NCT02303821 · CITED IN SOURCE DOCUMENTS

Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE1
Status at capture: COMPLETED
Registry last update: 2025-06-04

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.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination

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outcome · POSTED

Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib

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outcome · POSTED

Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib

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outcome · POSTED

Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle

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outcome · POSTED

Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle

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outcome · POSTED

Phase 2: Number of Participants Who Experienced TEAEs

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outcome · POSTED

Phase 2: Percentage of Participants With CR With Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status

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outcome · POSTED

Phase 2: Event Free Survival (EFS)

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outcome · POSTED

Phase 2: Overall Survival (OS)

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outcome · POSTED

Phase 2: Duration of Remission (DOR)

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outcome · POSTED

Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy

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outcome · POSTED

Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy

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outcome · POSTED

Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Consolidation Therapy

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outcome · POSTED

Phase 2: Percentage of Participants Who Underwent Stem Cell Transplant or Chimeric Antigen Receptor T-cell (CAR-T) Without Intervening Relapse Following Protocol-Specified Therapy

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outcome · POSTED

Phase 2: Percentage of Participants With CRi or Better Remission Status After Consolidation Therapy

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outcome · POSTED

Phase 2: AUClast of Carfilzomib

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outcome · POSTED

Phase 2: AUCinf of Carfilzomib

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outcome · POSTED

Phase 2: Cmax of Carfilzomib

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outcome · POSTED

Phase 2: Terminal Half-life (t1/2,z) of Carfilzomib

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outcome · POSTED

Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)

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outcome · POSTED

Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)

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outcome · POSTED

Phase 2: Percentage of Participants With Complete Remission (CR) After Induction Therapy

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Phase 1b Key Inclusion Criteria: 1. Age 21 years or younger at the time of initial ALL diagnosis and age \> 1 year at the time of study treatment initiation. 2. 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 3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment. 4. 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. 5. 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 6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects \> 16 years old or ≤ 16 years old, respectively. Phase 2 Inclusion Criteria: 1. 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. 2. 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. 3. Subjects must be diagnosed with relapsed or refractory relapsed ALL. 4. Subjects must have a documented first remission, less than 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease. 5. 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.. 6. 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. 7. 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. 8. Adequate cardiac function: shortening fraction greater than or equal to 30% or ejection fraction greater than or equal to 50%. 9. 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%. 10. 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). 11. Life expectancy of greater than 6 weeks per investigator's judgement at time of screening. Phase 1b Key Exclusion Criteria: 1. 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) 2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib) 3. Left ventricular fractional shortening \< 30% 4. History of ≥ Grade 2 pancreatitis 5. Active graft-versus-host disease requiring systemic treatment 6. Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment 7. Down Syndrome 8. 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. 9. Hepatitis B infection with positive hepatitis B DNA Phase 2 Exclusion Criteria: 1. Prior treatment with carfilzomib. 2. 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, 3. Autologous HSCT within 6 weeks prior to start of study treatment. 4. Allogeneic HSCT within 3 months prior to start of study treatment. 5. Active GVHD requiring systemic immune suppression. 6. Less than 30 days from discontinuation of immune suppressive therapy administered for the treatment of acute or chronic GVHD. 7. Isolated extramedullary relapse. 8. 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. 9. 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. 10. 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. 11. Down's syndrome. 12. Presence of another active cancer. 13. History of grade greater than or equal to 2 pancreatitis within 6 months to screening. 14. 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). 15. 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. 16. 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. 17. 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. 18. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of greater than 470 msec. 19. 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. 20. 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. 21. 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. 22. Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum or urine pregnancy test. 23. 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. 24. 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. 25. 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. 26. 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).
healthy Volunteers: false
maximum Age: 21 Years
minimum Age: 1 Month
sex: ALL
std Ages: CHILD
ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
Drug: Carfilzomib
Drug: Dexamethasone
Drug: Mitoxantrone
Drug: PEG-asparaginase
Drug: Vincristine
Drug: Intrathecal (IT) Methotrexate
Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
Drug: 6-Mercaptopurine
Drug: Cyclophosphamide
Drug: Cytarabine
label
Phase 1b: Dose Escalation 1
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Carfilzomib
Drug: Dexamethasone
Drug: PEG-asparaginase
Drug: Vincristine
Drug: Intrathecal (IT) Methotrexate
Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
Drug: 6-Mercaptopurine
Drug: Cyclophosphamide
Drug: Cytarabine
Drug: Daunorubicin
label
Phase 1b: Dose Escalation 2
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Carfilzomib
Drug: Dexamethasone
Drug: PEG-asparaginase
Drug: Vincristine
Drug: Intrathecal (IT) Methotrexate
Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
Drug: 6-Mercaptopurine
Drug: Cyclophosphamide
Drug: Cytarabine
Drug: Daunorubicin
label
Phase 2: Aged ≥ 12 months at screening
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Carfilzomib
Drug: Dexamethasone
Drug: PEG-asparaginase
Drug: Vincristine
Drug: Intrathecal (IT) Methotrexate
Drug: Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
Drug: 6-Mercaptopurine
Drug: Cyclophosphamide
Drug: Cytarabine
Drug: Daunorubicin
label
Phase 2: Aged < 12 months at screening
type
EXPERIMENTAL

interventions

arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Carfilzomib
other Names
PR-171
PR171
Kyprolis® (carfilzomib) for Injection
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Dexamethasone
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
name
Mitoxantrone
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
PEG-asparaginase
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Vincristine
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Intrathecal (IT) Methotrexate
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
6-Mercaptopurine
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Cyclophosphamide
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 1
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Cytarabine
type
DRUG
arm Group Labels
Phase 1b: Dose Escalation 2
Phase 2: Aged < 12 months at screening
Phase 2: Aged ≥ 12 months at screening
name
Daunorubicin
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 141
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
An adverse event (AE) is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. Treatment-related AEs (TRAEs) were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. A serious AE (SAE) was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
measure
Phase 1b: Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
time Frame
From first dose up to 30 days after the last dose of study treatment; maximum duration of treatment was 8 weeks
description
A DLT was defined as any of the following toxicities assessed by the investigator as possibly, probably, or definitely attributable to carfilzomib, with protocol defined exclusions: Any Grade 4 nonhematologic toxicity, ≥ Grade 4 neutropenia or ≥ Grade 3 thrombocytopenia.
measure
Phase 1b: Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
time Frame
Up to approximately 35 days
description
CR was defined as: 1. Attainment of M1 bone marrow status (less than 5% blasts in a bone marrow aspirate and at least 200 cells counted) with no evidence of circulating blasts or extramedullary disease. 2. Recovery of peripheral counts: * Absolute neutrophil count (ANC) greater than or equal to 1000/µL * Platelet count greater than or equal to 100000/µL. * Assessed between days 29 and 45 Data was adjusted as inverse probability of treatment weight (IPTW) for the average treatment effect of the treated (IPTW-ATTW).
measure
Phase 2: Percentage of Participants With Complete Remission (CR) After Induction Therapy
time Frame
Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [Day 36 to Day 50 for infants])

secondary Outcomes

description
The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval.
measure
Phase 1b: Maximum Concentration (Cmax) of Carfilzomib Alone and in Combination
time Frame
Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15 minutes (m) after the start of infusion, immediately (within 2m) before the end of infusion (EOI), EOI, 10m, 30m, 1 hour (h), 2 h, and 4h post-dose
description
The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval.
measure
Phase 1b: Area Under the Curve (AUC) From Time 0 to the Last Quantifiable Timepoint (AUClast) of Carfilzomib
time Frame
Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose
description
The PK parameter estimates for carfilzomib were estimated from plasma concentration-time profiles using standard noncompartmental approaches over the complete sampling interval.
measure
Phase 1b: AUC From Time 0 to Infinity (AUCinf) of Carfilzomib
time Frame
Lead-in Cycle Day 1 (7-day cycle) and Induction Cycle Day 8 (28-day cycle): pre-dose, 15m after the start of infusion, immediately (within 2m) before the EOI, EOI, 10m, 30m, 1h, 2 h, and 4h post-dose
description
CR was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC \> 750 mcl and platelet count \> 75,000 mcl). CRp was defined as the attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease and with recovery of ANCs (ANC \> 750 mcl), but with insufficient recovery of platelets (\< 75,000 mcl).
measure
Phase 1b: Percentage of Participants Who Achieved a Combined CR and CR Without Platelet Recovery (CRp) at the End of Induction Cycle
time Frame
Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day 29)
description
MRD was defined as the quantification of residual lymphoblast in the blood. Assessed by next generation sequencing (NGS).
measure
Phase 1b: Percentage of Participants Achieving Minimal Residual Disease (MRD) Status of <10-³ and <10-⁴ Lymphoblasts at the End of Induction Cycle
time Frame
Up to approximately Day 29 of Induction Cycle (28-days cycle, assessment on Day29)
description
An AE is any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs are AEs that occurred after the start of study treatment and up to the end of the study or 30 days of the last study treatment, whichever is earlier. Any clinically significant changes in vital signs, electrocardiograms, and clinical laboratory tests that occurred after study treatment administration were recorded as TEAEs. TRAEs were TEAEs considered related to at least one study drug by the investigator, including those with unknown relationship. An SAE was defined as any untoward medical occurrence that resulted in death, was immediately life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or another medically important serious event.
measure
Phase 2: Number of Participants Who Experienced TEAEs
time Frame
From first dose up to 30 days after the last dose of study treatment; maximum duration of treatment was 8 weeks
description
CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. ANC and platelet counts not fulfilling criteria for CR with partial hematologic recovery (CRh), CR without platelet recovery (CRp), or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: 1. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease 2. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL. Data was IPTW adjusted.
measure
Phase 2: Percentage of Participants With CR With Incomplete Hematologic Recovery (CRi) After Induction Therapy or Better Remission Status
time Frame
Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
description
EFS was 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 participants that did not receive consolidation), relapse, or death from any cause. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp, or CR. Data was IPTW adjusted. Medians were estimated using the Kaplan-Meier (KM) method.
measure
Phase 2: Event Free Survival (EFS)
time Frame
Up to approximately 2 years
description
OS was defined as time from initiation of therapy until death from any cause. Data was IPTW adjusted. Medians were estimated using the KM method.
measure
Phase 2: Overall Survival (OS)
time Frame
Up to approximately 2 years
description
DOR was defined as time from earliest of CR, CRp, CRh, or CRi to relapse or death from any cause. CR was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease. b. Recovery of peripheral counts: - ANC ≥ 1000/µL - Platelet count ≥ 100 000/µL. CRi was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. ANC and platelet counts not fulfilling criteria for CRh, CRp) or CR. CRp was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 1000/µL ii. Platelet count \< 100 000/µL. CRh was defined as: a. Attainment of M1 bone marrow status with no evidence of circulating blasts or extramedullary disease b. Recovery of peripheral counts: i. ANC ≥ 500/µL but \< 1000/µL ii. Platelet count ≥ 50 000/µL but \< 100 000/µL.
measure
Phase 2: Duration of Remission (DOR)
time Frame
Up to approximately 2 years
description
MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with next generation sequencing (NGS).
measure
Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CR After Induction Therapy
time Frame
Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])
description
MRD was defined as the number of leukemia cells that remained in a participant's body after treatment. MRD was measured with NGS.
measure
Phase 2: Percentage of Participants Achieving MRD Status of <10-³ and <10-⁴ Cells in Participants With CRi or Better Status After Induction Therapy
time Frame
Up to Day 50 (28-day cycle of induction therapy + recovery window from Day 29 to Day 45 [up to Day 50 for infants])

Full study description

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.

Source references

references

citation
Locatelli F, Karakukcu M, Huynh V, Gonzalez-Martinez B, Mendes Lins M, Lu MY, Sulis ML, Pauly M, Morris CL, Braunlin M, Talpes M, Gore L. Carfilzomib plus induction chemotherapy in children with relapsed or refractory acute lymphoblastic leukemia. Blood Adv. 2026 Jun 3:bloodadvances.2025019356. doi: 10.1182/bloodadvances.2025019356. Online ahead of print.
pmid
42234929
type
DERIVED
citation
Burke MJ, Ziegler DS, Bautista F, Attarbaschi A, Gore L, Locatelli F, M O'Brien M, Pauly M, Kormany WN, Tian S, Morris CL, Baruchel A. Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsed/refractory acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022 Dec;69(12):e29999. doi: 10.1002/pbc.29999. Epub 2022 Oct 10.
pmid
36215217
type
DERIVED