英文药名：Iclusig(ponatinib filmcoated tablets)
 
中文药名：普纳替尼薄膜片

生产厂家：Ariad制药公司
药品介绍
近日，欧洲医药局的顾问小组建议(European Medicine Agency's advisory panel)批准的口服酪氨酸激酶抑制剂（TKI）普纳替尼（ponatinib）（Iclusig，Ariad制药公司制药）治疗TKI耐药或不耐受的成人白血病。
这对于患者而言是个福音，人用药品委员会(Committee for Human Medicinal Products) 加速评估的积极意见如下： T315I突变常与TKI耐药活不耐受的白血病相关，然而目前却无针对此突变有效的药物。普纳替尼则是专门设计以克服此突变的。
普纳替尼曾在2012年12月14日获得美国食品和药物管理局（FDA）加速批准上市.
如果获得批准，ponatinib将用于治疗慢性期，加速期或急变期的慢性髓性白血病（CML）患者。这些患者为T315I突变携带者，并对达沙替尼、尼洛替尼耐药或不耐受，或者不适合使用伊马替尼。
Ponatinib也可用于治疗费城Ph染色体阳性的急性淋巴细胞白血病（ALL）。这些ALL患者亦为T315I突变携带者，并对达沙替尼耐药或不耐受，也无法在临床上使用伊马替尼治疗。

Iclusig 15mg and 45mg film-coated tablets
1. Name of the medicinal product

Iclusig 15 mg film-coated tablets
Iclusig 45 mg film-coated tablets
2. Qualitative and quantitative composition
Each 15 mg film-coated tablet contains 15 mg of ponatinib (as hydrochloride).
Each 45 mg film-coated tablet contains 45 mg of ponatinib (as hydrochloride).
Excipients with known effect
Each 15 mg film-coated tablet contains 40 mg of lactose monohydrate.
Each 45 mg film-coated tablet contains 120 mg of lactose monohydrate
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
15 mg tablet: white, biconvex, round film-coated tablet that is approximately 6 mm in diameter, with "A5" debossed on one side.
45 mg tablet: white, biconvex, round film-coated tablet that is approximately 9 mm in diameter, with "AP4" debossed on one side.
4. Clinical particulars
4.1 Therapeutic indications
Iclusig is indicated in adult patients with
• chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation
• Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.
4.2 Posology and method of administration
Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia. Haematologic support such as platelet transfusion and haematopoietic growth factors can be used during treatment if clinically indicated.
Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and therapy optimised during treatment with ponatinib.
Posology
The recommended starting dose is 45 mg of ponatinib once daily. For the standard dose of 45 mg once daily, a 45 mg film-coated tablet is available. Treatment should be continued as long as the patient does not show evidence of disease progression or unacceptable toxicity.
Dose adjustments or modifications
Dose modifications should be considered for the management of treatment toxicity. For a dose of 30 mg or 15 mg once daily, 15 mg film-coated tablets are available.
Myelosuppression
Dose modifications for neutropenia (ANC* < 1.0 x 109/L) and thrombocytopenia (platelet < 50 x 109/L) that are unrelated to leukaemia are summarized in Table 1.
Table 1 Dose modifications for myelosuppression

ANC* < 1.0 x 109/L or platelet < 50 x 109/L	First occurrence: • Withhold Iclusig and resume initial 45 mg dose after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L
	Second occurrence: • Withhold Iclusig and resume at 30 mg after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L
	Third occurrence: • Withhold Iclusig and resume at 15 mg after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L
*ANC = absolute neutrophil count

Non-haematological adverse reactions
If a severe non-haematological adverse reaction occurs, treatment should be withheld. After the event is resolved or attenuated in severity, Iclusig may be resumed at the same dose or at a reduced dose according to initial grade of the adverse reaction.
Vascular occlusion
In a patient suspected of developing an arterial or venous occlusive event, Iclusig should be immediately interrupted. A benefit-risk consideration should guide a decision to restart Iclusig therapy (see sections 4.4 and 4.8) after the event is resolved.
Hypertension may contribute to risk of arterial thrombotic events. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled.
Pancreatitis
Recommended modifications for pancreatic adverse reactions are summarized in Table 2.
Table 2 Dose modifications for pancreatitis and elevation of lipase/amylase

Asymptomatic Grade 2 pancreatitis and/or elevation of lipase/amylase	Continue Iclusig at the same dose
Grade 3 or 4 asymptomatic elevation of lipase/amylase ( > 2.0 x IULN*) only	Occurrence at 45 mg: • Withhold Iclusig and resume at 30 mg after recovery to ≤ Grade 1 ( < 1.5 x IULN) Recurrence at 30 mg: • Withhold Iclusig and resume at 15 mg after recovery to ≤ Grade 1 ( < 1.5 x IULN) Recurrence at 15 mg: • Consider discontinuing Iclusig
Grade 3 pancreatitis	Occurrence at 45 mg: • Withhold Iclusig and resume at 30 mg after recovery to < Grade 2 Recurrence at 30 mg: • Withhold Iclusig and resume at 15 mg after recovery to < Grade 2 Recurrence at 15 mg: • Consider discontinuing Iclusig
Grade 4 pancreatitis	Discontinue Iclusig
*IULN = institution upper limit of normal

For patients whose adverse reactions are resolved, escalation of the dose back to 45 mg once daily should be considered, if clinically appropriate.
Elderly patients
Of the 449 patients in the clinical study of Iclusig, 155 (35%) were ≥ 65 years of age. Compared to patients < 65 years, older patients are more likely to experience adverse reactions.
Hepatic impairment
Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, the presence of moderate to severe hepatic impairment may result in increased plasma concentrations. Caution is recommended when administering Iclusig to patients with varying degrees of hepatic impairment (see section 4.4).
Renal impairment
Renal excretion is not a major route of ponatinib elimination. Iclusig has not been studied in patients with renal impairment. Patients with estimated creatinine clearance of ≥ 50 mL/min should be able to safely receive Iclusig with no dosage adjustment. Caution is recommended when administering Iclusig to patients with estimated creatinine clearance of < 50 mL/min, or end-stage renal disease.
Paediatric population
The safety and efficacy of Iclusig in patients less than 18 years of age have not been established. No data are available.
Method of administration
The tablets should be swallowed whole. Patients should not crush or dissolve the tablets. Iclusig may be taken with or without food.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Important adverse reactions
Myelosuppression
Iclusig is associated with severe (National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4) thrombocytopenia, neutropenia, and anaemia. The frequency of these events is greater in patients with accelerated phase CML (AP-CML) or blast phase CML (BP-CML)/Ph+ ALL than in chronic phase CML (CP-CML). A complete blood count should be performed every 2 weeks for the first 3 months and then monthly or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Iclusig temporarily or reducing the dose (see section 4.2).
Vascular occlusion
Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in Iclusig-treated patients. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Vascular occlusion adverse events were more frequent with increasing age and in patients with prior history of ischaemia, hypertension, diabetes, or hyperlipidaemia.
Iclusig should not be used in patients with a history of myocardial infarction or stroke, unless the potential benefit of treatment outweighs the potential risk (see sections 4.2 and 4.8).
Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and therapy optimised during treatment with ponatinib.
Monitoring for evidence of thromboembolism and vascular occlusion should be performed and Iclusig should be interrupted immediately in case of vascular occlusion. A benefit -risk consideration should guide a decision to restart Iclusig therapy (see sections 4.2 and 4.8).
Hypertension may contribute to risk of arterial thrombotic events. During Iclusig treatment, blood pressure elevations should be monitored and managed and hypertension should be treated to normal. Iclusig treatment should be temporarily interrupted if hypertension is not medically controlled (see section 4.2).
Pancreatitis and serum lipase
Iclusig is associated with pancreatitis. The frequency of pancreatitis is greater in the first 2 months of use. Check serum lipase every 2 weeks for the first 2 months and then periodically thereafter. Dose interruption or reduction may be required. If lipase elevations are accompanied by abdominal symptoms, Iclusig should be withheld and patients evaluated for evidence of pancreatitis (see section 4.2). Caution is recommended in patients with a history of pancreatitis or alcohol abuse. Patients with severe or very severe hypertriglyceridemia should be appropriately managed to reduce the risk of pancreatitis.
Liver function abnormality
Iclusig may result in elevation in ALT, AST, bilirubin, and alkaline phosphatase. Liver function tests should be performed periodically, as clinically indicated.
Medicinal product interactions
Caution should be exercised with concurrent use of Iclusig and moderate and strong CYP3A inhibitors and moderate and strong CYP3A inducers (see section 4.5).
Elevated gastric pH
Caution should be exercised with concurrent use of Iclusig and medicinal products that elevate the gastric pH (such as proton pump inhibitors, H2 blockers, or antacids) as these may decrease the solubility of ponatinib and subsequently reduce its bioavailability.
QT prolongation
The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients and no clinically significant QT prolongation was observed (see section 5.1). However, a thorough QT study has not been performed; therefore a clinically significant effect on QT cannot be excluded.
Special populations
Hepatic impairment
Caution is recommended when administering Iclusig to patients with varying degrees of hepatic impairment (see section 4.2).
Renal impairment
Caution is recommended in when administering Iclusig to patients with estimated creatinine clearance of < 50 mL/min or end-stage renal disease (see section 4.2).
Lactose
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Substances that may increase ponatinib serum concentrations
CYP3A inhibitors
Ponatinib is metabolized by CYP3A4.
Co-administration of a single 15 mg oral dose of Iclusig in the presence of ketoconazole (400 mg daily), a strong CYP3A inhibitor, resulted in modest increases in ponatinib systemic exposure, with ponatinib AUC0-∞ and Cmax values that were 78% and 47% higher, respectively, than those seen when ponatinib was administered alone.
Caution should be exercised with concurrent use of Iclusig and moderate or strong CYP3A inhibitors such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit juice.
Substances that may decrease ponatinib serum concentrations
CYP3A inducers
The effect of CYP3A inducers on ponatinib pharmacokinetics has not been studied. Based on the role of CYP3A in the metabolism of ponatinib, it is anticipated that strong inducers will decrease ponatinib systemic exposures; however, the magnitude of decrease is unknown. Caution should be exercised with concurrent use of Iclusig and strong CYP3A inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John's Wort.
Elevated gastric pH
The aqueous solubility of ponatinib is pH dependent, with higher pH resulting in lower solubility. Medicinal products that elevate the gastric pH (such as proton pump inhibitors, H2 blockers, or antacids) may decrease the solubility of ponatinib and subsequently reduce its bioavailability. However, no clinical studies have been conducted.
Substances that may have their serum concentrations altered by ponatinib
Transporter substrates
In vitro, ponatinib is an inhibitor of P-gp and BCRP. Therefore, ponatinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine) and may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when ponatinib is administered with these medicinal products.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential/Contraception in males and females
Women of childbearing age being treated with Iclusig should be advised not to become pregnant and men being treated with Iclusig should be advised not to father a child during treatment. An effective method of contraception should be used during treatment.
Pregnancy
There are no adequate data from the use of Iclusig in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Iclusig should be used during pregnancy only when clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.
Breast-feeding
It is unknown whether Iclusig is excreted in human milk. Available pharmacodynamic and toxicological data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with Iclusig.
Fertility
The effect of Iclusig on male and female fertility is unknown.
4.7 Effects on ability to drive and use machines
Iclusig has a minor influence on the ability to drive and use machines. Adverse reactions such as lethargy, dizziness, and vision blurred have been associated with Iclusig. Therefore, caution should be recommended when driving or operating machines.
4.8 Undesirable effects
Summary of the safety profile
The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 CML and Ph+ ALL patients who were resistant or intolerant to prior TKI therapy including those with a BCR-ABL T315I mutation. All patients received 45 mg Iclusig once daily. Dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the management of treatment toxicity. At the time of reporting, the median duration of treatment with Iclusig was 281 days in CP-CML patients, 286 days in AP-CML patients, and 86 days in BP-CML/Ph+ ALL patients. The median dose intensity was 37 mg or, 83% of the expected 45 mg dose.
The most common serious adverse reactions >1% (treatment-emergent frequencies) were pancreatitis (5.1%), abdominal pain (3.6%), pyrexia (3.3%), anaemia, (2.9%), febrile neutropenia (2.9%), platelet count decreased (2.9%), myocardial infarction (2.9 %), diarrhoea (1.6%), lipase increased (1.3%), neutrophil count decreased (1.3%), and pancytopenia (1.3%). Overall, the most common adverse reactions ( ≥ 20%) were platelet count decreased, rash, dry skin, and abdominal pain. The rates of treatment-related adverse events resulting in discontinuation were 10% in CP-CML, 7% in AP-CML and 3% in BP-CML/Ph+ ALL.
Tabulated list of adverse reactions
Adverse reactions reported in all CML and Ph+ ALL patients are presented in Table 3. Frequency categories are very common ( ≥ 1/10), common ( ≥1/100 to < 1/10) and uncommon ( ≥ 1/1000 to < 1/100), rare ( ≥ 1/10,000 to < 1/1000), very rare ( < 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 3 Adverse reactions observed in CML and Ph+ ALL patients – frequency reported by incidence of treatment emergent events

 

System organ class	Frequency	Adverse reactions
Infections and infestations	Common	pneumonia, sepsis, upper respiratory tract infection, folliculitis
Blood and lymphatic system disorders	Very common	anaemia, platelet count decreased, neutrophil count decreased
	Common	pancytopenia, febrile neutropenia, white blood cell count decreased
Metabolism and nutrition disorders	Very common	decreased appetite
	Common	dehydration, fluid retention, hypocalcaemia, hyperglycaemia, hyperuricaemia, hypophosphataemia, hypertriglyceridaemia, hypokalaemia, weight decreased
	Uncommon	tumour lysis syndrome
Psychiatric disorders	Common	insomnia
Nervous system disorders	Very common	headache
	Common	cerebrovascular accident, neuropathy peripheral, lethargy, dizziness, migraine, hyperaesthesia, hypoaesthesia, paraesthesia
	Uncommon	cerebral infarction, cerebral artery stenosis
Eye disorders	Common	vision blurred, dry eye
	Uncommon	retinal vein thrombosis, retinal vein occlusion, visual impairment, eyelid oedema
Cardiac disorders	Common	cardiac failure, myocardial infarction, cardiac failure congestive, coronary artery disease, angina pectoris, pericardial effusion, atrial fibrillation, ejection fraction decreased
	Uncommon	myocardial ischemia, acute coronary syndrome, cardiac discomfort, ischemic cardiomyopathy, Prinzmetal Angina, left ventricular dysfunction, atrial flutter,
Vascular Disorders	Very common	hypertension
	Common	peripheral arterial occlusive disease, peripheral ischaemia, intermittent claudication, deep vein thrombosis, hot flush, flushing,
	Uncommon	peripheral artery stenosis, poor peripheral circulation, splenic infarction, embolism venous, venous thrombosis
Respiratory, thoracic and mediastinal disorders	Very common	dyspnoea, cough
	Common	pulmonary embolism, pleural effusion, epistaxis, dysphonia
Gastrointestinal disorders	Very common	abdominal pain, diarrhea, vomiting, constipation, nausea, lipase increased
	Common	pancreatitis, blood amylase increased, gastrooesophageal reflux disease, stomatitis, dyspepsia, abdominal distension, abdominal discomfort, dry mouth
	Uncommon	gastric hemorrhage
Hepatobiliary disorders	Very common	alanine aminotransferase increased
	Common	blood bilirubin increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased
	Uncommon	hepatotoxicity, jaundice
Skin and subcutaneous tissue disorders	Very common	rash, dry skin
	Common	rash pruritic, exfoliative rash, erythema, alopecia, pruritis, skin exfoliation, night sweats, hyperhidrosis, petechia, ecchymosis, pain of skin, periorbital oedema
	Uncommon	dermatitis exfoliative
Musculoskeletal and connective tissue disorders	Very common	bone pain, arthralgia, myalgia, pain in extremity, back pain
	Common	musculoskeletal pain, neck pain, musculoskeletal chest pain, muscle spasms
Reproductive system and breast disorders	Common	erectile dysfunction
General disorders and administrative site conditions	Very common	fatigue, asthenia, oedema peripheral, pyrexia
	Common	chills, influenza like illness, non-cardiac chest pain, pain, mass, face oedema

Description of selected adverse reactions
Vascular occlusion (see section 4.2 and 4.4).
Serious vascular occlusion has occurred in patients treated with Iclusig, including cardiovascular, cerebrovascular and peripheral vascular events, and venous thrombotic events. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Vascular occlusive adverse events were more frequent with increasing age and in patients with prior history of ischaemia, hypertension, diabetes, or hyperlipidaemia.
Myelosuppression
Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 thrombocytopenia, neutropenia, and anaemia was higher in patients with AP-CML and BP-CML/Ph+ ALL than in patients with CP-CML (see Table 4). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.
Discontinuation due to myelosuppression was infrequent (thrombocytopenia 3.6%, neutropenia and anaemia <1% each).
Table 4 Incidence of clinically relevant grade 3/4* laboratory abnormalities in ≥2% of patients in any disease group

Laboratory Test	All Patients (N=449) (%)	CP-CML (N=270) (%)	AP-CML (N=85) (%)	BP-CML/Ph+ ALL (N=94) (%)
Haematology
Thrombocytopenia (platelet count decreased)	39	34	47	45
Neutropenia (ANC decreased)	33	23	47	52
Leukopenia (WBC decreased)	25	12	33	53
Anaemia (Hgb decreased)	20	9	26	48
Lymphopenia	15	9	24	28
Biochemistry
Lipase increased	10	11	9	5
Phosphorus decreased	7	6	8	9
Glucose increased	5	6	7	0
ALT increased	8	6	8	12
Sodium decreased	4	4	6	2
AST increased	3	3	2	3
Potassium increased	2	2	1	3
Alkaline phosphatase increased	2	1	1	4
Bilirubin	1	<1	4	1
Potassium decreased	2	<1	4	2
Amylase decreased	<1	0	0	2
ALT=alanine aminotransferase, ANC=absolute neutrophil count, AST=aspartate aminotransferase, Hgb=hemoglobin, WBC=white blood cell count. *Reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United Kingdom:
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland:
Pharmacovigilance Section
Irish Medicines Board
Kevin O'Malley House ; Earlsfort Centre ; Earlsfort Terrace ; IRL - Dublin 2
Tel: +353 1 6764971 ; Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
4.9 Overdose
Isolated reports of unintentional overdose with Iclusig were reported in clinical trials. Single doses of 165 mg and an estimated 540 mg in two patients did not result in any clinically significant adverse reactions. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and asymptomatic, moderate pericardial effusion. Treatment was interrupted, the events resolved, and Iclusig was restarted at 45 mg, once daily. In the event of an overdose of Iclusig, the patient should be observed and appropriate supportive treatment given.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE24
Ponatinib is a potent pan BCR-ABL inhibitor with structural elements, including a carbon-carbon triple-bond, that enable high affinity binding to native BCR-ABL and mutant forms of the ABL kinase. Ponatinib inhibits the tyrosine kinase activity of ABL and T315I mutant ABL with IC50 values of 0.4 and 2.0 nM, respectively. In cellular assays, ponatinib was able to overcome imatinib, dasatinib, and nilotinib resistance mediated by BCR-ABL kinase domain mutations. In preclinical mutagenesis studies, 40 nM was determined as the concentration of ponatinib sufficient to inhibit viability of cells expressing all tested BCR-ABL mutants by >50% (including T315I) and suppress the emergence of mutant clones. In a cell-based accelerated mutagenesis assay, no mutation in BCR-ABL was detected that could confer resistance to 40 nM ponatinib.
Ponatinib elicited tumour shrinkage and prolonged survival in mice bearing tumours expressing native or T315I mutant BCR-ABL.
At doses of 30 mg or greater plasma steady state trough concentrations of ponatinib typically exceed 21 ng/mL (40 nM). At doses of 15 mg or greater, 32 of 34 patients (94%) demonstrated a ≥50% reduction of CRKL phosphorylation, a biomarker of BCR-ABL inhibition, in peripheral blood mononuclear cells.
Ponatinib inhibits the activity of other clinically relevant kinases with IC50 values below 20 nM and has demonstrated cellular activity against RET, FLT3, and KIT and members of the FGFR, PDGFR, and VEGFR families of kinases.
Clinical efficacy and safety
The safety and efficacy of Iclusig in CML and Ph+ ALL patients who were resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy were evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once-daily with the possibility of dose de-escalations and dose interruptions followed by dose resumption and re-escalation. Patients were assigned to one of six cohorts based on disease phase (CP-CML; AP-CML; or BP-CML/Ph+ ALL), resistance or intolerance (R/I) to dasatinib or nilotinib, and the presence of the T315I mutation. The trial is ongoing.
Resistance in CP-CML was defined as failure to achieve either a complete haematological response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months) while on dasatinib or nilotinib. CP-CML patients who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response or progression to AP-CML or BP-CML at any time on dasatinib or nilotinib were also considered resistant. Resistance in AP-CML and BP-CML/Ph+ ALL was defined as failure to achieve either a major haematological response (AP-CML by 3 months, BP-CML/Ph+ ALL by 1 month), loss of major haematological response (at any time), or development of kinase domain mutation in the absence of a major haematological response while on dasatinib or nilotinib.
Intolerance was defined as the discontinuation of dasatinib or nilotinib due to toxicities despite optimal management in the absence of a complete cytogenetic response for CP CML patients or major haematological response for AP CML, BP CML, or Ph+ ALL patients.
The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR). The secondary efficacy endpoints in CP-CML were complete haematological response (CHR) and major molecular response (MMR).
The primary efficacy endpoint in AP-CML and BP-CML/Ph+ ALL was major haematological response (MaHR), defined as either a complete haematological response (CHR) or no evidence of leukaemia (NEL). The secondary efficacy endpoints in AP-CML and BP-CML/Ph+ ALL were MCyR and MMR.
For all patients, additional secondary efficacy endpoints included: confirmed MCyR, time to response, duration of response, progression free survival, and overall survival.
The trial enrolled 449 patients of which 444 were eligible for analysis: 267 CP-CML patients (R/I Cohort: n=203, T315I Cohort: n=64), 83 AP-CML patients (R/I Cohort: n=65, T315I Cohort: n=18), 62 BP-CML (R/I Cohort: n=38, T315I Cohort: n=24), and 32 Ph+ ALL patients (R/I Cohort: n=10, T315I Cohort: n=22). A prior MCyR or better (MCyR, MMR, or CMR) to dasatinib or nilotinib was only achieved in 26% patients with CP-CML and a prior MaHR or better (MaHR, MCyR, MMR, or CMR) was only achieved in 21%, and 24% of AP-CML, and BP-CML/Ph+ALL patients, respectively. At the time of analysis, patients had a minimum follow-up of 6 months (median follow-up: 10 months). Baseline demographic characteristics are described in Table 5 below.
Table 5 Demographics and disease characteristics

 

Patient characteristics at entry	Total safety population N=449
Age
Median, years (range)	59 (18 - 94)
Gender, n (%)
Male	238 (53%)
Race, n (%)
Asian	59 (13%)
Black/African American	25 (6%)
White	352 (78%)
Other	13 (3%)
ECOG Performance Status, n (%)
ECOG=0 or 1	414 (92%)
Disease History
Median time from diagnosis to first dose, years (range)	6.09 (0.33 - 28.47)
Resistant to Prior TKI Therapy*, n (%)	374 (88%)
Prior TKI therapy– number of regimens, n (%)
1	32 (7%)
2	155 (35%)
≥3	262 (58%)
BCR-ABL mutation detected at entry, n (%)
None	198 (44%)
1	192 (43%)
≥2	54 (12%)
* of 427 patients reporting prior TKI therapy with dasatinib or nilotinib

Overall, 55% of patients had one or more BCR-ABL kinase domain mutation at entry with the most frequent being: T315I (29%), F317L (8%), E255K (4%) and E359V (4%). In 67% of CP-CML patients in the R/I cohort, no mutations were detected at study entry.
At the time of analysis, median duration of Iclusig treatment was 281 days in CP-CML patients, 286 days in AP-CML patients, 89 days in BP-CML patients, and 81 days in patients with Ph+ ALL. Efficacy results are summarized in Table 6, Table 7, and Table 8.
Table 6 Efficacy of Iclusig in resistant or intolerant chronic phase CML patients

Overall (N=267)	Resistant or Intolerant
	R/I Cohort (N=203)	T315I Cohort (N=64)
Cytogenetic Response
Major (MCyR) a % (95% CI)	54% (48-60)	49% (42-56)	70% (58-81)
Complete (CCyR) % (95% CI)	44% (38-50)	37% (31-44)	66% (53-77)
Major Molecular Response b % (95% CI)	30% (24-36)	23% (18-30)	50% (37-63)
a Primary endpoint for CP-CML Cohorts was MCyR, which combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses. b Measured in peripheral blood. Defined as a ≤0.1% ratio of BCR-ABL to ABL transcripts on the International Scale (IS) (ie, ≤0.1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR).

CP-CML patients who received fewer prior TKIs attained higher cytogenetic, haematological, and molecular responses. Of the CP-CML patients previously treated with one, two, or three prior TKIs, 81% (13/16), 61% (65/105), and 46% (66/143) achieved a MCyR while on Iclusig, respectively.
Of the CP-CML patients with no mutation detected at entry, 46% (63/136) achieved a MCyR.

For every BCR-ABL mutation detected in more than one CP-CML patient at entry, a MCyR was achieved following treatment with Iclusig.
In CP-CML patients who achieved MCyR, the median time to MCyR was 84 days (range: 49 to 334 days) and in patients who achieved MMR, the median time to MMR was 167 days (range: 55 to 421 days). At the time of reporting, the median durations of MCyR and MMR had not yet been reached. Based on the Kaplan-Meier estimates, 91% (95% CI: [85%–95%]) of CP-CML (median duration of treatment: 421 days) patients who achieved a MCyR and 81% (95% CI: [70%- 88%]) of CP-CML patients who achieved a MMR are projected to maintain that response at 12 months.
Table 7 Efficacy of Iclusig in resistant or intolerant advanced phase CML patients

Accelerated Phase CML			Blast Phase CML
Overall (N=83)	Resistant or Intolerant		Overall (N=62)	Resistant or Intolerant
	R/I Cohort (N=65)	T315I Cohort (N=18)		R/I Cohort (N=38)	T315I Cohort (N=24)
Haematological Response Rate
Majora (MaHR) % (95% CI)	58% (47-69)	60% (47-72)	50% (26 - 74)	31% (20 – 44)	32% (18 – 49)	29% (13 – 51)
Completeb (CHR) % (95% CI)	47% (36-58)	46% (34-49)	50% (26-74)	21% (12-33)	24% (11-40)	17% (5-37)
Major Cytogenetic Responsec % (95% CI)	39% (28-50)	34% (23-47)	56% (31-79)	23% (13-35)	18% (8-34)	29% (13-51)
a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines complete haematological responses and no evidence of leukaemia. b CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils <5% in peripheral blood, No extramedullary involvement (including no hepatomegaly or splenomegaly). c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses.

Table 8 Efficacy of Iclusig in resistant or intolerant Ph+ ALL patients

Overall (N=32)	Resistant or Intolerant
	R/I Cohort (N=10)	T315I Cohort (N=22)
Haematological Response Rate
Majora (MaHR) % (95% CI)	41% (24-59)	50% (19-81)	36% (17-59)
Completeb (CHR) % (95% CI)	34% (19-53)	40% (12-73)	32% (14-55)
Major Cytogenetic Responsec % (95% CI)	47% (29-65)	60% (26-88)	41% (21-64)
a Primary endpoint for AP-CML and BP-CML/Ph+ ALL Cohorts was MaHR, which combines complete haematological responses and no evidence of leukaemia. b CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils <5% in peripheral blood, No extramedullary involvement (including no hepatomegaly or splenomegaly). c MCyR combines both complete (No detectable Ph+ cells) and partial (1% to 35% Ph+ cells) cytogenetic responses.

The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ ALL was 21 days (range: 12 to 176 days), 29 days (range: 12 to 113 days), and 20 days (range: 11 to 168 days), respectively. The median duration of MaHR for AP-CML (median duration of treatment: 446 days) BP-CML (median duration of treatment: 89 days), and Ph+ ALL (median duration of treatment: 81 days) patients was estimated as 11.8 months (range: 1.2 to 21.5+ months), 4.7 months (range: 1 to 19.6+ months), and 3.2 months (range: 1.8 to 13.8+ months), respectively.
The anti-leukaemic activity of Iclusig was also evaluated in a phase 1 dose escalation study that included 65 CML and Ph+ ALL patients; the study is ongoing. Of 43 CP-CML patients, 31 CP-CML patients achieved a MCyR with a median duration of follow-up of 25.3 months (range: 1.7 to 38.4 months). At the time of reporting, 25 CP-CML patients were in MCyR (median duration of MCyR had not been reached).
Cardiac electrophysiology
The QT interval prolongation potential of Iclusig was assessed in 39 leukaemia patients who received 30 mg, 45 mg, or 60 mg Iclusig once daily. Serial ECGs in triplicate were collected at baseline and at steady state to evaluate the effect of ponatinib on QT intervals. No clinically significant changes in the mean QTc interval (i.e., > 20 ms) from baseline were detected in the study. In addition, the pharmacokinetic-pharmacodynamic models show no exposure-effect relationship, with an estimated QTcF mean change of –6.4 ms (upper confidence interval –0.9 ms) at Cmax for the 60 mg group.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Iclusig in children from birth to less than 1 year in CML and Ph+ ALL. The European Medicines Agency has deferred the obligation to submit the results of studies with Iclusig in paediatric patients from 1 year to less than 18 years in CML and Ph+ ALL (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Peak concentrations of ponatinib are observed approximately 4 hours after oral administration. Within the range of clinically relevant doses evaluated in patients (15 mg to 60 mg), ponatinib exhibited dose proportional increases in both Cmax and AUC. The geometric mean (CV%) Cmax and AUC(0-τ) exposures achieved for ponatinib 45 mg daily at steady state were 77 ng/mL (50%) and 1296 ng•hr/mL (48%), respectively. Following either a high-fat and low-fat meal, plasma ponatinib exposures (Cmax and AUC) were not different versus fasting conditions. Iclusig may be administered with or without food.
Distribution
Ponatinib is highly bound (>99%) to plasma proteins in vitro. The blood/plasma ratio of ponatinib is 0.96. At daily doses of 45 mg, the geometric mean (CV%) apparent steady state volume of distribution is 1101 L (94%) suggesting that ponatinib is extensively distributed in the extravascular space. In vitro studies suggested that ponatinib is either not a substrate or is a weak substrate for both P-gp and breast cancer resistance protein BCRP. Ponatinib is not a substrate for the human organic anion transporting polypeptides OATP1B1, OATP1B3 and the organic cation transporter OCT-1.
Biotransformation
Ponatinib is metabolized to an inactive carboxylic acid by esterases and/or amidases, and metabolized by CYP3A4 to an N-desmethyl metabolite that is 4 times less active than ponatinib. The carboxylic acid and the N-desmethyl metabolite comprise 58% and 2% of the circulating levels of ponatinib, respectively.
At therapeutic serum concentrations, ponatinib did not inhibit OATP1B1 or OATP1B3, OCT1 or OCT2, organic anion transporters OAT1 or OAT3, or bile salt export pump (BSEP) in vitro. Therefore, clinical medicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of substrates for these transporters. In vitro studies indicate that clinical medicinal product interactions are unlikely to occur as a result of ponatinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A or CYP2D6.
An in vitro study in human hepatocytes indicated that clinical medicinal product interactions are also unlikely to occur as a result of ponatinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, or CYP3A.
Elimination
Following single and multiple 45 mg doses of Iclusig, the terminal elimination half-life of ponatinib was 22 hours, and steady state conditions are typically achieved within 1 week of continuous dosing. With once-daily dosing, plasma exposures of ponatinib are increased by approximately 1.5-fold between first dose and steady state conditions. Ponatinib is mainly eliminated via feces. Following a single oral dose of [14C]-labeled ponatinib, approximately 87% of the radioactive dose is recovered in the feces and approximately 5% in the urine. Unchanged ponatinib accounted for 24% and <1% of the administered dose in feces and urine, respectively, with the remainder of the dose comprising metabolites.
Renal impairment
Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined (see section 4.2).
Hepatic impairment
Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for ponatinib, hepatic impairment may result in increased plasma ponatinib concentrations (see section 4.2).
Intrinsic factors affecting ponatinib pharmacokinetics
No specific studies have been performed to evaluate the effects of gender, age, race, and body weight on ponatinib pharmacokinetics. An integrated population pharmacokinetic analysis completed for ponatinib suggests that age may be predictive of variability for ponatinib apparent oral clearance (CL/F). Gender, race and body weight were not predictive in explaining ponatinib pharmacokinetic intersubject variability.
5.3 Preclinical safety data
Iclusig has been evaluated in safety pharmacology, repeat-dose toxicity, genotoxicity, reproductive toxicity, and phototoxicity studies.
Ponatinib did not exhibit genotoxic properties when evaluated in the standard in vitro and in vivo systems.
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use are described below.
Depletion of lymphoid organs was observed in repeat-dose toxicity studies in rats and cynomolgus monkeys. The effects were shown to be reversible after withdrawal of the treatment.
Hyper-/hypoplastic changes of the chondrocytes in the physis were noted in repeat-dose toxicity studies in rats.
In rats, inflammatory changes accompanied by increases in neutrophils, monocytes, eosinophils, and fibrinogen levels were found in the preputial and clitoral glands following chronic dosing.
Skin changes in the form of crusts, hyperkeratosis, or erythema were observed in toxicity studies in cynomolgus monkeys. Dry flaky skin was observed in toxicity studies in rats.
In a study in rats, diffuse corneal edema with neutrophilic cell infiltration, and hyperplastic changes in the lenticular epithelium suggestive of a mild phototoxic reaction were observed in animals treated with 5 and 10 mg/kg ponatinib
In cynomolgus monkeys, systolic heart murmurs with no macroscopic or microscopic correlates were noted in individual animals treated with 5 and 45 mg/kg in the single dose toxicity study and at 1, 2.5 and 5 mg/kg in the 4-week repeat-dose toxicity study. The clinical relevance of this finding is unknown.
In cynomolgus monkeys, thyroid gland follicular atrophy mostly accompanied by a reduction in T3 levels and a tendency toward increased TSH levels were observed in the 4-week repeat-dose toxicity study in cynomolgus monkeys.
Ponatinib-related microscopic findings in the ovaries (increased follicular atresia) and testes (minimal germ cell degeneration) in animals treated with 5 mg/kg ponatinib were noted in repeat-dose toxicity studies in cynomolgus monkeys.
Ponatinib at doses of 3, 10, and 30 mg/kg produced increases in urine output and electrolyte excretions and caused a decrease in gastric emptying in safety pharmacology studies in rats.
In rats, embryo-foetal toxicity in the form of post-implantation loss, reduced foetal body weight, and multiple soft tissue and skeletal alterations were observed at maternal toxic dosages. Multiple foetal soft tissue and skeletal alterations were also observed at maternal nontoxic dosages.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Lactose monohydrate
Microcrystalline cellulose
Sodium starch glycolate
Colloidal anhydrous silica
Magnesium stearate
Tablet coating
Talc
Macrogol 3000
Poly(vinyl alcohol)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original container in order to protect from light.
6.5 Nature and contents of container
High density polyethylene (HDPE) bottles with screw-top closures, containing either:
60 or 180 film-coated tablets – Iclusig 15 mg.
30 or 90 film-coated tablets– Iclusig 45 mg
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
7. Marketing authorisation holder
ARIAD Pharma Ltd.
Brooklands Business Park
Wellington Way
Weybridge, KT13 0TT
United Kingdom
8. Marketing authorisation number(s)
 EU/1/13/839/001 – Iclusig 15 mg
EU/1/13/839/002 – Iclusig 15 mg
EU/1/13/839/003 – Iclusig 45 mg
EU/1/13/839/004 – Iclusig 45 mg
9. Date of first authorisation/renewal of the authorisation
 Date of first authorisation: 1 July 2013
10. Date of revision of the text
 25 November 2013
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
FDA批准Ponatinib治疗两类罕见白血病
FDA于12月14日批准了ponatinib（Iclusig, Araid），该药属于三代酪氨酸激酶抑制剂，被批准用于两种耐药的白血病，即慢性粒细胞白血病（CML）和费城染色体阳性的急性淋巴细胞白血病（Ph+  ALL）成年患者。
FDA强调ponatinib的批准比官方截止日期提前3个月。这是基于上周第54届美国血液病学年会上公布的ponatinibII期临床试验结果。
临床实验表明该药物毒性通常较低，除了几例患者发生了严重的胰腺炎。ponatinib能避开最常见的一种导致酪氨酸激酶抑制剂耐受的突变——T315I突变，该突变阻断了目前已批准的三种酪氨酸酶抑制剂imatinib、dasatinib和nilotinib发挥作用。
Ponatinib被认为是费城染色体的抑制剂，因为它能有效阻断由费城染色体产生的原始和所有突变形式的蛋白。患者在该试验之前，对其他酪氨酸激酶抑制剂包括dasatinib和nilotinib抵抗或耐受。但是FDA在宣布批准时并没有说，患者不能接受ponatinib作为一线治疗方法。该药在治疗CML慢性期和急性期患者中反应率最高。常见的副作用是皮疹、皮肤干燥、腹痛、头痛和便秘，大多数情况下症状很轻微。然而，FDA称，这种药物的标签将包括一个关于血液凝块和肝毒性的黑框警告。
FDA血液学和肿瘤学产品办公室药物评价与研究中心主任Richard Pazdur，在一份声明中称“Iclusig的批准是很重要的，因为它为对其他药物不反应的CML患者提供了治疗选择，特别是那些几乎没有选择治疗的余地的携带T315I突变患者。”Ponatinib基于FDA加速批准程序而批准，这就要求Ariad制药公司进行更多的试验来确认产品的益处和安全。该机构没有指出需要何种形式的研究。Ponatinib将由Ariad制药出售。