Phase 1b/2 Study of Carfilzomib in Combination With Induction Chemotherapy in Children With Relapsed or Refractory Acute Lymphoblastic Leukemia

Phase 2

Conditions: Acute Lymphoblastic Leukemia
Cancer of White Blood Cells
10024324

Registration Number: NL-OMON56393

Lead Sponsor: Amgen

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Pending

Sex: Not specified

Target Recruitment: 1

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 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: o 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) OR o
Relapse after achieving a CR following the first or subsequent relapse (i.e., >=
2 relapses) OR o 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. For
those with hyperbilirubinemia due to Gilbert syndrome, subjects are only
eligible if they have a direct bilirubin . 1.5 ~ institutional ULN. • ALT <= 5
× institutional ULN 6. Performance status: Karnofsky or Lansky scores >= 50 for
subjects > 16 years old or <= 16 years old, respectively. 7. Females of
childbearing potential (FCBP) must have a negative serum or urine pregnancy
test within 48 hours prior to study treatment initiation. 8. Females of
childbearing potential and male subjects who are sexually active with a FCBP
must agree to use a highly effective method of contraception plus a male condom
during the study and for 6 months following the last dose of study treatment.
The methods of contraception are defined in the ICF. Where required by local
laws, regulations, and/or guidelines, additional countryspecific requirements
are outlined in a country-specific protocol addendum. 9. Subjects must provide
written informed consent and pediatric assent in accordance with federal,
local, and institutional laws and regulations. Phase 2: 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 Section 21.3 of the protocol. 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 with bone marrow relapse or refractory relapse (defined as >= 5% leukemia

Exclusion Criteria

1. Known allergy to any of the drugs used in the study. (Subjects who have had
a previous allergy to PEG-asparaginase but can receive Erwinia are eligible.)
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 received the last dose of a non-monoclonal
antibody biologic agent at least 7 days before study treatment initiation. For
agents that have known adverse events (AEs) occurring beyond 7 days after the
last administration, this period must be extended beyond the time during which
AEs are known to occur, and the Sponsor study medical monitor should be
contacted. • 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 have
completed any type of active immunotherapy (e.g., tumor vaccines) at least 42
days before study treatment initiation. • 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. Females who are pregnant and/or
breastfeeding. Phase 2: 1. Prior treatment with carfilzomib. 4. Intolerance,
hypersensitivity, or inability to receive any of the chemotherapy components of
the VXLD regimen (or acceptable substitutes as listed in the protocol). 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. Please see protocol (section 21.2) for additional
phase 2 exclusion criteria

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The primary endpoints for Phase 1b are: • Safety and tolerability of<br /><br>carfilzomib alone and in combination with induction chemotherapy as defined by<br /><br>the type, incidence, severity, and outcome of adverse events (AEs); changes<br /><br>from baseline in key laboratory analytes, vital signs, and physical findings.<br /><br>Time to toxicity will be evaluated to differentiate single agent carfilzomib<br /><br>from carfilzomib in combination with induction chemotherapy. • Determination of<br /><br>the MTD as the dose that has the highest posterior probability of having a DLT<br /><br>rate within the target toxicity interval (20%-33%), while the posterior<br /><br>probability of excessive /unacceptable toxicity (>33%-100%) is less than 40%.<br /><br>Phase 2: • CR after induction therapy</p><br>

Secondary Outcome Measures

Name	Time	Method

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