Evoltra

Therapeutic indication

Paediatric patients (Acute Lymphoblastic Leukemia)

Mechanism of action

Clofarabine is a purine nucleoside anti-metabolite. Its antitumour activity is believed to be due to 3 mechanisms: • DNA polymerase α inhibition resulting in termination of DNA chain elongation and/or DNA synthesis / repair. • Ribonucleotide reductase inhibition with reduction of cellular deoxynucleotide triphosphate (dNTP) pools. • Disruption of mitochondrial membrane integrity with the release of cytochrome C and other proapoptotic factors leading to programmed cell death even in non-dividing lymphocytes. Clofarabine must first diffuse or be transported into target cells where it is sequentially phosphorylated to the mono- and bi-phosphate by intracellular kinases, and then finally to the active conjugate, clofarabine 5’-triphosphate. Clofarabine has high affinity for one of the activating phosphorylating enzymes, deoxycytidine kinase, which exceeds that of the natural substrate, deoxycytidine. In addition, clofarabine possesses greater resistance to cellular degradation by adenosine deaminase and decreased susceptibility to phosphorolytic cleavage than other active substances in its class whilst the affinity of clofarabine triphosphate for DNA polymerase α and ribonucleotide reductase is similar to or greater than that of deoxyadenosine triphosphate.

DRUG

Evoltra 1 mg/ml
Each 20 ml vial contains 20 mg of clofarabine.

Therapeutic indication

Treatment of acute lymphoblastic leukaemia (ALL) in paediatric patients who have relapsed or are refractory after receiving at least two prior regimens and where there is no other treatment option anticipated to result in a durable response. Safety and efficacy have been assessed in studies of patients ≤ 21 years old at initial diagnosis (see section 5.1 of the SPC).

Reimbursement modalities

Conditions de remboursement
Chapitre : IV	Paragraphe : 4750000
a) La spécialité fait l’objet d’un remboursement si elle est administrée pour le traitement d’une leucémie lymphoblastique aiguë chez un patient âgé de moins de 21 ans chez qui: - Soit, la maladie est réfractaire à au moins 3 différents traitements de combinaison considérés comme adéquates dans cette pathologie selon les recommandations et les experts nationaux et internationaux; - Soit, une deuxième récidive s’est manifestée après au moins 2 différents traitements de combinaison considérés comme adéquates dans cette pathologie selon les recommandations et les experts nationaux et internationaux. b) Le remboursement est subordonné à la remise au pharmacien hospitalier d’un formulaire de demande, dont le modèle est repris à l’annexe A du présent paragraphe, complété et signé par un médecin spécialiste en médecine interne, porteur de la qualification particulière en hématologie selon l’Arrêté Ministériel du 18.10.2002 ou par un médecin spécialiste porteur de la qualification professionnelle particulière en hématologie et oncologie pédiatrique selon l’Arrêté Ministériel du 14.05.2007. En complétant de la sorte les rubriques ad hoc de ce formulaire, le médecin spécialiste dont il est question ci-dessus mentionne également : - les éléments relatifs à l’état du patient; - qu’il s’engage à tenir à la disposition du médecin conseil les éléments de preuve qui attestent de la situation décrite; - qu’il s’engage à arrêter le traitement lorsqu’il constate que la maladie progresse malgré le traitement. c) Le nombre de conditionnements remboursables tiendra compte d’un maximum de trois cycles et d’une posologie maximale de 52 mg/m² par jours pendant 5 jours consécutifs par cycle. d) Le formulaire repris à l’annexe A devra être tenu à la disposition du médecin conseil.

https://www.riziv.fgov.be/webprd/appl/pssp/SSP/CNS2/Pdf/Form_Dem/4/1/4750000_FormDem_fr.pdf

Administration and dosage

Therapy must be initiated and supervised by a physician experienced in the management of patients with acute leukaemias.

Adult population (including elderly)

There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients (see section 5.2 of SPC).

Paediatric population

Children and adolescents (≥ 1 year old)

The recommended dose in monotherapy is 52 mg/m2 of body surface area administered by intravenous infusion over 2 hours daily for 5 consecutive days. Body surface area must be calculated using the actual height and weight of the patient before the start of each cycle. Treatment cycles should be repeated every 2 to 6 weeks (from the starting day of the previous cycle) following recovery of normal haematopoiesis (i.e. ANC ≥ 0.75 × 109/l) and return to baseline organ function. A 25% dose reduction may be warranted in patients experiencing significant toxicities (see below). There is currently limited experience of patients receiving more than 3 treatment cycles (see section 4.4).

The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles (see section 5.1). Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 2 treatment cycles should be assessed by the treating physician (see section 4.4).

Children weighing < 20 kg

An infusion time of > 2 hours should be considered to help reduce symptoms of anxiety and irritability, and to avoid unduly high maximum concentrations of clofarabine (see section 5.2).

Children < 1 year old

There are no data on the pharmacokinetics, safety or efficacy of clofarabine in infants. Therefore, a safe and effective dosage recommendation for patients < 1 year old has yet to be established.

Method of administration

The recommended dosage should be administered by intravenous infusion although it has been administered via a central venous catheter in ongoing clinical trials. Evoltra must not be mixed with or concomitantly administered using the same intravenous line as other medicinal products (see section 6.2 of the SPC). For instructions on dilution of the medicinal product before administration (see section 6.6 of the SPC).

Dose modifications

Toxicity

Dose reduction for patients experiencing haematological toxicities

If the ANC does not recover by 6 weeks from the start of a treatment cycle, a bone marrow aspirate / biopsy should be performed to determine possible refractory disease. If persistent leukaemia is not evident, it is recommended that the dose for the next cycle be reduced by 25% of the previous dose following recovery of ANC to ≥ 0.75 × 109/l. Should patients experience an ANC < 0.5 × 109/l for more than 4 weeks from the start of the last cycle, it is recommended that the dose for the next cycle be reduced by 25%.

Dose reduction for patients experiencing non-haematological toxicities

Infectious events

If a patient develops a clinically significant infection, clofarabine treatment may be withheld until the infection is clinically controlled. At this time, treatment may be reinitiated at the full dose. In the event of a second clinically significant infection, clofarabine treatment should be withheld until the infection is clinically controlled and may be reinitiated at a 25% dose reduction.

Non-infectious events

If a patient experiences one or more severe toxicities (US National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 3 toxicities excluding nausea and vomiting), treatment should be delayed until the toxicities resolve to baseline parameters or to the point where they are no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a 25% dose reduction.

Should a patient experience the same severe toxicity on a second occasion, treatment should be delayed until the toxicity resolves to baseline parameters or to the point where it is no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a further 25% dose reduction.

Any patient who experiences a severe toxicity on a third occasion, a severe toxicity that does not recover within 14 days (see above for exclusions), or a life-threatening or disabling toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine (see section 4.4 of the SPC).

Hepatic impairment

There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine is contraindicated in patients with severe hepatic impairment (see section 4.3 of the SPC) and should be used with caution in patients with mild to moderate hepatic impairment (see section 4.4 of the SPC).

Renal impairment

The limited data available indicate that clofarabine may accumulate in patients with decreased creatinine clearance (see sections 4.4 and 5.2 of the SPC). Clofarabine is contraindicated in patients with severe renal insufficiency (see section 4.3 of the SPC) and should be used with caution in patients with mild to moderate renal insufficiency (see section 4.4 of the SPC).

Patients with moderate renal impairment (creatinine clearance 30 – < 60 ml/min) require a 50% dose reduction (see section 5.2).

Drug-drug interactions

No interaction studies have been performed. However, there are no known clinically significant interactions with other medicinal products or laboratory tests.

Clofarabine is not detectably metabolised by the cytochrome P450 (CYP) enzyme system. Therefore, it is unlikely to interact with active substances which inhibit or induce cytochrome P450 enzymes. In addition, clofarabine is unlikely to inhibit any of the major 5 human CYP isoforms (1A2, 2C9, 2C19, 2D6 and 3A4) or to induce 2 of these isoforms (1A2 and 3A4) at the plasma concentrations achieved following intravenous infusion of 52 mg/m2/day. As a result, it is not expected to affect the metabolism of active substances which are known substrates for these enzymes.

Clofarabine is predominately excreted via the kidneys. Thus, the concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion such as NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine, cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 day clofarabine administration period (see sections 4.4, 4.8 and 5.2 of the SPC).

The liver is a potential target organ for toxicity. Thus, the concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.4 and 4.8 of the SPC).

Patients taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.4 and 4.8 of the SPC).

Drug-food interactions

Not mentioned

Adverse events of special interest

Evoltra is a potent antineoplastic agent with potentially significant haematological and non-haematological adverse reactions (see section 4.8 of the SPC).

The following parameters should be closely monitored in patients undergoing treatment with clofarabine:

Complete blood and platelet counts should be obtained at regular intervals, more frequently in patients who develop cytopaenias.

Renal and hepatic function prior to, during active treatment and following therapy. Clofarabine should be discontinued immediately if substantial increases in creatinine, liver enzymes and/or bilirubin are observed.

Respiratory status, blood pressure, fluid balance and weight throughout and immediately after the 5 day clofarabine administration period.

Suppression of bone marrow should be anticipated. This is usually reversible and appears to be dose-dependent. Severe bone marrow suppression, including neutropaenia, anaemia and thrombocytopaenia have been observed in patients treated with clofarabine. Haemorrhage, including cerebral, gastrointestinal and pulmonary haemorrhage, has been reported and may be fatal. The majority of the cases were associated with thrombocytopaenia (see section 4.8 of the SPC).

In addition, at initiation of treatment, most patients in the clinical studies had haematological impairment as a manifestation of leukaemia. Because of the pre-existing immuno-compromised condition of these patients and prolonged neutropaenia that can result from treatment with clofarabine, patients are at increased risk for severe opportunistic infections, including severe sepsis, with potentially fatal outcomes. Patients should be monitored for signs and symptoms of infection and treated promptly.

Occurrences of enterocolitis, including neutropaenic colitis, caecitis, and C. difficile colitis, have been reported during treatment with clofarabine. This has occurred more frequently within 30 days of treatment, and in the setting of combination chemotherapy. Enterocolitis may lead to necrosis, perforation or sepsis complications and may be associated with fatal outcome (see section 4.8 of the SPC). Patients should be monitored for signs and symptoms of enterocolitis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), including fatal cases, have been reported (see section 4.8 of the SPC). Clofarabine must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected.

Administration of clofarabine results in a rapid reduction in peripheral leukaemia cells. Patients undergoing treatment with clofarabine should be evaluated and monitored for signs and symptoms of tumour lysis syndrome and cytokine release (e.g. tachypnoea, tachycardia, hypotension, pulmonary oedema) that could develop into Systemic Inflammatory Response Syndrome (SIRS), capillary leak syndrome and/or organ dysfunction (see section 4.8 of the SPC).

Prophylactic administration of allopurinol should be considered if hyperuricemia (tumour lysis) is expected.

Patients should receive intravenous fluids throughout the 5 day clofarabine administration period to reduce the effects of tumour lysis and other events.

The use of prophylactic steroids (e.g., 100 mg/m2 hydrocortisone on Days 1 through 3) may be of benefit in preventing signs or symptoms of SIRS or capillary leak.

Clofarabine should be discontinued immediately if patients show early signs or symptoms of SIRS, capillary leak syndrome or substantial organ dysfunction and appropriate supportive measures instituted. In addition, clofarabine treatment should be discontinued if the patient develops hypotension for any reason during the 5 days of administration. Further treatment with clofarabine, generally at a lower dose, can be considered when patients are stabilised and organ function has returned to baseline.

The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles (see section 5.1 of the SPC). Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 2 treatment cycles should be assessed by the treating physician.

Patients with cardiac disease and those taking medicinal products known to affect blood pressure or cardiac function should be closely monitored during treatment with clofarabine (see sections 4.5 and 4.8 of the SPC).

There is no clinical study experience in paediatric patients with renal insufficiency (defined in clinical studies as serum creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys. Pharmacokinetic data indicate that clofarabine may accumulate in patients with decreased creatinine clearance (see section 5.2 of the SPC). Therefore, clofarabine should be used with caution in patients with mild to moderate renal insufficiency (see section 4.2 of the SPC for dose adjustments). The safety profile of clofarabine has not been established in patients with severe renal impairment or patients receiving renal replacement therapy (see section 4.3 of the SPC). The concomitant use of medicinal products that have been associated with renal toxicity and those eliminated by tubular secretion such as NSAIDs, amphotericin B, methotrexate, aminosides, organoplatines, foscarnet, pentamidine, cyclosporin, tacrolimus, acyclovir and valganciclovir, should be avoided particularly during the 5 day clofarabine administration period; preference should be given to those medicinal products that are not known to be nephrotoxic (see sections 4.5 and 4.8 of the SPC). Renal failure or acute renal failure have been observed as a consequence of infections, sepsis and tumour lysis syndrome (see section 4.8 of the SPC). Patients should be monitored for renal toxicity and clofarabine should be discontinued as necessary.

It was observed that the frequency and severity of adverse reactions, in particular infection, myelosuppression (neutropenia) and hepatotoxicity, are increased when clofarabine is used in combination. In this regard, patients should be closely monitored when clofarabine is used in combined regimens.

Patients receiving clofarabine may experience vomiting and diarrhoea; they should, therefore, be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, fainting spells, or decreased urine output. Prophylactic anti-emetic medicinal products should be considered.

There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.2 and 4.3 of the SPC). The concomitant use of medicinal products that have been associated with hepatic toxicity should be avoided wherever possible (see sections 4.5 and 4.8 of the SPC).

If a patient experiences a hematologic toxicity of Grade 4 neutropaenia (ANC < 0.5 x 109/l) lasting ≥ 4 weeks, then the dose should be reduced by 25% for the next cycle.

Any patient who experiences a severe non-hematologic toxicity (US NCI CTC Grade 3 toxicity) on a third occasion, a severe toxicity that does not recover within 14 days (excluding nausea/vomiting) or a life-threatening or disabling non-infectious non-hematologic toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine (see section 4.2 of the SPC).

Patients who have previously received a hematopoietic stem cell transplant (HSCT) may be at higher risk for hepatotoxicity suggestive of veno-occlusive disease (VOD) following treatment with clofarabine (40 mg/m2) when used in combination with etoposide (100 mg/m2) and cyclophosphamide (440 mg/m2). In the post-marketing period, following treatment with clofarabine, serious hepatotoxic adverse reactions of VOD in paediatric and adult patients have been associated with a fatal outcome. Cases of hepatitis and hepatic failure, including fatal outcomes, have been reported with clofarabine treatment (see section 4.8 of the SPC).

Most patients received conditioning regimens that included busulfan, melphalan, and/or the combination of cyclophosphamide and total body irradiation. Severe hepatotoxic events have been reported in a Phase 1/2 combination study of clofarabine in paediatric patients with relapsed or refractory acute leukaemia.

There are currently limited data on the safety and efficacy of clofarabine when administered for more than 3 treatment cycles.

Each vial of Evoltra contains 180 mg of sodium chloride. This is equivalent to 3.08 mmol (or 70.77 mg) of sodium and should be taken into consideration for patients on a controlled sodium diet.

Management of adverse events

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SPC for how to report adverse reactions.

See also above: Adverse events of special interest

Initial work-up before start of treatment

Renal and hepatic function

Concomitant Treatment

Evoltra must not be mixed with or concomitantly administered using the same intravenous line as other medicinal products (see section 6.2 of the SPC).

Response evaluation

Clinical efficacy: To enable systematic evaluation of the responses seen in patients, an unblinded Independent Response Review Panel (IRRP) determined the following response rates based on definitions produced by the Children’s Oncology Group:

CR = Complete Remission	Patients who met each of the following criteria: • No evidence of circulating blasts or extramedullary disease • An M1 bone marrow (≤ 5% blasts) • Recovery of peripheral counts (platelets ≥ 100 x 109/l and ANC ≥ 1.0 x 109/l)
CRp = Complete Remission in the Absence of Total Platelet Recovery	• Patients who met all of the criteria for a CR except for recovery of platelet counts to > 100 x 109/l
PR = Partial Remission	Patients who met each of the following criteria: • Complete disappearance of circulating blasts • An M2 bone marrow (≥ 5% and ≤ 25% blasts) and appearance of normal progenitor cells • An M1 marrow that did not qualify for CR or CRp
Overall Remission (OR) Rate	- (Number of patients with a CR + Number of patients with a CRp) ÷ Number of eligible patients who received clofarabine

For the full SmPC visit: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000613/WC500031191.pdf