Etude : PENELOPE B / GBG78 / BIG 1-13 / NSABP-B-54-I



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Acronyme
Nom
Traitement
Type d'étude
MÀJ
Présentation de l'étude
Acronyme : PENELOPE B

Nom : GBG78 / BIG 1-13 / NSABP-B-54-I

Traitement : Adjuvant / Métastasique ou localement avancé

Type d'étude : Hors ciblage moléculaire

Dernière MÀJ : 16/07/2019
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : A Study of Palbociclib in Addition to Standard Endocrine Treatment in Hormone Receptor Positive Her2 Normal Patients With Residual Disease After Neoadjuvant Chemotherapy and Surgery

Spécialité : Seins, organes génitaux de la femme
Localisation : C50 - Tumeur maligne du sein
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : Primary Outcome Measures:
- Invasive disease free survival (iDFS) for palbociclib vs. placebo in patients with high CPS-EG score after neoadjuvant chemotherapy receiving standard adjuvant endocrine therapy for HR-positive/HER2-normal primary breast cancer. [ Time Frame: Time-to-Event Outcome measure. Final analysis on the primary endpoint and secondary efficacy endpoints (except for OS) Analysis will be conducted when 255 events observed. Assessed until approx. Dec 2020. ]
Invasive disease-free survival (iDFS) is defined according to Hudis (J Clin Oncol 2007) as the time period between randomization and first event (ipsi- or contralateral invasive in-breast or loco-regional recurrence, distant recurrence, death from breast cancer, death from non-breast cancer cause, death from unknown cause, invasive contralateral breast cancer, second primary invasive cancer (non-breast)).
Two interim efficacy analyses will be performed in the study. First interim analysis: Safety, early stopping Second interim analysis: Safety, early stopping, sample size adjustment


Secondary Outcome Measures:
- iDFS excluding second non-breast cancers [ Time Frame: Time-to-Event Outcome Measure up to 71 months ]
Invasive disease-free survival (iDFS) is defined according to Hudis (J Clin Oncol 2007) as the time period between randomization and first event.

- distant disease free survival (DDFS) [ Time Frame: Time-to-Event Outcome Measure up to 71 months ]
Distant disease free survival (DDFS) is defined as the time period between randomization and diagnosis of first distant breast cancer recurrences.

- overall survival (OS) [ Time Frame: Time-to-Event Outcome Measure up to 71 months - and post study ]
Overall survival (OS) is defined as the time period between randomization and death of any cause. An interim OS analysis will be conducted at the time of final iDFS analysis and final OS analysis will be conducted at a later time. In addition Relapse and Mortality data will be collected post study.

- iDFS per treatment group in patients with luminal-B tumors (as determined by e.g. PAM50 or any other commercially available test at the time of analysis) [ Time Frame: Time-to-Event Outcome Measure up to 71 months ]
see above for event definition

- compliance and safety according to NCI-CTCAE Version 4.0 [ Time Frame: 2019 and with interim analysis on 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.

- patients reported outcomes EORTC QLQ C30, • EORTC QLQ BR-23, • EORTC QLQ FA-13 Fatigue, • GAD7 patient self-rating mood scale [ Time Frame: Change Outcome up to 71 months ]
Screening, Cycle 1, 3, 5, 7, 9, 11, End of treatment and thereafter every 6 months until 233 events are observed

- quality-adjusted life years (QALY), health economic outcomes EQ-5D [ Time Frame: Change Outcome Measure up to 71 months ]
Screening, Cycle 1, 3, 5, 7, 9, 11, End of treatment and thereafter every 6 months

- Area under the Curve (AUC), Cmax [ Time Frame: pre-dose, 2, 4, 6, 8, and 24 hours ]
Drug-drug interactions (DDI) potential for palbociclib - endocrine combination therapy
In the first 24 patients receiving tamoxifen or anastrozol together with palbociclib/placebo plasma PK samples will be drawn on pre-dose and 2, 4, 6, 8, and 24 hours post-dose for DDI assessment.
In the first 24 patients receiving gosereline and tamoxifen together with palbociclib/placebo, plasma PK samples will be drawn on Cycle 2 and Cycle 3 Days 1 and Day 14 pre-dose for DDI assessment.
In addition in the first 24 patients receiving gosereline and tamoxifen together with palbociclib/placebo, plasma PK samples will be drawn on Cycle 2 and Cycle 3 Days 1 and Day 14 pre-dose for DDI assessment.

- correlations between exposure and efficacy and/or safety findings [ Time Frame: Pharmacokinetic Outcomes Measure mit Cmax and AUC ]
Trough concentrations of PD-0332991 will be collected pre-dose on Day 14 of cycle 1 and 2 for all patients (including letrozol taking patients).

Phase : III

Stade : NA

2, 3, 4
Critères d'inclusion
Critères de non-inclusion
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 1. Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements.
2. Willingness and ability to provide archived formalin fixed paraffin embedded tissue block or a partial block from surgery after neoadjuvant chemotherapy and from core-biopsy before start of neoadjuvant chemotherapy, which will be used for centralized retrospective confirmation of hormone- and HER2-status and to evaluate correlation between genes, proteins, and mRNAs relevant to the endocrine and cell cycle pathways and sensitivity/resistance to the investigational agents. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.
3. Histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast.
4. Residual invasive disease post-neoadjuvant either in the breast or as residual nodal invasion.
5. Centrally confirmed hormone-receptor-positive (≥1% ER and/or PR positive stained cells) and HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH) ratio) <2.0 status) assessed preferably on tissue from post-neoadjuvant residual invasive disease or core biopsy of the breast, or if no other tissue is available the residual tumor of the lymphnode can be assessed.
In case of bilateral breast cancer hormonreceptor positivity and HER2-normal status has to be centrally confirmed for both sides.
6. Centrally assessed Ki-67, pRB, and Cyclin D1 status assessed preferably on post-neoadjuvant residual invasive disease of the breast, or if not possible, of residual nodal invasion or core biopsy. In case of bilateral breast cancer, tumor tissue of both sides needs to be assessable.
7. Patients must have received neoadjuvant chemotherapy of at least 16 weeks. This period must include 6 weeks of a taxane -containing neoadjuvant therapy (Exception: For patients with progressive disease that occurred after at least 6 weeks of taxane-containing neoadjuvant treatment, a total treatment period of less than 16 weeks is also eligible).
8. Adequate surgical treatment including resection of all clinically evident disease and ipsilateral axillary lymph node dissection. Histologically complete resection (R0) of the invasive and ductal in situ tumor is required in case of breast conserving surgery as the final treatment. No evidence of gross residual disease (R2) is required after total mastectomy (R1 resection is acceptable). Axillary dissection is not required in patients with a negative sentinel-node biopsy before (pN0, pN+(mic)) or after (ypN0, ypN+(mic) neoadjuvant chemotherapy.
9. Less than 16 weeks interval since the date of final surgery or less than 10 weeks from completing radiotherapy (whichever occurs last) at date of randomization.
10. Completion of adjuvant radiotherapy according to standard guidelines (e.g. AGO Mamma, NCCN) is strongly recommended. If radiotherapy is not performed the reason for this needs to be documented in the eCRF.
11. No clinical evidence for locoregional or distant relapse during or after preoperative chemotherapy. Local progression during chemotherapy is not an exclusion criterion.
12. A clinical-pathologic stage - estrogen/grade (CPS-EG) score of ≥3, or score 2 if nodal status at surgery is ypN+, calculated using local estrogen receptor status and grade assessed on either core biopsies taken before start of neoadjuvant treatment or surgical specimen (see chapter 21.1).
13. Age at diagnosis at least 18 years.
14. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (see Appendix 21.2).
15. Resolution of all acute toxic effects of prior anti cancer therapy or surgical procedures to NCI CTCAE version 4.0 Grade ≤1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion).
16. Estimated life expectancy of at least 5 years irrespective of the diagnosis of breast cancer.
17. The patient must be accessible for scheduled visits, treatment and follow-up. Patients registered on this trial must be treated at the participating center which could be the Principal or a Co- investigator's site.

Critères de non-inclusion : 1. Known severe hypersensitivity reactions to compounds similar to palbociclib or palbociclib/placebo excipients or to endocrine treatments.
2. Inadequate organ function immediate prior to randomization including: Hemoglobin <10g/dL (100g/L); ANC < 2000/mm³ (< 2.0 x 109/L); Platelets <100,000/mm³ (< 100 x 109/L); AST or ALT >1.5 x upper limit of normal (ULN); alkaline phosphatase > 2.5 x ULN, total serum bilirubin > 1.25 x ULN; serum creatinine >1.25 x ULN or estimated creatinine clearance < 60 mL/min as calculated using the method standard for the institution; severe and relevant co-morbidity that would interact with the participation in the study
3. Evidence for infection including wound infections, Human Immunodeficiency Virus (HIV) or any type of Hepatitis
4. QTc >480 msec
5. Uncontrolled electrolyte disorders (eg, hypocalcemia, hypokalemia, hypo¬magnesemia).
6. Any of the following within 6 months of randomization: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
7. Active inflammatory bowel disease or chronic diarrhea, short bowel syndrome, or any upper gastrointestinal surgery including gastric resection.
8. Prior malignancy (including invasive or ductal in-situ breast cancer) within 5 years prior to randomization, except curatively treated basal cell carcinoma of the skin and carcinoma in situ of the cervix.
9. Current severe acute or uncontrolled chronic systemic disease (e.g. diabetes mellitus) or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
10. Recent (within the past year) or active suicidal behavior.
11. Pregnancy or lactation period. Women of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment and for 90 days after discontinuation. A serum pregnancy test must be negative in premenopausal women or women with amenorrhea of less than 12 months.
12. Major surgery within 2 weeks prior to randomization.
13. 10 weeks or more have passed since completion of radiotherapy at day of randomization and 16 weeks interval since the date of final surgery have passed.
14. Prior treatment with any CDK4/6 inhibitor.
15. Patients treated within the last 7 days prior to randomization and/or concurrent use of drugs known to be strong CYP3A4 inhibitors or inducers (see appendix 21.3)
16. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to randomization.
17. Male patients.
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
Promoteur :
GBG Forschungs GmbH, Neu-Isenburg
Type de sponsor : Institutionnel
Martin-Behaim-Str. 12 | 63263 Neu-Isenburg, Allemagne
00000 HORS FRANCE

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre François BACLESSE - 3 avenue du Général Harris - 14000 CAEN

Investigateur :
Christelle LEVY

TEC / ARC / IDE :
Sara GROSSI
s.grossi@
baclesse.unicancer.fr

Ouverture de l'essai : CLOS

MAJ : 16/07/2019