Phase I study of carfilzomib in combination with cyclophosphamide and etoposide for children with relapsed and refractory solid tumors and leukemias

This study evaluates the use of carfilzomib in combination with cyclophosphamide and
etoposide for children with relapsed/refractory solid tumors or leukemia. The medications
cyclophosphamide and etoposide are standard drugs often used together for the treatment of
cancer in children with solid tumors or leukemia.

Carfilzomib is FDA (Food and Drug Administration) approved in the United States for adults
with multiple myeloma (a type of cancer). However, this drug is not approved to treat
children with relapsed/refractory solid tumors or leukemia. With this research, we plan to
determine the DLTs and MTD of Carfilzomib given in combination with cyclophosphamide and
etoposide in pediatric patients with relapsed/refractory leukemias and solid tumors.

Inclusion Criteria:

1. Patients must have either of the following:

1. Relapsed/refractory leukemia in 2nd or greater relapse or who have failed at
least one re-induction attempt after relapse or for refractory disease. Patients
must meet the WHO classification with ≥ 5% blasts in the bone marrow or must have
definitive extramedullary disease (e.g. chloromas, skin lesions). Patients may
have asymptomatic CNS 1 or CNS 2 disease, but not CNS 3 or symptomatic CNS
disease.

OR

2. Relapsed/refractory non-CNS solid tumor that has not responded or has relapsed
and for which no standard treatment is available. Patients may not have primary
CNS tumors or CNS metastases. Lymphoma patients are permitted. Patients do not
need to have measurable disease.

2. Age 6 months - 29.99 years at enrollment

3. Life expectancy ≥ 3 months

4. Lansky or Karnofsky ≥50

5. Prior therapy

1. Patient must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, radiotherapy, or surgery prior to study entry.

2. Myelosuppressive therapy- At least 14 days must have elapsed since the
administration of previous therapy. Six weeks must have elapsed from the
administration of nitrosureas or mitomycin C. For patients with ALL on
maintenance therapy, they may be eligible if 7 days have elapsed and they are
recovered from the toxic effects of the chemotherapy. This restriction does not
include intrathecal chemotherapy, which is permitted.

3. Biologic agents- At least 14 days must have elapsed since the completion of
therapy with a biologic agent such as a monoclonal antibody. Seven days must have
elapsed since the last dose of retinoids

4. Radiation therapy - At least 14 days must have elapsed for local XRT. At least 90
days must have elapsed if prior radiation to ≥50% of the pelvis, the spine, or
other substantial bone marrow radiation including TBI.

5. Hematopoietic growth factors- At least 7 days must have elapsed since the last
dose of G-CSF or GM-CSF. At least 14 days must have elapsed since last dose of
pegfilgrastim (Neulasta®).

6. Patient must be ≥ 3 months from hematopoietic stem cell transplant, must not have
active GVHD, and must be off all immunosuppression

7. Organ function:

1. Either a serum creatinine ≤ ULN for age, or calculated or measured GFR ≥ 70
mL/min/1.73 m2

2. Total bilirubin ≤ 1.5 x ULN for age, direct bilirubin ≤ ULN for age

3. AST and ALT ≤ 3 x ULN for age unless elevation can be clearly attributed to liver
leukemia or metastases

4. ECHO shortening fraction ≥ 27%

5. Pulse Oximetry measurement ≥ 95% saturation without supplemental oxygen

8. Bone marrow function:

1. Hgb ≥10 g/dL - can be transfused

2. Plts ≥ 75,000 - cannot be transfused (must be ≥ 7 days from last plt transfusion)

3. ANC ≥ 750 - cannot be transfused (must be ≥ 72 hours from last neutrophil
infusion)

However, the plt and ANC requirements can be waived if low counts thought to be
secondary to leukemia or tumor bone marrow infiltration

9. Reproductive function:

1. Female patients of childbearing potential must have a negative serum pregnancy
test confirmed within 7 days prior to enrollment

2. Female patients with infants must agree not to breastfeed their infants while on
the study

3. 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 3 months after study treatment

10. Written informed consent

Exclusion Criteria:

1. Prior treatment with carfilzomib

2. Known allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).

3. Down syndrome

4. Fanconi Anemia or other underlying bone marrow failure syndrome

5. Pregnant or lactating females

6. Known history of Hepatitis B or C or HIV

7. Patient with any significant concurrent illness

8. Patient with uncontrolled systemic fungal, bacterial, viral or other infection with
ongoing signs/symptoms despite appropriate treatment

9. Patient with illness, psychiatric disorder or social issue that could compromise
patient safety or compliance with the protocol treatment or procedures, or interfere
with the consent, study participation, follow-up, or interpretation of study results.