Clinical trial to compare efficacy and safety of standard chemotherapy versus letrozole plus abemaciclib, chosen randomly, as neoadjuvant therapy (deliver before breast cancer surgery), with positive Hormone Receptors (female hormones) and negative HER2 (protein involved in cell division that is located in the surface of many cells), intermediate/high risk breast cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Aug 2020 → ongoing

Decision date (initial)

2024-10-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Lilly

External identifiers

EU CT number

2024-514395-40-00

EudraCT number

2019-002123-15

ClinicalTrials.gov

NCT04293393

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Pharmacodynamic, Efficacy, Pharmacogenetic, Therapy, Safety

To assess the Residual Cancer Burden (RCB) 0-I rate in both treatment arms.

Secondary objectives 9

1. Changes in Ki67 index value after 2 weeks of treatment in both treatment arms.
2. RCB 0+I vs. RCB-II vs. RCB-III in both treatment arms (TNM downstaging).
3. Changes in RCB value between both treatment arms.
4. Rate of PEPI score 0 at surgery in both treatment arms.
5. Clinical response measured by magnetic resonance imaging (MRI) according to RECIST v1.1 in both treatment arms.
6. Rate of breast conserving surgery (BCS) in both treatment arms.
7. iEFS (invasive Event Free Survival) in both treatment arms.
8. Assessment of safety profile by National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 classification.
9. To assess molecular downstaging for high risk genomic groups defined by a multigene expression panel.

Conditions and MedDRA coding

High/intermediate risk hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer patients with indication of neoadjuvant therapy.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. 1. Written informed consent prior to any specific study procedures.
2. 2. Women ≥ 18 years of age.
3. 3. Documentation of histologically confirmed primary invasive adenocarcinoma of the breast. Adenocarcinoma with another component of epithelial origin (for example, medullary or neuroendocrine) is allowed.
4. 4. Availability of a primary tumor tissue sample obtained during the diagnostic process before treatment for the central assessment of Ki67 index and biomarker exploratory analyses (following the specifications described in the Sample Management Manual of the study).
5. 5. Documentation of HR positive and HER2 negative BC based on local laboratory determination. a. HR positive is defined as more than or equal to 10% positive cells by IHC for ER and/or progesterone receptor (PgR). b. HER2 negative tumor is determined according to recommendations of ASCO/CAP 2018 guidelines.
6. 6. Intermediate and high risk patients based on Ki67 index value (≥ 20%) determined at a central laboratory.
7. 7. Patients should be in the following clinical stages of disease according to the 8th edition of the TNM Classification of Breast Cancer by the UICC (Union for International Cancer Control): T1c N1-2 M0 and T2 (> 2cm) – T3, T4a, T4b, N0 – N2, M0 (stages IIA, IIB, IIIA or IIIB). Subpopulation with tumors T2 N0 M0 will include high risk patients based on Ki67 index ≥ 30% or Ki67 index between ≥ 20% and < 30% if PgR negative and/or histological grade 3.
8. 8. Patients with diagnosis of suspicious for multifocal or multicentric breast cancer will be eligible for the study.. At least two tumor lesions should be biopsied. All histologically available tumor lesions must comply with the inclusion criterion no. 5. a. If all lesions have similar morphological characteristics (i.e. based on local assessment of type, grade, Ki67 index level, etc.…), only the largest tumor lesion will be assessed for central assessment of Ki67 index level. b. If lesions have different morphological characteristics, discordant tumor lesions will be centrally evaluated for Ki67 index level. Patients will be eligible if at least one tumor lesion complies with criteria 6 and 7.
9. 9. Indication of neoadjuvant treatment.
10. 10. At the time of presentation, patients must be candidates for potentially curative surgery by surgeon’s assessment.
11. 11. Sentinel lymph node biopsy (SLNB) will be preferable after the neoadjuvant treatment. Those patients with SLNB before the neoadjuvant treatment will be eligible for the study only if the SLNB has a negative result (N0). One Step Nucleic Acid Amplification (OSNA) method is not allowed.
12. 12. Pre- and postmenopausal women. Postmenopausal status is defined as: • Patient underwent bilateral oophorectomy, or • Age ≥ 60 years, or • Age < 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges. All women who do not meet the criteria for postmenopausal status are considered premenopausal for the purpose of this trial.
13. 13. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
14. 14. Patients are able to swallow oral medications.
15. 15. Adequate organ and bone marrow function: • ANC ≥ 1,500/mm3 (1.5x109/L); • Platelets ≥ 100,000/mm3 (100x109/L); • Hemoglobin (Hgb) ≥ 8g/dL (80g/L) (erythrocyte transfusions are permitted; initial treatment must not begin earlier than the day after the erythrocyte transfusion); • Total serum bilirubin ≤ 1.5xULN (≤ 2xULN and direct bilirubin within normal limits if Gilbert´s disease); • AST and ALT ≤ 3xULN.
16. 16. Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
17. 17. For premenopausal women: agreement to remain abstinent 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 3 weeks after the last dose of study treatment. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception. Examples of non-hormonal contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide.
18. 18. Negative serum pregnancy test within 7 days of the first dose of abemaciclib or chemotherapy for premenopausal women, and for women who have experienced menopause onset < 12 months prior to first dose of therapy.
19. 19. Patients consent to biological sample provision for biomarker exploratory analyses.
20. 20. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion criteria 10

1. 1. Previous anti-cancer treatment with therapeutic intent for current breast cancer is not allowed.
2. 2. Patients with inflammatory breast cancer or synchronous bilateral invasive breast cancers are not eligible.
3. 3. Serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated creatinine clearance < 30ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
4. 4. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption.
5. 5. Females who are pregnant or lactating.
6. 6. Active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment.
7. 7. Personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
8. 8. Diagnosis of any other malignancy within 5 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix, breast or colorectal.
9. 9. Prior hematopoietic stem cell or bone marrow transplantation.
10. 10. Other severe acute or chronic medical 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Evaluation of the number of patients with a Residual Cancer Burden (RCB) 0-I index as a measure of efficacy. RCB is a continuous variable derived from the primary tumor dimensions, cellularity of the tumor bed, and axillary nodal burden. It is estimated from routine pathological sections of the primary breast tumor site and the regional lymph nodes after the completion of neoadjuvant therapy.

Secondary endpoints 9

1. Percentage of decrease in the geometric mean of Ki67 index value after 2 weeks of treatment in both treatments arms. Number of patients with cell cycle arrest (Ki67 < 2.7%) after 2 weeks of treatment in both treatment arms.
2. RCB is classified in four classes based on the residual disease (RD): o RCB-0 defined as pathological complete response. o RCB-I defined as minimal RD. o RCB-II defined as moderate RD. o RCB-III defined as extensive RD.
3. Variation of RCB value based on the RD between both treatment arms.
4. PEPI (Preoperative Endocrine Prognostic Index)(24) requires pathological stage (tumor size and nodal status), level of Ki67 protein and Allred ER score measured on the surgical specimen. PEPI score 0 includes pT1 or pT2, pN0, Ki67 ≤ 2.7%, Allred score > 2.
5. Clinical Response Rate (CRR) is defined as the proportion of subjects with complete or partial radiographic response. Complete response (CR) and partial response (PR) definitions are assessed by MRI at baseline and prior to breast surgery, with or without regional lymph nodes surgery, and categorized according to percent reduction in tumor size.
6. Rate of breast conserving surgery (BCS): defined as the proportion of patients who achieved BCS between both treatment arms.
7. Invasive event free survival (iEFS): defined as time from randomization to progressive disease or invasive disease recurrence or death from any cause. Invasive disease recurrence is defined as: o Ipsilateral invasive breast tumor recurrence (including second primary invasive breast cancer) o Ipsilateral regional invasive breast cancer recurrence. o Distant recurrence o Contralateral invasive breast cancer o Second primary invasive cancer of non-breast origin.
8. Safety will be assessed by standard clinical and laboratory tests (hematology, serum chemistry). AEs grade will be defined by the NCI-CTCAE version 5.0. AEs terms will be coded according to MedDRA dictionary.
9. Gene expression data provided by a multigene expression panel in sequential tumor biopsies.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Sponsor organisation

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Address

Avenida De Los Pirineos 7 Oficina 1-14, Industrial Zona Sur Industrial Zona Sur

City

San Sebastian De Los Reyes

Postcode

28703

Country

Spain

Scientific contact point

Organisation

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Contact name

Clinical Operations Department

Public contact point

Organisation

Fundacion Grupo Espanol De Investigacion En Cancer De Mama

Contact name

Clinical Operations Department

Third parties 6

Locations

1 EU/EEA country · 24 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications