Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia
- Conditions
- Acute Lymphoblastic Leukemia (ALL)
- Interventions
- Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
- Registration Number
- NCT02303821
- Lead Sponsor
- Amgen
- Brief Summary
The purpose of Phase 1b of this study is to:
* Asses the safety, tolerability and activity of carfilzomib, alone and in combination with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic leukemia (ALL).
* Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy.
The purpose of Phase 2 of this study is to compare the rate of complete remission (CR) of carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin (VXLD) at the end of induction therapy to an appropriate external control.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 130
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Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.
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Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.
-To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:
- Early first relapse (< 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis after achieving a CR (T-ALL)
- First refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR
- Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR
- Failing to achieve a CR from original diagnosis after at least 1 induction attempt
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Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
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Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2.
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Adequate liver function, defined as both of the following:
- Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert Syndrome
- Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
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Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively.
Phase 2 Inclusion Criteria:
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Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated, except for standard of care local testing as permitted per protocol.
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Age greater than or equal to 1 month to less than 21 years. Subjects greater than or equal to 18 years must have had their original diagnosis at less than 18 years of age.
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Subjects must be diagnosed with relapsed or refractory relapsed ALL.
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Subjects must have a documented first remission, less than 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.
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T-cell ALL with bone marrow relapse (defined as greater than or equal to 5% leukemia blasts in bone marrow) or refractory relapse with or without extramedullary disease.
OR B-cell ALL bone marrow relapse or refractory relapse (defined as greater than or equal to 5% leukemia blasts in bone marrow) after having received a targeted B-cell immune therapy (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without extramedullary disease..
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Adequate liver function: bilirubin less than or equal to 1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) less than or equal to 5 x ULN.
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Adequate renal function: serum creatinine less than or equal to 1.5 x ULN or glomerular filtration rate (GFR) greater than or equal to 70 mL/min/1.73 m^2; or for children less than 2 years of age, greater than or equal to 50 mL/min/1.73 m^2.
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Adequate cardiac function: shortening fraction greater than or equal to 30% or ejection fraction greater than or equal to 50%.
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Karnofsky (subjects greater than or equal to 16 years of age) or Lansky (subjects 12 months to less than 16 years of age) performance status greater than or equal to 50%.
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Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for example: recovery from gastrointestinal toxicity may occur more rapidly than less reversible organ toxicities such as sinusoidal obstruction syndrome or non-infectious pneumonitis, for serious prior toxicities recommended discussion with Amgen medical monitor).
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Life expectancy of greater than 6 weeks per investigator's judgement at time of screening.
Phase 1b Key
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Known allergy to any of the drugs used in the study (Subjects who have had a previous allergy to PEG-asparaginase and if able, may receive Erwinia asparaginase at the investigator's discretion)
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Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
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Left ventricular fractional shortening < 30%
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History of ≥ Grade 2 pancreatitis
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Active graft-versus-host disease requiring systemic treatment
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Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
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Down Syndrome
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Prior therapy restrictions:
- Subjects must have completed therapy with granulocyte-colony stimulating factor (G-CSF) or other myeloid growth factors at least 7 days before study treatment initiation, or at least 14 days before study treatment initiation, if pegylated myeloid growth factors were administered.
- Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
- Subjects must have received the last dose of a non-monoclonal antibody biologic agent at least 7 days before study treatment initiation.
- At least 3 antibody half-lives must have elapsed since the last dose of monoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab) before subjects may initiate study treatment.
- Subjects must not have received other antineoplastic agents with therapeutic intent, excluding hydroxyurea and antimetabolites administered as part of maintenance chemotherapy, within 7 days prior to study treatment initiation.
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Hepatitis B infection with positive hepatitis B DNA
Phase 2 Exclusion Criteria:
- Prior treatment with carfilzomib.
- Intolerance, hypersensitivity, or inability to receive any of the chemotherapy components of the VXLD regimen. An exception is allowed for allergy to asparaginase products if Erwinia asparaginase is unable to be administered,
- Autologous HSCT within 6 weeks prior to start of study treatment.
- Allogeneic HSCT within 3 months prior to start of study treatment.
- Active GVHD requiring systemic immune suppression.
- Less than 30 days from discontinuation of immune suppressive therapy administered for the treatment of acute or chronic GVHD.
- Isolated extramedullary relapse.
- Positive bacterial or fungal infection within 14 days of enrollment (except for documented line infection, line has been removed, and blood culture after line removal is negative for 5 days prior to first dose of induction therapy). Antibiotics may be administered for prophylaxis as per institutional standards up to and after enrollment.
- Subjects with less than 3 antibody half-lives since the last dose of monoclonal antibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 36 days), prior to first dose of investigational product must be discussed with the Amgen medical monitor and may be allowed to enroll based on extent of disease or evidence of rapidly rising peripheral or bone marrow blast counts.
- Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor vaccines) within 42 days prior to first dose of investigational product. If the Amgen medical monitor agrees, an exception may be granted to the 42-day requirement for subjects with rapidly rising peripheral or bone marrow blast counts.
- Down's syndrome.
- Presence of another active cancer.
- History of grade greater than or equal to 2 pancreatitis within 6 months to screening.
- Unresolved toxicities from prior anticancer therapy, defined as not having resolved to CTCAE version 4.03 grade 1 or to levels dictated in the eligibility criteria apart from alopecia or toxicities from prior anticancer therapy that are considered irreversible and do not trigger another exclusion criterion (defined as having been present and stable for greater than 4 weeks).
- Antitumor therapy (chemotherapy, investigational agents, molecular-targeted therapy) within 7 days of day 1 of induction. Exception: hydroxyurea to control peripheral blood leukemic cell counts is allowed until start of investigational product.
- Active viral infection, including but not limited to cytomegalovirus (CMV), Hepatitis B infection with positive serum hepatitis surface antigen or hepatitis B DNA, HIV, Hepatitis C with detectable hepatitis C RNA. Subjects who have previously received a stem cell transplant must be screened for CMV infection, unless both subject and donor are known to be CMV negative.
- Currently receiving treatment in another investigational device or product study, or less than 14 days since ending treatment on another investigational device or product study.
- Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of greater than 470 msec.
- History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
- Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of any study treatment or for 12 months after last dose of cyclophosphamide if administered during optional consolidation cycle.
- Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 6 months after the last dose of any study treatment or for 12 months after last dose of cyclophosphamide if administered during optional consolidation cycle.
- Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum or urine pregnancy test.
- Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use a condom with spermicide during treatment and for an additional 6 months after the last dose of any study treatment, even if they have undergone a successful vasectomy.
- Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom with spermicide during treatment, for duration of pregnancy, and for an additional 6 months after the last dose of any study treatment.
- Male subjects unwilling to abstain from donating semen or sperm during treatment and for an additional 6 months after the last dose of any study treatment.
- Known allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib; for a complete listing of Captisol-enabled drugs, see the Ligand Pharmaceuticals, Inc. website).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Phase 1b: Dose Escalation 1 Intrathecal (IT) Methotrexate Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate) Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Intrathecal (IT) Methotrexate Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate) Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Intrathecal (IT) Methotrexate All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate) All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Intrathecal (IT) Methotrexate All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate) All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 Carfilzomib Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 Dexamethasone Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 Mitoxantrone Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 PEG-asparaginase Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 Vincristine Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 Cytarabine Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 6-Mercaptopurine Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 1 Cyclophosphamide Subjects will receive carfilzomib in combination with induction chemotherapy, comprising an R3 backbone of dexamethasone, mitoxantrone, PEG asparaginase, and vincristine. Subjects will have a 1 week carfilzomib single agent Lead in Window prior to the Induction Cycle. Subjects will receive a 4 week cycle of induction chemotherapy and have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Carfilzomib Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Dexamethasone Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 PEG-asparaginase Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Vincristine Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 6-Mercaptopurine Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Cyclophosphamide Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Cytarabine Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 1b: Dose Escalation 2 Daunorubicin Subjects will receive carfilzomib in combination with induction chemotherapy, comprising a VXLD backbone of vincristine, dexamethasone, PEG asparaginase, and daunorubicin. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy and then have the option to receive a 4 week cycle of consolidation chemotherapy (Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if stable disease or better response is achieved at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Carfilzomib All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Vincristine All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Dexamethasone All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening PEG-asparaginase All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening 6-Mercaptopurine All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Cyclophosphamide All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Cytarabine All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged ≥ 12 months at screening Daunorubicin All subjects aged ≥ 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a 4 week cycle of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 4 week cycle of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine) if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Carfilzomib All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Dexamethasone All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening PEG-asparaginase All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Vincristine All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening 6-Mercaptopurine All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Cyclophosphamide All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Cytarabine All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle. Phase 2: Aged < 12 months at screening Daunorubicin All subjects aged \< 12 months at screening. Subjects will receive the recommended phase 2 dose (RP2D) of carfilzomib determined in Phase 1b. Subjects will receive a modified 5 week cycle (based on Interfant-06) of carfilzomib and induction chemotherapy comprising of a VXLD backbone of vincristine, dexamethasone, PEG asparaginase and daunorubicin. Subjects will then have the option to receive a 5 week cycle (modified based on Interfant-06) of carfilzomib in combination with consolidation chemotherapy Children's Oncology Group (COG) modified Berlin Frankfurt Münster (BFM) chemotherapy backbone (6 mercaptopurine, cyclophosphamide, cytarabine, PEG asparaginase, vincristine), if subjects showed no disease progression at the end of the Induction Cycle.
- Primary Outcome Measures
Name Time Method Phase 1b: Number of Subjects who Experience a Clinically Significant Change from Baseline in Vital Signs 36 months Changes from baseline in vital signs
Phase 1b: Number of Subjects who Experience One or More Adverse Events (AE) 36 months Phase 1b: Number of Subjects who Experience One or More Serious Adverse Events (SAEs) 36 months Complete Remission (CR) after induction therapy Within 14 days of Induction and/or Consolidation cycle completion CR will be assessed in all subjects who do not show disease progression during induction therapy (Day 1 to Day 28) within 14 days, or start of alternative therapy, whichever comes first. Subjects can receive alternative therapy after completing induction therapy on Day 28.
Phase 1b: Number of Subjects who Experienced a Clinically Significant Change from Baseline in Key Laboratory Analytes 36 months Changes from baseline in key laboratory analytes.
Phase 1b: Time to Toxicity 36 months Time to toxicity will be evaluated to differentiate single-agent carfilzomib from carfilzomib in combination with induction chemotherapy
Complete Remission (CR) Rate After Induction Therapy in Subjects Aged Less Than 12 Months at Screening From Day 36 up to a maximum of Day 50 CR will be assessed in all subjects who do not show disease progression during induction therapy (Modified based on Interfant-06: Day 1 to Day 35) between Day 36 and Day 50, or start of alternative therapy, whichever comes first. Subjects can receive alternative therapy after completing induction therapy on Day 35.
Phase 1b: Number of Subjects who Experience a Clinically Significant Change from Baseline in Physical Findings 36 months Changes from baseline in physical findings
Phase 1b: Maximum Tolerated Dose (MTD) 36 months Maximum tolerated dose (MTD) of carfilzomib in combination with induction chemotherapy. Determination of the MTD as the dose that has the highest posterior probability of having a dose-limiting toxicity (DLT) rate within the target toxicity interval (20%-33%), while the posterior probability of excessive/unacceptable toxicity (\>33%-100%) is less than 40%.
- Secondary Outcome Measures
Name Time Method Phase 2: Number of Subjects who Experience a Severe Adverse Event 29 months Phase 2: Event Free Survival (EFS) 29 months EFS, defined as time from initiation of therapy until treatment failure (defined as failure to reach at least a CRi after consolidation or after induction in subjects that do not receive consolidation), relapse, or death from any cause.
Number of Subjects who Experience a Stem Cell Transplant or Chimeric Antigen Receptor T Cell Therapy (CAR-T) 29 months Number of Subjects who Experience Complete Remission (CR), CR with Incomplete Recovery of Platelets (CRp), or CR with Incomplete Hematological Recovery (CRi) After Consolidation Therapy in Subjects Aged Less than 12 Months at Screening Day 36 to 50 Phase 2: Maximum Plasma Concentration (Cmax) 29 months Phase 1b: Minimal Residual Disease (MRD) Status 36 months Proportion of subjects who achieve MRD status \< 10-3 and \< 10-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative immunoglobulin/T-cell receptor (Ig/TcR) polymerase chain reaction (PCR)
Phase 2: Minimal Residual Disease (MRD) Status in Subjects Achieving CR 29 months Proportion of subjects who achieve MRD status less than 10\^-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative immunoglobulin/T-cell receptor (Ig/TcR) polymerase chain reaction (PCR)
Number of Subjects who Experience Complete Remission (CR), CR with Incomplete Recovery of Platelets (CRp), or CR with Incomplete Hematological Recovery (CRi) After Consolidation Therapy in Subjects Aged Greater Than or Equal to 12 Months at Screening Day 29 and 45 Phase 1b: Maximum plasma concentration (Cmax) 36 months Maximum plasma concentration (Cmax), alone and in combination with induction chemotherapy, will be derived from levels of carfilzomib assayed in Pharmacokinetic (PK) samples. Estimates for Cmax will be tabulated and summarized (i.e., mean, standard deviation).
Phase 1b: Number of Subjects who Experience Complete Remission (CR) or Complete Remission with Incomplete Hematological Recovery (CRi) 36 months Phase 2: Number of Subjects who Experience a Treatment-emergent Adverse Event (TEAE) 29 months Phase 2: Number of Subjects who Experience a Treatment-related Adverse Event 29 months Phase 2: Number of Subjects who Experience Complete Remission (CR), Complete Remission with Incomplete Recovery of Platelets (CRp), CR with Partial Hematological Recovery (CRh) or Complete Remission with Incomplete Hematological Recovery (CRi) 29 months Phase 1b: Total Plasma Exposure - Area Under the Curve (AUC) 36 months Total Plasma Exposure - Area Under the Curve (AUC), alone and in combination with induction chemotherapy, will be derived from levels of carfilzomib assayed in Pharmacokinetic (PK) samples. Estimates for AUC will be tabulated and summarized (i.e., mean, standard deviation).
Phase 2: Number of Subjects who Experience a Laboratory Abnormality 29 months Phase 2: Overall Survival (OS) 29 months OS defined as time from initiation of therapy until death from any cause.
Phase 2: Duration of Response (DOR) 29 months DOR, defined as time from earliest of CR, CRp, CRh, or CRi to relapse or death from any cause.
Phase 2: Area Under the Concentration-time Curve (AUC) 29 months Phase 2: Half-life (t1/2) of Carfilzomib 29 months Minimal Residual Disease (MRD) Status in Subjects with Complete Remission (CR), CR with Incomplete Recovery of Platelets (CRp), CR with Partial Hematological Recovery (CRh) or CR with Incomplete Hematological Recovery (CRi) 29 months Proportion of subjects who achieve MRD status less than 10\^-3 and less than 10\^-4 lymphoblasts at the end of the Induction Cycle as assessed by quantitative immunoglobulin/T-cell receptor (Ig/TcR) polymerase chain reaction (PCR).
Phase 2: Number of Subjects who Experience a Clinically Significant Change from Baseline in Laboratory Analytes 29 months
Trial Locations
- Locations (119)
Childrens Healthcare of Atlanta, Egleston
🇺🇸Atlanta, Georgia, United States
West Virginia University Medicine Childrens
🇺🇸Morgantown, West Virginia, United States
Medical Park Bahcelievler Hastanesi
🇹🇷Istanbul, Turkey
Mackay Memorial Hospital Taipei Branch
🇨🇳Taipei, Taiwan
Chris Hani Baragwanath Hospital
🇿🇦Johannesburg, South Africa
Ramathibodi Hospital
🇹🇭Bangkok, Thailand
Karolinska Universitetssjukhuset Solna
🇸🇪Solna, Sweden
Ankara Bilkent Sehir Hastanesi
🇹🇷Ankara, Turkey
The Royal Marsden NHS Foundation Trust
🇬🇧Sutton, United Kingdom
Bursa Uludag Universitesi Tip Fakultesi
🇹🇷Bursa, Turkey
Ege Universitesi Tip Fakultesi
🇹🇷Izmir, Turkey
Erciyes Universitesi Tip Fakultesi Mustafa Eraslan ve Fevzi Mercan Cocuk Hastanesi
🇹🇷Kayseri, Turkey
Hospital Universitario Infantil Niño Jesus
🇪🇸Madrid, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Phramongkutklao Hospital
🇹🇭Bangkok, Thailand
Acibadem Adana Hastanesi
🇹🇷Adana, Turkey
Ankara Universitesi Tip Fakultesi Hastanesi
🇹🇷Ankara, Turkey
Childrens Hospital and Clinics of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Hospital São Rafael - IDOR
🇧🇷Salvador, Bahia, Brazil
Perth Childrens Hospital
🇦🇺Nedlands, Western Australia, Australia
Hospital da Crianca de Brasília
🇧🇷Brasília, Distrito Federal, Brazil
Hospital de Clinicas de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital da Crianca Santo Antonio Irmandade Santa Casa de Misericordia de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Siriraj Hospital
🇹🇭Bangkok, Thailand
Hospital Italiano de Buenos Aires
🇦🇷Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
King Fahad Medical City
🇸🇦Riyadh, Saudi Arabia
National University Hospital
🇸🇬Singapore, Singapore
KK Womens and Childrens Hospital
🇸🇬Singapore, Singapore
King Chulalongkorn Memorial Hospital
🇹🇭Bangkok, Thailand
Linkou Chang Gung Memorial Hospital
🇨🇳Taoyuan, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Medical Park Antalya Hastanesi
🇹🇷Antalya, Turkey
Medipol Mega Universite Hastanesi
🇹🇷Istanbul, Turkey
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
University of Utah Medical Center Primary Childrens Medical Center
🇺🇸Salt Lake City, Utah, United States
University of California San Francisco Benioff Childrens Hospital Oakland
🇺🇸Oakland, California, United States
Childrens Hospital of Orange County
🇺🇸Orange, California, United States
The Sidney Kimmel Comprehensive Cancer Center at John Hopkins
🇺🇸Baltimore, Maryland, United States
Lurie Childrens Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Childrens Hospital of New York Presbyterian
🇺🇸New York, New York, United States
The Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Nationwide Childrens Hospital
🇺🇸Columbus, Ohio, United States
Cincinnati Childrens Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Childrens Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Saint Judes Childrens Research Hospital
🇺🇸Memphis, Tennessee, United States
Childrens Medical Center
🇺🇸Dallas, Texas, United States
Texas Childrens Hospital West Tower
🇺🇸Houston, Texas, United States
University of Texas Health Science Center at San Antonio
🇺🇸San Antonio, Texas, United States
Hospital Aleman
🇦🇷Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
The Childrens Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Sydney Childrens Hospital
🇦🇺Randwick, New South Wales, Australia
Hospital Universitario Austral
🇦🇷Pilar, Buenos Aires, Argentina
St Anna Kinderspital
🇦🇹Wien, Austria
The Royal Childrens Hospital
🇦🇺Parkville, Victoria, Australia
Liga Paranaense do Combate ao Cancer - Hospital Erasto Gaertner
🇧🇷Curitba, Paraná, Brazil
Hospital Pequeno Principe
🇧🇷Curitiba, Paraná, Brazil
Instituto de Medicina Integral Professor Fernando Figueira
🇧🇷Recife, Pernambuco, Brazil
University Multiprofile Hospital for Active Treatment Tsaritsa Yoanna-ISUL EAD
🇧🇬Sofia, Bulgaria
Fundacao Pio 12 Hospital de Amor de Barretos
🇧🇷Barretos, São Paulo, Brazil
Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo
🇧🇷Ribeirao Preto, São Paulo, Brazil
Itaci Instituto de Tratamento do Cancer Infantil
🇧🇷Sao Paulo, São Paulo, Brazil
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦Montreal, Quebec, Canada
Hospital Luis Calvo Mackenna
🇨🇱Santiago de Chile, Chile
Beneficencia Portuguesa de Sao Paulo
🇧🇷São Paulo, Brazil
Hospital Roberto del Rio
🇨🇱Santiago, Chile
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
Sociedad de Oncologia y Hematologia del Cesar
🇨🇴Valledupar, Cesar, Colombia
Clinica Imbanaco S.A.S
🇨🇴Cali, Valle Del Cauca, Colombia
University Hospital Rigshospitalet
🇩🇰Kobenhavn O, Denmark
Centre Hospitalier Universitaire de Bordeaux - Hopital Pellegrin
🇫🇷Bordeaux Cedex, France
Centre Hospitalier Regional Universitaire de Lille
🇫🇷Lille, France
Hopital Armand Trousseau
🇫🇷Paris, France
Centre Hospitalier Universitaire de Toulouse - Hopital des enfants
🇫🇷Toulouse Cedex 9, France
Agia Sofia Children Hospital
🇬🇷Goudi, Greece
Centre Hospitalier Universitaire de Nancy - Hopital Enfants de Brabois
🇫🇷Vandoeuvre les Nancy Cedex, France
Hopital Robert Debre
🇫🇷Paris, France
General Children Hospital Panagioti and Aglaias Kyriakou
🇬🇷Goudi, Greece
General University Hospital of Patras Panagia i Voithia
🇬🇷Patra, Greece
Ippokrateio General Hospital of Thessaloniki
🇬🇷Thessaloniki, Greece
Hong Kong Childrens Hospital
🇭🇰Kowloon Bay, Hong Kong
Azienda Ospedaliera Universitaria Policlinico Vittorio Emanuele Presidio Ospedaliero G Rodolico
🇮🇹Catania, Italy
Sheba Medical Center
🇮🇱Tel Hashomer, Israel
Azienda Ospedaliera di Rilievo Nazionale Santobono Pausilipon
🇮🇹Napoli, Italy
Fondazione IRCCS San Gerardo dei Tintori
🇮🇹Monza (MB), Italy
Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari
🇮🇹Bari, Italy
IRCCS Istituto Giannina Gaslini
🇮🇹Genova, Italy
Azienda Ospedaliera di Padova
🇮🇹Padova, Italy
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
IRCCS Ospedale Pediatrico Bambino Gesu
🇮🇹Roma, Italy
Azienda Ospedaliera Citta della Salute e della Scienza Torino Ospedale Infantile Regina Margherita
🇮🇹Torino, Italy
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Pusan National University Yangsan Hospital
🇰🇷Yangsan-si, Gyeongsangnam-do, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
BRCR Global Mexico
🇲🇽Puebla, Mexico
Instituto Nacional de Pediatria
🇲🇽Mexico, Distrito Federal, Mexico
Prinses Maxima Centrum voor Kinderoncologie
🇳🇱Utrecht, Netherlands
Oslo Universitetssykehus Rikshospitalet
🇳🇴Oslo, Norway
Uniwersytecki Szpital Dzieciecy w Krakowie
🇵🇱Krakow, Poland
CSK Uniwersytetu Medycznego w Lodzi Uniwersyteckie Centrum Pediatrii im Marii Konopnickiej
🇵🇱Lodz, Poland
Uniwersytecki szpital dzieciecy
🇵🇱Lublin, Poland
Uck wum dzieciecy szpital kliniczny im jozefa polikarpa brudzinskiego
🇵🇱Warszawa, Poland
SPSK nr 1 im Prof Stanislawa Szyszko Slaskiego Uniwersytetu Medycznego w Katowicach
🇵🇱Zabrze, Poland
Centro Hospitalar Universitario de Coimbra
🇵🇹Coimbra, Portugal
Uniwersytecki Szpital Kliniczny im Jana Mikulicza-Radeckiego we Wroclawiu
🇵🇱Wroclaw, Poland
Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE
🇵🇹Lisboa, Portugal
Instituto Portugues de Oncologia do Porto Francisco Gentil, EPE
🇵🇹Porto, Portugal
Institutul Clinic Fundeni
🇷🇴Bucharest, Romania
Institutul Oncologic Prof Dr Ion Chiricuta Cluj-Napoca
🇷🇴Cluj Napoca, Romania
Spitalul Clinic de Urgenta pentru Copii Louis Turcanu Timisoara
🇷🇴Timisoara, Romania
FSBI N N Blokhin Russian Oncology Research Center Ministry of Health of Russian Federation
🇷🇺Moscow, Russian Federation
FSBI FSCC of pediatric hematology, oncology and immunology n a Dmitry Rogachev
🇷🇺Moscow, Russian Federation
SBEI of HPE Saint Petersburg State Medical University na academic I P Pavlov of MoH of RF
🇷🇺Saint Petersburg, Russian Federation
Levine Childrens Hospital at Carolinas Medical Center d/b/a Atrium Health
🇺🇸Charlotte, North Carolina, United States
Hospital Sant Joan de Deu
🇪🇸Esplugues de Llobregat, Cataluña, Spain
Queensland Childrens Hospital
🇦🇺South Brisbane, Queensland, Australia
Childrens Hospital Colorado
🇺🇸Aurora, Colorado, United States
Childrens Mercy Hospital
🇺🇸Kansas City, Missouri, United States