Phase I Trial of the Selective Inhibitor of Nuclear Export, KPT-330, in Relapsed Childhood ALL and AML

The investigators are trying to determine a safe dose of KPT-330 and will be giving
participants different dose levels of the study drug. Three to six participants will receive
the starting dose of the drug. If the side effects are not too severe, the next group of
participants will take the study drug at a higher dose level. Up to 3 dose levels of the
study drug will be tested, but once each participant has been assigned a dose level, the
participant will always receive the same dose. The highest dose that people can be given
safely is called the maximum tolerated dose (MTD). Once the MTD is determined, up to 10
additional participants will receive that dose to further study the drug.

Participants between the age of ≥18 months (540 days) and ≤ 21 years with relapsed (second or
subsequent relapse) or refractory ALL or AML will be eligible to enroll. KPT-330 will be
administered twice a week on Days 1 and 3 for four weeks (a cycle is 4 weeks). All
participants will receive intrathecal chemotherapy on Day 1 of each cycle. Participants with
CNS-2 disease will receive additional doses of IT chemo. Pharmacokinetic (PK) samples will be
collected during Cycle 1 on Days 1-3 and 15. PK samples will be collected during Cycle 2 on
Day 15. Pharmacodynamic (PD) samples will be collected during Cycle 1 on Days 1-3. PD samples
will be collected during Cycle 2 on Day 15. Additional optional correlative biology sample
will be collected. Participants are monitored closely for adverse events. Participants will
have physical exams and blood work more than once a week during all cycles.

Inclusion Criteria:

- Age: Patient must be ≥ 12 months (365 days) and ≤ 21 years.

- Histologically confirmed diagnosis of relapsed or refractory ALL (including Burkitt
leukemia), AML, mixed lineage leukemia, biphenotypic leukemia, or chronic myelogenous
leukemia (CML) in blast crisis.

- Refractory disease defined as: Persistent disease after at least two induction
cycles.

- Relapsed disease: Second or subsequent relapse, any relapse refractory to salvage
chemotherapy

- Subjects must have bone marrow with ≥ 5% blasts (M2 or M3 marrow) definitively
identified either on a bone marrow aspirate or biopsy sample, as assessed by
morphology, immunohistochemical studies, flow cytometry, karyotype, cytogenetic
testing such as fluorescent in situ hybridization (FISH) or other molecular studies.

- Subject would not benefit from additional cytotoxic chemotherapy as determined by the
treating physician.

- Patients with CNS 1 or CNS 2 disease are eligible. Patients with isolated CNS relapse
or CNS 3 disease are not eligible. Please refer to Section 11.1.3 for definitions of
CNS disease status and interpretation of traumatic lumbar punctures.

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study and meet all
of the following criteria:

- Myelosuppressive chemotherapy: 14 days must have elapsed since the completion of
myelosuppressive therapy. Individuals may have received any of the following
medications within 14 days without a "wash-out" period:

- Standard maintenance therapy (vincristine, 6MP, corticosteroids, low dose
methotrexate)

- Hydroxyurea

- Intrathecal chemotherapy with methotrexate, hydrocortisone and/or
cytarabine.

- Radiation therapy (XRT):

- Total Body Irradiation (TBI) or craniospinal radiation therapy: Must have
been completed more than 90 days from study entry

- Palliative XRT: XRT for chloromas does not require a washout period.

- Biologic (anti-neoplastic agent): At least 7 days after 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.

- Immunotherapy: At least 6 weeks after the completion of any type of
immunotherapy, e.g. tumor vaccines and chimeric antigen receptor T-cells.

- Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose
of a monoclonal antibody. (See table on DVL homepage listing monoclonal antibody
half-lives: https://members.childrensoncologygroup.

- Performance status:

-- Lansky ≥ 50 for individuals 18 months- ≤ 16 years old; Karnofsky > 50% for
individuals 17-21 years old (See Appendix I).

- Adequate organ function defined as the following:

- Direct bilirubin ≤1.5 X institutional upper limit of normal (ULN)

- AST (SGOT)/ALT (SGPT) ≤ 3X institutional ULN

- Creatinine below institutional ULN or creatinine clearance ≥ 60 mL/min/1.73 m2
for subjects with creatinine levels above institutional normal

- Echocardiogram must have a shortening fraction or an ejection fraction greater
than institutional lower limit of normal for age and gender. Echocardiogram must
be obtained while patient is not receiving cardiotropic medications (eg.,
pressors or afterload reducers).

- Oxygen saturation over 90% by pulse oximetry without administration of supplemental
oxygen.

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.

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

- The effects of KPT-330 on the developing human fetus are unknown. For this reason and
because many chemotherapeutic agents are known to be teratogenic, women of
childbearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

- Ability of participant (or parent/guardian for participants who are minors) to
understand and the willingness to sign the written informed consent document.

Exclusion Criteria:Participants who exhibit any of the following conditions at screening
will not be eligible for admission into the study.

- Inability to take or tolerate enteral medications

- Individuals with CNS 3 leukemia

- Individuals with Down syndrome

- Patients with prior hematopoietic stem cell transplant (HSCT) are eligible, with the
exception of the following:

- Autologous HSCT within 60 days of study entry

- Allogeneic HSCT within 90 days of study entry

- Evidence of graft-versus-host-disease (GVHD)

- Treatment with immunosuppressive medications within 14 days; however, weaning or
stable doses of steroids (must be ≤ 20 mg/m2/day of prednisone equivalents)
and/or calcineurin inhibitors are permitted.

- Treatment with hematopoietic growth factors (G-CSF):

- Long-acting (e.g., Neulasta) within 14 days prior to study entry

- Short-acting (e.g., Neupogen) within 7 days prior to study entry

- Treatment with an investigational agent within 28 days of study entry, or 3
half-lives, whichever is longer.

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

- Any ECG abnormality that in the opinion of the principal investigator would preclude
safe participation in the study

- Patients refractory to red blood cell or platelet transfusions.

- Patients receiving anti-coagulation therapy are eligible as long as anti-coagulation
regimen has been stable for > 1 month.

- Patients with 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.

- For dose-escalation cohort only, known positivity for human immunodeficiency virus
(HIV); baseline testing for HIV is not required. HIV positive patients will be
eligible for the dose-expansion cohort.

- Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or
HBsAg (HBV surface antigen); baseline testing for viral hepatitis is not required.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of KPT-330 (e.g. ulcerative colitis, uncontrolled
nausea, vomiting, diarrhea, malabsorption or history of small bowel resection)

- Individuals with significant concurrent disease, illness, psychiatric disorder or
social issue that would compromise patient safety or compliance, interfere with
consent, study participation, follow up, or interpretation of study results.

- Individuals with a history of a different malignancy (other than acute leukemia) are
ineligible except for the following circumstances: Individuals are eligible if the
different malignancy is in complete remission at the time of study entry.

- Pregnant women are excluded from this study because KPT-330 is a chemotherapeutic
agent with unknown teratogenic or abortifacient effects.

- Individuals who are eligible for allogeneic hematopoietic stem cell transplantation
(HSCT) as determined by the treating physician, and have a suitable donor or
appropriate stem cell source available

- Individuals who would benefit from additional cytotoxic chemotherapy as determined by
the treating physician