Zalmoxis - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Zalmoxis 5–20 × 106 cells/mL dispersion for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION2.1 General description

Allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (ALNGFR) and the herpes simplex I virus thymidine kinase (HSV-TK Mut2).

2.2 Qualitative and quantitative composition

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Each bag of Zalmoxis contains a volume of 10–100 mL of frozen dispersion at the concentration of 5–20 × 106 cells/mL. The cells are of human origin and genetically modified with a replicationde­fective Y-retroviral vector coding for the HSV-TK and ALNGFR genes so that these sequences are integrated in the genome of the host cells.

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The cellular composition and the final cell number will vary according to the weight of the patient. In addition to T cells, NK cells and residual levels of monocytes and of B cells may be present.

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Excipient with known effect

Each bag contains approximately 13.3 mmol (305.63 mg) of sodium per dose.

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For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Dispersion for infusion.

Opaque, off-white frozen dispersion.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Zalmoxis is indicated as adjunctive treatment in haploidentical haematopoietic stem cell transplantation (HSCT) of adult patients with high-risk haematological malignancies (see section 5.1).

4.2 Posology and method of administration

Zalmoxis must be administered under the supervision of a physician experienced in HSCT for haematological malignancies.

Posology

The recommended dose and schedule is 1 ± 0.2 × 107 cells/kg given as an intravenous infusion at a time interval of 21–49 days from transplantation, in the absence of spontaneous immune reconstitution and/or development of graft-versus-host disease (GvHD). Additional infusions are administered at approximately one month intervals for a maximum of four times, until a circulating T lymphocyte count is equal to or more than 100 per pL.

Zalmoxis should not be administered if the circulating T lymphocytes are >100 per pL at the day of planned infusion after haploidentical HSCT.

Paediatric population

The safety and efficacy in children and adolescents (less than 18 years) have not been established. No data are available. Zalmoxis is therefore not recommended for use in children and adolescent below 18 years.

Method of administration

Zalmoxis is solely for use as patient specific medicinal product to be administered after HSCT and it is administered by intravenous infusion.

Zalmoxis should be infused intravenously over a period of 20–60 minutes. The entire volume of the bag should be infused.

If the infusion must be interrupted, it should not be resumed if the infusion temperature (15 °C-30 °C) for more than 2 hours.

Precautions to be taken before handling or administering the medicinal product

Before infusion it must be confirmed that the patient identity matches the essential unique information reported on the Zalmoxis bag label and on the related Certificate of Analysis (CoA).

The bag should be removed from the liquid nitrogen, put in a double bag container and thawed in a pre-warmed water bath at 37 °C. Upon full cell dispersion thawing, the bag is dried, disinfected and ready to be infused at a rate prescribed by the physician. Once the bag is infused, it is flushed 2 to 3 times with sodium chloride solution in order to completely administer Zalmoxis. The entire volume of the bag has to be infused.

4.3 Contraindications ce or to any of the excipients listed in section 6.1.Hypersensitivity to the active su

Immune reconstitution defined as circulating T lymphocytes >100 per pL at the day of planned infusion after haploidentical HSCT.

GvHD requiring systemic immunosupressive therapy.

4.4 Special warnings and precautions for use

General

Zalmoxis is a patient specific product and should under no circumstances be administered to other patients. It must not be administered if the following conditions occur:

• a) infections requiring administration of ganciclovir (GCV) or valganciclovir (VCV) at the time of infusion;

• b) GvHD requiring systemic immunosupressive therapy;

• c) ongoing systemic immunosupressive therapy or administration of granulocyte colony stimulating factor (G-CSF) after haploidentical HSCT.

Patients characterized by condition a) could be administered Zalmoxis 24 hours following the antiviral therapy discontinuation; patients characterized by conditions b) and c) could be administered Zalmoxis after an adequate wash out period.

Zalmoxis 5–20 × 106 cells/mL cell dispersion for infusion contains 13.3 mmol (305.63 mg) of sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

It is strongly recommended that, at the end of Zalmoxis infusion, the product label is removed from the bag and placed in the patient record sheet.

Treatment should be discontinued in case of occurrence of any 3–4 grade event related to Zalmoxis administration or grade 2 adverse event not resolving in a grade 1 or less in the next 30 days.

Zalmoxis is obtained by donor blood cells. Even if donors are preliminary tested and found negative for transmissible infectious disease, precautions should be employed when handling Zalmoxis.

Healthcare professionals handling Zalmoxis should therefore take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases.

Cases in which Zalmoxis cannot be supplied / infused

In some cases, the patient may be unable to receive Zalmoxis because of manufacturing issues.

There may be cases in which the treating physician may still consider preferable to give the treatment or select an alternative treatment.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

The risk on virus shedding vertical viral transmission is theoretically negligible however not excluded. Women of childbearing potential have to provide a negative pregnancy test (serum or urine) within 14 days prior to start the treatment. Both male and female patients (to be) treated with Zalmoxis and their partners need to use effective contraception during and up to 6 months after treatment with Zalmoxis.

Studies in animals have not been performed. Given the intended clinical use in the context of a haploidentical bone marrow transplantation, a need for treatment during pregnancy is not expected.

As a precautionary measure, Zalmoxis must not be administered during pregnancy and in women of childbearing potential not using contraception.

It has been shown that Zalmoxis cells may circulate for years after the last administration. In the event of pregnancy following Zalmoxis treatment adverse effect on pregnancy and the developing foetus are not expected as lymphocytes do not pass the placenta.

Breast-feeding

There are no data on the use of Zalmoxis during breast-feeding. Immune cells are excreted in human milk in low amounts.

It is recommended not to breast-feed during or after treatment with Zalmoxis therapy.

Fertility

There are no data on the effect of Zalmoxis treatment on fertility. However myeloablative conditioning regimens performed in the context of a haploidentical bone marrow transplantation is associated with sterility.

4.7 Effects on ability to drive and use machines

Zalmoxis has no or negligible influence on the ability to drive and use machines.

No detrimental effects on such activities are predicted from the pharmacology of the medicinal product. The clinical status of the patient and the ADR profile of Zalmoxis should be born in mind when considering the patient’s ability to perform tasks that require judgement, motor or cognitive skills.

4.8 Undesirable effects

Summary of the safety profile

In the clinical study TK007, 30 patients with high-risk haematological malignancies undergoing

HSCT received Zalmoxis monthly up to a maximum of four infusions.

The most common adverse reaction reported by patients treated with Zalmoxis in clinical trial TK007 was acute GvHD.

Tabulated list of adverse reactions

Undesirable effects recorded in the clinical study TK007 are listed in Table 1 by system organ class and by frequency of occurrence.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

• Table 1. Zalmoxis adverse reactions recorded in TK007 study

  System Organ Class

  
  

  Frequency and Adverse rea

  Very common (> 1/10)

  
  

  Common

  (> 1/100 to < 1/10)

  Post transplant lymphoproliferative disorder

  
  

Neoplasm benign, malignant and unspecified (including cysts and polyps)

Description of selected adverse reactions

Globally, acute episodes of GvHD occurred in 10 patients (33%) with a median time to onset of 90 days after HSCT and 42 days after last infusion of Zalmoxis cells. Severity of acute GvHD was grade 1 in one case (3%), grade 2 in seven (23%), grade 3 in one (3%) and grade 4 in one (3%). All acute GvHD events fully resolved after a median duration of 12 days. Only one patient (3%) developed an extensive chronic GvHD that occurred 159 days and 129 days from HSCT and last infusion, respectively, and fully resolved after 107 days. There were no GvHD-related deaths or long-term complications. Both acute and chronic GvHD events developed only in patients who had achieved immune reconstitution.

For treating Zalmoxis-related GvHD through activation of the suicide gene, patients received GCV intravenously or VCV orally, for better patient convenience. All signs and symptoms of grade 2 to 4 acute and extensive chronic GvHD fully resolved after a median treatment duration of GCV or VCV of 15 days. One patient with grade 1 acute GvHD did not receive any treatment. Seven patients needed to add an immunosuppressive treatment consisting of steroids, mycophenolate and/or cyclosporine.

Paediatric population

No specific paediatric group has been studied at present. Only one 17-year-old male, affected by T lymphoblastic lymphoma, was treated in the TK007 trial with two infusions of Zalmoxis. No adverse reactions were reported for this patient.

Other special populations

In the TK007 clinical study only one 66-year-old female was treated with one infusion of Zalmoxis.

The patient did not experience any adverse reactions. No implications on the use of Zalmoxis in patients of 65 and older have been established.

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 the national reporting system listed in Appendix V.

4.9 Overdose

Symptoms of overdose are not known. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted immediately.

5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: not yet assigned

Mechanism of action

The primary mechanism of action of Zalmoxis relies on its ability to engraft and stimulate immune-reconstitution.

Zalmoxis is constituted of donor’s T lymphocytes genetically modified to express the HSV-TK Mut2, as suicide gene. This allows the selective killing of dividing cells upon administration of the pro-drug GCV, which is enzymatically phosphorylated to an active triphosphate analogue by HSV-TK. Triphosphate GCV competitively, inhibits incorporation of deoxyguanosine triphosphate (dGTP) into elongating DNA, thus killing the proliferating ce­lls.

If GvHD occurs, GCV/VCV will be administered. The activated, transduced T lymphocytes that are causing the GvHD should convert the GCV to its toxic form and thereby undergo apoptosis. This strategy allows the direct targeting of those T lymphocytes that are initiating the GvHD response.

Pharmacodynamic effects

Overall, in the clinical study TK007, the 30 treated patients received their first infusion of Zalmoxis cells at a median time of 43 days from the date of HSCT. The median interval time between the first and the subsequent infusions of Zalmoxis cells was 30 days.

Immune-reconstituted patients reached a CD3+ cell count > 100/p.L at a median of 77 days after HSCT. In particular, at immune reconstitution Zalmoxis represents a high proportion of the circulating lymphocytes, while at later time points the proportion of Zalmoxis progressively decreases and untransduced lymphocytes expand from donor-derived precursors. One year post-Zalmoxis administration the newly reconstituted T cell repertoire is dominated by untransduced cells of donor origin which displayed a polyclonal pattern comparable to healthy individuals.

Clinical efficacy and safety

Zalmoxis was evaluated in a phase I/II clinical study (TK007) in adult patients with haematological malignancies at high risk of relapse who have received a stem-cell transplantation from a human leukocyte antigen (HLA) mismatched (haploidentical) donor. High-risk haematological malignancies treated with Zalmoxis included acute myeloid leukaemia (AML), secondary AML, acute lymphoblastic leukaemia, myelodysplastic syndrome and non-Hodgkin lymphoma.

Treatment plan consisted of the administration of genetically modified donor’s T lymphocytes (ranging from 1 × 106 to 1 × 107 cells/kg body weight). Primary aims of the TK007 study were to evaluate incidence and time to immune reconstitution, defined by the number of circulating CD3+ > 100/^L for two consecutive observations, and incidence of GvHD and response to GCV. Criteria for receiving Zalmoxis infusions included the lack of both immune reconstitution and GvHD.

Of 30 patients receiving Zalmoxis, 23 patients (77%) obtained immune reconstitution, with a median time of 31 days after the first infusion. For the patients who achieved immune reconstitution, a nonrelapse mortality (NRM) of 17% was reported, with 35% of these patients being disease free at 5 years and 34% alive at 10 years.

Results from a matched-pair analyses that included 36 Zalmoxis patients (22 from TK007 trial and 14 from the ongoing phase III TK008 trial) and 127 control patients, showed that the Zalmoxis treated patients that had survived the first 3 weeks post-transplant without relapse benefited in terms of 1 year overall survival (OS) (40% vs 51% (p=0.03)) and 1-year NRM (42% vs 23% (p=0.04)). There was no significant difference regarding leukaemia free survival and the chance for relapse.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Zalmoxis in one or more subsets of the paediatric population in the following condition: adjunctive treatment in haematopoietic cell transplantation (see section 4.2 for in ormation on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

The nature and the intended use of the

including absorption, distribution, m

5.3 Preclinical safety data

Conventional toxicology, carcinogenicity, mutagenicity and reproductive toxicology studies have not been performed.

Non clinical safety data obtained in two different immunedeficient animal models for GvHD did not indicate special hazards for humans, but allowed only a very limited safety assessment. In vitro evaluation of oncological potential indicate that the risk of malignant transformation is low.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sodium chloride

Human serum albumin

Dimethyl sulfoxide

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

• 18 months when stored in liquid nitrogen vapour.

The product should be administered immediately after thawing. In-use storage times and conditions should not exceed 2 hours at room temperature (15 °C – 30 °C).

6.4 Special precautions for storage

Store in liquid nitrogen vapour.

6.5 Nature and contents of container and special equipment for use, administration or implantation

One individual treatment dose in 50–500 mL ethylene-vinyl-acetate cryo bag, inside a plastic bag and then a metal box.

6.6 Special precautions for disposal and other handling

Zalmoxis is a patient specific medicinal product. The identity of the patient must be matched with the essential unique donor information prior to infusion.

Zalmoxis is obtained by donor blood cells. Even if donors are preliminary tested and found negative for transmissible infectious disease, precautions should be employed when handling Zalmoxis (see section 4.4).

This medicinal product contains genetically-modified cells. Local biosafety guidelines applicable for such products should be followed for unused medicinal product or waste material.

Work surfaces and material which have potentially been in contact with Zalmoxis must be decontaminated with appropriate disinfectant.

MolMed S.p.A. Via Olgettina 58 20132 Milano Italy +39–02–212771 +39–02–21277220 e-mail:

8. MARKETING AUTHORISATION NUMBER

EU/1/16/1121/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION