Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children

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.

Part 1 of the study will include a dose escalation based on Dose limiting toxicities (DLTs) until the MTD or highest dose level is reached, whichever comes first.

At the MTD or highest dose level (if no MTD is reached), an additional 6 patients will be enrolled to further evaluate safety of the regimen (Part 2).

Part 2 of this study will enroll additional patients at the highest tolerable dose found in Part 1 in order to get more information on side effects and make sure the dose is tolerable

Once an MTD is determined for Strata A or B, if the Study Principal Investigator determines that the study treatment should not be further pursued due to safety or enrollment barriers, the expansion Part or the study will be discontinued.

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.