PO Ixazomib in Combination With Chemotherapy for Childhood Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

The phase 1 study is to determine the maximum tolerated dose (MTD) of the PO formulation,
followed by a screening phase 2 study to investigate the efficacy of ixazomib in combination
with chemotherapy in children with relapsed ALL and lymphoblastic lymphoma (LLy). The single
arm, screening phase 2 design will allow us to use a minimal number of patients to obtain
preliminary information about treatment efficacy. Discovering a safe and tolerable dose of
ixazomib in a PO formulation and the preliminary efficacy data will significantly increase
the possibility of ixazomib moving forward in frontline pediatric treatment protocols in both
intense chemotherapy courses and maintenance courses.

Inclusion Criteria:

- Age Patients must be ≤21 years of age at the time of enrollment.

1. Phase 1 - Initial enrollment will be restricted to patients < 18 years of age
until 9 such patients are enrolled

2. Phase 2 - Initial enrollment will be restricted to patients < 18 years of age
until 6 such patients are enrolled

- Diagnosis Patients must have a diagnosis of relapsed/refractory ALL or LLy with or
without extramedullary disease (including CNS2 and CNS3). Patient with mixed phenotype
ALL or mature B (Burkitt-like) leukemia are not eligible.

1. Patients with ALL must have ≥ 5% blasts by morphology.

2. Patients with LLy must have measurable disease documented by clinical, radiologic
or histologic criteria

- Performance Level Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for
patients ≤ 16 years of age.

- Prior Therapy A. Prior therapeutic attempts

- Phase 1 - Any patients with relapsed/refractory ALL or LLy

- Phase 2

1. B-cell ALL/LLy: all patients must have failed two or more therapeutic
attempts.

2. T-cell ALL/LLy: all patients must have failed one or more therapeutic
attempts. B. Recent prior chemotherapy Patients must have fully recovered
from the acute toxic effects of all prior chemotherapy, immunotherapy, or
radiotherapy prior to entering this study.

- Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up
to 24 hours prior to the start of protocol therapy.

- Patients who relapsed while they are receiving cytotoxic therapy At least 14 days
must have elapsed since the completion of the last dose of chemotherapy,except
Intrathecal chemotherapy, and/or maintenance therapy such as vincristine,
mercaptopurine, methotrexate or glucocorticoids. There is no waiting period for
those relapsing on maintenance therapy.

C. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a
HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host
Disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days
post-transplant at the time of enrollment.

D. Hematopoietic growth factors: It must have been at least 7 days since the completion of
therapy with G-CSF or other growth factors at the time of enrollment. It must have been at
least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

E. Biologic (anti-neoplastic agent): At least 7 days since the last dose of a biologic
agent. For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse events
are known to occur. The duration of this interval must be discussed with the study chair

1. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after
the last dose of monoclonal antibody. (i.e., blinatumomab = 6 hours,44 inotuzumab = 37
days, rituximab = 66 days)

2. Immunotherapy: At least 30 days after the completion of any type of immunotherapy,
e.g., tumor vaccines, CAR T cells.

F. XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is
necessary for radiation given to any extramedullary site other than CNS; ≥90 days must have
elapsed if prior total body irradiation (TBI) or craniospinal XRT.

G. Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin
equivalents of anthracyclines.

H. Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g.,
bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a
partial response to a proteasome inhibitor with chemotherapy combination.

-Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following
laboratory values:

A. Adequate renal function defined as: Patient must have a calculated creatinine clearance
or radioisotope GFR 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender

B. Adequate Liver Function Defined as: Direct bilirubin ≤ 1.5 x upper limit of normal (ULN)
for age or normal (except in the presence of Gilbert's syndrome), AND alanine transaminase
(ALT) ≤ 5 x ULN for age. The hepatic requirements are waived for patients with known or
suspected liver involvement by leukemia or lymphoma. This must be reviewed by and approved
by the study chair or vice chair.

- Adequate Cardiac Function Defined as: Shortening fraction of more than or equal to 27%
by echocardiogram, OR ejection fraction of equal to or more than 50% by radionuclide
angiogram (MUGA).

- Reproductive Function A. Female patients of childbearing potential must have a
negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.

B. Female patients with infants must agree not to breastfeed their infants while on this
study.

C. Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study and for a minimum of
6 months after study treatment.

- Informed Consent Patients and/or their parents or legal guardians must be capable of
understanding the investigational nature, potential risks and benefits of the study.
All patients and/or their parents or legal guardians must sign a written informed
consent. Age appropriate assent will be obtained per institutional guidelines. To
allow non-English speaking patients to participate in this study, bilingual health
services will be provided in the appropriate language when feasible.

- All institutional, FDA, and OHRP requirements for human studies must be met.

Exclusion Criteria:

Patients will be excluded if they have isolated CNS or testicular disease.

Patients will be excluded if they have ≥grade 2 peripheral sensory or motor neuropathy
(defined by the Modified "Balis" Pediatric Scale of Pediatric Neuropathies) at the time of
enrollment (see section 4.7.1.1).

Patients will be excluded if they have a known allergy or intolerance to any of the drugs
used in the study - except for PEG-asparaginase for which erwinia asparaginase may be
substituted

Patients will be excluded if they have a systemic fungal, bacterial, viral or other
infection that is exhibiting ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics or other treatment. The patient needs to be off
pressors and have negative blood cultures for 48 hours.

Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, or immunotherapy during the study period.

Patients will be excluded if they have significant concurrent disease, illness, psychiatric
disorder or social issue that would compromise patient safety or compliance with the
protocol treatment or procedures, interfere with consent, study participation, follow up,
or interpretation of study results.

Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
excluded.

Patients will be excluded if they have had a lifetime exposure of ≥400 mg/m2 doxorubicin
equivolents of anthracyclines (anthracycline equivalence to doxorubicin conversion see
appendix iv) .

Concomitant medications Investigational drugs: Patients currently receiving another
investigational drug are not eligible.

Anti-GVHD agents post transplant: patients who are receiving cyclosporine, tacrolimus or
other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant
are not eligible.

CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of
CYP3A4 are not eligible. Strong inducers of CYP3A4 should be avoided from 14 days prior to
enrollment to the end of the study. See appendix ii for a list of agents which fall into
this category.

Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy

Infants or Patients with Down Syndrome will be excluded in phase 2 of the study