Efficacy of Letrozole + Palbociclib Combination as Neoadjuvant Treatment of Stage II-IIIA PAM 50 ROR-defined Low or Intermediate Risk Luminal Breast Cancer, in Postmenopausal Women (NeoPAL)

Open-label, Randomized, Multicenter, International, Parallel Exploratory Phase II Study, Comparing 3 FEC-3 Docetaxel Chemotherapy to Letrozole + Palbociclib Combination as Neoadjuvant Treatment of Stage II-IIIA PAM 50 ROR-defined Low or Intermediate Risk Luminal Breast Cancer, in Postmenopausal Women

The investigators propose in the present study an innovative approach, combining the most recent therapeutic opportunities in high risk ER+ breast cancer with the most recent and innovative diagnostic approaches such as the PAM50 signature and the RCB tumor response evaluation method. In line with the most recent recommendations on targeted anticancer therapies, the investigators have designed a parallel phase II randomized trial with early stopping rules 26, which will able in the meantime to build a unique prospective collection of tumor tissue, pre- and post-treatment.

Study Overview

• Status: Completed
• Conditions: Neoadjuvant Operable Breast Cancer
• Intervention / Treatment: Drug: Epirubicin; Drug: Palbociclib; Drug: Cyclophosphamide; Drug: Letrozole; Drug: Fluorouracile

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Institut Curie
  • Villejuif, France
    • Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Aged ≥ 18 years, Post-menopausal women
2. Newly diagnosed and operable unilateral invasive breast cancer, not candidate or uncertain for breast conservation - Note: Multicentric/multifocal tumors are allowed provided a maximum of 3 lesions are present, and all share the same characteristics: ER Allred 4, Her2- (PAM50 will be performed in the largest lesion)
3. Stage II-IIIA
4. Assessment of nodal status available (Ultrasound guided FNA or biopsy if necessary)
5. Non metastatic, M0
6. ER-positive by IHC (Allred Score≥4)
7. HER2-negative by IHC (score 0 or 1+) and/or Fish/Cish
8. Either Luminal A AND proven nodal involvement (cytology or histology), or Luminal B through PAM50 ROR (Prosigna™) centralized evaluation
9. ECOG 0-1
10. No prior systemic therapy for the present tumor

11. Adequate renal, hepatic, and hematopoietic functions as defined by the following criteria:

    • Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L
    • Platelets ≥100,000/mm3 or ≥100 x 109/L
    • Hemoglobin ≥9 g/dL
    • Serum Aspartate Transaminase (AST) and serum Alanine Aminotransferase Transaminase (ALT) ≤2.5 x upper limit of normal (ULN)
    • Alkaline phosphatase ≤2.5 x ULN
    • Total serum bilirubin ≤1 x ULN
    • Serum creatinine ≤1.5 x ULN or estimated creatinine clearance ≥ 60 mL/min as calculated using the method standard for the institution

12. Adequate cardiac functions, including:

    • 12 Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention.
    • QTc interval ≤480 msec
    • No history of Torsades de Pointes or other symptomatic QTc abnormality.
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures
14. Signed informed consent and health insurance coverage

Exclusion Criteria:

1. Non operable, bilateral, T4 or metastatic breast cancer
2. Limited T2 breast cancer immediately accessible to conservative surgery
3. Previous homolateral breast cancer (including in situ carcinoma), and/or contralateral breast cancer except if treated by surgery +/- radiation therapy alone without any systemic treatment
4. Previous hormone replacement therapy (HRT) stopped less than 2 weeks before beginning of treatment
5. Previous use of SERMs such as raloxifene
6. Any surgery (not including minor procedures such as lymph node biopsy, primary tumor core biopsy, fine needle aspiration) within 4 weeks of start of study treatment; or not fully recovered from any side effects of previous procedures.
7. Diagnosis of any previous malignancy within the last 5 years, except for adequately treated basal cell carcinoma, or squamous cell skin carcinoma, or in situ cervical carcinoma
8. History of any previous anti-cancer chemotherapy and any previous treatment using AI
9. Concurrent administration of herbal preparations as complementary medicine.
10. Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drugs, such as the inability to take oral medication in tablet form and malabsorption syndrome
11. Patient with any psychological, familial, social or geographical condition which could potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Chemotherapy; 3 cycles of FEC 100 followed by 3 cycles of Docetaxel Drugs: Fluorouracile, Epirubicine, Cyclophosphamide, Docetaxel	Drug: Epirubicin; Drug: Cyclophosphamide; Drug: Fluorouracile
Experimental: Letrozole Palbociclib; Drugs: letrozole + palbociclib combination	Drug: Palbociclib; Drug: Letrozole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the number of patients with a Residual Cancer Burden (RCB) 0-I index as a measure of efficacy	Residual cancer burden (RCB) is estimated from routine pathologic sections of the primary breast tumor site and the regional lymph nodes after the completion of neoadjuvant therapy. 6 variables are included in a calculation formula.	21 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the clinical response in each treatment arm as defined by clinical and ultrasound examination.		21 weeks
Determination of the number and type of Adverse Events as a Measure of Safety and Tolerability	The toxicity will be evaluated according to the scale CTC-AE version 4.0	21 weeks
Correlation of the PAM50 risk of recurrence (ROR) score to its ability to predict RCB as defined in outcome 1		21 weeks
Calculation of the rates of breast conservation therapy in the two arms with regard to the initially planned surgery.		21 weeks

Collaborators and Investigators

• Sponsor: UNICANCER
• Collaborators: Pfizer; NanoString Technologies, Inc.
• Investigators: Principal Investigator: Paul Cottu, MD, Institut Curie Paris; Principal Investigator: Suzette Delaloge, MD, Gustave Roussy, VILLEJUIF

Publications and helpful links

General Publications

• Cottu P, D'Hondt V, Dureau S, Lerebours F, Desmoulins I, Heudel PE, Duhoux FP, Levy C, Mouret-Reynier MA, Dalenc F, Frenel JS, Jouannaud C, Venat-Bouvet L, Nguyen S, Ferrero JM, Canon JL, Grenier J, Callens C, Gentien D, Lemonnier J, Vincent-Salomon A, Delaloge S. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018 Dec 1;29(12):2334-2340. doi: 10.1093/annonc/mdy448.

Helpful Links

• Ann Oncol . 2018 Dec 1;29(12):2334-2340. doi: 10.1093/annonc/mdy448

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2015
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): September 1, 2020

Study Registration Dates

• First Submitted: August 5, 2014
• First Submitted That Met QC Criteria: March 26, 2015
• First Posted (Estimate): March 27, 2015

Study Record Updates

• Last Update Posted (Actual): March 15, 2022
• Last Update Submitted That Met QC Criteria: March 14, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Neoadjuvant; Luminal; Post menopausal; Breast conservation
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Cyclophosphamide; Epirubicin; Letrozole; Palbociclib
• Other Study ID Numbers: NeoPal - UC-0140/1404; 2014-002560-33 (EudraCT Number); CARMINA04 (Other Identifier: UNICANCER); NEOPAL (Other Identifier: UNICANCER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Unicancer will share de-identified individual data that underlie the results reported. A decision concerning the sharing of other study documents, including protocol and statistical analysis plan will be examined upon request.
• IPD Sharing Time Frame: Unicancer will consider access to study data upon written detailed request sent to Unicancer, from 6 months until 5 years after publication of summary data.
• IPD Sharing Access Criteria: The data shared will be limit to that required for independent mandated verification of the published results, the applicant will need authorization from Unicancer for personal access, and data will only be transferred after signing of a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No