We're building a better ClinicalTrials.gov. Check it out and tell us what you think!
Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Neoadjuvant Treatment of Locally-advanced Breast Cancer Patients With Ribociclib and Letrozole (NEOLETRIB)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05163106
Recruitment Status : Not yet recruiting
First Posted : December 20, 2021
Last Update Posted : July 22, 2022
Sponsor:
Collaborators:
Novartis
Vestre Viken Hospital Trust
Information provided by (Responsible Party):
Jurgen Geisler, University Hospital, Akershus

Brief Summary:
Patients with locally advanced (stage III) breast cancer (LABC) are characterized by a significantly worse prognosis compared to patients with primarily operable breast cancer. While neoadjuvant chemotherapy has been the first choice in this situation for several decades, recent evidence suggests that some patients may experience an extraordinary effect from neoadjuvant endocrine treatments involving aromatase inhibitors as monotherapy or in modern drug combinations.Selected LABC patients admitted for treatment will be offered combination therapy including letrozole and ribociclib. The overall goal of the project is to improve understanding of tumor responses and resistance in patients suffering from ER-positive/HER-2 negative locally advanced breast cancer, focusing on the role of the immune system including the gut microbiome.

Condition or disease Intervention/treatment Phase
Breast Cancer HER2-negative Breast Cancer ER-positive Breast Cancer Locally Advanced Breast Cancer Luminal A Breast Cancer Luminal B Breast Cancer Drug: Letrozole 2.5mg oral tablet; Ribociclib 600mg oral tablet Drug: Goserelin Phase 2

Show Show detailed description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Multicentre, single-arm, open-label, neoadjuvant study model
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Presurgical Treatment With Ribociclib and Letrozole in Patients With Locally Advanced Breast Cancer: the NEOLETRIB Study.
Estimated Study Start Date : December 1, 2022
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : December 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Ribociclib and Letrozole Arm
Patients entered into this study will be given letrozole (FemarTM) in combination with ribociclib (KisqaliTM) for at least 6 months. Premenopausal women will also receive treatment with goserelin 3.6 mg s.c. every 4 weeks.
Drug: Letrozole 2.5mg oral tablet; Ribociclib 600mg oral tablet
Patients will be given letrozole 2.5mg and ribociclib 600mg daily, per oral for a period of 21 days followed by 7 days of letrozole only.
Other Name: Femara; Kisqali

Drug: Goserelin
Premenopausal women will be given goserelin 3.6 mg (subcutaneous) every 4 weeks in concert with their Letrozole and Ribociclib treatment.
Other Name: Zoladex




Primary Outcome Measures :
  1. To study the change in levels of direct and indirect immunologic biomarkers of targeted cancer therapy with letrozole and ribociclib given in combination for patients with locally-advanced, ER-positive, HER-2 negative, luminal A7B breast cancer [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]
    In order to accurately profile changes in the composition of the tumor over time and identify potentially-related biomarkers of response within the tumor, single cell RNA panels will be performed at three points during the treatment period. Samples of tumor tissue will be obtained, and the cells dissociated at the single cell level. These dissociated cells will then be subjected to RNA profiling via scRNA-seq. Genes expressed at a rate higher than the threshhold (generally 50 reads per kb per million reads) will be examined using t-Distributed Stochastic Neighbor Embedding, (tSNE) clustering, generally shown as a scatterplot, to allow the characterisation of phenotypes (clones). Using this technique, it will be evident which tumour phenotypes are eradicated by the treatment combination and which are not. This examination will also help to monitor patient response.


Secondary Outcome Measures :
  1. Measurement of changes in the tumor through DNA profiling throughout the treatment cycle with letrozole and ribociclib [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]
    In order to examine the potential genetic changes within the tumor during treatment, samples of tumor tissue will be taken and examined using standard DNA profiling. Baseline samples will be compared to those at day 21 and at the time of surgery (6 months). This outcome will allow identification of overall tumour composition and changes to over the course of the therapy.

  2. Confirmation of the breast cancer subtype [ Time Frame: Baseline ]
    To determine the subtypes of the tumor, a PROSIGNA-test will be undertaken on all samples to confirm their subtype.

  3. Changes in neoantigens and single T-cell receptor function after treatment with letrozole and ribociclib [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]
    In order to examine the effects of letrozole and ribociclib on the presence of immune cells within the tumor throughout treatment, samples of tumor tissue will be extracted and cells will be dissociated at the single-cell level using enzymatic and mechanical means. Measurement of tumor neoantigens and testing of the ability of the T-cell receptors to recognise these neoantigens will assist in the understanding of the "rules" and molecular events underlying immune-mediated tumor destruction. Further, responders and non-responders will be compared to identify whether they belong to a new yet undiscovered subtype.

  4. Determination of the histopathological sub-type and status of the tumour [ Time Frame: Baseline, Day 21 and at time of surgery (Day 180) ]
    To ensure the correct patients are identified for participation in this study, and to record overall baseline information, samples of tumor tissue will be examined via standard histopathological investigations including subtyping, grading, ER-status, PGR-status, HER-2 status and level of Ki67-expression will be undertaken by a qualified pathologist. After the baseline, examination will confirm that biopsies consist of tumor tissue.

  5. Determination of the early and late mechanisms of adaptation and/or resistance to letrozole in combination with ribociclib [ Time Frame: Baseline and at time of surgery (Day 180) ]
    Using single-cell RNA-seq (scRNA-seq), thousands of individual cells will be profiled to build a cellular atlas of whole tumor biomarkers for targeted cancer treatments. scRNA-seq allows the characterisation of phenotypes (clones) to assist in determination of the phenotypes eradicated by the treatment, and to find biomarkers of response. Further knowledge of the phenotypes of the cells most affected by the therapy may assist in the identification of further drugs targeting any cells that remain or thrive.

  6. Change in PEPI status from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib [ Time Frame: Baseline, Day 21, Day 90, Day 180 ]
    Preoperative endocrine prognostic index (PEPI) status will be evaluated across the treatment period using the procedure outlined in Ellis et al, 2008.

  7. Change in Ki67 from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib [ Time Frame: Baseline, Day 21, Day 90, Day 180 ]
    Levels of Ki67 will be evaluated across the study period using the XXXXX protocol. Complete Cell Cycle Arrest (CCCA) will be recorded as a Ki67 of less than 2.7%.

  8. Change in PROSIGNA Risk of Recurrence (ROR) score from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib [ Time Frame: Baseline, Day 21, Day 90, Day 180 ]
  9. Changes in the composition of the gut microbiota [ Time Frame: Baseline, 21 and 90, at time of surgery (Day 180), and annually in years 1-5 (extension if patient relapses) ]
    A DNA-based approach to determination of fecal microbial composition will be performed. Stool samples will be collected at baseline, and during follow ups at day 21, day 90 and at time of surgery (day 180), and thereafter annually in years 1-5 (further if patient relapses). DNA purification from fecal samples will be performed using PSP Spin Stool DNA Plus Kit (Stratec Molecular GMBH). Next generation amplicon sequencing targeting the V4 region of the 16S rRNA gene (DNA) will be applied to detect the members of the fecal microbiota.

  10. Identification of anti-tumor effects via changes in levels of circulating serum cytokines in liquid biopsies [ Time Frame: Baseline, 21 and 90, and at time of surgery (Day 180). ]
    Serum cytokines will be measured using 54-plex cytokine panel, and analyzed with Luminex xMAP 200. The assay includes a series of known concentrations giving standard curves. Samples will be analyzed in duplicate.

  11. Identification of anti-tumor effects via changes in levels of circulating serum metabolites in liquid biopsies [ Time Frame: Baseline, 21 and 90, and at time of surgery (Day 180). ]
    Circulating metabolites will be identified using high resolution magic angle spinning mass spectrometry as described in Bathen et al (2013).

  12. Identification of anti-tumor effects via circulating free tumor DNA (cftDNA) in liquid biopsies [ Time Frame: Baseline, 21 and 90, and at time of surgery (Day 180). ]
    Circulating free tumor DNA will be collected and identified using standard DNA extraction and analysis techniques.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Females ≥ 18 years old at the time of the ICF signature
  • histologically confirmed locally advanced breast carcinoma, defined as either large T2 (>3cm in diameter) or T3-T4, and/or N2-3 primary breast cancer
  • ER-positive (defined by ER-pos. in ≥ 50% of cancer cells) and HER-2 negative, luminal A/B breast cancer
  • postmenopausal status (natural status or induced by treatment with the LHRH-analogue goserelin 3.6mg implant s.c. given every 4 weeks); definition of natural post-menopausal status: age above 55 years or age above 50 years and at least 2 years of amenorrhea in addition to LH-, FSH-, and plasma estradiol levels in the post-menopausal range.
  • Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory eligibility): Absolute neutrophil count ≥ 1.0x109/L; platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0g/dL; INR≤1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug); Estimated glomerular filtration rate (eGFR) ≥ 30mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula; total bilirubin < ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN; aspartate transaminase (AST) < 2.5 x ULN; Alanine transaminase (ALT) < 2.5 x ULN; patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication: potassium, magnesium, total calcium (corrected for serum albumin).
  • Standard 12-lead ECG values defined as the mean of the triplicate ECGs [QTcF interval at screening < 450 msec (QT interval using Fridericia's correction), mean resting heart rate 50-90 bpm (determined from the ECG)]
  • Performance status: Eastern Cooperative Oncology Group (ECOG) score 0-1
  • Ability and willingness to comply with study visits, treatment, testing and to comply with the protocol.

Exclusion Criteria:

  • Any prior treatment for primary invasive breast cancer
  • Patient with a known hypersensitivity to any of the excipients of ribociclib or letrozole
  • Patient with known hypersensitivity to peanuts or soya-products
  • Any evidence of distant metastasis
  • Triple-negative breast cancer
  • HER-2 positive disease, suitable for neoadjuvant therapy with trastuzumab, pertuzumab and taxanes, etc.
  • Other conditions rendering patients in need of other treatment options with immediate effect like chemotherapy
  • Concomitant medications that are known strong inducers of CYP3A4/5
  • Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry; documented cardiomyopathy; Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO); Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia, Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug) or Inability to determine the QTcF interval; Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block); Systolic Blood Pressure (SBP) >160 or <90 mmHg
  • Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intraarticular).
  • Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial
  • Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study treatment and for 21 days after stopping the treatment. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment; Male partner sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient and the success of the vasectomy must be medically confirmed as per local practice; Placement of an intrauterine device (IUD); Note: Use of oral (estrogen and progesterone), transdermal, injected, implanted, hormone containing intrauterine systems (IUS) or any other hormonal methods of contraception is not allowed in this study
  • Autoimmune disorders or significant allergies (i.e. rheumatoid arthritis, asthma, psoriasis, etc.)
  • Known HIV infection, Hepatitis B or C infection (testing not mandatory)
  • History of autoimmune celiac, inflammatory bowel disease, or other chronic GI disease
  • Recent use (within past month) of more than 3 days of antibiotics use
  • Current use of probiotic supplements
  • Taking proton pump inhibitors, steroids, other non-steroidal antiinflammatory drugs such as ibuprofen or acetyl salicylic acid
  • Past bariatric surgery

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05163106


Contacts
Layout table for location contacts
Contact: Jürgen Geisler, MD, PhD +47 91187447 jurgen.geisler@medisin.uio.no
Contact: Thale D JH Patrick-Brown, MSc +47 94866958 d.j.patrick-brown@medisin.uio.no

Locations
Layout table for location information
Norway
Akershus University Hospital
Lørenskog, Viken, Norway, 1478
Contact: Jürgen Geisler, MD, PhD    +47 91187447    jurgen.geisler@medisin.uio.no   
Contact: Thale D JH Patrick-Brown, MSc    +47 94866958    d.j.patrick-brown@medisin.uio.no   
Principal Investigator: Jürgen Geisler, MD, PhD         
Sponsors and Collaborators
University Hospital, Akershus
Novartis
Vestre Viken Hospital Trust
Investigators
Layout table for investigator information
Principal Investigator: Jürgen Geisler, MD, PhD University Hospital, Akershus
  Study Documents (Full-Text)

Documents provided by Jurgen Geisler, University Hospital, Akershus:
Publications:
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236. Epub 2017 Nov 2.

Layout table for additonal information
Responsible Party: Jurgen Geisler, Chief Physician, University Hospital, Akershus
ClinicalTrials.gov Identifier: NCT05163106    
Other Study ID Numbers: 2021/193780(REK)
First Posted: December 20, 2021    Key Record Dates
Last Update Posted: July 22, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Norwegian data protection laws are very strict, and free access to patient data is not possible. Authorised Norwegian researchers who wish to gain access to the data may apply individually to the study PI.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jurgen Geisler, University Hospital, Akershus:
Breast Cancer
Letrozole
Ribociclib
Combination Therapy
Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Letrozole
Goserelin
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal