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

  • STATUS
    Recruiting
  • End date
    Jan 22, 2024
  • participants needed
    142
  • sponsor
    Amgen
Updated on 18 February 2021

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 response (CR) of carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin (VXLD) at the end of induction therapy to an appropriate external control.

Details
Condition childhood ALL, Lymphocytic Leukemia, Acute, acute lymphoblastic leukemia, leukemia, acute lymphoblastic, acute lymphoid leukaemia, acute lymphocytic leukemia, acute lymphoblastic leukemia (all)
Treatment cyclophosphamide, cytarabine, Dexamethasone, vincristine, Mitoxantrone, Daunorubicin, PEG-asparaginase, Carfilzomib, 6-mercaptopurine, Intrathecal (IT) Methotrexate, Intrathecal Triple Therapy (Intrathecal Cytarabine, Hydrocortisone, and Methotrexate)
Clinical Study IdentifierNCT02303821
SponsorAmgen
Last Modified on18 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 1 yrs and 21 yrs?
Gender: Male or Female
Do you have any of these conditions: childhood ALL or Lymphocytic Leukemia, Acute?
Do you have any of these conditions: childhood ALL or acute lymphoblastic leukemia (all) or acute lymphoblastic leukemia or acute lymphoid leukaemia or Lymphocytic Leukemia, Acute or acut...?
Do you have any of these conditions: acute lymphoid leukaemia or Lymphocytic Leukemia, Acute or acute lymphoblastic leukemia (all) or acute lymphoblastic leukemia or childhood ALL or acut...?
Do you have any of these conditions: acute lymphoid leukaemia or Lymphocytic Leukemia, Acute or acute lymphocytic leukemia or childhood ALL or acute lymphoblastic leukemia (all) or leukem...?
Do you have any of these conditions: acute lymphoid leukaemia or acute lymphocytic leukemia or childhood ALL or Lymphocytic Leukemia, Acute or acute lymphoblastic leukemia or leukemia, ac...?
Do you have any of these conditions: childhood ALL or leukemia, acute lymphoblastic or acute lymphoblastic leukemia or Lymphocytic Leukemia, Acute or acute lymphoid leukaemia or acute lym...?
Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation
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
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
Age 1 month to < 21 years. Subjects 18 years must have had their original diagnosis at < 18 years of age
Subjects must be diagnosed with relapsed or refractory relapsed ALL
Subjects must have a documented first remission, 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease
T-cell ALL with bone marrow relapse (defined as 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 5%
leukemia blasts in bone marrow) after having received a targeted B-cell immune
therapy as treatment for a prior relapse (eg, blinatumomab, inotuzumab or a
CAR-T therapy) with or without extramedullary disease. Subjects that receive
blinatumomab for treatment of MRD positive disease during first remission do
not qualify
\. Adequate liver function: bilirubin 1.5 x upper limit of normal (ULN)
alanine aminotransferase (ALT) 5 x ULN
\. Adequate renal function: serum creatinine 1.5 x ULN or glomerular
filtration rate (GFR) 70 ml/min/1.73m^2; or for children < 2 years of age 50
ml/min/1.73m^2
\. Adequate cardiac function: shortening fraction > 30% or ejection fraction
%
\. Karnofsky (subjects 16 years of age) or Lansky (subjects 12 months to < 16
years of age) performance status 50%
\. 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)
\. Life expectancy of 6 weeks per investigator's judgement at time of
screening

Exclusion Criteria

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)
Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
Left ventricular fractional shortening < 30%
History of Grade 2 pancreatitis
Active graft-versus-host disease requiring systemic treatment
Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
Down Syndrome
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
Hepatitis B infection with positive hepatitis B DNA
Phase 2 Exclusion Criteria
Prior treatment with carfilzomib
Prior treatment with a proteasome inhibitor (other than carfilzomib) within < 3 months of enrollment or to which a subject did not respond (response is defined as bone marrow with < 5% blasts)
Treatment with a chemotherapy regimen including a vinca alkaloid, steroid, L-asparaginase, and anthracycline combination with or without other chemotherapy agents within 2 months of enrollment (eg VXLD, VPLD, R3)
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, or if PEG-Asparaginase or Erwinia Asparaginase are not available in the country, these subjects may still be included
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
< 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
< 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
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 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 > 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 CMV, Hepatitis B infection with positive serum hepatitis surface antigen or hepatitis B DNA, HIV, Hepatitis C with detectable hepatitis C RNA
Currently receiving treatment in another investigational device or product study, or < 14 days since ending treatment on another investigational device or product study
Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of > 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 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 12 months after the last dose of any study treatment. Refer to Section 28 for additional contraceptive information
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
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