E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Brain tumors, 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 | 20.0 |
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 |
The primary objective of this study is to evaluate abemaciclib with respect to OIRR (complete response [CR] + partial response [PR]) based on tumor assessments and Response Assessment in Neuro-Oncology brain metastases response assessment criteria (RANO-BM):
• in patients with brain metastases secondary to HR+, HER2+ breast cancer.
• in patients with brain metastases secondary to HR+, HER2- breast cancer.
• in patients with brain metastases secondary to NSCLC.
• in patients with brain metastases secondary to melanoma.
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E.2.2 | Secondary objectives of the trial |
Evaluate abemaciclib with respect to:
- Intracranial disease per RANO-BM
- 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
- Overall survival (OS)
- Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and RANO-BM
- Disease control rate (DCR) (CR+ PR+ SD) per RECIST v1.1 and RANO-BM
- Progression free survival (PFS) per RECIST v1.1 and RANO-BM
- Change in symptoms as assessed by MD Anderson Symptom Inventory – Brain Tumor (MDASI-BT)
- Safety and tolerability
- PK of abemaciclib 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 brain metastases secondary to histologically or cytologically confirmed HR+ breast cancer, NSCLC, or melanoma.
For Parts A and B: have confirmed HR+ 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) (Hammond et al. 2010).
For Part A: have HR+ breast cancer with 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) (Wolff et al. 2013).
For Part B: have HR+ breast cancer which does not demonstrate HER2 overexpression (HER2-) by either IHC or ISH.
For Part C: have HR+ breast cancer, NSCLC, or melanoma with brain lesions for which surgical resection is clinically indicated and agree to provide posttreatment (5 to 14 days after initiating abemaciclib) brain tumor tissue.
For Part D: have NSCLC of any subtype. Patients must have known KRAS mutation status by local test. If unknown or not done, whole block, partial block, or unstained slides must be available for submission.
For Part E: have melanoma of any subtype
For Part F: have HR+ breast cancer, NSCLC, or melanoma with leptomeningeal metastases by documented positive CSF cytology or by clinical signs and symptoms associated with abnormal magnetic resonance imaging (MRI) features. Concomitant parenchymal brain metastases are allowed (not required), but must be stable for at least 4 weeks following whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS).
[2] Deleted criterion.
[3] For Parts A,B, D and E: 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).
For Part C (surgical): have 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 (see Attachment 4).
[7] have a life expectancy ≥12 weeks.
[8] for HR+ breast cancer patients in Parts A, B, C, and F: 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 CNS 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.
For HER2+ breast cancer patients in Parts A, C, and F: patients may receive concurrent treatment (ongoing or initiated simultaneously with abemaciclib) with intravenous (IV) trastuzumab. Concurrent treatment with trastuzumab emtansine (T-DM1) is not allowed.
For NSCLC patients in Parts C, D, and F: if currently receiving gemcitabine or pemetrexed (single-agent or in combination with another therapy), a patient may continue to receive 1 of these 2 therapies as a single agent provided that extracranial disease is stable for at least 6 weeks and CNS disease progression has occurred while on this therapy. Combination therapies (aside from gemcitabine or pemetrexed) must be discontinued for at least 14 days 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.
[10] for HER2+ breast cancer patients in Parts A, C, and F: patients receiving concurrent IV trastuzumab, must have left ventricular ejection fraction within investigative site’s normal range. |
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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.
[18] are taking concurrent enzyme-inducing antiepileptic drugs (EIAED).
[19] have evidence of significant (ie, symptomatic) intracranial hemorrhage.
[20] for Parts A, B, C, D, and E: have evidence of leptomeningeal metastases by clinical signs and symptoms associated with abnormal MRI features or by documented CSF cytology.
[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] for Parts A, B, D, E, and F: have previously received treatment with any CDK4 and CDK6 inhibitor. Part C patients may have received prior palbociclib or ribociclib, but not abemaciclib, treatment.
[24] have known contraindication to Gd-MRI.
[25] deleted criterion.
[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 IV 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) assessed using RANO-BM |
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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) (CR + PR)
Intracranial disease control rate (IDCR)
Intracranial Clinical Benefit Rate (ICBR)
Overall Survival (OS)
Objective Response Rate (ORR)
Disease Control Rate (DCR)
Progression Free Survival (PFS)
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 | 6 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
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 | 6 |
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 |
Australia |
Austria |
Belgium |
Canada |
France |
Israel |
Italy |
New Zealand |
Spain |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
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 |