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Adj. Marker-adjusted Personalized Therapy Comparing ET+Ribociclib vs Chemotherapy in Intermediate Risk, HR+/HER2- EBC (ADAPTcycle)

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ClinicalTrials.gov Identifier: NCT04055493
Recruitment Status : Recruiting
First Posted : August 13, 2019
Last Update Posted : August 13, 2019
Sponsor:
Collaborators:
Novartis
Genomic Health®, Inc.
Information provided by (Responsible Party):
West German Study Group

Brief Summary:
The study investigates, whether the patient group with intermediate-risk early breast cancer benefits from treatment with ribociclib in combination with endocrine therapy compared to standard-of-care chemotherapy (followed by adjuvant endocrine therapy).

Condition or disease Intervention/treatment Phase
Breast Cancer Female Drug: Ribociclib 200Mg Oral Tablet Phase 3

Detailed Description:

The WSG ADAPT trial program is one of the first new generation trials addressing the issue of individualization of (neo)-adjuvant decision-making in early breast cancer (EBC) in a subtype-specific manner. The first WSG ADAPT umbrella trial (NCT01779206) aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment.

The goals of the WSG ADAPT trial program - early response assessment and subtype-specific therapy tailoring to those patients who are most likely to benefit - have contributed to the very positive national and international feedback to the ADAPT concept as a whole.

The aim of this ADAPTcycle phase-III-trial is to investigate whether the intermediate-risk patient group identified during the screening phase derives additional benefit from treatment with ribociclib in combination with ET compared to chemotherapy (followed by adjuvant ET).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1670 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter, interventional, prospective, two-arm, randomized, open-label, controlled (neo)adjuvant, phase-III trial evaluating the efficacy and safety of ribociclib combined with endocrine therapy (ET) versus standard-of-care chemotherapy in early breast cancer (EBC) patients with molecular HR+/HER2- subtype.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Endocrine Therapy Plus Ribociclib Versus Chemotherapy in Intermediate Risk, HR+/HER2- Early Breast Cancer
Actual Study Start Date : July 2, 2019
Estimated Primary Completion Date : July 31, 2027
Estimated Study Completion Date : July 31, 2027

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Ribociclib

Arm Intervention/treatment
Experimental: Ribociclib plus ET
Ribociclib 600mg / day over 26 cycles + endocrine treatment of physician´s choice
Drug: Ribociclib 200Mg Oral Tablet
3 x 200 MG per os
Other Name: Kisqali

No Intervention: Standard-of-care chemotherapy
Standard-of-care chemotherapy according to the clinical guidelines, e.g., of the Breast Committee of the German Gynecological Oncology Group (AGO), and regional prescribing information depending on patient's needs for 16-24 weeks,



Primary Outcome Measures :
  1. invasive disease-free survival (iDFS) [ Time Frame: at end of study, on average 5 years after start of treatment ]
    superiority in invasive disease-free survival (iDFS) of ribociclib + ET vs. standard-of-care chemotherapy

  2. distant disease-free survival (dDFS) [ Time Frame: at end of study, on average 5 years after start of treatment ]
    distant disease-free survival (dDFS) in the ribociclib + ET-group to demonstrate survival rate >92%


Secondary Outcome Measures :
  1. overall survival (OS) [ Time Frame: at end of study, on average 5 years after start of treatment ]
    95 %-confidence interval (CI) for OS in both arms

  2. distant disease-free survival (dDFS) [ Time Frame: at end of study, on average 5 years after start of treatment ]
    95 %-confidence interval (CI) for dDFS in both arms

  3. QoL [ Time Frame: at end of study, on average 5 years after start of treatment ]
    quality of life (QoL) and correlation to treatment-related symptoms measured by EQ-VAS and triggered symptom questionnaire,

  4. treatment adherence [ Time Frame: at end of study, on average 5 years after start of treatment ]
    treatment adherence measured by drug intake compared between treatment arms

  5. pathological complete response (pCR) [ Time Frame: at end of study, on average 5 years after start of treatment ]
    Pathological response rate (defined as ypT0/is/ypN0), as well as further definitions (ypT0/ypN0; ypT0/is/any ypN, near pCR (ypT1a/any ypN)), in neoadjuvant treated patients

  6. clinical response rate [ Time Frame: at end of study, on average 5 years after start of treatment ]
    clinical response rate (by palpation, ultrasound, and further methods) compared between treatment arms

  7. rate of breast-conservation therapy [ Time Frame: at end of study, on average 5 years after start of treatment ]
    prevalence of breast conservation therapy vs. mastectomy compared between treatment arms



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pre- and postmenopausal women 18 years or older.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

A. Prior to REGISTRATION in the study:

1. Written informed consent prior to any screening procedures. 2. Female. 3. ≥ 18 years of age. 4a. EITHER: (Post)menopausal status at the time of initiation of (neo)adjuvant study medication

  • patient underwent bilateral oophorectomy, or
  • age ≥ 60, or
  • age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and/or FSH and estradiol in the postmenopausal range per local normal range.

    4b. OR: Pre-menopausal patients:

  • confirmed negative serum pregnancy test (β-hCG) before starting study treatment, or
  • patient has had a hysterectomy. 5. Histologically confirmed diagnosis of primary estrogen-receptor positive and/or progesterone-receptor positive (> 1%) early breast cancer by local laboratory.

    6. Patient has HER2-negative breast cancer defined as

  • a negative in-situ hybridization test or an IHC status of 0, 1+, or 2+,
  • if IHC is 2+, a negative in-situ hybridization (FISH, CISH, or SISH) test is required (based on the most recently analyzed tissue sample and all tested by a local laboratory).

    7. Local therapy of breast cancer (if adjuvant treatment or planned if neoadjuvant treatment) according to current guidelines.

Note: This may include radiotherapy of breast cancer.

B. Prior to RANDOMIZATION in the study 8. No evidence of distant metastasis (confirmed prior to randomization by, preferentially, CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT).

9. Patient has available tumor tissue from diagnostic biopsy. 10. Patient is classified as intermediate risk according to the ADAPT intermediate-risk definition (i) (as follows), or (only in case of missing Oncotype DX or Ki-67 response data), according to the clinical intermediate-risk definition (ii) (as follows).

(i). ADAPT intermediate-risk definition: Patient meets one of the following criteria:

  • c/pN0, RS ≤ 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 without endocrine response (post-endocrine Ki-67 > 10 %)
  • c/pN1, RS ≤ 25 without endocrine response (post-endocrine Ki-67 > 10 %)
  • c/pN0, RS > 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 with endocrine response (Ki-67 ≤ 10 %)
  • c/pN1, RS > 25 with endocrine response (Ki-67 ≤ 10 %)
  • c/pN2-3, RS ≤ 25 with endocrine response (Ki-67 ≤ 10 %). Note: Postmenopausal patients with pT1-2/pN0 disease and RS < 25, as well as premenopausal patients with pT1-2/pN0 disease and RS<16, are recommended to be treated by endocrine therapy alone and not to be randomized (at investigator´s discretion).

(ii). Clinical intermediate-risk definition (ascertained by investigator): Clinical intermediate risk may be ascertained by the investigator prior to randomization if at maximum two of the following three risk factors are present (according to primary diagnosis / 1st sample):

  1. cT2-4
  2. c/pN positive
  3. G3 and / or Ki-67 ≥ 20% Note: Inclusion of a patient according to "clinical intermediate risk" is permitted only in case of missing baseline Oncotype DX® or Ki-67 decrease. In this case, investigators will follow a risk-based, step-wise assessment process.

11. No contraindication for (neo)-adjuvant ET. 12. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 13. Patient has adequate bone marrow and organ function as defined by the following laboratory values:

  • absolute neutrophil count ≥ 1.5 × 109/L,
  • platelets ≥ 100 × 109/L,
  • hemoglobin ≥ 9.0 g/dL,
  • estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula,
  • INR ≤ 1.5,
  • serum creatinine < 1.5 mg/dL,
  • total bilirubin < ULN, except for patients with Gilbert's Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN,
  • aspartate transaminase (AST) < 2.5 × ULN,
  • alanine transaminase (ALT) < 2.5 × ULN. 14. 2-lead-ECG (CANKADO) with:
  • QTcF interval at screening < 450 msec (using Fridericia's correction),
  • mean resting heart rate 50-90 bpm (determined from the ECG). 15. Ability to swallow ribociclib tablets or to administer other study medication, respectively.

    16. Ability to communicate with the investigator and comply with study procedures.

    17. Willing to remain during therapy at the clinical site, as required by the protocol.

Exclusion Criteria:

Patients eligible for inclusion in this study must not meet any of the following criteria:

  1. Patient with distant metastases of breast cancer beyond regional lymph nodes.
  2. Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or any CDK4/6 inhibitor for breast cancer.
  3. Patient has received tamoxifen, raloxifene, or aromatase inhibitors (AIs) for reduction in risk ("chemoprevention") of breast cancer and/or treatment for osteoporosis within last 2 years prior to screening.
  4. Patient has received prior neoadjuvant/adjuvant treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin.
  5. Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, or standard-of-care chemotherapy.
  6. Patient with inflammatory breast cancer at screening.
  7. Patient is concurrently using other anti-cancer therapy.
  8. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
  9. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant for treatment, prophylaxis, or otherwise.
  10. Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.
  11. Patient has a concurrent malignancy, or malignancy within 5 years of randomization, or known history of invasive breast cancer.
  12. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small-bowel resection).
  13. Patient has a known history of HIV infection.
  14. Patient has known active hepatitis-B-virus (HBV) or hepatitis-C-virus (HCV) infection.
  15. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study, or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.).
  16. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

    • history of 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, family history of idiopathic sudden death, congenital long QT syndrome, or any of the following:

      • risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia,
      • concomitant medications 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),
      • 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 3rd-degree AV block),
      • systolic blood pressure (SBP) > 160 or < 90 mmHg.
  17. Patient is currently receiving any of the following substances, which cannot be discontinued 7 days prior to Cycle 1 Day 1:

    • concomitant medications, herbal supplements, fruits (e.g. grapefruit, pomegranates, pomelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
    • medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
  18. 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.
  19. Participation in a prior investigational study within 30 days prior to enrollment or within five half-lives of the investigational product, whichever is longer.
  20. Not able to understand and to comply with study instructions and requirements.
  21. Pregnant or nursing (lactating) woman.
  22. Woman of child-bearing potential defined as woman physiologically capable of becoming pregnant, unless she is using highly effective methods of contraception during the study treatment and for 21 days after stopping the treatment:

    • total abstinence (when this is in line with the preferred and usual lifestyle of the patient).
    • female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment.
    • male partner sterilization (at least 6 months prior to study screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
    • placement of an intrauterine device (IUD).
  23. Use of oral (estrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.

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): NCT04055493


Contacts
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Contact: Anja Braschoss, MD +49-176-82119153 anja.braschoss@wsg-online.com
Contact: Julian Moellers +49-2161-56623 ext 11 julian.moellers@wsg-online.com

Locations
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Germany
Klinikum der Universität München Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Brustzentrum Not yet recruiting
Munich, Bavaria, Germany, 80337
Contact: Nadia Harbeck, Prof. Dr.    +49-89-440054170    nadia.harbeck@med.uni-muenchen.de   
Contact: Rachel Würstlein, Dr.    +49-89-440054170    Rachel.wuerstlein@med.uni-muenchen.de   
Universitätsklinikum Aachen, Frauenklinik - Senologie Recruiting
Aachen, NRW, Germany, 52074
Contact: Katja Krauss, Dr    +49-241-8080700    kkrauss@ukaachen.de   
Kliniken Essen-Mitte, Klinik für Senologie/Interdisziplinäres Brustzentrum Recruiting
Essen, NRW, Germany, 45136
Contact: Sherko Kuemmel, PD Dr    +49-201-17433005    s.kuemmel@kliniken-essen-mitte.de   
Contact: Dorothea Schindowski    +49-201-17433005    d.schindowski@kliniken-essen-mitte.de   
Praxis für gynäkologische Onkologie am Ev. Krankenhaus Bethesda Recruiting
Moenchengladbach, NRW, Germany, 41061
Contact: Monika Graeser, PD Dr    +49-2161-8493577    monika.graeser@brustzentrum-rhein-ruhr.com   
Contact: Raquel von Schumann, Dr    +49-2161-8493577    raquel.vonSchumann@brustzentrum-rhein-ruhr.com   
Sponsors and Collaborators
West German Study Group
Novartis
Genomic Health®, Inc.
Investigators
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Principal Investigator: Nadia Harbeck, Prof. Dr. Ludwigs-Maximilians-University Munich, Breast Cancer Centre

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Responsible Party: West German Study Group
ClinicalTrials.gov Identifier: NCT04055493     History of Changes
Other Study ID Numbers: WSG-AM08
First Posted: August 13, 2019    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

The sponsor is committed to following high ethical standards for reporting study results, including the timely communication and publication of clinical trial results, whatever their outcome. The sponsor assures that the key design elements of this protocol will be posted on a publicly accessible database, e.g., www.clinicaltrials.gov, before study start.

As part of its commitment to full transparency in publications, the sponsor supports the full disclosure of all funding sources for the study and publications, as well as any actual and potential conflicts of interest of financial and non-financial nature by all authors, including medical writing / editorial support, if applicable.

Supporting Materials: Clinical Study Report (CSR)
Time Frame: Within 1 year after end of study.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by West German Study Group:
early breast cancer
ADAPT
endocrine therapy
ribociclib
intermediate risk
HER2 negative
HR positive
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases