CARFI NMSG#20/13klinikinio tyrimo pristatymas

Valdas Pečeliūnas

Carfilzomibas

• Antros kartos proteosomų inhibitorius• Epoximicino derivatas (natūraliai bakterijų iškiriama

medžiaga)• Negrįžtamai inhibuoja 20S proteosomą• Carfi/Len/Dex FDA patvirtintas recidyvavusios

mielomos gydymui 2012 metais.

Carfilzomib Bortezomib

Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma

by Hervé Avet-Loiseau, Rafael Fonseca, David Siegel, Meletios A. Dimopoulos, Ivan Špička, Tamás Masszi, Roman Hájek, Laura Rosiñol, Vesselina Goranova-Marinova,

Georgi Mihaylov, Vladimír Maisnar, Maria-Victoria Mateos, Michael Wang, Ruben Niesvizky, Albert Oriol, Andrzej Jakubowiak, Jiri Minarik, Antonio Palumbo, William Bensinger, Vishal Kukreti, Dina Ben-Yehuda, A. Keith Stewart, Mihaela Obreja, and

Philippe Moreau

BloodVolume 128(9):1174-1180

September 1, 2016

©2016 by American Society of Hematology

ASPIRE trial

Kaplan-Meier estimate of PFS by cytogenetic risk status at baseline.

Hervé Avet-Loiseau et al. Blood 2016;128:1174-1180

©2016 by American Society of Hematology

ASPIRE trial

Carfilzomibas/ciklofosfamidas deksametazonasatsakas į I-os eilės gydymą

VISTA trial VMP- CR30%- >PR71%

OS CCD &MPV (VISTA)

Šalutinės reakcijosŠIRDIES NEPAKANKAMUMAS, MIOKARDO INFARKTAS, IŠEMIJA (7 – 2 – 1 %)

In clinical studies with Kyprolis, cardiac failure was reported in approximately 7% of subjects, MI was reported in approximately 2% of subjects and myocardial ischaemia was reported in approximately 1% of subjects. These events typically occurred early in the course of Kyprolis therapy (< 5 cycles).

DUSULYS (30%)

Dyspnoea was reported in approximately 30% of subjects in clinical studies with Kyprolis. The majority of dyspnoea adverse reactions were non-serious (< 5% of subjects had grade ≥ 3 events), resolved, rarely resulted in treatment discontinuation, and had an onset early in the course of study (< 3 cycles).

HIPERTENZIJA IR HIPERTENZINĖS KRIZĖS (20%)

Hypertensive crises (hypertensive urgency or hypertensive emergency) have occurred following administration of Kyprolis. Some of these events have been fatal. In clinical studies, hypertension adverse events occurred in approximately 20% of subjects and approximately 6% of subjects had grade ≥ 3 hypertension events, but hypertensive crises occurred in < 0.5% of subjects. The incidence of hypertension adverse events was similar between those with or without a prior medical history of hypertension.

Šalutinės reakcijos

TROMBOCITOPENIJA (40%)

Thrombocytopenia was reported in approximately 40% of subjects in clinical studies with Kyprolis and approximately 20% of subjects had grade ≥ 3 events. Kyprolis causes thrombocytopenia through inhibition of platelet budding from megakaryocytes resulting in a classic cyclical thrombocytopenia with platelet nadirs occurring on day 8 or 15 of each 28-day cycle and usually associated with recovery to baseline by the start of the next cycle.

VENŲ TROMBOEMBOLIJA (10,6%)

Cases of venous thromboembolic events, including deep vein thrombosis and pulmonary embolism with fatal outcomes, have been reported in patients who received Kyprolis (see section 4.4). The overall incidence of venous thromboembolic events was higher in the Kyprolis arms of two phase 3 studies. In study 2011 003 the incidence of venous thromboembolic events was 10.6% in the Kd arm and 3.1% in the bortezomib plus dexamethasone (Vd) arm. Grade ≥ 3 venous thromboembolic events were reported in 3.0% of patients in the Kd arm and 1.5% of patients in the Vd arm.

POLINEUROPATIJA (6%)

In a randomised, open-label multicentre study in patients receiving Kyprolis 20/56 mg/m2 infused over 30 minutes in combination with dexamethasone (Kd, n = 464) vs bortezomib plus dexamethasone (Vd, n = 465), cases of grade 2 and higher peripheral neuropathy were reported in 6% compared with 32% in the Vd arm

CARFI NMSG#20/13įtraukimo/atmetimo kriterijai

Įtraukimas

• Myeloma diagnosis according to IMWG criteria

• First treatment demanding relapse after HDT

• More than 2.0 x 106 CD34+ stem cells/kg body weight in the freezer for stem cell support

• Signed informed consent given prior to any study related activities have been performed

• Age > 18 years

Atmetimas• Allogeneic transplantation scheduled as a part of the treatment• Treatment demanding relapse less than one year after HDT• Myeloma treatment after the first HDT• Patients not having received HDT as first line treatment• Previous treatment with carfilzomib• Expected survival of less than six months• Performance status (WHO) 3• Serum M-component < 5 g/l and urine M-component < 200 mg/l• Any of the following laboratory abnormalities:• Absolute neutrophil count (ANC) < 1.0 × 109/L• Hemoglobin < 5 mmol/L ( 50%)• Serum ALT or AST > 3.5 times, direct bilirubin > 34 μmol/L (2 mg/dL)• Creatinine clearance (CrCl) < 15 mL/minute.• Neuropathy rrades 3–4, or grade 2 with pain within 14 days prior to enrolment• Severe cardiovascular disease ( MI

CARFI NMSG#20/13tyrimo eiga

Tyrimo procedūros: ištyrimas

Tyrimo procedūro: gydymas

Tyrimo eigaPaciento Nr. Lytis Gimimo data Amžius BSA (m²) Dozė (mg) Pradžios data (A1) Sulašinta dozių

1. 79 moteris 1952‐04‐05 64 2,2 79 2016‐07‐19 13

2. 81 moteris 1950‐04‐22 66 1,7 60 2016‐07‐28 12

3. 87 moteris 1959‐05‐11 57 2,0 71 2016‐09‐05 4

Screening Period

Evaluation Visit E (

Karfilzomibas

• Milteliai infuziniam tirpalui;• 60 mg karfilzomibo buteliuke (atskiedus – 2 mg/ml);

• Laikymo sąlygos ‐ šaldytuve (2‐8°C).

Karfilzomibo paruošimas1. Vaistas išimamas iš šaldytuvo prieš pat naudojimą.2. Dozė (mg/m²) ir buteliukų kiekis apskaičiuojamas pagal pradinį kūno 

paviršiaus plotą (BSA), nustatytą prieš pirmąją infuziją (A1 vizito metu).• Pacientai, kurių BSA > 2.2 m², turėtų gauti dozę, skaičiuojamą pagal BSA=2.2 m².• Dozė nekoreguojama, svoriui keičiantis 

Karfilzomibo suleidimas• Paruoštas vaistas iki suleidimo gali būti laikomas:

• šaldytuve (2‐8°C) iki 24 valandų;• kambario temperatūroje (15‐30°C) iki 4 valandų.

• Prieš karfilzomibo infuziją pacientui leidžiama 250 ml 0,9% NaCltirpalo.

• A1 ir A2 vizitų metu leidžiama 20 mg/m² karfilzomibo dozė, per 10 min;

• likusių vizitų metu leidžiama 36 mg/m² karfilzomibo dozė, per 30 min.

Šalutiniai reiškiniai

AE\Pacientas 79 81 87

Prakaitavimas ✓Hipertenzija ✓Silpnumas ✓Subfebrilus karščiavimas ✓Atsiradęs/sustiprėjęs nugaros skausmas ✓ ✓Padažnėjęs šlapinimasis ✓Mėšlungis ✓