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.
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.
2. Age ≥ 1 month to < 21 years. Subjects ≥ 18 years must have had their original
diagnosis at < 18 years of age.
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL.
4. Subjects must have a documented first remission, ≤ 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 ≥ 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 received blinatumomab for treatment
of MRD positive disease during first remission or for primary induction failure to
achieve a first remission do not qualify.
6. Adequate liver function: bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine
aminotransferase (ALT) ≤ 5 x ULN.
7. Adequate renal function: serum creatinine ≤ 1.5 x ULN or glomerular filtration rate
(GFR) ≥ 70 mL/min/1.73 m^2; or for children < 2 years of age ≥ 50 mL/min/1.73 m^2.
8. Adequate cardiac function: shortening fraction ≥ 30% or ejection fraction ≥ 50%.
9. Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects 12 months to < 16 years of
age) performance status ≥ 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 > 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. 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).
3. 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).
4. 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,
5. Autologous HSCT within 6 weeks prior to start of study treatment.
6. Allogeneic HSCT within 3 months prior to start of study treatment.
7. Active GVHD requiring systemic immune suppression.
8. < 30 days from discontinuation of immune suppressive therapy administered for the
treatment of acute or chronic GVHD.
9. Isolated extramedullary relapse.
10. 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.
11. < 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.
12. 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.
13. Down's syndrome.
14. Presence of another active cancer.
15. History of grade ≥ 2 pancreatitis within 6 months to screening.
16. 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).
17. 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.
18. 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. Subjects who have previously received a stem cell
transplant must be screened for CMV infection.
19. Currently receiving treatment in another investigational device or product study, or <
14 days since ending treatment on another investigational device or product study.
20. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of > 470
msec.
21. 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.
22. 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.
23. 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.
24. Female subjects of childbearing potential with a positive pregnancy test assessed at
Screening by a serum or urine pregnancy test.
25. 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.
26. 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.
27. 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.
