Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2011-00386 | Registry Identifier | CTRP (Clinical Trial Reporting Program) | |
| 1743.00 | Other Identifier | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | |
| P30CA015704 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
This phase I/II trial studies the side effects of giving reduced-intensity conditioning followed by donor peripheral blood stem cell transplant (PBSCT) and how well it works in treating patients with multiple myeloma (MM). Giving low doses of chemotherapy, such as fludarabine phosphate and melphalan, and total-body irradiation (TBI) before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine after transplant may stop this from happening.
PRIMARY OBJECTIVES:
I. To evaluate the efficacy of this approach by determining the 1-year progression-free survival (PFS) and overall survival (OS).
II. To evaluate day 100 non-relapse mortality.
III. To determine the incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD.
OUTLINE:
PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0.
TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0.
IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or thrice daily (TID) on days 0-40 with taper to day 96 (unrelated donors).
After completion of study treatment, patients are followed up at 3, 6, 12, 18, and 24 months, and then annually thereafter for 5 years.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Related Donor | Experimental | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). |
|
| Unrelated Donor | Experimental | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| fludarabine phosphate | Drug | Given IV |
|
| Measure | Description | Time Frame |
|---|---|---|
| PFS | PFS will be calculated for all patients from the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission. Progressive disease is defined as greater than 25% increase in serum or urine M proteins compared to best response status after autologous transplant and/or appearance of new lytic bone lesions or plasmocytomas. | At 1 year post-transplant |
| Non-relapse Mortality | Early NRM will be monitored in a sequential fashion. | At day 100 |
| Incidence of Acute GVHD (Grades III-IV) | Number of patients with Grade III-IV acute GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion. | Up to 5 years |
| Incidence of Chronic (Extensive) GVHD | Number of subjects with chronic extensive GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion. | Up to 5 years |
| Measure | Description | Time Frame |
|---|---|---|
| OS | Number of subjects surviving. OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated. | At 6 months and then every year thereafter, up to 5 years |
| Engraftment |
Not provided
Inclusion Criteria:
Meet Salmon and Durie criteria for initial diagnosis of MM; transplant will be offered to patients with previously treated MM who meet one of the following criteria:
Patients must have the capacity to give informed consent
DONOR: Human leukocyte antigen (HLA) genotypically identical sibling or phenotypically matched relative
DONOR: HLA phenotypically matched unrelated donor (according to Standard Practice HLA matching criteria)
DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis for PBSC collection
DONOR: Donor must have adequate veins for leukapheresis or agree to placement of a temporary central venous catheter
Exclusion Criteria:
Karnofsky score < 60%
Left ventricular ejection fraction < 40% or symptomatic heart failure; ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease
Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL,or symptomatic biliary disease
Diffusion capacity of carbon monoxide (DLCO) < 50% (corrected) or receiving continuous supplemental oxygen
Creatinine clearance < 40 mL/min
Patients with poorly controlled hypertension
Seropositive for the human immunodeficiency virus (HIV)
Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
Pregnancy or breastfeeding
Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment
Not fully recovered from previous high-dose therapy:
Patients with active bacterial or fungal infections unresponsive to medical therapy
DONOR: Identical twin
DONOR: Donors unwilling to donate PBSC
DONOR: Pregnancy
DONOR: Infection with HIV
DONOR: Inability to achieve adequate venous access
DONOR: Known allergy to G-CSF
DONOR: Current serious systemic illness
DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) criteria for stem cell donation
DONOR: Age < 12 years
DONOR: A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Marco Mielcarek | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Seattle | Washington | 98109 | United States | ||
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | Related Donor | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). fludarabine phosphate: Given IV melphalan: Given IV total-body irradiation: Undergo TBI mycophenolate mofetil: Given PO cyclosporine: Given PO nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT laboratory biomarker analysis: Correlative s |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| melphalan | Drug | Given IV |
|
|
| total-body irradiation | Radiation | Undergo TBI |
|
|
| mycophenolate mofetil | Drug | Given PO |
|
|
| cyclosporine | Drug | Given PO |
|
|
| nonmyeloablative allogeneic hematopoietic stem cell transplantation | Procedure | Undergo reduced-intensity allogeneic PBSCT |
|
| peripheral blood stem cell transplantation | Procedure | Undergo reduced-intensity allogeneic PBSCT |
|
|
| laboratory biomarker analysis | Other | Correlative studies |
|
Number of subjects who engrafted post-transplant. Engraftment will be monitored in a sequential fashion.
| Up to 5 years |
| Relapse Rate | Number of subjects who relapsed after achieving CR post-transplant. Relapse rate will be summarized using cumulative incidence estimates. | Up to 5 years |
| Response Rate | Number of subjects who achieved CR post-transplant. Response rate will be summarized using cumulative incidence estimates. | Up to 5 years |
| University of Torino |
| Torino |
| 10126 |
| Italy |
| FG001 | Unrelated Donor | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). fludarabine phosphate: Given IV melphalan: Given IV total-body irradiation: Undergo TBI mycophenolate mofetil: Given PO cyclosporine: Given PO nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT laboratory biomarker analysis: Correlative s |
| COMPLETED |
|
| NOT COMPLETED |
|
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | Related Donor | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). fludarabine phosphate: Given IV melphalan: Given IV total-body irradiation: Undergo TBI mycophenolate mofetil: Given PO cyclosporine: Given PO nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT laboratory biomarker analysis: Correlative s |
| BG001 | Unrelated Donor | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). fludarabine phosphate: Given IV melphalan: Given IV total-body irradiation: Undergo TBI mycophenolate mofetil: Given PO cyclosporine: Given PO nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT laboratory biomarker analysis: Correlative s |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | PFS | PFS will be calculated for all patients from the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission. Progressive disease is defined as greater than 25% increase in serum or urine M proteins compared to best response status after autologous transplant and/or appearance of new lytic bone lesions or plasmocytomas. | There were 4 patients who, although they did not have progression/relapse, died before the 1 year mark, and thus are not included in the 1 year PFS count. | Posted | Count of Participants | Participants | At 1 year post-transplant |
|
|
| |||||||||||||||||||||||||||||
| Primary | Non-relapse Mortality | Early NRM will be monitored in a sequential fashion. | Posted | Count of Participants | Participants | At day 100 |
| ||||||||||||||||||||||||||||||||
| Primary | Incidence of Acute GVHD (Grades III-IV) | Number of patients with Grade III-IV acute GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion. | Posted | Count of Participants | Participants | Up to 5 years |
| ||||||||||||||||||||||||||||||||
| Primary | Incidence of Chronic (Extensive) GVHD | Number of subjects with chronic extensive GVHD post-transplant. Severe GVHD will be monitored in a sequential fashion. | Posted | Count of Participants | Participants | Up to 5 years |
| ||||||||||||||||||||||||||||||||
| Secondary | OS | Number of subjects surviving. OS will be estimated by the method of Kaplan and Meier. Confidence intervals will be estimated. | Posted | Count of Participants | Participants | At 6 months and then every year thereafter, up to 5 years |
| ||||||||||||||||||||||||||||||||
| Secondary | Engraftment | Number of subjects who engrafted post-transplant. Engraftment will be monitored in a sequential fashion. | Posted | Count of Participants | Participants | Up to 5 years |
| ||||||||||||||||||||||||||||||||
| Secondary | Relapse Rate | Number of subjects who relapsed after achieving CR post-transplant. Relapse rate will be summarized using cumulative incidence estimates. | Posted | Count of Participants | Participants | Up to 5 years |
| ||||||||||||||||||||||||||||||||
| Secondary | Response Rate | Number of subjects who achieved CR post-transplant. Response rate will be summarized using cumulative incidence estimates. | Posted | Count of Participants | Participants | Up to 5 years |
|
AEs: Conditioning through Day 100; SAEs: Conditioning through Day 200
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Related Donor | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). fludarabine phosphate: Given IV melphalan: Given IV total-body irradiation: Undergo TBI mycophenolate mofetil: Given PO cyclosporine: Given PO nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT laboratory biomarker analysis: Correlative s | 4 | 12 | 4 | 12 | 9 | 12 |
| EG001 | Unrelated Donor | PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -3 and intermediate-dose melphalan IV over 15-20 minutes on day -2. Patients also undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID on days -3 to 80 with taper to day 180 (related donors) or on days -3 to 100 with taper to day 180 (unrelated donors). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related donors) or TID on days 0-40 with taper to day 96 (unrelated donors). fludarabine phosphate: Given IV melphalan: Given IV total-body irradiation: Undergo TBI mycophenolate mofetil: Given PO cyclosporine: Given PO nonmyeloablative allogeneic hematopoietic stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT peripheral blood stem cell transplantation: Undergo reduced-intensity allogeneic PBSCT laboratory biomarker analysis: Correlative s | 1 | 4 | 1 | 4 | 2 | 4 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Adult respiratory distress syndrome | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Blood bilirubin increased | Investigations | Systematic Assessment |
| ||
| Multi-organ failure | General disorders | Systematic Assessment |
| ||
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute kidney injury | Renal and urinary disorders | Systematic Assessment |
| ||
| Adult respiratory distress syndrome | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Alanine aminotransferase increased | Investigations | Systematic Assessment |
| ||
| Anorexia | Metabolism and nutrition disorders | Systematic Assessment |
| ||
| Blood bilirubin increased | Investigations | Systematic Assessment |
| ||
| Bone marrow hypocellular | Blood and lymphatic system disorders | Systematic Assessment |
| ||
| Creatinine increased | Investigations | Systematic Assessment |
| ||
| Fatigue | General disorders | Systematic Assessment |
| ||
| Fever | General disorders | Systematic Assessment |
| ||
| Generalized muscle weaknes | Musculoskeletal and connective tissue disorders | Systematic Assessment |
| ||
| Heart failure | Cardiac disorders | Systematic Assessment |
| ||
| Hypotension | Vascular disorders | Systematic Assessment |
| ||
| Hypoxia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Lung infection | Infections and infestations | Systematic Assessment |
| ||
| Mucositis oral | Gastrointestinal disorders | Systematic Assessment |
| ||
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
| ||
| Supraventricular tachycardia | Cardiac disorders | Systematic Assessment |
| ||
| Syncope | Nervous system disorders | Systematic Assessment |
| ||
| Thrombotic thrombocytopenic purpura | Blood and lymphatic system disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Marco Mielcarek, MD | Fred Hutch | mmielcar@fredhutch.org |
| ID | Term |
|---|---|
| D009101 | Multiple Myeloma |
| ID | Term |
|---|---|
| D054219 | Neoplasms, Plasma Cell |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010265 | Paraproteinemias |
| D001796 | Blood Protein Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006474 | Hemorrhagic Disorders |
| D008232 | Lymphoproliferative Disorders |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C042382 | fludarabine phosphate |
| D008558 | Melphalan |
| D014916 | Whole-Body Irradiation |
| D009173 | Mycophenolic Acid |
| D016572 | Cyclosporine |
| D036102 | Peripheral Blood Stem Cell Transplantation |
| ID | Term |
|---|---|
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D010649 | Phenylalanine |
| D024322 | Amino Acids, Aromatic |
| D000598 | Amino Acids, Cyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011878 | Radiotherapy |
| D013812 | Therapeutics |
| D008919 | Investigative Techniques |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D003524 | Cyclosporins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D010455 | Peptides |
| D018380 | Hematopoietic Stem Cell Transplantation |
| D033581 | Stem Cell Transplantation |
| D017690 | Cell Transplantation |
| D064987 | Cell- and Tissue-Based Therapy |
| D001691 | Biological Therapy |
| D014180 | Transplantation |
| D013514 | Surgical Procedures, Operative |
Not provided
Not provided
| >=65 years |
|
| Male |
|
| Italy |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|