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

Acute Lymphoblastic Leukemia (ALL) is the most common malignancy of childhood.
Although the majority of children with newly diagnosed ALL will achieve a
complete remission and enjoy long-term survival, approximately 20% will
experience bone marrow relapse. The remission rates of relapsed ALL are less
than the rates for newly diagnosed ALL, which demonstrates the need for novel
agents to improve outcomes for patients with relapsed disease.
Current standard of care therapies for relapsed ALL include salvage regimens
such as the UK R3 (R3; dexamethasone, mitoxantrone, PEG-asparaginase, and
vincristine) and VXLD (vincristine; dexamethasone; PEG-asparaginase; and
doxorubicin or daunorubicin) chemotherapy backbones (R3). The addition of a
proteasome inhibitor to this these backbones could further boost clinical
response through a mechanism of action that differs from any of the current
chemotherapy agents in the R3 or VXLD regimens.
Treatment with proteasome inhibitors results in the accumulation of
pro-apoptotic proteins, promotion of autophagy, and an increase in the
stability of negative regulators of the cell cycle.
Carfilzomib is a proteasome inhibitor. In vitro, carfilzomib has shown to have
antiproliferative and proapoptotic activities across a range of solid and
hematologic tumor cells, including cells that are resistent to bortezomib, a
proteasome inhibitor that showed good response rates in combination with
standard chemotherapy in B-cell relapsed ALL. In vivo, carfilzomib results in
rapid and sustained inhibition of proteasome activity in blood and tissues, and
delays tumor growth in multiple myeloma and hematologic and solid tumor animal
models, including bortezomib-insensitive human tumor xenograft models.
Based on the mechanism of action, carfilzomib combined with induction
chemotherapy is anticipated to show activity within the relapsed and refractory
pediatric population with ALL.

Phase 2:
Outcomes for patients with relapsed or refractory ALL remain poor for subjects
with T-cell ALL and those with B-cell ALL that have relapsed after targeted
immune therapy, therefore these subjects represent a significant unmet need.
Thus, there is a clear need for novel agents to improve outcomes for these
patients.

The Primary Objectives of the Phase 1b are: • To assess the safety and
tolerability of carfilzomib, alone and in combination with induction
chemotherapy, for the treatment of children with relapsed or refractory ALL •
To determine the maximum tolerated dose (MTD) of carfilzomib in combination
with induction chemotherapy The Secondary Objectives of the Phase 1b are: • To
characterize the pharmacokinetics (PK) of carfilzomib alone and in combination
with induction chemotherapy • To evaluate the combined rate of bone marrow
complete response (CR) and bone marrow CR without platelet recovery (CRp) at
the end of the Induction Cycle • To estimate the proportion of subjects who
achieve minimal residual disease (MRD) status < 10 -3 and < 10 -4 lymphoblasts
at the end of the Induction Cycle The Exploratory Objectives of the Phase 1b
are: • To characterize the pharmacodynamic (PDn) response in subjects treated
with carfilzomib • To estimate the proportion of subjects with a decreased
percentage of lymphoblasts in the bone marrow at the end of a 1 week
carfilzomib single agent Lead in Window • To estimate the overall response rate
(ORR) at the end of the Induction Cycle • To explore potential genomic and gene
expression biomarkers that may predict response and resistance following
treatment with carfilzomib • To assess the safety and tolerability of
carfilzomib in combination with a single cycle of consolidation chemotherapy •
To evaluate the proportion of subjects with equal or better response status at
the end of a single cycle of consolidation chemotherapy, after stable disease
(SD) or better response was achieved at the end of the Induction Cycle. Phase
2: Main objective: Compare the rate of CR of CFZ-VXLD at the end of induction
therapy to an appropriate external control. Secondary objectives: -Compare the
rate of CR, CRp, CRh, and CRi of CFZ-VXLD at the end of induction therapy
relative to an appropriate external control -Compare EFS for CFZ VXLD to an
appropriate external control -Compare OS for CFZ-VXLD relative to an
appropriate external control -Estimate the DOR for CFZ-VXLD relative to an
appropriate external control -Estimate the rate of MRD[-] at the end of
induction in subjects receiving CFZ-VXLD Refer to protocol (section 19) for
additional secondary objectives.

This is a nonrandomized, multicenter, Phase 1b dose-escalation study of
carfilzomib in combination with induction chemotherapy, comprising either an R3
backbone of dexamethasone, mitoxantrone, PEG-asparaginase, and vincristine
(Dose Escalation 1) or a VXLD backbone of vincristine, dexamethasone,
PEG-asparaginase, and daunorubicin (Dose Escalation 2) in children with
relapsed or refractory ALL. During the Dose Escalation 1 (R3) portion of the
study only, the Induction Cycle will be preceded by a 1-week carfilzomib
single-agent Lead-in Window. Subjects in both dose escalation portions of the
study will receive a 4-week cycle of induction chemotherapy and have the option
to receive a 4-week cycle of consolidation chemotherapy, if stable disease or
better response is achieved at the end of the Induction Cycle. The Phase 1b
dose escalation design will use the Bayesian 2 parameter logistic regression
model, the new continual reassessment method (N- CRM) applied to observed dose
limiting toxicities (DLTs) occurring during the Lead in Window and Induction
Cycle. The prior distribution and the data available after each dose cohort are
applied to an algorithm that computes the posterior distribution of the DLT
rate at each dose level. The posterior probabilities of the estimated DLT rate
at each dose to fall into target toxicity interval (20%-33%) or
excessive/unacceptable toxicity interval (>33%-100%) will be used in the dose
escalation decision and the final determination of the MTD. A cohort size of 2
will be used in Dose Escalation 1 (R3). The starting dose is 20 mg/m2; the
maximum planned dose and the minimum planned dose are 45 mg/m2 and 20 mg/m2,
respectively. One or more cohorts of 2 subjects may be enrolled to each dose
level, depending on the toxicity observed. The Cohort Safety Review Committee
(CSRC) will review the safety data and dose level recommended by the algorithm
after every cohort has completed the 4 week Induction Cycle. The CSRC will
expand the dose level by 2 subjects, advance to the next dose level, or de
escalate to a lower dose level, based on the available data. No dose level
skipping will be allowed in dose escalation decisions. There is no such
constraint on de-escalation decisions. The algorithm will stop when the sample
size reaches 18 or when the DLT rate of the recommended MTD has a 95% posterior
credible interval within the pre-specified range of 5% to 60%. A cohort size of
3 will be used in Dose Escalation 2 (VXLD). The starting dose is27 mg/m2; the
planned dose levels are 27, 36, and 45 mg/m2. One or more cohorts of 3 subjects
may be enrolled to each dose level, depending on the toxicity observed. The
CSRC will review the safety data and dose level recommended by the algorithm
after every cohort has completed the 4-week Induction Cycle. The CSRC will
expand the dose level by 3 subjects, advance to the next dose level, or
de-escalate to a lower dose level, on the basis of the available data. No
dose-level skipping will be allowed in dose-escalation decisions. There is no
such constraint on de-escalation decisions. The algorithm will stop when the
sample size reaches 18 or if both of following criteria are met: • The
probability of the Target Toxicity interval at the candidate MTD exceeds 40%
AND • A minimum of 2 cohorts (6 subjects) are accrued and treated at the
candidate MTD A minimum of 2 subjects (1 cohort) will be enrolled at the
starting dose level in Dose Escalation 1 (R3). For the NCRM, the relationship
between dose and the probability of DLT will be updated as additional subject
safety information becomes available (e.g., after the last subject in the
cohort completes the Induction Cycle). After all subjects enrolled at the
starting dose level are DLT evaluable, the Bayesian Logistic Regression (BLR)
model will be updated, and the NCRM will recommend the next dose level from the
updated probabilities for target toxicity interval and excessive/unacceptable
toxicity interval. The next dose level (e.g., the Dose Level 2 or continuation
of Dose Level 1) will be the dose with the highest posterior probability of
having a toxicity rate in the target toxicity interval, which is defined as 20%-
33%, and will be subject to the constraint that the probability of
excessive/unacceptable toxicity, which is defined as > 33%-100%, is less than
40%. The MTD will be selected based on the above criteria and the clinical
judgment of the CSRC. A minimum of 3 subjects (1 cohort) will be enrolled at
the starting dose level in Dose Escalation 2 (VXLD). The dose level selection
algorithm will be same as in Dose Escalation 1 (R3). When the algorithm
recommends an MTD, the CSRC will review the data and recommend a dose for the
Phase 2 study. A DLT is defined as any of the following toxicities assessed by
the investigator as possibly, probably, or definitely attributable to
carfilzomib during the Lead-in Window or Induction Cycle: • Any Grade 4
nonhematologic toxicity, excluding: - Alopecia - Infection - Tumor lysis
syndrome (TLS) - Fever and neutropenia - Fatigue - Nausea or vomiting - Sensory
neuropathy or neuropathic pain - The following, provided there is a return to
Grade 1 status or subject*s baseline by the time of induction treatment course
completion and blood count recovery (no later than Day 42 of the Induction
Cycle): electrolyte abnormalities, hyper or hypoglycemia, or elevations of AST,
ALT, GGT, triglycerides, or bilirubin >= Grade 4 neutropenia or >= Grade 3
thrombocytopenia persisting beyond Day 42 45 (Day 42 prior to Protocol
Amendment 3) of the Induction Cycle in a subject with who otherwise has a CR.
Phase 2: The phase 2 portion of the study is a multicenter, single-group,
externally-controlled study of carfilzomib in combination with VXLD in a
minimum of 100 subjects, unless futility is met. A minimum of 30 subjects with
T-cell ALL and 50 subjects with B-cell ALL will be enrolled. Eligible subjects
must be >= 1 month to < 21 years old, with their original diagnosis at < 18
years of age, and must have ALL with bone marrow relapse (>= 5% leukemia blasts
in bone marrow) or refractory relapse with or without extramedullary disease of
the T-cell phenotype or of the B-cell phenotype after having received a
targeted B-cell immune therapy following a prior relapse (eg, blinatumomab,
inotuzumab, CAR-T therapy). Infants enrolling on this study will receive a
modified VXLD and optional consolidation based on the dose and schedule used in
COG AALL15P1 study. The carfilzomib dose for phase 2 will be 20 mg/m2 on day 1
of induction, 56 mg/m2 on days 2, 8, 9, 15, and 16 of induction and days 1, 2,
8, 9, 15, and 16 of consolidation. Eligible subjects will be treated with VXLD
plus carfilzomib for 1 cycle (induction), followed by assessment of treatment
response. All subjects who do not show progression during induction will
undergo a bone marrow and extramedullary disease evaluation after completion of
induction therapy between days 29 to 45 of induction (between days 36 to 50 for
infants), based on blood count recovery but before the start of post-induction
therapy, whichever comes first. Response will be assessed per local and central
laboratory review of bone marrow, peripheral blood, and differential, and local
assessment for sites of extramedullary disease. MRD will be assessed by NGS
central laboratory review and local evaluation by flow cytometry and/or PCR or
NGS when available. Subjects without disease progression after induction may,
at the investigator*s discretion, be treated with 1 cycle of consolidation
chemotherapy plus carfilzomib. Subjects who do not show disease progression
during consolidation will be assessed for treatment response between day 29 to
45 of consolidation (between day 36 to 50 for infants), based on blood count
recovery or start of alternative therapy, whichever comes first. Treatment
response after consolidation therapy will also be assessed per local and
central laboratory review of bone marrow, peripheral blood and differential,
and local assessment for sites of extramedullary disease. When available, local
laboratory assessments of MRD by flow cytometry and/or PCR or NGS will be
collected. The consolidation treatment will consist of one 28-day cycle of
Children*s Oncology group-modified Berlin-Frankfurt-Munster (BFM) therapy;
cyclophosphamide, cytarabine, 6-mercaptopurine, PEG-asparaginase, vincristine,
and intrathecal therapy, or for < 12 months of age a modified infant
consolidation from COG AALL15P1; cyclophosphamide, cytarabine,
6-mercaptopurine, and intrathecal therapy, combined with carfilzomib at a dose
of 56 mg/m2 (or lower if dose reduction was required during induction) at the
same schedule as the induction therapy. After completion of study therapy,
subjects will be followed for subsequent treatment(s), event-free and overall
survival. For selected objectives, the treatment response to induction of
subjects receiving CFZ-VXLD will be compared to an external control arm of
subjects from an observational study of relapsed pediatric ALL (study 20180065)
that received standard-of-care (SoC) chemotherapy, after appropriate
adjustment.

Lead-in Window (Dose Escalation 1 [R3] only): Carfilzomib will be given as an
intravenous infusion over 30 ± 5 minutes on Days 1 and 2 of the carfilzomib
single agent Lead in Window. Subjects in all cohorts will receive 20 mg/m2 of
carfilzomib on Day 1 of the Lead in Window; the Day 2 carfilzomib infusions
will be given at the assigned dose level for each cohort:
• Dose Level 1: 20 mg/m2
• Dose Level 2: 27 mg/m2
• Dose Level 3: 36 mg/m2
• Dose Level 4: 45 mg/m2

Induction Cycle (Dose Escalation 1 [R3] and Dose Escalation 2 [VXLD]):
Carfilzomib will be given as an intravenous infusion over over 30 ± 5 minutes
on Days 1, 2, 8, 9, 15, and 16 of the Induction Cycle. During the Phase 1b,
Carfilzomib infusions will be given at the assigned dose level for each cohort:
Dose Escalation 1 (R3)
* Dose Level 1: 20 mg/m2
* Dose Level 2: 27 mg/m2
* Dose Level 3: 36 mg/m2
* Dose Level 4: 45 mg/m2
Dose Escalation 2 (VXLD)
* Dose Level 2: 27 mg/m2
* Dose Level 3: 36 mg/m2
* Dose Level 4: 45 mg/m2

The Induction Chemotherapy Backbone for Dose Escalation 1 (R3) consists of:
• Dexamethasone 10 mg/m2 given orally twice daily on Days 1 to 5 and 15 to 19
• Mitoxantrone, 10 mg/m2 IV on Days 1 and 2
• PEG asparaginase 1000 U/m2 IV on Days 3 and 18
• Vincristine 1.5 mg/m2 (maximum 2 mg dose) IV on Days 3, 10, 17, and 24

Induction Chemotherapy Backbone for Dose Escalation 2 (VXLD)
• Daunorubicin, 25 mg/m2 IV on Days 1, 8, 15, and 22
• Dexamethasone 6 mg/m2 given orally twice daily on Days 1 to 21
• PEG asparaginase 2500 U/m2 IV on Days 4 and 18
• Vincristine 1.5 mg/m2 (maximum 2-mg dose) IV on Days 1, 8, 15, and 22

The following Central Nervous System (CNS) Treatment will be administered
(According to age based dosing):
Preservative free forms of cytarabine, hydrocortisone, and methotrexate should
be used for intrathecal (IT) administration.
Dose escalation 1:
• CNS negative subjects: IT methotrexate given on Day 1
• CNS positive subjects: IT Triple Therapy (cytarabine, hydrocortisone, and
methotrexate) given on Days 1, 8, 15, and 29
Dose escalation 2:
• Intrathecal chemotherapy in accordance with institutional practice given
within 7 days before enrollment or on Day 1
• CNS negative subjects: IT methotrexate () given on Day 8
• CNS positive subjects: IT Triple Therapy (cytarabine, hydrocortisone, and
methotrexate) given on Days 8, 15, 22, and 29

Subjects who participate in the Optional Consolidation Cycle will receive
carfilzomib as an IV infusion over 30 ± 5 minutes on Days 1, 2, 8, 9, 15, and
16. Carfilzomib will be administered at the same dose level to which the
subject was assigned during the Lead in Window and/or Induction Cycle.
The Consolidation Backbone consists of:
• 6 mercaptopurine, 60 mg/m2 given orally on Days 1-14
• Cyclophosphamide 1000 mg/m2 IV on Day 1
• Cytarabine 75 mg/m2 IV or subcutaneously on Days 1-4 and 8-11
• PEG asparaginase 1000 U/m2 IV on Day 15
• Vincristine 1.5 mg/m2 (maximum 2 mg per dose) IV on Days 15 and 22

The following CNS Treatment will be administered (According to age based
dosing):
Preservative free forms of cytarabine, hydrocortisone, and methotrexate should
be used for intrathecal administration.
• CNS negative subjects: IT methotrexate given on Days 1, 8, 15, and 22
• CNS positive subjects: IT Triple Therapy (cytarabine, hydrocortisone, and
methotrexate) given on Days 1, 8, 15, and 22

Carfilzomib will be immediately omitted for any DLT. Subjects may continue with
the remainder of the backbone therapy, at the investigator*s discretion, should
this occur. Carfilzomib may be reintroduced at a lower dose, once the toxicity
has improved to <= Grade 2 status. If carfilzomib is not reintroduced, the
subject is considered to be withdrawn from study treatment.

Subjects will also have bone marrow biopsies/ aspirations, lumbar punctures,
blood sampling (Catheter), echocardiograms, and electrocardiograms.

Phase 2:
Subjects will be treated with VXLD plus carfilzomib for 1 cycle (induction),
followed by assessment of treatment response. All subjects who do not show
progression during induction and at the discretion of the investigator will be
treated with 1 cycle of consolidation chemotherapy plus carfilzomib . Response
assessments will be performed by the investigator. Response will be assessed
per central laboratory review of stained slides of bone marrow aspirate,
peripheral blood count and differential, and MRD, and local assessment for
sites of extramedullary disease.

ALL is the most common malignancy of childhood. Although the majority of
children with newly diagnosed ALL will achieve a complete remission and enjoy
long-term survival, approximately 20% will experience bone marrow relapse. The
remission rates of relapsed ALL are less than the rates for newly diagnosed
ALL, which demonstrates the need for novel agents to improve outcomes for
patients with relapsed disease.
Current standard of care therapies for relapsed ALL include salvage regimens
such as the UK R3 backbone and the VXLD backbone. The addition of a proteasome
inhibitor to this backbones could further boost clinical response through a
mechanism of action that differs from any of the current chemotherapy agents in
these backbones.
The safety profile of Carfilzomib in adults with multiple myeloma and solid
tumors is consistent with the mechanism of action of proteasome inhibitors, but
with predictably lower rates of peripheral neuropathy, based on the epoxyketone
structure that improves proteasome inhibition selectivity. A complete overview
of the reported (serious) adverse events and reactions can be found in the
Investigator's Brochure.

Phase 2:
The potential benefits of the carfilzomib-VXLD regimen include improved disease
response with an improved chance of achieving a remission that is deep and
durable enough to permit subjects to undergo hematopoietic stem cell transplant
or other potential curative treatments. An improved CR rate and increased
number of MRD negative responses may translate into a better chance for disease
free and overall survival.
Please refer to section 18.3 of the protocol for the complete Benefit/Risk
Assessment.