Vincristine Sulfate Liposome Injection (Marqibo®) in Combination With UK ALL R3 Induction Chemotherapy for Children, Adolescents, and Young Adults With Relapsed ALL

This study will utilize Marqibo® as a replacement for standard vincristine in combination
with chemotherapy for children with relapsed ALL. The hypothesis is that the incorporation of
Marqibo® with combination chemotherapy will be safe and feasible. In the context of this
pilot study, overall outcomes and efficacy will be a secondary objective. It is hypothesized
that data from this combination may show improved efficacy including, complete remission
(CR), minimal residual disease (MRD) negativity, and progression free survival (PFS) rates
and safety (i.e., neurotoxicity) in comparison to outcomes in historical regimens, including
the UK ALL R3 with standard vincristine.

Inclusion Criteria

Age

-Patients must be ≥ 1 and ≤ 21 years of age at the time of enrollment.

Diagnosis

- Cohort A: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) or
mixed phenotypic acute leukemia with ≥ 5% blasts in the bone marrow (M2 or M3), with
or without extramedullary disease) or a diagnosis of lymphoblastic lymphoma.

- Cohorts B & C: Patients must have a diagnosis of acute lymphoblastic leukemia (ALL),
lymphoblastic lymphoma, or mixed phenotypic acute leukemia with any level of
detectable disease (minimal residual disease level acceptable) with or without
extramedullary disease

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

Prior Therapy

- Patients must have recovered from the acute toxic effects (≤ Grade 2 or baseline) of
all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study,
unless otherwise specified. Subjects with disease related cytopenias will be eligible.

- Patients must have relapsed or refractory disease after attaining at least a first
remission. They may be in first to third relapse..

- Patients with Philadelphia chromosome t(9;22) positive disease must have received at
least two prior tyrosine kinase inhibitors.

- Patients who have experienced their relapse after a Hematopoietic stem cell
transplantation (HSCT) are eligible, provided they have no evidence of
graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the time
of enrollment.

- Prior anthracycline lifetime cumulative exposure: Patients must have less than 320
mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline
chemotherapy.

1. Cohort A: Patients must have less than 320 mg/m2 (or 400 mg/m2 if prior
cardioprotection) lifetime exposure of anthracycline chemotherapy (See Appendix 2
for anthracycline calculation worksheet).

2. Cohorts B & C: There is no limit on prior anthracycline exposure.

- Hematopoietic growth factors: It must have been at least seven days since the
completion of therapy with granulocyte colony-stimulating factor (GCSF) 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®).

- Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic
agent. For agents that have known adverse events occurring beyond seven 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 or vice chair.

- Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) of
the antibody must have elapsed after the last dose of monoclonal antibody. (e.g.,
Rituximab = 66 days, Epratuzumab = 69 days)

- Immunotherapy: At least 30 days after the completion of any type of immunotherapy,
e.g. tumor vaccines, chimeric antigen receptor T-cells.

- Recent prior chemotherapy: At least 10 days after standard vincristine and the
completion of any type of chemotherapy induction regimen. At least 3 weeks after
radiation therapy. At least 30 days after the completion of any investigational
neoplastic agent is also required. An investigational agent is defined as any drug
that is not approved and licensed for sale by the FDA for institutions in the United
States, by Health Canada for institutions in Canada and by The Therapeutic Goods
Administration for institutions in Australia.

Exceptions:

- There is no time restriction in regard to prior intrathecal chemotherapy provided
there is complete recovery from any acute toxic effects of such; it is allowable to
enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or
triple IT therapy within 14 days of enrollment as part of their evaluation to diagnose
disease relapse. The IT therapy given within 14 days of initiation of protocol
specified chemotherapy, may substitute for the day 1 IT in cohorts A and B

- Subjects with rapidly progressive disease may receive hydroxyurea until they begin
study therapy;

- Patients who relapse while on maintenance-type ALL therapy or are receiving
maintenance therapy for disease stabilization will not require a wash-out period
before entry into this study. However, there must be at least 10 days after any dose
of standard vincristine.

Renal and Hepatic Function

- Renal function: Patient's serum creatinine must be ≤ 1.5 x institutional upper limit
of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times
normal, the patient must have a calculated creatinine clearance or radioisotope
glomerular filtration rate (GFR) ≥ 70milliliter/min/1.73m2. Alternatively, a 24-hour
creatinine clearance may also be used.

- Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
must be < 5 x institutional upper limit of norm ULN. Total bilirubin must be ≤ 1.5 x
ULN (except in the case of subjects with documented Gilbert's disease ≤ 5 × ULN).

Cardiac Function

-Patients must have a shortening fraction ≥ 27% or an ejection fraction ≥ 55% by
echocardiogram, cardiac MRI or multigated acquisition scan (MUGA).

Reproductive Function

- Female patients must not be pregnant and those of childbearing potential must have a
negative urine or serum pregnancy test confirmed within one week prior to enrollment.

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

- Male and female patients of childbearing potential must agree to use an effective
method of contraception during the study.

Exclusion Criteria

Patients will be excluded if they have isolated testicular disease.

Patients will be excluded if they have previously received Marqibo®.

Patients will be excluded if they have a known allergy to any of the drugs used in the
study, with the exception that patients with an allergy to PEG-asparaginase who can receive
Erwinia asparaginase are eligible. Patients unable to receive any formulation of
asparaginase may only enroll on cohort C

Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial,
viral or other infection despite appropriate antibiotics or other treatment.

Patients who require azole antifungal agents will be excluded. Azoles must be discontinued
at least one week prior to the start of Marqibo®.

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

Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from
any cause will be excluded.

Patients will be excluded if they have, significant concurrent disease, illness,
psychiatric disorder or social issue that would compromise patient safety or adherence with
the protocol treatment or procedures or interfere with consent, study participation, follow
up, or interpretation of study results.Patients with Down syndrome will not be eligible for
enrollment on Cohort A

Patients with a known history of human immunodeficiency virus (HIV) will will be excluded
due to the increased risk of complications such as severe infection and unknown interaction
of Marqibo® with antiretroviral drugs.

Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B
surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above
the ULN per the institution normal ranges).