnen ohne negativen Schwangerschaftstest in den letzten 7 Tagen vor Studienrandomisierung oder mit unsicheren Verhütungsmethoden
-Medizinische oder psychologische Gegebenheiten, die das Verständnis oder die Wiedergabe der informierten Einwilligung verhindern oder die Beendigung der Studie stören. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is defined as the proportion of patients that experience any adverse events (as defined by the modified adverse event score and assessed based on NCI CTCAE Version 4.03) during the treatment period.
The modified adverse event score includes all adverse events grade 3 or higher with the exception of neutropenia, which is only included if rated grade 4, and alopecia, rash, peripheral neuropathy and hand-foot syndrome, all of which are included if rated grade 2 or higher.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| every 9 weeks during treatment phase |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints are
1. Specific modified adverse event score including nausea, vomiting, diarrhea and stomatitis grade 2 (in addition to the adverse events included in the modified adverse event score as used for the primary analysis)
2. Quality-adjusted survival (as assessed by the Q-TWiST method), with the utility scores for the different health states being prospectively determined in the clinical trial subjects based on the EORTC QOL C30 questionnaire
3. Progression free survival (PFS): Time interval from randomization until progressive disease (PD) or death from any cause, whichever comes first (to be assessed by investigator)
4. Overall response rate (ORR): Rate of complete (CR) and partial responses (PR) in patients with whom target lesions were defined
5. Clinical benefit rate: Rate of patients who were assessed PR or CR or who had stable disease (SD) for at least 6 months
6. Overall survival (OS): Time from randomization until death of any cause
7. Quality of life (QoL): As assessed by evaluation of the EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires
8. Prevalence of CTCs at baseline and at different time points after the start of palliative treatment including the time of progression (as assessed using the CellSearch® System)
9. Endocrine responsiveness score (ERS) of CTCs at baseline and at different time points after the start of palliative treatment including the time of progression
(CR, PR, SD, and PD are defined according to the RECIST Version 1.1 criteria) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| every 9 weeks during treatment phase |
|
| 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) | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 120 |
| 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
|
| LPLV (last patient last visit) in the follow-up-period |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
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