qanastek/EMEA-V3 huggingface dataset:
In locally recurrent and metastatic breast cancer, Grade 3-5 wound healing complications were observed in 1.1% of patients receiving Avastin + paclitaxel and in none of the patients receiving paclitaxel alone.
F’ kanċer tas- sider lokalizzat, rikorrenti u li mmetastatizza, kienu osservati komplikazzjonijiet ta ’ Grad 3- 5 fil- fejqan tal- feriti f’ 1. 1% tal- pazjenti li kienu qed jirċievu Avastin + paclitaxel u fl- ebda wieħed mill- pazjenti li kienu qed jirċievu paclitaxel waħdu.
Hypertension (see section 4.4):
Pressjoni Għolja (ara sezzjoni 4. 4):
An increased incidence of hypertension (all grades) of up to 34% has been observed in Avastin-treated patients in clinical trials compared with up to 14% in those treated with comparator.
Żjieda fl- inċidenza ta ’ pressjoni għolja (kull grad) sa 34% ġiet osservata fi provi kliniċi f’ pazjenti kkurati b’ Avastin meta mqabbla ma ’ żjieda sa 14% f’ dawk ikkurati bil- paragun.
Grade 3 and 4 hypertension (requiring oral anti-hypertensive medication) in patients receiving Avastin ranged from 3.0% to 17.9%.
Pressjoni għolja ta ’ Grad 3 u 4 (li kienet tinħtieġu mediċini anti- ipertensivi) f’ pazjenti li kienu qed jirċievu Avastin varjat minn 3. 0% sa 17. 9%.
Grade 4 hypertension (hypertensive crisis) occurred in up to 1.0% of patients treated with Avastin and chemotherapy compared to up to 0.2% of patients treated with the same chemotherapy alone.
Pressjoni għolja ta ’ Grad 4 (kriżi ipertensiva) seħħet f’ mhux aktar minn 1. 0% tal- pazjenti kkurati b’ Avastin u kimoterapija meta mqabbla ma ’ mhux aktar minn 0. 2% tal- pazjenti kkurati bl- istess kimoterapija waħedha.
Hypertension was generally adequately controlled with oral anti-hypertensives such as angiotensin-converting enzyme inhibitors, diuretics and calcium-channel blockers.
Il- pressjoni għolja ġeneralment kienet ikkontrollata b’ mod xieraq permezz ta ’ anti- ipertensivi orali bħal inibituri ta ’ l- enżima li tibdel angiotensin, dijuretiċi u mblokkaturi tal- kanali tal- kalċju.
It rarely resulted in discontinuation of Avastin treatment or hospitalisation.
Rarament irriżultat fil- waqfien tal- kura b’ Avastin jew żmien fl- isptar.
Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal.
9 Każijiet rari ħafna ta ’ enċefalopatija ipertensiva, uħud minnhom fatali, ġew irrapurtati.
The risk of Avastin-associated hypertension did not correlate with the patients’ baseline characteristics, underlying disease or concomitant therapy.
Ir- riskju ta ’ pressjoni għolja assoċjata ma ’ Avastin ma kkorrelax mal- linja bażi tal- karatteristiċi tal - pazjenti, mard eżistenti jew kura oħra fl- istess waqt.
Proteinuria (see section 4.4):
Proteina fl- awrina (ara sezzjoni 4. 4):
In clinical trials, proteinuria has been reported within the range of 0.7% to 38% of patients receiving Avastin.
Fi provi kliniċi, proteina fl- awrina kienet irrappurtata fil- firxa ta ’ 0. 7% sa 38% tal- pazjenti li kienu qed jirċievu Avastin.
Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the great majority as Grade 1 proteinuria.
Proteina fl- awrina, varjat fis- severità minn klinikament bla sintomi, temporanja, traċċa ta ’ proteina fl - awrina għal sindromu nefrotiku, bil- maġġoranza tkun proteina fl- awrina ta ’ Grad 1.
Grade 3 proteinuria was reported in < 3% of treated patients: however, in patients treated for advanced and/ or metastatic renal cell carcinoma this was up to 7%.
Proteina fl- awrina ta ’ Grad 3 kienet irrappurtata f ’ < 3% tal- pazjenti kkurati; iżda, f’ pazjenti kkurati għall- karċinoma avvanzata u/ jew metastatika taċ- ċelluli renali dan kien sa 7%.
Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients.
Proteina fl- awrina ta ’ Grad 4 (sindromu nefrotiku) kienet osservata f’ mhux aktar minn 1. 4% tal- pazjenti kkurati.
The proteinuria seen in clinical trials was not associated with renal dysfunction and rarely required permanent discontinuation of therapy.
Il- proteina fl- awrina li dehret fil- provi kliniċi ma kienetx assoċjata ma ’ funżjoni ħażina tal- kliewi u rarament kienet teħtieġ waqfien għal kollox tal- kura.
Testing for proteinuria is recommended prior to start of Avastin therapy.
Ittestjar għall- proteina fl- awrina huwa rakkomandat qabel tinbeda terapija b’ Avastin.
In most clinical studies urine protein levels of ≥ 2g / 24 hrs led to the holding of Avastin until recovery to < 2g/ 24 hrs.
Fil- biċċa l- kbira ta ’ l- istudji kliniċi livelli ta ’ proteina fl- awrina ta ’ ≥ 2g / 24 hrs wasslu għal twaqqif ta ’ Avastin sakemm irpiljaw għal < 2g/ 24 hrs.
9 Haemorrhage (see section 4.4):
Emorraġija (ara sezzjoni 4. 4):
In clinical trials across all indications the overall incidence of NCI-CTC Grade 3-5 bleeding events ranged from 0.4% to 5% in Avastin treated patients, compared with up to 2.9% of patients in chemotherapy control group.
Fi provi kliniċi bl- indikazzjonijiet kollha, l- inċidenza globali ta ’ episodji ta ’ fsada ta ’ Grad NCI- CTC 3 - 5 varjat minn 0. 4% sa 5% fil- pazjenti kkurati b’ Avastin, meta mqabbla ma ’ inċidenza sa 2. 9% tal - pazjenti fil- grupp ta ’ kontroll b’ kimoterapija.
The haemorrhagic events that have been observed in clinical studies were predominantly tumour- associated haemorrhage (see below) and minor mucocutaneous haemorrhage (e. g. epistaxis).
L- episodji ta ’ emorraġija li ġew osservati fl- istudji kliniċi kienu fil- maġġoranza emorraġija assoċjata mat- tumur (ara isfel) u emorraġija mukokutanja ħafifa (e. ż. epistassi).
Tumour-associated haemorrhage (see section 4.4).
Emorraġija assoċjata mat- tumur (ara sezzjoni 4. 4).
Major or massive pulmonary haemorrhage/ haemoptysis has been observed primarily in studies in patients with non-small cell lung cancer (NSCLC).
Emorraġija fil- pulmun/ emoptisi maġġuri jew massiva kienet osservata primarjament fi studji b’ pazjenti b’ kanċer taċ- ċelluli mhux żgħar tal- pulmun (NSCLC).
Possible risk factors include squamous cell histology, treatment with antirheumatic/ anti-inflammatory drugs, treatment with anticoagulants, prior radiotherapy, Avastin therapy, previous medical history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy.
Fatturi ta ’ riskju possibli jinkludu istoloġija ta ’ ċelluli skwamużi, kura b’ mediċini anti- rewmatiċi/ anti- infjammatorji, kura b’ sustanzi kontra l- koagulazzjoni tad- demm, radjuterapija minn qabel, terapija b’ Avastin, passat mediku minn qabel ta ’ arterjosklerożi, tumur f’ lok ċentrali u formazzjoni ta ’ ħofra fir- tumuri qabel jew waqt it - terapija.
The only variables that showed statistically significant correlations with bleeding were Avastin therapy and squamous cell histology.
L- uniċi varjabbli li wrew relazzjoni statistikament sinifikanti ma ’ fsada kienu terapija b’ Avastin u istoloġija ta ’ ċelluli skwamużi.
Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell histology were excluded from subsequent phase III studies, while patients with unknown tumour histology were included.
Pazjenti b’ NSCLC b’ istoloġija ta ’ ċelluli skwamużi magħrufa jew tipi ta ’ ċelluli mħallta bi predominanza ta ’ ċelluli skwamużi kienu esklużi minn studji ta ’ wara ta ’ fażi III, waqt li pazjenti b’ tumuri b’ istoloġija mhux magħrufa kienu inklużi.
In patients with NSCLC excluding predominant squamous histology, all grade events were seen with a frequency of up to 9% when treated with Avastin plus chemotherapy compared with 5% in the patients treated with chemotherapy alone.
F’ pazjenti b’ NSCLC, barra minn istoloġija bi predominanza ta ’ ċelluli skwamużi, l- episodji ta ’ kull grad dehru bi frekwenza sa 9% meta kkurati b’ Avastin flimkien ma ’ kimoterapija meta mqabbel ma ’ 5% f’ pazjenti kkurati b’ kimoterapija biss.
Grade 3-5 events have been observed in up to 2.3% of patients treated with Avastin plus chemotherapy as compared with < 1% with chemotherapy alone.
Episodji ta ’ Grad 3- 5 kienu osservati f’ sa 2. 3% tal- pazjenti kkurati b’ Avastin flimkien ma ’ kimoterapija meta mqabbel ma ’ < 1% b’ kimoterapija biss.
Major or massive pulmonary haemorrhage/ haemoptysis can occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in a fatal outcome.
Emorraġija fil- pulmun/ emoptisi maġġuri jew massiva tista ’ sseħħ f’ daqqa waħda u sa żewġ terzi tal- emorraġiji serji fil- pulmun irriżultaw f’ fatalità.
Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectal cancer patients, and have been assessed as tumour-associated haemorrhages.
Emorraġiji gastro- intestinali, inkluż fsada mir- rektum u melaena kienu rrappurtati f’ pazjenti b’ kanċer tal- kolorektum, u kienu stmati bħala emorraġiji assoċjati mat- tumur.
Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including a case of central nervous system (CNS) bleeding in a patient with hepatoma with occult CNS metastases (see section 4.3) and another patient who developed continuous oozing of blood from a thigh sarcoma with necrosis.
Emorraġija assocjata mat- tumur rarament dehret wkoll f’ tipi u postijiet oħra ta ’ tumur, inkluż każ ta ’ fsada fis- sistema nervuża ċentrali (CNS) f’ pazjent b’ hepatoma b’ metastażi okkulta fis- CNS (ara sezzjoni 4. 3) u pazjent ieħor li żviluppa fsada kontinwa minn sarkoma b’ nekrożi fil- koxxa.
Across all clinical trials, mucocutaneous haemorrhage has been seen in 20% - 40% of Avastin- treated patients.
Tul il- provi kliniċi kollha, emorraġija mukokutanja dehret f’ 20% - 40% tal- pazjenti kkurati b’ Avastin.
These were most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes in the Avastin treatment regimen.
Dawn kienu l- biċċa l- kbira epistassi ta ’ Grad NCI- CTC 1 li damu inqas minn 5 minuti, fiequ mingħajr kura medika u ma ’ kienux jinħtieġu tibdil fid- dożaġġ ta ’ kura b’ Avastin.
Clinical safety data suggest that the incidence of minor mucocutaneous haemorrhage (e. g. epistaxis) may be dose-dependent.
Tagħrif dwar is- sigurtà klinika jissuġġerixxi li l- inċidenza ta ’ emorraġija mukokutanja minuri (e. ż. epistassi) tista ’ tkun dipendenti mid- doża.
There have also been less common events of minor mucocutaneous haemorrhage in other locations, such as gingival bleeding or vaginal bleeding.
10 Kien hemm ukoll episodji anqas komuni ta ’ emorraġija mukokutanja ħafifa f’ postijiet oħra, bħal fsada mil- ħanek jew fsada mil- vaġina.
Thromboembolism (see section 4.4):
Trombo- emboliżmu (ara sezzjoni 4. 4):
Arterial thromboembolism:
Trombo- emboliżmu arterjali:
An increased incidence of arterial thromboembolic events was observed in patients treated with Avastin across indications, including cerebrovascular accidents, myocardial infarction, transient ischemic attacks, and other arterial thromboembolic events.
Żjieda fl- avvenimenti trombo- embolitiċi arterjali kienet osservata f’ pazjenti kkurati b’ Avastin fil- firxa ta ’ l- indikazzjonijiet kollha, inkluż aċċidenti cerebrovaskulari, infart mijokardijaku, attakki iskemiċi li jgħaddu u avvenimenti trombo- embolitiċi arterjali oħrajn.
In clinical trials, the overall incidence of arterial thromboembolic events ranged up to 3.8% in the Avastin containing arms compared with up to 1.7% in the chemotherapy control arms.
Fi provi kliniċi, l- inċidenza globali ta ’ episodji trombo- embolitiċi arterjali varjaw sa 3. 8% fil- grupp b’ Avastin meta mqabbla ma ’ inċidenza sa 1. 7% fil- gruppi ta ’ kontroll b’ kimoterapija.
Fatal outcome was reported in 0.8% of patients receiving Avastin compared to 0.5% in patients receiving chemotherapy alone.
Riżultat fatali kien irrappurtat f’ 0. 8% tal- pazjenti li ngħataw Avastin, meta mqabbla ma ’ 0. 5% fil- pazjenti li rċievew kimoterapija biss.
Myocardial infarction was reported in 1.4% of patients
Aċċidenti cerebrovaskulari (inkluż attakki iskemiċi li jgħaddu) kienu rrappurtati f’ mhux aktar minn 2. 3% tal- pazjenti kkurati b’ Avastin flimkien ma ’ kimoterapija meta mqabbla ma ’ 0. 5% tal- pazjenti kkurati b’ kimoterapija biss.
10 treated with Avastin in combination with chemotherapy compared to 0.7% of patients treated with chemotherapy alone.
Infart mijokardijaku kien irrappurtat f’ 1. 4% tal- pazjenti kkurati b’ Avastin flimkien ma ’ kimoterapija meta mqabbla ma ’ 0. 7% tal- pazjenti kkurati b’ kimoterapija biss.
In one clinical trial, AVF2192g, patients with metastatic colorectal cancer who were not candidates for treatment with irinotecan were included.
Fi prova klinika, AVF2192g, kienu inklużi pazjenti b’ kanċer tal- kolorektum li mmetastatizza li ma kienux kandidati għall- kura b’ irinotecan.
In this trial arterial thromboembolic events were observed in 11% (11/ 100) of patients compared to 5.8% (6/ 104) in the chemotherapy control group.
F’ din il- prova avvenimenti trombo- embolitiċi arterjali kienu osservati f’ 11% (11/ 100) tal- pazjenti meta mqabbla ma ’ 5. 8% (6/ 104) fil- grupp ta ’ kontroll b’ kimoterapija.
Venous thromboembolism:
Trombo- emboliżmu venuż:
The incidence of venous thromboembolic events in clinical trials was similar in patients receiving Avastin in combination with chemotherapy compared to those receiving the control chemotherapy alone.
L- inċidenza ta ’ avvenimenti trombo- embolitiċi venużi fi provi kliniċi f’ pazjenti li kienu qed jirċievu Avastin flimkien ma ’ kimoterapija kienet simili għal dawk tal- kontroll li rċievew kimoterapija biss.
Venous thromboembolic events include deep venous thrombosis, pulmonary embolism and thrombophlebitis.
Avvenimenti trombo- embolitiċi venużi jinkludu trombożi fil- vini l- kbar, emboliżmu fil- pulmun u tromboflebite.
In clinical trials across indications, the overall incidence of venous thromboembolic events ranged from 2.8% to 17.3% of Avastin-treated patients compared with 3.2% to 15.6% in the control arms.
Fi provi kliniċi fil- firxa ta ’ l- indikazzjonijiet kollha, l- inċidenza globali ta ’ avvenimenti trombo - embolitiċi venużi varjaw minn 2. 8% sa 17. 3% fil- pazjenti kkurati b’ Avastin meta mqabbla ma ’ 3. 2% sa 15. 6% fil- gruppi ta ’ kontroll.
Grade 3-5 venous thromboembolic events have been reported in up to 7.8% of patients treated with chemotherapy plus bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone.
Episodji trombo- embolitiċi venużi ta ’ Grad 3- 5 ġew irrapportati f’ sa 7. 8% tal- pazjenti kkurati b’ kimoterapija flimkien ma ’ bevacizumab meta mqabbla ma ’ sa 4. 9% f’ pazjenti kkurati b’ kimoterapija waħidha.
Patients who have experienced a venous thromboembolic event may be at higher risk for a recurrence if they receive Avastin in combination with chemotherapy versus chemotherapy alone.
Pazjenti li kellhom esperjenza ta ’ avvenimenti trombo- embolitiċi venużi jistgħu jkunu f’ riskju akbar li dan jerġa jseħħ jekk jirċievu Avastin flimkien ma ’ kimoterapija kontra kimoterapija waħedha.
Congestive Heart Failure (CHF) In clinical trials with Avastin, congestive heart failure (CHF) was observed in all cancer indications studied to date, but occurred predominantly in patients with metastatic breast cancer.
Insuffiċjenza tal- Qalb Konġestiva (CHF) Fi provi kliniċi b’ Avastin, insuffiċjenza tal- qalb konġestiva (CHF) kienet osservata fl- indikazzjonijiet tal- kanċer kollha studjati s’ issa, iżda seħħet l- aktar f’ pazjenti b’ kanċer tas- sider li mmetastatizza.
In two phase III studies (AVF2119g and E2100) in patients with metastatic breast cancer an increase of CHF Grade 3 or more with Avastin was seen.
F’ żewġ provi kliniċi ta ’ Fażi III (AVF2119g u E2100) f’ pazjenti b’ kanċer tas- sider li mmetastatizza, kienet osservata żjieda fis- CHF ta ’ Grad 3 jew aktar b’ Avastin.
CHF was reported in up to 3.5% of patients treated with Avastin compared with up to 0.9% in the control arms.
CHF kienet irrapportata f’ sa 3. 5% tal - pazjenti kkurati b’ Avastin meta mqabbla ma ’ mhux aktar minn 0. 9% fil- gruppi ta ’ kontroll.
Most of these patients showed improved symptoms and/ or left ventricular function following appropriate medical therapy.
Il- biċċa l - kbira ta ’ dawn il- pazjenti kellhom titjieb fis- sintomi u/ jew fil- funzjoni ventrikolari tax- xellug wara kura medika xierqa.
In most clinical trials of Avastin, patients with pre-existing CHF of NYHA (New York Heart Association (NYHA) II-IV were excluded, therefore, no information is available on the risk of CHF in this population.
Fil- biċċa l- kbira tal- provi kliniċi b’ Avastin, pazjenti li kellhom minn qabel CHF ta ’ NYHA (New York Heart Association (NYHA) II- IV) kienu esklużi, għalhekk m’ hemm l- ebda informazzjoni disponnibli dwar ir- riskju ta ’ CHF f’ din il- popolazzjoni.
Prior anthracyclines exposure and/ or prior radiation to the chest wall may be possible risk factors for the development of CHF.
Espożizzjoni minn qabel għal anthracyclines u/ jew radjazzjoni minn qabel tal- ħajt tas- sider, jistgħu jkunu fatturi ta ’ riskju possibli għall- iżvilupp ta ’ CHF.
Elderly Patients In randomised clinical trials, age > 65 years was associated with an increased risk of developing arterial thromboembolic events, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and myocardial infarctions (MIs).
11 Pazjenti anzjani Fi provi kliniċi randomised, età > 65 sena kienet assoċjata ma ’ żjieda fir- riskju ta ’ żvilupp ta ’ episodji trombo- embolitiċi arterjali, inkluż aċcidenti ċerebrovaskulari (CVAs), attakki iskemiċi temporanji (TIAs) u infarti mijokardiċi (MIs).
Other reactions with a higher frequency seen in patients over 65 were grade 3-4 leucopenia and thrombocytopenia; and all grade neutropenia, diarrhoea, nausea, headache and fatigue as compared to those aged ≤ 65 years when treated with Avastin (see sections 4.4 and 4.8 under Thromboembolism).
Reazzjonijiet oħra bi frekwenza ogħla li kienu osservati f’ pazjenti b’ età ta ’ aktar minn 65 kienu lewkopenja u tromboċitopenja ta ’ grad 3- 4; u newtropenja ta ’ kull grad, dijarea, tqalligħ, uġigħ ta ’ ras u għejja meta mqabbla ma ’ dawk b’ età ≤ 65 sena meta kkurati b’ Avastin (ara sezzjoni 4. 4 u 4. 8 taħt Trombo- emboliżmu).
No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, hypertension, proteinuria, congestive heart failure, and haemorrhage was observed in elderly patients (> 65 years) receiving Avastin as compared to those aged ≤ 65 years treated with Avastin.
L- ebda żjieda fl- inċidenza ta ’ reazzjonijiet oħra, inkluż perforazzjoni gastro- intestinali, komplikazzjonijiet fil- fejqan tal- ferita, pressjoni għolja, proteina fl- awrina, insuffiċjenza tal- qalb konġestiva u emorraġija, ma ġew osservati f’ pazjenti anzjani (> 65 sena) li kienu qed jirċievu Avastin kif imqabbla ma ’ dawk b’ età ≤ 65 sena kkurati b’ Avastin.
Laboratory Abnormalities:
Anormalitajiet fir- riżultati tal- Laboratorju:
Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with Avastin treatment.
Tnaqqis fl- għadd ta ’ newtrofili, tnaqqis fl- għadd ta ’ ċelluli bojod tad- demm, u l- preżenza ta ’ proteina fl- awrina, jistgħu jkunu assoċjati ma ’ terapija b’ Avastin.
Across clinical trials, the following Grade 3 and 4 laboratory abnormalities occurred in patients treated with Avastin with at least a 2% difference compared to the corresponding control groups:
Tul il- provi kliniċi, l- anormalitajiet fir- riżultati tal- laboratorju ta ’ Grad 3 u 4 li ġejjin seħħew f’ pazjenti kkurati b’ Avastin b’ ta ’ mill- inqas differenza ta ’ 2% meta mqabbel mal- gruppi ta ’ kontroll li jikkorrispondu: ipergliċemija, emoglobina mnaqqsa, ipokalimja, iponatrimja, għadd ta ’ ċelluli bojod tad- demm imnaqqas, żjieda fil- proporzjon normalizzat internazzjonali (INR).
Adverse reactions reported in post-marketing setting
Reazzjonijiet avversi rrapportati fl- ambjent ta ’ wara t- tqegħid fis- suq
System Organ Class (SOC)
Sistema tal- Klassifika ta ’ l- Organi (SOC)
Reactions (frequency*)
Reazzjonijiet (frekwenza *)
Hypertensive encephalopathy (very rare) (see also section 4.4 Special warnings and precautions for use, and Hypertension in section 4.8 Undesirable Effects)
Enċefalopatija ipertensiva (rari ħafna) (ara wkoll sezzjoni 4. 4, Disturbi fis- sistema Twissijiet speċjali u prekawzjonijiet għall- użu, u Pressjoni għolja nervuża f’ sezzjoni 4. 8, Effetti mhux mixtieqa) Sindrome ta ’ Lewkoenċefalopatija Posterjuri Riversibli (rari) (ara wkoll sezzjoni 4. 4, Twissijiet speċjali u prekawzjonijiet għall- użu)
Renal Thrombotic Microangiopathy, clinically manifested as proteinuria (frequency not known).
Mikroanġjopatija Trombotika Renali, klinikament tidher bħala Disturbi vaskulari proteina fl- awrina (frekwenza mhux magħrufa).
For further information on proteinuria see section 4.4 Special warnings and precautions for use, and Proteinuria in section 4.8 Undesirable Effects.
Għall- aktar tagħrif dwar proteina fl- awrina ara sezzjoni 4. 4, Twissijiet speċjali u prekawzjonijiet għall- użu, u Proteina fl- awrina f’ sezzjoni 4. 8, Effetti mhux mixtieqa.
Dysphonia (common) * if specified, the frequency has been derived from clinical trial data
Disturbi Respiratorji, Perforazzjoni tas- septum ta ’ l- imnieħer (mhux magħrufa) Toraċiċi u Pressjoni pulmonari għolja (mhux magħrufa) Medjastinali Disfonija (komuni) * jekk speċifikata, l- frekwenza ġiet derivata minn tagħrif minn provi kliniċi
The highest dose tested in humans (20 mg/ kg of body weight, intravenous every 2 weeks) was associated with severe migraine in several patients.
L- għola doża studjata fil- bniedem (20 mg/ kg ta ’ piż tal- ġisem, ġol- vini kull ġimagħtejn) kienet assoċjata ma ’ emikranja qawwija f’ bosta pazjenti.
Antineoplastic agents, monoclonal antibody, ATC code:
Aġenti antineoplastiċi, antikorp monoklonali, Kodiċi ATC:
Mechanism of action Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells.
Mekkaniżmu ta ’ azzjoni Bevacizumab jeħel ma ’ fattur ta ’ l- iżvilupp ta ’ l- endotelju vaskulari uman (VEGF), il- mutur kruċjali ta ’ vaskuloġenesi u ta ’ anġjoġenesi u b’ hekk jimpedixxi lil VEGF milli jeħel mar- riċetturi tiegħu, Flt- 1 (VEGFR- 1) u KDR (VEGFR- 2), fuq il- wiċċ taċ- ċelluli ta ’ l- endotelju.
Neutralising the biological activity of VEGF regresses the vascularisation of tumours, normalises remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth.
Newtralizazzjoni ta ’ l- attività bijoloġika ta ’ VEGF treġġa ’ lura l- vaskularizazzjoni ta ’ tumuri, tinnormalizza l- vaskulatura tat- tumur li tibqa ’, u tinibixxi l- formazzjoni ta ’ vaskulatura ġdida tat- tumur, u b’ hekk timpedixxi t- tkabbir tat - tumur.
Pharmacodynamic effects Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in nude mice resulted in extensive anti-tumour activity in human cancers, including colon, breast, pancreas and prostate.
Effetti farmakodinamiċi L- għotja ta ’ bevacizumab, jew l- antikorp mill- ġrieden li jiġi minnhu, lill- mudelli xenotransplant ta ’ kanċer fi ġrieden għerwiena wassal għall- attività estensiva kontra t- tumur f’ kanċer uman, inkluż kolon, sider, frixa u prostata.
Metastatic disease progression was inhibited and microvascular permeability was reduced.
Progressjoni metastatika tal- marda kienet imwaqqfa u l- permjabilità mikrovaskulari mnaqqsa.
12 Clinical efficacy
Effikaċja klinika
Metastatic carcinoma of the colon or rectum (mCRC)
Karċinoma tal- kolon jew tar- rektum li mmetastatizzat (mCRC)
The safety and efficacy of the recommended dose (5 mg/ kg of body weight every two weeks) in metastatic carcinoma of the colon or rectum were studied in three randomised, active-controlled clinical trials in combination with fluoropyrimidine-based first-line chemotherapy.
Is- sigurtà u l- effikaċja tad- doża rakkomandata (5 mg/ kg ta ’ piż tal- ġisem kull ġimagħtejn) f’ karċinoma metastatika tal- kolon jew rektum ġew studjati fi 3 provi kliniċi randomised u active- controlled f’ taħlita ma ’ kimoterapija primarja bbażata fuq fluorinopyrimidine.
Avastin was combined with two chemotherapy regimens:
Avastin kien ikkombinat ma ’ żewġ dożaġġi ta ’ kimoterapija:
A weekly schedule of irinotecan/ bolus 5-fluorouracil/ folinic acid (IFL) for a total of 4 weeks of each 6 week-cycle (Saltz regimen). • AVF0780g:
Skeda ta ’ kull ġimgħa ta ’ irinotecan/ bolus 5- fluorouracil/ folinic acid (IFL) għal total ta ’ 4 ġimgħat ta ’ kull ċiklu ta ’ 6 ġimgħat (dożaġġ Saltz). • AVF0780g:
In combination with bolus 5-fluorouracil/ folinic acid (5-FU/ FA) for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen). • AVF2192g:
F’ taħlita ma ’ 5- fluorouracil / folinic acid (5- FU/ FA) bħala bolus għal total ta ’ 6 ġimgħat ta ’ kull ċiklu ta ’ 8 ġimgħat (dożaġġ Roswell Park). • AVF2192g:
In combination with bolus 5-FU/ FA for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) in patients who were not optimal candidates for first-line irinotecan treatment.
F’ taħlita ma ’ 5- FU/ FA bħala bolus għal total ta ’ 6 ġimgħat ta ’ kull ċiklu ta ’ 8 ġimgħat (dożaġġ Roswell Park) f’ pazjenti li ma kienux l- aħjar kandidati għall- kura primarja b ’ irinotecan.
Two additional studies were conducted in first (NO16966) and second line (E3200) treatment of metastatic carcinoma of the colon or rectum, with Avastin administered in the following dosing regimens, in combination with FOLFOX-4 (5FU/ LV/ Oxaliplatin) and XELOX (Capecitabine/ Oxaliplatin):
Saru żewġ studji oħra fil- kura preferita (NO16966) u sekondarja (E3200) ta ’ karċinoma metastatika tal- kolon jew tar- rektum, b’ Avastin mogħti fil- korsijiet ta ’ dożaġġ li gejjin, flimkien ma ’ FOLFOX- 4 (5FU/ LV/ Oxaliplatin) u XELOX (Capecitabine/ Oxaliplatin):
Avastin 7.5 mg/ kg of body weight every 3 weeks in combination with oral capecitabine and intravenous oxaliplatin (XELOX) or Avastin 5 mg/ kg every 2 weeks in combination with leucovorin plus 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4).
Avastin 7. 5 mg/ kg ta ’ piż tal- ġisem kull 3 ġimgħat flimkien ma ’ capecitabine orali u oxaliplatin (XELOX) ġol- vini jew Avastin 5 mg/ kg kull ġimagħtejn flimkien ma ’ leucovorin u bolus ta ’ 5- fluorouracil, seġwit minn infużjoni ta ’ 5- fluorouracil, b’ oxaliplatin (FOLFOX- 4) ġol - vini.
Avastin 10 mg/ kg of body weight every 2 weeks in combination with leucovorin and 5-fluorouracil bolus, followed by 5-fluorouracil infusion, with intravenous oxaliplatin (FOLFOX-4).
Avastin 10 mg/ kg ta ’ piż tal- ġisem kull ġimagħtejn flimkien ma ’ leucovorin u bolus ta ’ 5- fluorouracil, seġwit minn infużjoni ta ’ 5- fluorouracil, b’ oxaliplatin (FOLFOX- 4) ġol- vini.
This was a phase III randomised, double-blind, active-controlled clinical trial evaluating Avastin in combination with IFL as first-line treatment for metastatic carcinoma of the colon or rectum.
Din kienet prova klinika randomised, double- blind u active- controlled ta ’ fażi III li stmat lil Avastin f’ taħlita ma ’ IFL bħala kura primarja ta ’ karċinoma metastatika tal- kolon jew rektum.
Eight hundred and thirteen patients were randomised to receive IFL + placebo (Arm 1) or IFL + Avastin (5 mg/ kg every 2 weeks, Arm 2).
Tmien mija u tlettax- il pazjent kienu magħżula bl- addoċċ biex jirċievu IFL + placebo (Kategorija 1) jew IFL + Avastin (5 mg/ kg kull ġimgħatejn, Kategorija 2).
A third group of 110 patients received bolus 5-FU/ FA+Avastin (Arm3).
It- tielet grupp ta ’ 110 pazjent irċieva 5- FU/ FA+Avastin (Kategorija 3) bħala bolus.
Enrollment in Arm 3 was discontinued, as pre-specified, once safety of Avastin with the IFL regimen was established and considered acceptable.
Kif is- sigurtà tad- dożaġġ ta ’ Avastin ma ’ IFL ġiet stabbilita u kkunsidrata bħala aċċettabli, ma baqgħux jiddaħħlu pazjenti f’ Kategorija 3 hekk kif kien speċifikat minn qabel.
All treatments were continued until disease progression.
Kull kura tkompliet sal- progressjoni tal- marda.
The overall mean age was 59.4 years; 56.6% of patients had an ECOG performance status of 0, 43% had a value of 1 and 0.4% had a value of 2.
L- eta medja totali kienet ta ’ 59. 4 sena; 56. 6% tal- pazjenti kellhom performance status ECOG ta ’ 0, 43% kellhom valur ta ’ 1 u
15.5% had received prior radiotherapy and 28.4% prior chemotherapy.
15. 5% kienu rċevew radjuterapija minn qabel u 28. 4% kimoterapija minn qabel.
The primary efficacy variable of the trial was overall survival.
L- ewwel varjabbli tal- effikaċja tal- prova kien is- sopravivenza totali.
The addition of Avastin to IFL resulted in statistically significant increases in overall survival, progression-free survival and overall response rate (see Table 3).
Iż- żjieda ta ’ Avastin ma ’ IFL wassal għal żjiediet statistikament sinnifikanti fis- sopravivenza totali, fis- sopravivenza mingħajr progressjoni u fir- rata ta ’ rispons totali (ara Tabella 3).
The clinical benefit, as measured by overall survival, was seen in all pre-specified patient subgroups, including those defined by age, sex, performance status, location of primary tumour, number of organs involved and duration of metastatic disease.
Il- benefiċċju kliniku, hekk kif imkejjel mis - sopravivenza totali, deher f’ kull sotto grupp ta ’ pazjenti speċifikat minn qabel, inkluż dawk magħżula skond l- età, sess, performance status, post tat- tumur primarju, numru ta ’ organi involuti u t- tul tal - marda metastatika.
The efficacy results of Avastin in combination with IFL-chemotherapy are displayed in Table 3.
Tabella 3
Efficacy results for study AVF2107g
Riżultati ta ’ effikaċja għall- istudju AVF2107g
Arm 1
Kategorija 1
Arm 2
Kategorija 2
Number of Patients Overall survival
IFL + Avastina IFL + Plaċebo
IFL
Numru ta ’ pazjenti Sopravivenza totali
Median time (months)
Ħin medjan (xhur)
15.6
15. 6
20.3
20. 3
95% Confidence Interval b
Intervall ta ’ Konfidenza 95%
14.29 – 16.99
14. 29 – 16. 99
18.46 – 24.18
18. 46 – 24. 18
Hazard ratio
Hazard ratiob
0.660
(valur
(p-value = 0.00004) Progression-free survival
0. 660 p = 0. 00004)
Median time (months) Hazard ratio
Ħin medjan (xhur) Hazard ratio
10.6
10. 6
(p-value < 0.0001)
(valur p < 0. 0001)
Overall response rate
Rata ta ’ Rispons totali
34.8
34. 8
44.8
0036)
a b
44. 8
Relative to control arm.
5 mg/ kg kull ġimagħtejn. b Relattiv għall- kategorija ta ’ kontroll.
Among the 110 patients randomised to Arm 3 (5-FU/ FA + Avastin) prior to discontinuation of this arm, the median overall survival was 18.3 months and the median progression free survival was 8.8 months.
Fost il- 110 pazjent randomised għall- Kategorija 3 (5- FU/ FA + Avastin) qabel it- twaqqif ta ’ din il - kategorija, is- sopravivenza medjana totali kienet ta ’ 18. 3 xhur u s- sopravivenza bla progressjoni medjana kienet ta ’ 8. 8 xhur.
This was a phase II randomised, double-blind, active-controlled clinical trial evaluating the efficacy and safety of Avastin in combination with 5-FU/ FA as first-line treatment for metastatic colorectal cancer in patients who were not optimal candidates for first-line irinotecan treatment.
Din kienet prova klinika ta ’ fażi II randomised, double- blind u active- controlled li stmat l- effikaċja u s- sigurtà ta ’ Avastin f’ taħlita ma ’ kimoterapija b’ 5- FU/ FA għall- kura primarja ta ’ kanċer metastatiku tal- kolon jew rektum f’ pazjenti li ma kienux kandidati idejali għall- kura primarja b’ irinotecan.
One hundred and five patients were randomised to 5-FU/ FA + placebo arm and 104 patients to 5-FU/ FA + Avastin (5 mg/ kg every 2 weeks) arm.
Mija u ħames pażjent magħżula bl- addoċċ għall- kategorija 5- FU/ FA + plaċebo u 104 pazjent għall- kategorija 5- FU/ FA + Avastin (5 mg/ kg kull ġimagħtejn).
All treatments were continued until disease progression.
Kull kura tkompliet sal - progressjoni tal- marda.
The addition of Avastin 5 mg/ kg every two weeks to 5-FU/ FA resulted in higher objective response rates, significantly longer progression-free survival, and a trend in longer survival as compared to 5-FU/ FA chemotherapy alone.
Iż- żjieda ta ’ 5 mg/ kg Avastin kull ġimagħtejn ma ’ 5- FU/ FA wasslet għall- rati ta ’ rispons oġġettiv għola, żjieda sinnifikanti fis- sopravivenza bla progressjoni, u tendenza għal sopravivenza itwal, meta mqabbla ma ’ kimoterapija b’ 5- FU/ FA weħedha.
This was a phase II randomised, active-controlled, open-labelled clinical trial investigating Avastin in combination with 5-FU/ FA as first-line treatment of metastatic colorectal cancer.
Din kienet prova klinika ta ’ fażi II randomised, active- controlled u open- labelled li stmat lil Avastin f’ taħlita ma ’ kimoterapija b ’ 5- FU/ FA għall- kura primarja ta ’ kanċer metastatiku tal- kolon jew rektum.
The median age was 64 years.
L- età medjana kienet ta ’ 64 sena.
19% of the patients had received prior chemotherapy and 14% prior radiotherapy.
19% tal- pazjenti rċevew kimoterapija minn qabel u 14% radjuterapija minn qabel.
Seventy-one patients were randomised to receive bolus 5-FU/ FA or 5-FU/ FA + Avastin (5 mg/ kg every 2 weeks).
Wieħed u sebgħin pazjent kienu magħzula bl- addoċċ biex jingħataw 5- FU/ FA bħala bolus jew 5- FU/ FA + Avastin (5 mg/ kg kull ġimagħtejn).
A third group of 33 patients received bolus 5-FU/ FA + Avastin (10 mg/ kg every 2 weeks).
It- tielet grupp ta ’ 33 pazjent irċevew 5- FU/ FA + Avastin (10 mg/ kg kull ġimgħatejn) bħala bolus.
Patients were treated until disease progression.
Pazjenti kienu kkurati sal - progressjoni tal- marda.
The primary endpoints of the trial were objective response rate and progression-free survival.
Il- miri prinċipali tal- prova kienu r- rata oġġettiva ta ’ rispons u s- sopravivenza
The addition of Avastin 5 mg/ kg every two weeks to 5-FU/ FA resulted in higher objective response rates, longer progression-free survival, and a trend in longer survival, compared with 5-FU/ FA chemotherapy alone (see Table 4).
Iż- żjieda ta ’ Avastin 5 mg/ kg kull ġimagħtejn ma ’ 5- FU/ FA wassal għal rata oġġettiva ta ’ rispons għola, sopravivenza bla progressjoni itwal, u tendenza ta ’ sopravivenza itwal, meta mqabbla ma ’ kimoterapija b’ 5- FU/ FA weħedha (ara Tabella 4).
These efficacy data are consistent with the results from study AVF2107g.
Dan it- tagħrif dwar l- effikaċja kien konsistenti mar- riżultati osservati fl- istudju AVF2107g.
The efficacy data from studies AVF0780g and AVF2192g investigating Avastin in combination with 5-FU/ FA-chemotherapy are summarised in Table 4.
It- tagħrif dwar l- effikaċja mill- istudji AVF0780g u AVF2192g li studjaw lil Avastin f’ taħlita ma ’ kimoterapija b’ 5- FU/ FA huma miġbura f’ Tabella 4.
14 Table 4:
Tabella 4:
Efficacy results for studies AVF0780g and AVF2192g
Riżultati dwar l- effikaċja għall- istudji AVF0780g u AVF2192g
Avastina Avastinb placebo
Avastina Avastinb plaċebo 105
Number of Patients Overall survival
Numru ta ’ pazjenti Sopravivenza totali
104
16. 6
17.7 15.2 12.9
17. 7 15. 2
95% Confidence Interval c
Intervall ta ’ Konfidenza 95%
10.35 - 16.95
10. 35 - 16. 95
13.63 – 19.32
13. 63 – 19. 32
1.01
0. 52
0.79
1. 01
0.073
0. 073
0.978
0. 978
Progression-free survival
Sopravivenza mingħajr progressjoni
Median time (months)
5. 5
5.2
9. 2
9.0
Ħin medjan (xhur)
7.2
5. 2
5.5
9. 0
9.2
7. 2
p
Valur p
0.217
0. 217
15.2
15. 2
95% CI
95% CI Valur p tar- rispons
7.0 − 33.5
7. 0 − 33. 5
24.4 − 57.8
24. 4 − 57. 8 0. 029
11.7 – 42.6
11. 7 – 42. 6 0. 43
18.1 - 35.6
9. 2 - 23. 9 6. 8
0.43
18. 1
Duration of response
- 35. 6 0. 055 9. 2
6.8
9. 3
9.2
5. 0
25– 75 percentile (months)
25– 75 perċentali (xhur)
5.5 − NR
5. 5 − NR
6.1 − NR
6. 1 − NR
3.8 – 7.8
3. 8 – 7. 8
5.59 - 9.17
5. 59 - 9. 17
5.88 - 13.01
5. 88
b
- 13. 01
5
5 b
mg/ kg every 2 weeks.
mg/ kg kull ġimagħtejn.
10 mg/ kg every 2 weeks. c Relative to control arm.
10 mg/ kg kull ġimagħtejn. c Relattiv għall- kategorija ta ’ kontroll.
NR = Not reached.
NR = Ma ntlaħaqx.
NO16966 This was a phase III randomised, double-blind (for bevacizumab), clinical trial investigating Avastin 7.5 mg/ kg in combination with oral capecitabine and IV oxaliplatin (XELOX), administered on a 3- weekly schedule; or Avastin 5 mg/ kg in combination with leucovorin with 5-fluorouracil bolus, followed by 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule.
NO16966 Din kienet prova klinika ta ’ fażi III, randomised, double- blind (għal bevacizumab), li nvestigat Avastin 7. 5 mg/ kg f’ taħlita ma ’ capecitabine orali u oxaliplatin IV (XELOX), mogħti fuq skeda ta ’ kull 3 ġimgħat; jew Avastin 5 mg/ kg f’ taħlita ma ’ leucovorin u bolus ta ’ 5- fluorouracil, segwit minn infużjoni ta ’ 5- fluorouracil, ma ’ oxaliplatin IV (FOLFOX- 4), mogħti fuq skeda ta ’ kull ġimagħtejn.
The study contained two parts: an initial unblinded 2-arm part (Part I) in which patients were randomised to two different treatment groups (XELOX and FOLFOX-4) and a subsequent 2 x 2 factorial 4-arm part (Part II) in which patients were randomised to four treatment groups (XELOX + placebo, FOLFOX-4 + placebo, XELOX + Avastin, FOLFOX-4 + Avastin).
L - istudju kien fih żewġ partijiet: parti tal- bidu b’ żewġ kategoriji unblinded (l- ewwel Parti) fejn il - pazjenti kienu randomised f’ żewġ gruppi ta ’ kura differenti (XELOX u FOLFOX- 4) u parti sussegwenti b’ 4 kategoriji 2 x 2 fattorjali (Parti II) fejn il- pazjenti kienu randomised f’ erba ’ gruppi ta ’ kura (XELOX + plaċebo, FOLFOX- 4 + plaċebo, XELOX + Avastin, FOLFOX- 4 + Avastin).
In Part II, treatment assignment was double-blind with respect to Avastin.
Fit- tieni parti, t- tqassim tal- kura kien double- blind f’ dak li jikkonċerna Avastin.
Approximately 350 patients were randomised into each of the 4 study arms in the Part II of the trial.
Madwar 350 pazjent kienu randomised f’ kull waħda mill- erba ’ kategoriji ta ’ l- istudju fit- tieni Parti tal - prova.
15 Table 5
15 Tabella 5
Treatment Regimens in Study N016966 (mCRC)
kura fi Studju N016966 (mCRC)
Treatment Starting Dose
Kura Doża tal- Bidu 85 mg/ m2 IV 2 h
FOLFOX-4
FOLFOX- 4 jew
Oxaliplatin on Day 1
Oxaliplatin fl- Ewwel Ġurnata Leucovorin fl- Ewwel u fit- Tieni
200 mg/ m IV 2 h
200 mg/ m IV 2 h 400 mg/ m2 IV bolus,
Leucovorin on Day 1 and 2
Ġurnata
FOLFOX-4 + Avastin
Avastin
5-Fluorouracil Placebo or Avastin
Plaċebo jew Avastin
5-fluorouracil IV bolus/ infusion, each on Days 1 and 2 Day 1, prior to FOLFOX-4, every 2 weeks
Fl- Ewwel Ġurnata, qabel FOLFOX- 4, kull ġimagħtejn
XELOX
XELOX jew
Oxaliplatin on Day 1
Oxaliplatin fl- Ewwel Ġurnata Capecitabine orali bid għal
Capecitabine
Capecitabine
1000 mg/ m oral bid
1000 mg/ m orali bid
Capecitabine oral bid for 2 weeks (followed by 1 week off treatment)
ġimagħtejn (segwit b’ ġimgħa mingħajr kura)
Placebo or Avastin
Plaċebo jew Avastin
Day 1, prior to XELOX, q 3 weeks
Fl- Ewwel Ġurnata, qabel XELOX, q 3 ġimgħat
IV bolus injection immediately after leucovorin
injezzjoni bolus IV minnufih wara leucovorin
The primary efficacy parameter of the trial was the duration of progression-free survival.
Il- parametru primarju ta ’ l- effikaċja tal- prova kien it- tul tas- sopravivenza mingħajr progressjoni.
In this study, there were two primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to show that Avastin in combination with FOLFOX-4 or XELOX chemotherapy was superior to chemotherapy alone.
F’ dan l- istudju, kien hemm żewġ oġġettivi primarji: biex jintwera li XELOX ma kienx inferjuri għal FOLFOX- 4 u biex jintwera li Avastin f’ taħlita ma ’ kimoterapija b’ FOLFOX- 4 jew XELOX kien superjuri għall- kimoterapija weħedha.
Both co-primary objectives were met:
Iż- żewġ oġġettivi primarji ntlaħqu:
Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall comparison was demonstrated in terms of progression-free survival and overall survival in the eligible per-protocol population.
In- nuqqas ta ’ inferjorità tal- kategoriji li fihom XELOX meta mqabbla mal- kategoriji li fihom FOLFOX- 4 fil- paragun totali ntweriet f’ termini ta ’ sopravivenza mingħajr progressjoni u sopravivenza totali fil- popolazzjoni eliġibbli ta ’ qabel il- protokoll.
Superiority of the Avastin-containing arms versus the chemotherapy alone arms in the overall comparison was demonstrated in terms of progression-free survival in the ITT population (Table 6)
Is- superjorità tal- kategoriji li fihom Avastin kontra l- kategoriji b’ kimoterapija biss fil - paragun totali ntweriet f’ termini ta ’ sopravivenza mingħajr progressjoni fil- popolazzjoni ITT (Tabella 6)
Secondary PFS analyses, based on ‘ on-treatment’ -based response assessments, confirmed the significantly superior clinical benefit for patients treated with Avastin (analyses shown in Table 6), consistent with the statistically significant benefit observed in the pooled analysis.
Analiżi sekondarja tal- PFS, ibbażata fuq valutazzjonijiet tar- rispons ta ’ ‘ wara l- kura ’, ikkonfermat il - benefiċċju kliniku ta ’ superjorità sinifikanti għall- pazjenti kkurati b’ Avastin (analiżi mniżżla f’ Tabella 6), konsistenti mal- benefiċċju statistikament sinifikanti osservat f’ analiżi miġbura.
16 Table 6
16 Tabella 6 Riżultati importanti tal- effikaċja għall- analiżi tas- superjorità (popolazzjoni ITT, Studju NO16966)
Endpoint (months)
Mira (xhur)
FOLFOX-4 or XELOX
FOLFOX- 4 jew XELOX
P Value
Valur P
Primary endpoint
Mira primarja
+ Placebo (n=701)
+ Plaċebo (n=701)
Median PFS**
PFS medjan **
Hazard ratio (97.5% CI)a
Hazard ratio (97. 5% CI)
0.83 (0.72– 0.95)
0. 83 (0. 72– 0. 95)
Secondary endpoints
Miri sekondarji
Median PFS (on treatment)**
medjan (wara l- kura) **
Hazard ratio (97.5% CI)
Hazard ratio (97. 5% CI)
0.63 (0.52-0.75)
0. 63 (0. 52- 0. 75)
Assessment)**
Rata ta ’ Rispons totali (Valutazzjoni invest.) **
Median overall survival*
Sopravivenza totali medjana *
21.2
21. 2
0.89 (0.76-1.03)
0. 89 (0. 76- 1. 03)
* Overall survival analysis at clinical cut-off 31 January 2007 ** Primary analysis at clinical cut-off 31 January 2006 a relative to control arm
* Analiżi tas- sopravivenza totali fit- twaqqif kliniku fil- 31 ta ’ Jannar 2007 ** Analiżi primarja fit- twaqqif kliniku fil- 31 ta ’ Jannar 2006 a relattiv għall- kategorija ta ’ kontroll
9.3 months, HR = 0.77, 97.5% CI = [0.63; 0.94]; p-value = 0.0026.
Fis- sottogrupp ta ’ kura b’ FOLFOX, il- PFS medjan kien 8. 6 xhur fil- pazjenti kkurati bil- plaċebo u 9. 4 xhur fil- pazjenti kkurati b’ bevacizumab, HR = 0. 89, 97. 5% CI = [0. 73; 1. 08]; valur p = 0. 1871, ir - riżultati li jikkorrispondu fis- sottogrupp ta ’ kura b’ XELOX ikunu 7. 4 kontra 9. 3 xhur, HR = 0. 77, 97. 5% CI = [0. 63; 0. 94]; valur p = 0. 0026.
21.4 months, HR = 0.84, 97.5% CI = [0.68; 1.04]; p-value = 0.0698.
Il- medjan tas- sopravivenza globali kien 20. 3 xahar fil- pazjenti kkurati bil- plaċebo u 21. 2 xahar fil - pazjenti kkurati b’ bevacizumab fis- sottogrupp ta ’ kura b’ FOLFOX, HR=0. 94, 97. 5% CI = [0. 75; 1. 16]; valur p = 0. 4937, ir- riżultati li jikkorrespondu fis- sottogrupp ta ’ kura b’ XELOX, ikunu 19. 2 kontra 21. 4 xahar, HR = 0. 84, 97. 5% CI = [0. 68; 1. 04]; valur p = 0. 0698.
ECOG E3200 This was a phase III randomised, active-controlled, open-label study investigating Avastin 10 mg/ kg in combination with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), administered on a 2-weekly schedule in previously-treated patients (second line) with advanced colorectal cancer.
ECOG E3200 Dan kien studju ta ’ fażi III, randomised, ikkontrollat b’ mod attiv, open- label li nvestiga Avastin 10 mg/ kg f’ taħlita ma ’ leucovorin b’ bolus ta ’ 5- fluorouracil u wara infużjoni ta ’ 5- fluorouracil, b’ oxaliplatin IV (FOLFOX- 4), mogħti fuq skeda ta ’ kull ġimagħtejn f’ pazjenti kkurati minn qabel (it - tieni linja) b’ kanċer avvanzat tal- kolorektum.
In the chemotherapy arms, the FOLFOX-4 regimen used the same doses and schedule as shown in Table 5 for Study NO16966.
Fil- kategoriji tal- kimoterapija, il- kors ta ’ FOLFOX- 4 uża l- istess dożi u skeda kif muri f’ Tabella 5 għall- Istudju NO16966.
The primary efficacy parameter of the trial was overall survival, defined as the time from randomization to death from any cause.
Il- parametru primarju ta ’ l- effikaċja tal- prova kien is- sopravivenza totali, definit bħala l- ħin mir - randomisation sal- mewt minn kull kawża.
Eight hundred and twenty-nine patients were randomised (292 FOLFOX-4, 293 Avastin +_FOLFOX-4 and 244 Avastin monotherapy).
Tmin mija u disgħa u għoxrin pazjent kienu randomised (292 FOLFOX- 4, 293 Avastin +_ FOLFOX- 4 u 244 b’ monoterapija ta ’ Avastin).
The addition of Avastin to FOLFOX-4 resulted in a statistically significant prolongation of survival.
Iż- żjieda ta ’ Avastin ma ’ FOLFOX- 4 wasslet f’ titwil statistikament sinifikanti tas- sopravivenza.
Statistically significant improvements in progression-free survival and objective response rate were also observed (see Table 7).
Kien osservat ukoll titjib statistikament sinifikanti fis- sopravivenza mingħajr progressjoni u fir- rata ta ’ rispons oġġettiv (ara Tabella 7).
17 Table 7
17 Tabella 7
Efficacy Results for Study E3200
Riżultati ta ’ l- Effikaċja għall- Istudju E3200
Number of Patients Overall Survival
Numru ta ’ Pazjenti
Median (months)
Medjan (xhur)
95% confidence
95% intervall ta ’ kunfidenza b
(p-value = 0.0012) Progression-Free Survival
Sopravivenza Mingħajr Progressjoni
Median (months) Hazard ratio
Medjan (xhur) Hazard ratio
(p-value < 0.0001) Objective Response Rate
(valur p < 0. 0001) Rata ta ’ Rispons Oġġettiv
8.6%
8. 6%
No significant difference was observed in the duration of overall survival between patients who received Avastin monotherapy compared to patients treated with FOLFOX-4.
Ma kienet osservata l- ebda differenza sinifikanti fit- tul tas- sopravivenza totali bejn pazjenti li rċevew monoterapija ta ’ Avastin meta mqabbel ma ’ pazjenti kkurati b’ FOLFOX- 4.
Progression-free survival and objective response rate were inferior in the Avastin monotherapy arm compared to the FOLFOX-4 arm.
Sopravivenza mingħajr progressjoni u rata ta ’ rispons oġġettiv kienu inferjuri fil- kategorija ta ’ monoterapija ta ’ Avastin meta mqabbel mal- kategorija ta ’ FOLFOX- 4.
The benefit of Avastin re-treatment in metastatic colorectal cancer patients who were exposed to Avastin in previous therapies has not been addressed in randomized clinical trials.
Il- benefiċċju ta ’ kura mill- ġdid b’ Avastin f’ pazjenti b’ kanċer metastatiku tal- kolorektum li kienu esposti għal Avastin f’ terapiji ta ’ qabel ma ġietx studjata fi provi kliniċi randomised.
Study E2100 was an open-label, randomised, active controlled, multicentre clinical trial evaluating Avastin in combination with paclitaxel for locally recurrent or metastatic breast cancer in patients who had not previously received chemotherapy for locally recurrent and metastatic disease.
Studju E2100 kien prova klinika open- label, randomised, ikkontrollat b’ mod attiv u multicentre li evalwa Avastin flimkien ma ’ paclitaxel għal kanċer tas- sider rikorrenti lokalment jew li mmetastatizza f’ pazjenti li ma kienux irċievew kimoterapija minn qabel għall- mard metastatiku jew rikorrenti lokalment.
Patients were randomised to paclitaxel alone (90 mg/ m2 IV over 1 hour once weekly for three out of four weeks) or in combination with Avastin (10 mg/ kg IV infusion every two weeks).
Il- pazjenti kienu randomised għal paclitaxel waħdu (90 mg/ m2 IV fuq medda ta ’ siegħa darba fil- ġimgħa għal tlieta minn erba ’ ġimgħat) jew flimkien ma ’ Avastin (10 mg/ kg infużjoni IV kull ġimagħtejn).
Prior hormonal therapy for the treatment of metastatic disease was allowed.
Terapija ormonali minn qabel għall- kura ta ’ mard metastatiku kienet permessa.
Adjuvant taxane therapy was allowed only if it was completed at least 12 months prior to study entry.
Terapija awżiljarja b’ taxane kienet permessa biss jekk intemmett ta ’ l- anqas 12- il xahar qabel il- bidu ta ’ l- istudju.
Of the 722 patients in the study, the majority of patients had HER2-negative disease (90%), with a small number of patients with unknown (8%) or confirmed HER2-positive status (2%), who had previously been treated with or were considered unsuitable for trastuzumab therapy.
Minn 722 pazjent fl- istudju, il- maġġoranza tal- pazjenti kellhom marda negattiva għal HER2 (90%), b’ numru żgħir ta ’ pazjenti bi stat HER2 mhux magħruf (8%) jew ikkonfermat bħala pożittiv (2%), li kienu kkurati minn qabel jew ikkunsidrati bħala mhux adattati għal terapija b’ trastuzumab.