Phase I Study of Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children With Relapsed and Refractory Solid Tumors and Leukemias

Study Overview

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 for the disease being treated in this study. Since carfilzomib has not yet been used in this setting to treat this condition, the investigators must first find the best dose to give. The investigators are looking for the highest dose of carfilzomib that can be given safely. Therefore, not all children taking part in this study will receive the same dose of the study drug in the first part of the trial.

The purpose of this study is to find out what effects, good and/or bad, treatment with a new combination of drugs, cyclophosphamide, etoposide, and carfilzomib has on cancer.
In part 1 of the trial, small groups of children will be enrolled in steps. The first group will be given a certain dose of carfilzomib. If these children do not have side effects which are too bad, the next small group of children enrolled will receive a higher dose. This increase in doses with groups of people will continue until we find the highest dose of the drug that can be given without causing severe or unmanageable side effects.

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.

Study Eligibility

Inclusion Criteria

1. Patients must have either of the following:

 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

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

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

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.

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

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.

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:

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

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

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

ECHO shortening fraction ≥ 27%

Pulse Oximetry measurement ≥ 95% saturation without supplemental oxygen

8. Bone marrow function:

Hgb ≥10 g/dL - can be transfused

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

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:

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

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

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

Exclusion Criteria