Studieoverzicht - 2015-01 Monarch-3

 
Number 2015-01 Monarch-3
Nickname Monarch-3
Status Follow up Date: 14-08-2015
Inclusion closed
Other study number(s) I3Y-MC-JPBM
Participating parties/groups
Full title A randomized, double-blind, placebo-controlled, Phase 3 study of non-steroidal aromatase inhibitors (anastrozole or letrozole) plus LY2835219, a CDK4/6 inhibitor, or placebo in women with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer who have not received prior systemic therapy for locally advanced or metastatic disease
Phase and type Randomized Phase III
Age Age ≥60 years or Age <60 years and amenorrheic for at least 12 months (in the absence of tamoxifen, toremifene, ovarian suppression, or chemotherapy) and FSH and estradiol in the postmenopausal range
Menopausal status Postmenopausal
Indication Advanced/metastatic
Subindication HER2- HR+
Target sample size 450
Actual accrual 477(NL: 8) Date: 27-10-2015
Estimated study completion date 01-05-2022
CCMO approval Yes Date: 03-11-2014 Nr: NL51156.028.14
EudraCT nr. 2014-001502-18
Trial Register
METC approval Yes Date: 23-12-2014 METC: Brabant Nr: P1452
Amendments No Date:
KWF-CKS approval Date: Nr:
News item
Website http://www.boogstudycenter.nl
Sponsor Lilly
Principal Investigator(s)
Study manager Sevda Caliskan-Demirel (Lilly)
Jeany Rademaker-Lakhai (BOOG)
Central datamanagement and randomization Lilly
Monitoring Lilly
Local datamanagement
Funding
Extra

Design:

Objectives:

Primary Objective

The primary objective of this study is to compare treatment with LY2835219 plus NSAI therapy versus placebo plus NSAI therapy with respect to PFS in postmenopausal women with HR+, HER2- locoregionally recurrent or metastatic breast cancer who have not received prior systemic therapy in this disease setting.

 

Secondary Objectives

The secondary objectives of the study are to compare the combination treatment of LY2835219 and NSAI therapy versus placebo plus NSAI therapy with respect to the following: OS; OS rate at 1, 2, and 3 years; ORR (CR + PR); duration of response (CR + PR); DCR (CR + PR + SD); CBR (CR + PR + SD ≥6 months); the safety and tolerability; change in symptom burden from baseline using the EORTC QLQ-C30, EORTC QLQBR23 (breast) questionnaire, and health status scores from the EQ-5D 5L; the PK of LY2835219, its metabolites, and NSAI therapy.

 

Exploratory Objectives

- To explore potential biomarkers related to the mechanism of action of LY2835219, the cell cycle, and/or the pathogenesis of breast cancer.

- To explore change in tumor size.

Endpoints:

Endpoints:

- The primary efficacy measure is PFS as defined by [RECIST v1.1]

- The following secondary efficacy measures will be collected: OS, ORR, DCR, CBR, DoR

Main eligibility criteria:

Inclusion criteria

  1. have a diagnosis of HR+, HER2- breast cancer. Although not required as a protocol procedure, metastatic disease should be considered for biopsy whenever possible to reassess HR and HER2 status if clinically indicated.
    To fulfill the requirement for HR+ disease, a breast cancer must express, by immunohistochemistry (IHC), at least one of the hormone receptors (ER, progesterone receptor [PgR]) as defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010).
    To fulfill the requirement of HER2- disease, a breast cancer must not demonstrate, at initial diagnosis or upon subsequent biopsy, overexpression of HER2 by either IHC or in-situ hybridization (ISH) as defined in the relevant ASCO/CAP guidelines (Wolff et al. 2013).
  2. have locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease
  3. have postmenopausal status, defined as meeting one of the following conditions:

    • Prior bilateral oophorectomy

    • Age ≥60 years

    • Age <60 years and amenorrheic (non-treatment-induced amenorrhea secondary to tamoxifen, toremifene, ovarian suppression, or chemotherapy) for at least 12 months. Follicle-stimulating hormone (FSH) and estradiol must be in the postmenopausal range.

  4. have one of the following as defined by the RECIST v1.1

    • Measurable disease

    • Nonmeasurable bone-only disease. Nonmeasurable bone-only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft tissue component, or mixed lyticblastic bone lesions without a measurable soft tissue component.

  5. have a PS of ≤1 on the ECOG scale
  6. have adequate organ function, including:

    • hematologic: absolute neutrophil count (ANC) ≥1.5 × 109/L, platelets ≥100 × 109/L, and hemoglobin ≥8 g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator; however, initial study drug treatment must not begin earlier than the day after the erythrocyte transfusion.

    • Hepatic: bilirubin ≤1.5 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 times ULN (or ALT and AST ≤5 times ULN if liver metastases are present).

    • renal: serum creatinine ≤1.5 times ULN.

  7. have discontinued previous localized radiotherapy for palliative purposes or for lytic lesions at risk of fracture at least 2 weeks prior to randomization and recovered from the acute effects of therapy (until the toxicity resolves to either baseline or at least Grade 1) except for residual alopecia or peripheral neuropathy.
  8. are female and ≥18 years of age
  9. are able to swallow capsules
  10. have given written informed consent prior to any study-specific procedures
  11. are reliable, willing to be available for the duration of the study, and are willing to follow study procedures.

 

Exclusion Criteria

Patients will be excluded from the study if they meet any of the following criteria:

  1. have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis. Visceral crisis is not the mere presence of visceral metastases but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of the disease.
  2. have inflammatory breast cancer.
  3. have clinical evidence or a history of CNS metastasis. Screening is not required for enrollment.
  4. are currently receiving or have previously received endocrine therapy for locoregionally recurrent or metastatic breast cancer. [Note: A patient may be enrolled if she received prior (neo)adjuvant endocrine therapy (including , but not limited to anti-estrogens or aromatase inhibitors) for localized disease. In addition, a patient may be enrolled if she has received ≤2 weeks of NSAI in this disease setting immediately preceding screening and agrees to discontinue NSAI until study treatment initiation.]
  5. have received prior (neo)adjuvant endocrine therapy (e.g., anti-estrogens or aromatase inhibitors) with a disease-free interval ≤12 months from completion of treatment.
  6. are currently receiving or have previously received chemotherapy for locoregionally recurrent or metastatic breast cancer. [Note: Patients may be enrolled if they received prior (neo)adjuvant chemotherapy for localized disease.]
  7. have received prior treatment with everolimus
  8. have received prior treatment with any CDK4/6 inhibitor (or participated in any CDK4/6 inhibitor clinical trial for which treatment assignment is still blinded)
  9. have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents (for example, denosumab) <7 days prior to randomization
  10. are currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study. If a patient is currently enrolled in a clinical trial involving non-approved use of a device, then agreement with the investigator and Lilly clinical research physician (CRP) is required to establish eligibility.
  11. have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of randomization for a nonmyelosuppressive or myelosuppressive agent, respectively.
  12. have had major surgery within 14 days prior to randomization to allow for post-operative healing of the surgical wound and site(s).
  13. have received recent (within 28 days prior to randomization) yellow fever vaccination.
  14. have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study (for example, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis).
  15. have a personal history within the last 12 months of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest.
  16. have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years.
  17. have received an autologous or allogeneic stem-cell transplant
  18. have active bacterial or fungal infection or detectable viral infection (for example, human immunodeficiency virus [HIV] or viral hepatitis). Screening is not required for enrollment.
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