| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of Study JPBL is to compare LY2835219 plus fulvestrant versus placebo plus fulvestrant with respect to PFS for women with HR+, HER2- locally advanced or metastatic breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to compare LY2835219 plus fulvestrant versus placebo plus fulvestrant with respect to each of the following:
•overall survival (OS)
•OS rate at 1, 2, and 3 years
•objective response rate
•duration of response
•disease control rate
•clinical benefit rate
•safety and tolerability
•pain and symptom burden using the Brief Pain Inventory (BPI), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the EORTC QLQ-BR23 (breast) questionnaires, and health status scores from the EuroQol 5-Dimension 5 Level (EQ-5D 5L)
•pharmacokinetics (PK) of LY2835219, its metabolites, and fulvestrant |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum I3Y-MC-JPBL(7.3) MONARCH 2: A Randomized,
Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or
without Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone
Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast
Cancer.
The purpose of the addendum: This protocol addendum contains specific
information for MONARCH 2 study and applies only to the Endocrine-
Naive (EN) Addendum Cohort.
Rationale for Addendum 7.3: FDA feedback indicated that a 95% Confidence Interval (CI) should be used for the analysis of the primary
endpoint Objective Response Rate (ORR), instead of the 90% CI. As a
result, the 90% CI was changed to a 95% CI for the ORR analysis
throughout the document. Sample size determination was also adjusted
accordingly for a 95% CI.
Protocol Addendum I3Y-MC-JPBL(8) MONARCH 2 : A Randomized,
Double-Blind, Placebo-Controlled, Phase 3 Study of Fulvestrant with or
without Abemaciclib, a CDK4/6 Inhibitor, for Women with Hormone
Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast
Cancer.
The primary objective of the tissue addendum is to profile the molecular
changes after a prolonged response to treatment. |
|
| E.3 | Principal inclusion criteria |
•Have a diagnosis of HR+, HER2- breast cancer
•Have locally advanced disease not amenable to curative treatment by surgery or metastatic disease. In addition, participants must fulfill 1 of
the following criteria:
- relapsed with radiologic evidence of progression while receiving
neoadjuvant or adjuvant endocrine therapy, with no subsequent
endocrine therapy received following progression
- relapsed with radiologic evidence of progression within 1 year from
completion of adjuvant endocrine therapy, with no subsequent endocrine
therapy received following progression
- relapsed with radiologic evidence of progression more than 1 year from
completion of adjuvant endocrine therapy and then subsequently
relapsed with radiologic evidence of progression after receiving
treatment with either an antiestrogen or an aromatase inhibitor as
firstline
endocrine therapy for metastatic disease. Patients may not have
received more than 1 line of endocrine therapy or any prior
chemotherapy for metastatic disease
- presented de novo with metastatic disease and then relapsed with
radiologic
evidence of progression after receiving treatment with either an
antiestrogen or an aromatase inhibitor as first-line endocrine therapy for
metastatic disease. Patients may not have received more than 1 line of
endocrine therapy or any prior chemotherapy for metastatic disease
•Have postmenopausal status due to either surgical/natural menopause or ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin
•Have a negative serum pregnancy test at baseline (within 14 days prior to randomization) and agree to use medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of abemaciclib if postmenopausal status is due to ovarian suppression with a GnRH agonist
•Have either measurable disease or nonmeasurable bone only disease
•Have a performance status ≤1 on the ECOG scale
•Have discontinued previous therapies for cancer (including specifically, aromatase inhibitors, anti-estrogens, chemotherapy, radiotherapy, and immunotherapy) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, 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 |
|
| E.4 | Principal exclusion criteria |
• 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
• 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
• Have clinical evidence or history of central nervous system metastasis
• Have received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant, everolimus, or any CDK4/6 inhibitor
• Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days prior to randomization of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively
• Have received recent (within 28 days prior to randomization) yellow fever vaccination
• Have had major surgery within 14 days prior to randomization of study drug to allow for post-operative healing of the surgical wound and site(s)
• 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
• Have a personal history of any of the following conditions: presyncope or syncope of either unexplained or cardiovascular etiology, ventricular tachycardia, ventricular fibrillation, or sudden cardiac arrest
• Have inflammatory breast cancer or a history of any other cancer (except nonmelanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission with no therapy for a minimum of 3 years
• Have received an autologous or allogeneic stem-cell transplant
• Have active bacterial or fungal infection, or detectable viral infection
• Have initiated bisphosphonates or approved RANK ligand (RANK-L)
targeted agents (for example, denosumab) <7 days prior to
randomization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline up to Approximately 31 Months |
|
| E.5.2 | Secondary end point(s) |
- Overall Survival (OS)
- Objective Response Rate
- Duration of Response (DoR)
- Disease Control Rate (DCR)
- Clinical Benefit Rate (CBR)
- Pharmacokinetics (PK): Area Under the Concentration Curve (AUC) of LY2835219, Its Metabolites, and Fulvestrant
- Change from Baseline in Health Status Using the EuroQol 5-Dimension 5 Level (EQ-5D 5L)
- Change from Baseline in Quality of Life Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
- Change from Baseline in Quality of Life using the EORTC QLQ-BR23 (breast) Questionnaire
- Change from Baseline in Pain and Symptom Burden Assessment Using the Brief Pain Inventory (BPI) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Baseline up to Approximately 80 Months for OS.
-Baseline up to Approximately 31 Months for ORR, DoR, DCR, CBR, PK, time to worsening of ECOG, time to SRE.
-Baseline, End of Study (up to approximately 31 months) for changes from baseline in EQ-5D 5L, EORTC QLQ-C30, EORTC QLQ-BR23, BPI.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| United States |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Italy |
| Poland |
| Romania |
| Spain |
| Switzerland |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 9 |
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