Studieoverzicht - 2015-02 MonaLEEsa-3

 
Number 2015-02 MonaLEEsa-3
Nickname MonaLEEsa-3
Status Follow up Date: 21-07-2015
Inclusion closed 14-06-2016
Other study number(s)
Participating parties/groups
Full title A randomized double-blind, placebo-controlled study of ribociclib in combination with fulvestrant for the treatment of postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment
Phase and type Randomized Phase III, Interventional
Age Age ≥60 or Age <60 and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and FSH and estradiol in the postmenopausal range per local normal range
Menopausal status Postmenopausal
Indication Advanced/metastatic
Subindication HER2- HR+
Target sample size 660
Actual accrual 727 (NL: 56) Date: 10-06-2016
Estimated study completion date 31-12-2016
CCMO approval Yes Date: 19-05-2015 Nr: NL53067.028.15
EudraCT nr. 2015-000617-43
Trial Register NCT02422615 (ct.gov)
METC approval Yes Date: 18-06-2015 METC: onafhankelijke METC Noord-Brabant Nr: P1517
Amendments No Date:
KWF-CKS approval Date: Nr:
News item
Website http://www.boogstudycenter.nl
Sponsor Novartis
Principal Investigator(s) M. de Boer (MUMC)
Study manager Michiel van de Wetering (Novartis)
Jeany Rademaker-Lakhai (BOOG)
Central datamanagement and randomization Novartis
Monitoring Novartis
Local datamanagement
Funding
Extra

Design:

Objectives:

Primary objective:

To compare PFS between ribociclib in combination with fulvestrant to placebo in combination with fulvestrant among postmenopausal women with HR+, HER2-negative advanced breast cancer who received no or only one prior endocrine treatment for advanced disease

 

Secondary objectives:

  • To compare the two treatment arms with respect to Overall Survival
  • To evaluate the two treatment arms with respect to centrally assessed PFS
  • To evaluate the two treatment arms with respect to overall response rate, clinical benefit rate, time to response and duration of response
  • To evaluate the two treatment arms with respect to time to deterioration of ECOG performance status
  • To evaluate the safety and tolerability of ribociclib in combination with fulvestrant
  • To evaluate patient reported outcomes for health-related quality of life in the two treatment arms
  • To characterize the pharmacokinetics (PK) of ribociclib (and relevant metabolites such as LEQ803) when given in combination with fulvestrant
Endpoints:

Primary endpoint:

  • PFS based on local radiology assessments and using RECIST 1.1 criteria

Secondary endpoints:

  • Overall Survival
  • PFS per blinded independent review committee (BIRC) and RECIST 1.1 criteria
  • ORR and as defined by RECIST 1.1. CBR, defined as percentage of patients with CR, PR or SD lasting 24 weeks or longer, TOR, DOR per RECIST 1.1
  • Time to definitive deterioration of ECOG performance status from baseline
  • Frequency/severity of AEs, laboratory abnormalities
  • Time to 10% deterioration in the global health status/QOL scale score of the EORTC QLQ-C30
  • Change from baseline in the global health status/QOL scale score of the EORTC QLQ-C30
  • Summary statistics for PK parameters at steady state, including but not limited to Cmax, Tmax, Ctrough for ribociclib (and relevant metabolites such as LEQ803)
Main eligibility criteria:

Inclusion criteria:

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

Written informed consent must be obtained prior to any screening procedures.

  1. Patient is an adult ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.
  2. Patient is postmenopausal. Postmenopausal status is defined either by:

    • Prior bilateral oophorectomy
    • Age ≥60
    • Age <60 and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and FSH and estradiol in the postmenopausal range per local normal range

    Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol are needed to ensure postmenopausal status (NCCN 2.2015). Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (LH-RHa) (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression in this trial.

  3. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
  4. 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 by local laboratory testing.
  5. Patient must have either:
    • Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1. (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation).
    • If no measurable disease is present, then at least one predominantly lytic bone lesion must be present (patients with no measurable disease and only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).
  6. Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer.

    Patients may be :

    • newly diagnosed advanced breast cancer, treatment naïve
    • relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease
    • relapsed with documented evidence of progression on or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for metastatic disease
    • relapsed with documented evidence of progression more than 12 months from completion of adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for metastatic disease
    • newly diagnosed advanced breast cancer, then progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor)

     

    Note: Patient who relapsed with documented evidence of relapse on/or within 12 months from completion of adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for metastatic disease will NOT be included in the study.

  7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  8. Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory for eligibility):         

• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelets ≥ 100 × 109/L
• Hemoglobin ≥ 9.0 g/dL
• 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, except for patients with liver metastasis, who are only included if the AST is < 5 × ULN
• Alanine transaminase (ALT) < 2.5 × ULN, except for patients with liver metastasis, who are only included if the AST is < 5 × 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:

      • Sodium
      • Potassium
      • Magnesium
      • Phosphorus
      • Total Calcium (corrected for serum albumin)

 

Exclusion criteria:

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

  1. Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator’s best judgment.
  2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant or any CDK4/6 inhibitor.
  3. Patients has received prior neoadjuvant/adjuvant treatment with antracyclines at cumulative doses of 450mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin.
  4. Patient with a known hypersensitivity to any of the excipients of ribociclib or fulvestrant.
  5. Patient with inflammatory breast cancer at screening.
  6. Patient is concurrently using other anti-cancer therapy.
  7. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.
  8. Patients with Child pugh score B or C.
  9. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
  10. Patient has not recovered from all toxicities related to prior anticancer therapies to NCI CTCAE version 4.03 Grade ≤1. Exception to this criterion: patients with any grade of alopecia are allowed to enter the study.
  11. Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) and/or from whom ≥ 25% (Ellis 1961) of the bone marrow was irradiated.
  12. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
  13. Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
    • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment.
    • Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
  14. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

  15. Patient has a known history of HIV infection (testing not mandatory)

  16. 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.)

  17. Clinically significant, uncontrolled heart disease and/or recent cardiac events including any of the following:
    • History of angina pectoris, symptomatic pericarditis, or myocardial infarction within 12 months prior to study entry
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV)
    • Documented cardiomyopathy
    • Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
    • History of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
    • Congenital long QT syndrome or family history of long QT syndrome
    • Systolic Blood Pressure (SBP) >160 or <90 mmHg
    • Bradycardia (heart rate < 50 at rest), by ECG or pulse.
    • On screening, inability to determine the QTcF interval on the ECG (ie: unreadable or not interpretable) or QTcF >450 msec (using Fridericia’s correction). All as determined by screening ECG (mean of triplicate ECGs).

  18. Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1:
    • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges.
    • That have a known risk to prolong the QT interval or induce Torsades de Pointes.
    • That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
    • Herbal preparations/medications, dietary supplements.
  19. 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: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).

  20. Participation in a prior investigational study within 30 days prior to enrollment or within 5-half lives of the investigational product, whichever is longer.

  21. Not able to understand and to comply with study instructions and requirements.

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