E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Brain tumours, Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 |
To evaluate abemaciclib with respect to objective intracranial response rate (OIRR; complete response [CR] + partial response [PR]) based on tumor assessments and brain metastases response criteria in women with brain metastases secondary to HR+, HER2+ and HR+, HER2- breast cancer. |
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E.2.2 | Secondary objectives of the trial |
To evaluate abemaciclib with respect to:
• Intracranial disease per brain metastases response criteria
- Best overall intracranial response (BOIR)
- Duration of intracranial response (DOIR) (CR + PR)
- Intracranial disease control rate (IDCR) (CR + PR + stable disease [SD])
- Intracranial clinical benefit rate (ICBR) (CR + PR + SD ≥6 months)
• Overall
- OS
- Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and brain metastases response criteria
- Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1 and brain metastases response criteria
- Progression free survival (PFS) per RECIST v1.1 and brain metastases response criteria
Change in symptoms as assessed by MD Anderson Symptom Inventory – Brain Tumor (MDASI-BT)
To evaluate the safety and tolerability
To determine the pharmacokinetics (PK) and its metabolites
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1] have histologically confirmed HR+ metastatic breast cancer. To fulfill the requirement for HR+ disease, a breast cancer must express, at least 1 of the hormone receptors (ER or progesterone receptor [PgR]). For ER and PgR assays to be considered positive, ≥1% of tumor cell nuclei must be immunoreactive by immunohistochemistry (IHC)
[2] For Part A: have confirmed HER2 overexpression (HER2+) status. To fulfill the requirement for HER2+ disease, tumor tissue must demonstrate 3+ by IHC or gene amplification by in-situ hybridization (ISH). For Part B: have disease which does not demonstrate HER2 overexpression (HER2-) by either IHC or ISH. For Part C (surgical): have either HER2+ or HER2- status with brain lesion(s) for which surgical resection is clinically indicated and agree to provide posttreatment (5 to 14 days after initiating abemaciclib) brain tumor tissue.
[3] For Parts A and B: have ≥1 new or not previously irradiated measurable metastatic brain lesion ≥10 mm in the longest diameter (LD) or a progressive previously irradiated metastatic brain lesion on radiographic imaging by gadolinium-enhanced magnetic resonance imaging (Gd MRI). Note: for patients with prior WBRT or SRS, previously irradiated lesion(s) must demonstrate unequivocal progression on baseline Gd MRI in the opinion of the investigator. Otherwise new or not previously irradiated lesions must be present. For Part C (surgical): have 1 to 3 metastatic brain lesion(s) for which surgical resection is clinically indicated.
[4] have completed local therapy (surgical resection, WBRT, or SRS) ≥14 days prior to initiating abemaciclib and recovered from all acute effects. Patients are not required to have received prior local therapy for study participation.
[5] if receiving concomitant corticosteroids, must be on a stable or decreasing dose for at least 7 days prior to the baseline Gd-MRI.
[6] have a Karnofsky performance status of ≥70
[7] have a life expectancy ≥12 weeks.
[8] if currently receiving endocrine therapy, a patient may continue to receive the same endocrine therapy provided that extracranial disease is stable for at least 3 months and intracranial disease progression has occurred while on this endocrine therapy. If these conditions are not met, patients must discontinue endocrine therapy prior to initiation of abemaciclib.
[9] have discontinued all previous therapies for cancer (including cytotoxic chemotherapy, targeted therapy [including, but not limited to, everolimus], radiotherapy, immunotherapy, and investigational therapy) for at least 14 days prior to receiving abemaciclib and recovered from the acute effects of therapy (treatment related toxicity resolved to baseline) except for residual alopecia or peripheral neuropathy. Note: patients currently receiving trastuzumab and receiving clinical benefit may continue to receive trastuzumab throughout the study. Concurrent treatment with trastuzumab emtansine (T-DM1) is not allowed.
[10] for patients receiving concurrent trastuzumab, must have left ventricular ejection fraction within investigative site’s normal range.
[11] have adequate organ function including:
• Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and hemoglobin ≥ 8 g/dL. Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator.
• Hepatic: Bilirubin ≤ 1.5 times upper limits of normal (ULN), 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.
[12] are female and ≥ 18 years of age.
[13] if a female of childbearing potential, must have a negative serum pregnancy test within 7 days of the first dose of abemaciclib and agree to use a medically approved nonhormonal contraceptive method during the treatment period and for 3 months following the last dose of abemaciclib. Contraceptive methods may include an intrauterine device [IUD] or barrier method. If condoms are used as a barrier method, a spermicidal agent should be added as a double barrier protection.
[14] are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures.
[15] are able to swallow capsules.
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E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[16] require immediate local therapy, including but not limited to WBRT, SRS, or surgical resection, for treatment of brain metastases.
[17] require concurrent anticancer treatment at any time during the study treatment period. Note: exceptions are endocrine therapy, trastuzumab (HER2+ patients), or surgical resection (Part C patients only).
[18] are taking concurrent enzyme-inducing antiepileptic drugs (EIAED).
[19] have evidence of significant (ie, symptomatic) intracranial hemorrhage.
[20] have evidence of leptomeningeal metastases on brain Gd-MRI or by previously documented CSF cytology. Note: discrete dural metastases are permitted.
[21] have experienced >2 seizures within 4 weeks prior to study entry.
[22] have visceral crisis. 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.
[23] have previously received treatment with any CDK4/6 inhibitor.
[24] have known contraindication to Gd-MRI.
[25] are currently receiving lapatinib.
[26] are currently enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or device (other than the study drug used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
[27] have received treatment with a drug that has not received regulatory approval for any indication within 14 days of the initial dose of abemaciclib.
[28] have a personal history within the last 12 months of any ventricular arrhythmia (including but not limited to ventricular tachycardia and ventricular fibrillation) or sudden cardiac arrest.
[29] 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).
[30] have a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea.
[31] have 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.
[32] are lactating.
[33] have an active systemic fungal and/or known viral infection (for example, human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C antibodies). Screening is not required for enrollment.
[34] have an acute bacterial infection requiring intravenous antibiotics.
[35] have received recent (within 28 days of initial dose of abemaciclib) or concurrent yellow fever vaccination.
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective Intracranial Response Rate (OIRR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to Objective Disease Progression (Approximately 6 Months) |
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E.5.2 | Secondary end point(s) |
Best Overall Intracranial Response (BOIR)
Duration of Intracranial Response (DOIR)
Intracranial Clinical Benefit Rate (ICBR)
Overall Survival
Objective Response Rate (ORR)
Disease Control Rate (DCR)
Progression Free Survival
Change from Baseline to End of Study in Neurologic Symptoms on the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) Scale
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Abemaciclib and its Metabolites
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline to Earliest Objective Progression or Start of New Anticancer Therapy (Approximately 6 Months)
Date of Complete Response or Partial Response to Date of Objective Disease Progression or Death from Any Cause (Approximately 6 Months)
Baseline to Disease Progression or Start of New Anticancer Therapy (Approximately 6 Months)
Baseline to Death from Any Cause (Approximately 18 Months)
Baseline to Disease Progression (Approximately 6 Months)
Baseline to Disease Progression or Start of New Anticancer Therapy (Approximately 6 Months)
Baseline to Objective Disease Progression or Death from Any Cause (Approximately 6 Months)
Baseline, End of Study (Approximately 6 Months)
Cycle 1 through Cycle 4 (Approximately 3 Months)
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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 | No |
E.6.11 | Pharmacogenomic | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Austria |
Belgium |
Canada |
France |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
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End of trial refers to the date of the last visit or last scheduled procedure for the last patient. The end of trial occurs after study completion and after the last patient has discontinued study treatment and completed any applicable continued access follow-up |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |