- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
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 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
Allogeneic T cells genetically modified with a retroviral vector encoding for a truncated form of the human low affinity nerve growth factor receptor (ΔLNGFR) and the herpes simplex I virus thymidine kinase
2.2Qualitative and quantitative composition
Each bag of Zalmoxis contains a volume of
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.
Excipient with known effect
Each bag contains approximately 13.3 mmol (305.63 mg) of sodium per dose.
For the full list of excipients, see section 6.1.
Dispersion for infusion.
Zalmoxis is indicated as adjunctive treatment in haploidentical haematopoietic stem cell transplantation (HSCT) of adult patients with
4.2Posology and method of administration
Zalmoxis must be administered under the supervision of a physician experienced in HSCT for haematological malignancies.
The recommended dose and schedule is 1 ± 0.2 x 107 cells/kg given as an intravenous infusion at a time interval of
and/or development of
Zalmoxis should not be administered if the circulating T lymphocytes are ≥100 per μL at the day of planned infusion after haploidentical HSCT.
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
If the infusion must be interrupted, it should not be resumed if the infusion bag has been held at room temperature (15
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
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Immune reconstitution defined as circulating T lymphocytes ≥100 per μL at the day of planned infusion after haploidentical HSCT.
GvHD requiring systemic immunosupressive therapy.
4.4Special warnings and precautions for use
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
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.
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
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.
4.5Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
4.6Fertility, 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.
There are no data from the use of Zalmoxis in pregnant women.
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.
There are no data on the use of Zalmoxis during
It is recommended not to
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.
4.7Effects 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.
Summary of the safety profile
In the clinical study TK007, 30 patients with
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 reactions
(≥ 1/100 to < 1/10)
Neoplasm benign, malignant and
unspecified (including cysts and
Immune system disorders
Acute GvHD (33% of
Blood and lymphatic system disorders
Platelet count decreased
Infections and infestations
General disorders and administration
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
No specific paediatric group has been studied at present. Only one
Other special populations
In the TK007 clinical study only one
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 the national reporting system listed in Appendix V.
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.
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
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.
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.
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
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
leukocyte antigen (HLA) mismatched (haploidentical) donor.
Treatment plan consisted of the administration of genetically modified donor’s T lymphocytes (ranging from 1 x 106 to 1 x 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/μL 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 non- relapse 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
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 information on paediatric use).
This medicinal product has been authorised under a
The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The nature and the intended use of the product are such that conventional studies on pharmacokinetics including absorption, distribution, metabolism and excretion are not applicable.
5.3Preclinical 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.
6.1List of excipients
Human serum albumin
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
18 months when stored in liquid nitrogen vapour.
The product should be administered immediately after thawing.
6.4Special 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
6.6Special 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
Work surfaces and material which have potentially been in contact with Zalmoxis must be decontaminated with appropriate disinfectant.
7.MARKETING AUTHORISATION HOLDER
Via Olgettina 58
20132 Milano Italy
8.MARKETING AUTHORISATION NUMBER
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.