Oral administration of Allopurinol (Zyloric®) for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure

Adenylosuccinate Lyase Deficiency

Allopurinol

LA PITIE-SALPETRIERE Hospital, AP-HP

Department of Pediatry. Reference centre of Hereditary diseases of the metabolism of child and adult. Necker - Enfants malades Hospital

Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency

Evaluation of a Treatment With Allopurinol on Autistic Disorders and Epilepsy in Adenylosuccinate Lyase Deficiency (ADSL)

to assess Efficacy of Allopurinol (Zyloric)® treatment from Baseline : For each scale : Mean : 100 SD : 15
Adaptive behaviour composite : Range 20 to 180 -Domains scores : Range 20 to 140 -Communication : Range 20 to 140 -Daily living skills : Range 20 to 140 -Socialization : 20 to 140 -Motor skills : 20 to 140 For each scale values are considered to be better or worse outcome :High 130 to 140 -Moderately High 115 to 129 -Adequate 86 to 114 -Moderately Low 71 to 85 -Low 20 to 70 Total score is obtained by summing the subdomains scores

Clinical evolution for developmental and cognitive assessment

Clinical evaluation for autistic symptoms : scale ranges :
A : Social interactions: 0 to 30 (significative if >10)
B : Communication : 0 to 26 (significative if > 7 or 8)
C : Repetitive and restricted interests : 0 to 16 (significative if >3)
D : Developmental abnormality present before 36 months : 0 to 5 (significative if >1)
better score : 0 (non autistic) - worse score : the higher score is the worst

Clinical evaluation for autistic symptoms. Scale ranges :
A : Socialization : social interactions and communication : 0 to 20 (social interactions : 0 to 6 -communication : 0 to 14)
B : Restricted and repetitive interests : 0 to 8
Total : A+B : 0 to 28
Autism : total score>12 - Autism Spectrum Disorder : total score >8
Better score : 0 - Worse score : the highest score is the worst

Clinical evolution for behavioral disorders and adaptive functioning
Conners Scale for Parents :
- Subscales : Behavioural difficulties (items 2-8-14-19-20-27-35-39) : 0 to 24 Learning difficulties (items 10-25-31-37) : 0 to 12 Somatisation (items 32-41-43-44) : 0 to 12 Impulsivity, hyperactivity (items 4-5-11-13): 0 to 12 Anxiety (items 12-16-24-47): 0 to 12
-Hyperactivity index : sum of the items (4-7-11-13-14-25-31-33-37-38) divided by 10 : 0 to 3
Conners Scale for teachers :
- Subscales : Behavioural difficulties (items 4-5-6-10-11-12-23-27) : 0 to 24 Impulsivity, hyperactivity (items 1-2-3-8-14-15-16) : 0 to 21 Inattention, passivity (items 7-9-18-20-21-22-26-28) : 0 to 24
-Hyperactivity index (sum of the items 1-5-7-8-10-11-14-15-21-26 divided by 10) : 0 to 3
Better score : 0 - Worse score : the highest score is the worst -Hyperactivity index : Significative if> 1,5

Clinical evolution for behavioral disorders and adaptive functioning scale ranges :
Irritability : 0 to 45
Lethargy : 0 to 48
Stereotypy : 0 to 21
Hyperactivity : 0 to 48
Inappropriate speech : 0 to 12
Better score : 0 -Worse score : the highest score is the worst on each scale- there is no total score

Evolution of the quantity of urinary metabolites from Baseline

Evolution of the quantity of plasma metabolites from Baseline

at baseline, performing neurological examinations and interrogation

Assistance Publique - Hôpitaux de Paris

URC-CIC Paris Descartes Necker Cochin

Patients with mitochondrial disease, investigated by blood samples and exercise test.

Patients with metabolic myopathy, investigated by blood samples and exercise test.

Patients with muscular dystrophy, investigated by blood samples and exercise test.

Healthy controls, investigated by blood samples and exercise test.

Mitochondrial Disease

Metabolic Myopathy

Muscular Dystrophy

Rigshospitalet

GDF-15 as a Biomarker for Mitochondrial Disease

The blood sample will be analysed with a Luminex analyser to determine the concentration of GDF-15.

The subjects perform an incremental exercise test until exhaustion on a cycle ergometer. The concentration of GDF-15 is measured afterwards with a Luminex analyser.

Lactate is a muscle marker, that is measured in this study.

Pyruvate is a muscle marker, that is measured in this study.

Creatin kinase is a muscle marker, that is measured in this study.

FGF-21 (Fibroblast Growth Factor 21) is a muscle marker that is measured in this study.

During the exercise test, the subjects will breath through a mask, that is connected to a machine. The machine is able to calculate the VO2max.

The Wmax will be calculated during the exercise test.

Nanna Scharff Nielsen

Student researcher

Rigshospitalet, Denmark

Level 1: Bendamustine 70mg/m^2 Ofatumumab, Carboplatin, and Etoposide

Level -1: Bendamustine 50mg/m^2 Ofatumumab, Carboplatin, and Etoposide

Level 2: Bendamustine 90mg/m^2 Ofatumumab, Carboplatin, and Etoposide

Level 3: Bendamustine 120mg/m^2 Ofatumumab, Carboplatin, and Etoposide

Phase II: Bendamustine at MTD from Phase I, Ofatumumab, Carboplatin, and Etoposide

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine: Phase 1: Given via IV at the following dose levels:
- Level 1: 70 mg/m2

Bendamustine 70 mg/m2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine: Phase 1: Given via IV at the following dose levels:
- Level -1: 50 mg/m2

Bendamustine 50 mg/m2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine: Phase 1: Given via IV at the following dose levels:
- Level 2: 90 mg/m2

Bendamustine 90 mg/m2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine: Phase 1: Given via IV at the following dose levels:
- Level 3: 120 mg/m2

Bendamustine 120 mg/m2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide Phase II: Given via IV on Days 1 and 2 of each cycle at the maximum-tolerated dose level found in the Phase I portion of the study.
Ofatumumab: Phase II
Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
Cycles 2 and 3: 1000 mg via IV on Day 1
Carboplatin: Phase II: AUC 5 via IV on Day 2 of each cycle
Etoposide: Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

Bendamustine at MTD

Total

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Region of Enrollment

To determine the maximum-tolerated dose of bendamustine in combination with ofatumumab, carboplatin and etoposide for patients with refractory or relapsed aggressive B cell lymphomas. Toxicity levels will be assessed after every cycle until a dose-limiting toxicity (DLT) is found. Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria (CTCAE version 4.0). DLT will be defined as any grade 4 infection, or grade >/= 3 non-hematologic toxicity that persists for 7 days or more.

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine: Phase 1: Given via IV at the following dose levels:
Level 1: 70 mg/m2
Level -1: 50 mg/m2
Level 2: 90 mg/m2
Level 3: 120 mg/m2
Phase II: Given via IV on Days 1 and 2 of each cycle at the maximum-tolerated dose level found in the Phase I portion of the study.
Ofatumumab: Phase II
Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
Cycles 2 and 3: 1000 mg via IV on Day 1
Carboplatin: Phase II: AUC 5 via IV on Day 2 of each cycle
Etoposide: Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

Bendamustine, Ofatumumab, Carboplatin, and Etoposide (BOCE)

Phase I: Maximum-Tolerated Dose of Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide (BOCE)

To determine the overall frequency of response with combination bendamustine, ofatumumab, carboplatin, and etoposide for refractory or relapsed aggressive B-cell lymphomas. Overall response is determined as cumulative Complete Response (CR) and Partial Response (PR).

Overall Frequency of Response With Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide at Maximum Tolerated Dose (MTD)

To determine the overall frequency of response--overall response will include all subjects with complete response (CR) and partial response (PR). Based on the revised response criteria for malignant lymphoma [Cheson 2007]
CR= complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy PR= >/= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of other nodes, liver or spleen;

Phase I: Overall Frequency of Response

Based on the revised response criteria for malignant lymphoma [Cheson 2007]
CR= complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy PR= >/= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of other nodes, liver or spleen;

Overall Complete Response (CR) and Partial Response (PR) Rate

To determine 1 and 2 year progression-free survival [Cheson 2007] CR= complete disappearance of all detectable clinical evidence of disease and disease related symptoms if present before therapy PR= >/= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses; no increase in size of other nodes, liver or spleen;

Overall Progression-Free Survival

1 and 2 year overall survival for those who received Stem Cell Transplant (SCT) versus those who did not receive SCT

Total Overall Survival for Transplant vs Non-transplant

To determine the proportion of patients who are able to undergo stem cell transplant among transplant-eligible patients. Patients can receive SCT after Cycle 2.

Overall Proportion of Patients Who Are Able to Undergo Stem Cell Transplant (SCT)

To define safety and tolerability of the combination of ofatumumab, bendamustine, carboplatin and etoposide as measured by the number of dose modifications made to Bendamustine..
Determined through dose modifications for bendamustine according to patient's toxicity levels:
Initial 120 mg/m2 dose decreased to 90 mg/m2
Initial 90 mg/m2 dose decreased to 70 mg/m2
Initial 70 mg/m2 dose decreased to 50 mg/m2
Initial 50 mg/m2 dose decreased to Withdrawn from study

Overall Safety and Tolerability of the Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine:
- Level 1: 70 mg/m2

Bendamustine 70mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine:
- Level -1: 50 mg/m2

Bendamustine 50mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine:
- Level 2: 90 mg/m2

Bendamustin 90mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine:
- Level 3: 120 mg/m^2

Bendamustine 120mg/m^2

Combination of Bendamustine, Ofatumumab, Carboplatin, and Etoposide
Bendamustine:
Phase II at the MTD

Period 1: 70mg/m^2

Period 2: 50mg/m^2

Period 3: 90mg/m^2

Period 4: 120mg/m^2

Period 5: Maximum Tolerated Dose (MTD)

Joanna Filicko-O'Hara, MD

Phase II: Given via IV on Days 1 and 2 of each cycle at the maximum-tolerated dose level found in the Phase I portion of the study.
Ofatumumab: Phase II
Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
Cycles 2 and 3: 1000 mg via IV on Day 1
Carboplatin: Phase II: AUC 5 via IV on Day 2 of each cycle
Etoposide: Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

Non-Hodgkin's Lymphoma

Phase 1: Given via IV at the following dose levels:
Level 1: 70 mg/m2
Level -1: 50 mg/m2
Level 2: 90 mg/m2
Level 3: 120 mg/m2
Phase II: Given via IV on Days 1 and 2 of each cycle at the maximum-tolerated dose level found in the Phase I portion of the study.

Bendamustine

Phase II
Cycle 1: 300 mg via IV on Day 1 and 1000 mg via IV on Day 3
Cycles 2 and 3: 1000 mg via IV on Day 1

Ofatumumab

Phase II: AUC 5 via IV on Day 2 of each cycle

Carboplatin

Phase II: 100 mg/m2 via IV on Days 1, 2, and 3 of each cycle

Etoposide

CT Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment

CT Scan

PET Scan to assess disease after Cycle 2 (approximately 25 days) and 3-8 weeks post-treatment

PET Scan

For potential transplant candidates:
Autologous STC: after 2 cycles of BOCE upon discretion of Thomas Jefferson University hematopoietic stem cell transplant group and in agreement with the study PI or her designee
Allogeneic STC: after 2 cycles of BOCE upon discretion of Thomas Jefferson University hematopoietic stem cell transplant group and in agreement with the study PI or her designee

Stem Cell Transplant (STC)

Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center

Sidney Kimmel Cancer Center at Thomas Jefferson University

Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed Aggressive B-Cell Lymphomas

Phase I/II Study of Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed Aggressive B-cell Lymphomas

GlaxoSmithKline

Novartis

valproic acid, oral daily intake, combined with 2-chlorodeoxyadenosine administered intravenously for 4 cycles

Chronic Lymphocytic Leukemia

VPA : daily, oral, starting dose 10mg/kg/day total dose, taken in 2 separate administrations of around 5 mg/kg/day each, for a maximum of 6 months CdA : 5.6 mg/m²/day IV during 3 days, every 28 days, for a maximum of 4 cycles

valproic acid and 2-chlorodeoxyadenosine

Clinique Sud Luxembourg

Institut Jules Bordet

ULB Erasme

Cliniques universitaires Saint Luc

Grand Hôpital de Charleori - Site notre Dame

Clinique Notre-Dame de Grâce

Hôpital de Jolimont

CHU ULg

Clinique Saint Pierre

Heilig-Hartziekenhuis

Cliniques de Mont Godinne

Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia(B-CLL)

Phase I-II Study of Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia (CLL) Patients

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Pentostatin/Busulfan/Rituximab/Allogeneic Hematopoietic Cell Transplant (HCT).
Pre-conditioning therapy:
All participants will receive pentostatin 4 mg/m^2 on day -28. Patients may receive additional doses on days -21 & -14 depending on cell counts.
Conditioning:
Patients will receive anti-seizure prophylaxis with lorazepam 0.5 mg every 6 hours beginning day -6.
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4.
Patient will then receive pentostatin at a dose of 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3.
Intravenous Busulfan (2nd dose) will be administered on day (-2) to target a total AUC of 16,000 +/- 1600.
Hematopoietic progenitor cells to be infused at least 36 hours after last dose of Busulfan.
Rituximab: Patients with CD20+ expressing malignancies will be treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines.

Pentostatin/Busulfan/Rituximab/Allogeneic Hematopoietic Cell Transplant (HCT)
Pre-conditioning therapy:
All participants receive pentostatin 4 mg/m^2 on day -28, may receive additional doses on days -21 & -14 depending on cell counts.
Conditioning:
Anti-seizure prophylaxis with lorazepam 0.5 mg every 6 hours beginning day -6
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4
Pentostatin, 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3
Intravenous Busulfan (2nd dose) on day (-2) to target a total AUC of 16,000 +/- 1600
Hematopoietic progenitor cells infused at least 36 hours after last dose of Busulfan
Patients with CD20+ expressing malignancies treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines

Conditioning Followed by HCT

The primary endpoint was achievement of >/= 50% donor chimerism in CD3+ peripheral blood lymphocytes by day +28 (± 7) after allogeneic hematopoietic cell transplantation (allo-HCT).

Incidence of Greater Than or Equal to 50% Donor Chimerism

Hematologic engraftment: defined as time to achieve an absolute neutrophil count (ANC) >/= 500/µl for 3 consecutive days or a platelet count of >/= 20,000//µl without the need for platelet support.

Cumulative Incidence of Hematopoietic Cell Engraftment

Median Percentage of Donor Cells in Study Population (Chimerism).

Rate of T-cell (CD3+) and Myeloid (CD33+) Chimerism by Day +28

Rate of T-cell (CD3+) and Myeloid (CD33+) Chimerism by Day +100

The cumulative incidence of NRM after allo-HCT.

Non-relapse Mortality Rate (NRM)

Infections: Incidence of infections (opportunistic and non-opportunistic) following conditioning.

Incidence of Infections

The median time from allo-HCT to the initiation of tacrolimus (TAC) taper.
The median time to onset of acute GVHD (aGVHD). Clinical manifestations of acute GVHD include a classic maculopapular rash; persistent nausea and/or emesis; abdominal cramps with diarrhea; and a rising serum bilirubin concentration.

Time to Incidence of Graft Versus Host Disease (GVHD)

By day +100, the cumulative incidence of GVHD, acute of grades 2-4, and 3-4.
At 2 years, the cumulative incidence of chronic GVHD of any severity according to National Institutes of Health (NIH) consensus criteria. Diagnosis of chronic GVHD requires the presence of at least one diagnostic clinical sign of chronic GVHD or the presence of at least one distinctive manifestation confirmed by pertinent biopsy or other relevant tests in the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD.
At 2 years, the cumulative incidence of moderate/severe chronic GVHD.

Incidence of Graft Versus Host Disease (GVHD)

PFS at 2 years post-transplant. PFS, defined as time from day of hematopoietic cell infusion to disease relapse. Relapsed disease: Disease was in complete remission post-transplant but returned (e.g., >5% blast in bone marrow or any peripheral blasts).

Percentage of Participants With Progression Free Survival (PFS)

OS at 2 years post-transplant. OS, defined as time from day of hematopoietic cell infusion to death from any cause.

Percentage of Participants With Overall Survival (OS)

Pentostatin/Busulfan/Rituximab/Allogeneic Hematopoietic Cell Transplant (HCT)
Pre-conditioning therapy:
All participants receive pentostatin 4 mg/m^2 on day -28, may receive additional doses on days -21 & -14 depending on cell counts.
Conditioning:
Anti-seizure prophylaxis with lorazepam 0.5 mg every 6 hours beginning day -6
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4
Pentostatin, 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3
Intravenous Busulfan (2nd dose) on day (-2) to target a total area under curve (AUC) of 16,000 +/- 1600
Hematopoietic progenitor cells infused at least 36 hours after last dose of Busulfan
Patients with CD20+ expressing malignancies treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines

Overall Study

Marcie Riches, MD

Hematologic Malignancies

Pre-conditioning therapy:
All participants will receive pentostatin 4 mg/m^2 on day -28. Patients may receive additional doses on days -21 & -14 depending on cell counts.
Participant will receive pentostatin at a dose of 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3.

Pentostatin

Pre-conditioning therapy:
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4.
Intravenous Busulfan (2nd dose) will be administered on day (-2) to target a total AUC of 16,000 +/- 1600.

Busulfan

Pre-conditioning therapy:
Patients with CD20+ expressing malignancies will be treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines.

Rituximab

Hematopoietic progenitor cells to be infused at least 36 hours after last dose of Busulfan.

Allogeneic Hematopoietic Cell Transplant

H. Lee Moffitt Cancer Center & Research Institute

Phase II Trial of Pentostatin and Targeted Busulfan

Phase II Trial of Pentostatin and Targeted Busulfan as a Novel Reduced Intensity Regimen for Allogeneic Hematopoietic Stem Cell Transplantation Using Laboratory-Guided (CD4-guided) Immunosuppression.

purine/seizures

Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency

GDF-15 as a Biomarker for Mitochondrial Disease

Bendamustine in Combination With Ofatumumab, Carboplatin and Etoposide for Refractory or Relapsed Aggressive B-Cell Lymphomas

Low Dose CdA Combined With Valproic Acid (VPA) in Previously Treated B-cell Chronic Lymphocytic Leukemia(B-CLL)

Phase II Trial of Pentostatin and Targeted Busulfan

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