Treatment With Combination Chemotherapy for Relapsed or Refractory Acute Lymphoblastic Leukemia

RELPALL is a single center, St Jude initiated, non-randomized single-arm phase I study to
characterize the toxicity profile and to determine the maximum tolerated combination (MTC)
and recommended phase II combination of palbociclib when given with chemotherapy in pediatric
patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Palbociclib is a
reversible inhibitor of cyclin-dependent kinase 4 (CDK4) and the closely related
cyclin-depending kinase 6 (CDK6) that has shown high anti-leukemic activity in several
pre-clinical models. The mechanism of palbociclib, which reversibly arrests cells in G1,
argues that combination treatment, as opposed to single agent treatment, will be more likely
to provide clinical benefit. Timing of combination treatment with standard cytotoxic
chemotherapy drugs that kill actively dividing cells is important to maximize the chance of
activity. This study will build on prior multiple myeloma experience with palbociclib in
combination with dexamethasone and bortezomib while tailoring the treatment to pediatric
relapsed/refractory ALL. To maximize G1 arrest, dexamethasone will be given concurrently with
palbociclib for five days. Patients will receive a 48 hour "washout" before receiving
bortezomib and doxorubicin, both cytotoxic anti-leukemic drugs that preferentially kills
cells when synchronized in S phase. Patients with Philadelphia Chromosome positive ALL (Ph+)
and Philadelphia-like (Ph-like) ALL will also receive a tyrosine kinase inhibitor (TKI)
beginning on Day 7 until count recovery. The primary objective is to determine a tolerable
combination of palbociclib plus chemotherapy in pediatric patients with relapsed or
refractory ALL. The secondary objective is to estimate the overall response rate to the
combination of palbociclib and chemotherapy in pediatric patients with relapsed or refractory
ALL. Exploratory objectives include measuring cell cycle kinetics of ALL cells following
administration of palbociclib and an evaluation of modes of resistance in non-responders.

Inclusion Criteria:

Participants must be < 22 years of age.

Diagnosis:

Participants must have a diagnosis of acute lymphoblastic leukemia and disease meets at
least one of the following criteria:

- relapsed or refractory to chemotherapy as defined by ≥5% leukemic blasts in the bone
marrow

- relapsed after hematopoietic stem cell transplantation (HSCT)

Patients must have had histologic, morphologic or flow cytometric verification of the
malignancy at relapse.

Performance Level:

Karnofsky or Lansky performance score is ≥ 50% (corresponding to ECOG Score of ≤ 2). The
Lansky performance score should be used for participants < 16 years and the Karnofsky
performance score for participants ≥ 16 years. Patients who are unable to walk because of
paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of
assessing the performance score.

Prior Therapy:

Patients who relapse while receiving standard ALL maintenance chemotherapy will not be
required to have a waiting period before entry onto this study.

Patients who relapse on therapy other than standard ALL maintenance must have fully
recovered from the acute toxic effects of all prior anti-cancer therapy, defined as
resolution of all such toxicities to ≤ Grade 2 or lower per the inclusion/exclusion
criteria prior to entering this study.

At least 14 days must have elapsed since the completion of cytotoxic therapy, with the
exception of standard maintenance therapy and steroids.

At least 7 days must have elapsed since completion of therapy with a biologic agent. For
agents that have known adverse events occurring beyond 7 days after administration, this
period prior to enrollment must be extended beyond the time during which adverse events are
known to occur.

At least 3 half-lives must have elapsed since prior therapy that included a monoclonal
antibody with the exception of blinatumomab. Patients must have been off blinatumomab
infusion for at least 7 days and all drug related toxicity must have resolved to grade 2 or
lower as outlined in the inclusion/exclusion criteria.

At least 42 days must have elapsed since CAR-T cell therapy. At least 90 days have elapsed
since bone marrow transplant and participant is off immune suppression for ≥ 2 weeks, if
applicable with no evidence of active GVHD.

At least 2 weeks must have elapsed since local XRT (small port); ≥ 3 months must have
elapsed if prior cranial or craniospinal XRT was received, if ≥ 50% of the pelvis was
irradiated, or if TBI was received; ≥ 6 weeks must have elapsed if other substantial bone
marrow irradiation was given.

Organ Function Requirements:

Adequate renal function defined as glomerular filtration rate ≥ 60 cc/min/1.73m2 or serum
creatinine based on age as follows:

- Age: <6 months; maximum serum creatinine (mg/dL): 0.4 (male, female); Age: 6 months to
<1 year; maximum serum creatinine (mg/dL): 0.5 (male, female); Age: 1 to < 2 years;
maximum serum creatinine (mg/dL): 0.6 (male, female); Age: 2 to < 6 years; maximum
serum creatinine (mg/dL): 0.8 (male, female); Age: 6 to <10 years; maximum serum
creatinine (mg/dL): 1 (male, female); Age: 10 to <13 years; maximum serum creatinine
(mg/dL): 1.2 (male, female); Age: 13 to <16 years; maximum serum creatinine (mg/dL):
1.5 (male), 1.4 (female); Age: ≥ 16 years; maximum serum creatinine (mg/dL): 1.7
(male), 1.4 (female)

Adequate hepatic function defined as:

- Total bilirubin ≤ 2 x upper limit of normal (ULN) for age, and

- ALT ≤ 3 x ULN for age, unless elevation is due to leukemic infiltration.

Adequate cardiac function defined as shortening fraction of ≥ 27% or ejection fraction ≥
45%.

Adequate pulmonary function defined as:

- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94%.

- No evidence of acute pulmonary infiltrates on chest radiograph.

Adequate central nervous system (CNS) function defined as:

- Patients with seizure disorder may be enrolled if on allowed anti-convulsants and well
controlled. Benzodiazepines and gabapentin are acceptable.

- CNS toxicity < Grade 2

Adequate peripheral nervous system (PNS) function defined as:

- PNS toxicity < Grade 2.

Exclusion Criteria:

Extramedullary disease status: patients with isolated CNS disease or isolated testicular
disease are not eligible.

Concurrent chemotherapy or targeted anti-cancer agents, other than intrathecal therapy.

Patients who have previously received bortezomib or other proteasome inhibitors that did
not have a response while receiving the inhibitor are not eligible. Patients that responded
but had a subsequent relapse are eligible.

Patients who have previously received palbociclib or other CDK4/6 inhibitors are not
eligible.

Patient with concurrent severe and/or uncontrolled medical conditions that, in the opinion
of the investigator, may impair participation in the study or the evaluation of safety
and/or efficacy.

Patients that have an active, uncontrolled infection are not eligible. Known HIV infection
or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as
hepatitis C antibody-positive).

Pregnant or lactating (female participant of childbearing potential must have negative
serum or urine pregnancy test required within 7 days prior to start of treatment).

Male or female participant of reproductive potential must agree to use appropriate methods
of contraception for the duration of study treatment and for at least 30 days after last
dose of protocol treatment.

Cumulative anthracyclines must not exceed 450mg/m2 doxorubicin equivalents following
completion of treatment on protocol. Therefore for patients receiving one course on
protocol cumulative anthracyclines must be less than or equal to 400mg/m2 doxorubicin
equivalents at the time of enrollment Inability or unwillingness or research participant or
legal guardian/representative to give written informed consent.