Lintuzumab-Ac225 in Combination with Cladribine + Cytarabine + Filgastrim + Mitoxantrone (CLAG-M) for Relapsed/Refractory Acute Myeloid Leukemia

October 3, 2024 updated by: Sameem M. Abedin, MD, Medical College of Wisconsin

A Phase I Study of Lintuzumab-Ac225 in Combination with CLAG-M Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

This is a prospective, single-center phase I clinical study aimed at determining the maximum-tolerated dose, recommended phase 2 dose and safety of Lintuzumab-Ac225 in combination with CLAG-M chemotherapy in the management of relapsed/refractory acute myeloid leukemia. This study uses a 3+3 design with a five-patient cohort at the recommended phase 2 dose.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Relapsed/refractory acute myeloid leukemia (RR-AML) in adults is an important therapeutic challenge. Nearly 60% of AML patients ultimately relapse or have refractory disease, and failure to achieve remission in this population is almost universally fatal. Therefore, a critical need exists for the development of novel therapies.

Currently, for RR-AML, many institutions utilize the chemotherapy regimen of CLAG-M (cladribine, cytarabine, G-CSF, mitoxantrone) based on a reported morphological complete remission (CR) rate of 58% in prospective clinical trials. Because of this, and its favorable performance when compared with outcomes reported for other regimens utilized in RR-AML, we believe enhancing the efficacy of CLAG-M is a rational approach to improve therapy in RR-AML.

A promising approach that could enhance the clearance of leukemic blasts when added to CLAG-M chemotherapy is a monoclonal antibody radioconjugate directed against markers expressed in leukemic cells. Radiation has known cytotoxic properties in chemo-resistant AML. The benefit of an antibody radioconjugate would be leukemic specific delivery of potent radiotherapy with potentially minimal systemic off-target side-effects. One such antibody radioconjugate is Lintuzumab-Ac225, a highly cytotoxic alpha radiation emitter that targets the cluster of differentiation 33 (CD33) cell surface antigen, which is expressed on leukemic cells.

In this novel study, we aim to add the radioconjugated antibody Lintuzumab-Ac225 to salvage CLAG-M chemotherapy in order to improve the treatment response for patients with RR-AML.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
26

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Wisconsin
      • Milwuakee, Wisconsin, United States, 53226
        • Froedtert Hospital and the Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age ≥18 years at the time of informed consent.
  2. Morphologically documented primary AML or secondary AML [from prior conditions such as Myelodysplastic Syndrome (MDS), myeloproliferative neoplasm (MPN)] or therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria.
  3. In first or subsequent relapse or refractory status after prior therapy, with or without prior hematopoietic stem cell transplant (HSCT). Patients with MDS and progression to AML on hypomethylating agents will also be included.
  4. Eastern Cooperative Oncology Group (ECOG) performance score 0-2.
  5. Greater than 25% of blasts must be CD33 positive on flow cytometry using Phycoerythrin (PE) labeled anti-CD33 antibody.

  6. Patients must meet the following clinical laboratory criteria:

    • Total bilirubin ≤ 2 x the upper limit of the normal range (ULN)
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN.
    • Calculated creatinine clearance ≥ 50 mL/min
    • Resting left ventricular ejection fraction (LVEF) > 40%
  7. Female patients must agree to avoid becoming pregnant, and male patients should avoid impregnating a female partner.

Exclusion Criteria:

  1. Acute Promyelocytic Leukemia.
  2. Active severe infection not well controlled by antibacterial or antiviral therapy.
  3. Known infection with human immunodeficiency virus.
  4. Patients with documented pulmonary disease, with a diffusing capacity of the lungs for carbon monoxide (DLCO) and/or forced expiratory volume in one second (FEV1) <65%, or history of dyspnea at rest, or requiring oxygen.
  5. Pregnant or breast feeding women.
  6. Prior chemotherapy or radiotherapy within 14 days of study entry unless fully recovered from adverse effects due to treatment, at investigator's discretion.
  7. Active malignancy within 2 years of entry, except previously treated melanoma grade 2 or less, non-melanoma skin cancer, carcinoma in situ, or cervical intraepithelial neoplasia, and organ confined prostate cancer with no evidence of progressive disease based on prostate-specific antigen (PSA) levels and are not on active therapy. Active malignancy is malignancy receiving treatment.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Lintuzumab Ac225 (Dose 1 - 0.25 μCi/kg Ac-225 with 1.6 μg/kg lintuzumab)
Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Biological: Lintuzumab-Ac-225
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Drug: Cladribine
Cladribine is a purine antimetabolite.
Other Names:
  • Leustatin
  • Mavenclad
Drug: Cytarabine
Cytarabine is an antineoplastic anti-metabolite.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)
Drug: Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.
Other Names:
  • Mitozantrone
  • Novantrone
Drug: G-CSF
G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.
Other Names:
  • colony-stimulating factor 3 (CSF 3)
Experimental: Lintuzumab Ac225 (Dose 2 - 0.50 μCi/kg Ac-225 with 3.2 μg/kg lintuzumab)
Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Biological: Lintuzumab-Ac-225
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Drug: Cladribine
Cladribine is a purine antimetabolite.
Other Names:
  • Leustatin
  • Mavenclad
Drug: Cytarabine
Cytarabine is an antineoplastic anti-metabolite.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)
Drug: Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.
Other Names:
  • Mitozantrone
  • Novantrone
Drug: G-CSF
G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.
Other Names:
  • colony-stimulating factor 3 (CSF 3)
Experimental: Lintuzumab Ac225 (Dose 3 - 0.75 μCi/kg Ac-225 with 4.7μg/kg lintuzumab)
Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Biological: Lintuzumab-Ac-225
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Drug: Cladribine
Cladribine is a purine antimetabolite.
Other Names:
  • Leustatin
  • Mavenclad
Drug: Cytarabine
Cytarabine is an antineoplastic anti-metabolite.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)
Drug: Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.
Other Names:
  • Mitozantrone
  • Novantrone
Drug: G-CSF
G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.
Other Names:
  • colony-stimulating factor 3 (CSF 3)
Experimental: Lintuzumab Ac225 (Dose 4 - 1.00 μCi/kg Ac-225 with 6.4 μg/kg lintuzumab)
Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Biological: Lintuzumab-Ac-225
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Drug: Cladribine
Cladribine is a purine antimetabolite.
Other Names:
  • Leustatin
  • Mavenclad
Drug: Cytarabine
Cytarabine is an antineoplastic anti-metabolite.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)
Drug: Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.
Other Names:
  • Mitozantrone
  • Novantrone
Drug: G-CSF
G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.
Other Names:
  • colony-stimulating factor 3 (CSF 3)
Experimental: Lintuzumab Ac225 (Dose 5 - 1.25 μCi/kg Ac-225 with 8.0 μg/kg lintuzumab)
Dose escalation for lintuzumab-Ac225 will be conducted according to a 3+3 design. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Biological: Lintuzumab-Ac-225
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Drug: Cladribine
Cladribine is a purine antimetabolite.
Other Names:
  • Leustatin
  • Mavenclad
Drug: Cytarabine
Cytarabine is an antineoplastic anti-metabolite.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)
Drug: Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.
Other Names:
  • Mitozantrone
  • Novantrone
Drug: G-CSF
G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.
Other Names:
  • colony-stimulating factor 3 (CSF 3)
Experimental: Lintuzumab Ac225 Recommended Phase 2 Dose (RP2D)
The maximum-tolerated dose for lintuzumab-Ac225 is defined as the highest level at which no more than one patient experiences a dose-limiting toxicity. The RP2D is defined as the dose level below the dose where two or more dose-limiting toxicities were observed. CLAG-M chemotherapy will be administered at a fixed dose and schedule (cladribine 5mg/m^2/day IV over two hours on days 2-6; cytarabine 2 gm/m^2/day IV over four hours on days 2-6, starting two hours after the cladribine infusion is complete; mitoxantrone 10mg/m^2/day IV on days 2-4 and G-CSF at a dose of 300 µg on days 1-6). Lintuzumab-Ac225 will be administered as a single dose on day 8 of therapy.
Biological: Lintuzumab-Ac-225
Lintuzumab-Ac225 is an immunoconjugate [antibody: anti-CD 33 antibody and radioactive isotope: Actinium (225Ac)] for the treatment of relapsed/refractory acute myeloid leukemia.
Other Names:
  • HuM195-Ac225
  • Actimab-A
Drug: Cladribine
Cladribine is a purine antimetabolite.
Other Names:
  • Leustatin
  • Mavenclad
Drug: Cytarabine
Cytarabine is an antineoplastic anti-metabolite.
Other Names:
  • Cytosar-U
  • Depocyt
  • cytosine arabinoside (ara-C)
Drug: Mitoxantrone
Mitoxantrone is an anthracenedione antineoplastic agent.
Other Names:
  • Mitozantrone
  • Novantrone
Drug: G-CSF
G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells.
Other Names:
  • colony-stimulating factor 3 (CSF 3)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
The number of subjects with dose-limiting toxicities.
Time Frame: 28 Days

Dose-escalation will be conducted according to a 3+3 design with a five-patient expansion cohort at the recommended phase 2 dose. The initial dose of Lintuzumab-Ac225 will be 0.25 micro-Curie (μCi)/kg (Dose level 1), and the highest dose administered will be 1.25 μCi/kg.

  • if 0/3 pts have no dose-limiting toxicity (DLT), new patients enter next dose level.
  • if 1/3 pts has DLT, 3 pts treated at same dose level.
  • if 0/3 pts at that dose level has DLT, new pts enter higher level.
  • if 1 or more of the additional 3 pts has a DLT, no further pts started at dose level, preceding dose is the MTD.
  • if 2/3 of initially dosed patients have a DLT on first dose, study terminated.
  • if 0/3 have DLT at highest dose, additional 3 enrolled.
28 Days
Maximum-tolerated dose.
Time Frame: 28 Days
Defined as the dosage with the highest level at which no more than one subject experiences a DLT.
28 Days
The number of subjects who have at least one serious adverse event related to the study.
Time Frame: 60 days
All subjects who receive study drug will be closely monitored for serious adverse events (SAEs). The NCI's CTCAE (Common Toxicity Criteria for Adverse Effects) v4.03 will be used.
60 days
Overall survival
Time Frame: 2 years
The number of subjects alive at two years from the first day of salvage therapy.
2 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
The number of subjects with a complete response (CR).
Time Frame: Up to Day 60
A complete response will be defined as bone marrow blasts <5% with absolute neutrophil count ≥1000/μL and platelet ≥100,000/μL.
Up to Day 60
The number of subjects with CR with incomplete hematologic recovery (CRi)
Time Frame: Up to Day 60
CRi is defined as CR without platelet recovery or neutrophil recovery. This will be defined as bone marrow blasts <5% with absolute neutrophil count <1000/L and platelet <100,000/L.
Up to Day 60
The number of subjects in a morphologic leukemia-free state (MLFS).
Time Frame: Up to Day 60
MLFS is bone marrow blasts <5% with absolute neutrophil count <1000/μL AND platelet <100,000/μL.
Up to Day 60
The number of subjects experiencing partial remission.
Time Frame: Up to Day 60
Partial remission (PR) is defined by a decrease of at 50% or more in the percentage of blasts to less than 25% in the bone marrow. and normalized blood counts ( ANC>1000, Platelets>100,000/ml).
Up to Day 60
Progression-free Survival
Time Frame: 1 Year
The number of subjects, who from the first day of remission until one year, do not relapse or progress.
1 Year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Medical College of Wisconsin

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Sameem Abedin, MD, Medical College of Wisconsin

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
May 22, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 22, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 22, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 15, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 15, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 22, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 8, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 3, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • PRO00031633

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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