| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Brain tumors, Breast Cancer |
| Tumore del cervello, Carcinoma della mammella |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancer |
| Carcinoma della mammella |
|
| 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 |
|
| 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.
|
l¿obiettivo primario di questo studio ¿ esaminare abemaciclib in termini di OIRR (risposta completa [CR] + risposta parziale [PR]) in base alle valutazioni del tumore e ai criteri di valutazione della risposta RANO-BM (Response Assessment in Neuro-Oncology-Brain Mestastases):
¿ in pazienti con metastasi cerebrali secondarie a carcinoma mammario HR+, HER2+;
¿ in pazienti con metastasi cerebrali secondarie a carcinoma mammario HR+, HER2-;
¿ in pazienti con metastasi cerebrali secondarie a NSCLC;
¿ in pazienti con metastasi cerebrali secondarie a melanoma.
|
|
| 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 |
Gli obiettivi secondari dello studio consistono nella valutazione di abemaciclib in termini di:
¿ Malattia intracranica secondo i criteri RANO-BM
o migliore risposta intracranica globale (BOIR)
o durata della risposta intracranica (DOIR) (CR + PR)
o tasso di controllo della malattia intracranica (IDCR: CR + PR + malattia stabile [SD])
o tasso di beneficio clinico intracranico (ICBR) (CR + PR + SD =6 mesi)
¿ Malattia nel suo complesso
o sopravvivenza globale (OS)
o tasso di risposta obiettiva (ORR) secondo i criteri RECIST (Response Evaluation Criteria in Solid Tumors) versione 1.1 e RANO-BM
o tasso di controllo della malattia (DCR) (CR+ PR+ SD) secondo i criteri RECIST versione 1.1 e RANO-BM
o Sopravvivenza libera da progressione (PFS) secondo i criteri RECIST versione 1.1 e RANO-BM
¿ Variazione dei sintomi valutata mediante il questionario MDASI-BT (MD Anderson Symptom Inventory ¿ Brain Tumor)
¿ Sicurezza e tollerabilit¿
¿ PK di abemaciclib e dei relativi metaboliti
|
|
| 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.
[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. |
| 1) metastasi cerebrali secondarie a carcinoma mammario HR+, NSCLC o melanoma confermato istologicamente o citologicamente; 2) criterio eliminato; 3) =1 lesione cerebrale metastatica misurabile di nuova formazione o precedentemente irradiata con diametro massimo di =10 mm o una lesione cerebrale metastatica progressiva precedentemente irradiata (Parti A, B, D ed E) o lesioni cerebrali metastatiche per le quali è clinicamente indicata la resezione chirurgica (Parte C [chirurgica]); 4) completamento della terapia a livello locale (resezione chirurgica, radioterapia panencefalica o radiochirurgia stereotassica) =14 giorni prima dell’inizio del trattamento con abemaciclib e risoluzione di tutti gli effetti acuti; 5) se in trattamento concomitante con steroidi, la dose deve essere stabile o in diminuzione da almeno 7 giorni prima della risonanza magnetica con gadolinio (Gd); 6) performance status di Karnofsky =70; 7) aspettativa di vita =12 settimane; 8) pazienti con carcinoma mammario HR+ nelle Parti A, B, C ed F: se in trattamento con terapia endocrina, potranno proseguirla a condizione che la malattia extracranica sia stabile da almeno 3 mesi e la progressione della malattia del SNC si sia verificata durante la terapia endocrina (in assenza di questi requisiti, i pazienti dovranno interrompere la terapia endocrina prima di iniziare il trattamento con abemaciclib); pazienti con carcinoma mammario HER2+ nelle Parti A, C ed F: i pazienti potranno essere sottoposti a trattamento concomitante (in corso o iniziato contemporaneamente ad abemaciclib) con trastuzumab per via endovenosa (ev). Il trattamento concomitante con trastuzumab emtansine (T-DMI1) non è consentito; pazienti con NSCLC nelle Parti C, D ed F: se attualmente in trattamento con gemcitabina o pemetrexed (in monoterapia o in associazione a un’altra terapia), i pazienti potranno continuare a ricevere 1 di questi 2 farmaci in monoterapia a condizione che la malattia extracranica sia stabile da almeno 6 settimane e la progressione della malattia del SNC sia avvenuta durante tale terapia. Le terapie di associazione (eccetto gemcitabina e pemetrexed) devono essere state interrotte almeno 14 giorni prima dell’inizio del trattamento con abemaciclib; 9) interruzione di tutte le precedenti terapie antitumorali da almeno 14 giorni prima di iniziare la somministrazione di abemaciclib e risoluzione di tutti gli effetti acuti della terapia (nota: le eccezioni relative ai trattamenti concomitanti sono indicate al criterio [8]; 10) pazienti con carcinoma mammario HER2+ nelle Parti A, C ed F:i pazienti in trattamento concomitante con trastuzumab devono presentare una frazione di eiezione ventricolare sinistra entro il normale intervallo previsto dal centro di sperimentazione |
|
| 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. |
| I pazienti saranno esclusi dallo studio se soddisferanno uno qualsiasi dei seguenti criteri: 16) necessità immediata di sottoporsi a terapie locali, quali, a titolo di esempio, radioterapia panencefalica, radiochirurgia stereotassica o resezione chirurgica, per il trattamento delle metastasi cerebrali; 17) necessità di terapie antitumorali concomitanti in qualsiasi momento durante il periodo di trattamento in studio (a eccezione delle terapie indicate al criterio [8] o della resezione chirurgica [solo pazienti nella Parte C]); 18) trattamento concomitante con farmaci antiepilettici induttori enzimatici; 19) evidenze di significativa (ovvero sintomatica) emorragia intracranica; 20) Parti A, B, C, D ed E: evidenze di metastasi leptomeningee in base a segni e sintomi clinici associati ad anomalie alla RM o in base a una citologia del LCS precedentemente documentata; 21) >2 crisi epilettiche nelle 4 settimane precedenti l’ingresso nello studio; 22) crisi viscerale; 23) Parti A, B, D, E ed F: pregresso trattamento con un qualsiasi inibitore della CDK4 e della CDK6; i pazienti nella Parte C potranno essere stati sottoposti a un precedente trattamento con palbociclib o ribociclib, ma non con abemaciclib; 24) controindicazione nota alla RM con Gd; 25) criterio eliminato; 26) attuale partecipazione a uno studio clinico che prevede l’impiego di un prodotto sperimentale o l’utilizzo non approvato di un farmaco o un dispositivo (diverso dal farmaco sperimentale utilizzato in questo studio) o partecipazione concomitante a qualsiasi altro tipo di ricerca medica giudicata non compatibile con il presente studio da un punto di vista scientifico o medico; 27) trattamento con un farmaco che non abbia ricevuto l’approvazione regolatoria per una qualsiasi indicazione nei 14 giorni precedenti la dose iniziale di abemaciclib; 28) anamnesi personale di aritmia ventricolare di qualsiasi tipo (inclusa a titolo di esempio la tachicardia ventricolare e la fibrillazione ventricolare) o arresto cardiaco improvviso negli ultimi 12 mesi; 29) condizioni mediche preesistenti serie che, secondo il giudizio dello sperimentatore, impedirebbero la partecipazione allo studio; 30) condizione cronica preesistente che provoca diarrea di grado pari o superiore a 2 al basale; 31) anamnesi positiva per qualsiasi altro tipo di cancro (a eccezione del tumore cutaneo non melanomatoso e del carcinoma in situ della cervice), salvo in caso di remissione completa senza terapia da almeno 3 anni; 32) donne in allattamento; 33) infezione fungina sistemica in atto e/o virale nota; 34) infezione batterica acuta che richiede la somministrazione di antibiotici per via endovenosa (ev); 35) vaccinazione per la febbre gialla recente o concomitante. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Intracranial Response Rate (OIRR) assessed using RANO-BM |
| OIRR valutata utilizzando la RANO-BM |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline to Objective Disease Progression (Approximately 6 Months) |
| Dal Basaline alla Progressione obiettiva della patologia (circa 6 mesi) |
|
| 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 |
¿ Migliore risposta intracranica complessiva (BOIR)
¿ Durata della risposta intracranica (DOIR)
¿ Tasso di controllo della risposta intracranica (IDCR)
¿ Tasso di beneficio clinico a livello intracranico (ICBR)
¿ Sopravvivenza complessiva (OS)
¿ Tasso di risposta obiettiva (ORR)
¿ Tasso di controllo della patologia (DCR)
¿ Progressione libera da malattia (PFS)
¿ Cambiamento dal Basale alla Fine dello Studio nei sintomi neurologici sulla scala MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT)
¿ Farmacocinetica (PK): minima concentrazione (Cmin) di Abemaciclib e suoi metaboliti
|
|
| 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) |
¿ Dal Basale alla prima progressione obiettiva o all'inizio di una nuova terapia anti-cancro (circa 6 mesi)
¿ Data di risposta completa o risposta parziale alla data dell'obiettivo di progressione di malattia o morte da qualsiasi altra causa (circa 6 mesi)
¿ Dal Baseline alla morte per qualsiasi causa (circa 18 mesi)
¿ Dal Baseline alla progressione di malattia (circa 6 mesi)
¿ Dal Baseline ala Progressione di malattia o l'inizio di una nuova terapia anti tumorale (circa 6 mesi)
¿ Dal Baseline alla progressione di malattia obiettiva o morte per qualsiasi causa (approssimativamente 6 mesi)
¿ Baseline, Fine dello Studio (circa 6 mesi)
¿ Dal Ciclo 1 al Ciclo 4 (Circa 3 mesi) |
|
| 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 | Yes |
| 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) | Yes |
| 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
| 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 | 4 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| 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 |
| La fine dello studio si riferisce all'ultima visita o all'ultima procedura programmata per l'ultimo paziente. La fine dello studio avviene dopo il completamento dello studio e dopo che l'ultimo paziente ha sospeso il trattamento in studio e completato ogni continued access follow up applicabile |
|
| 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 | 0 |
| 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 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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