Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children

Status: Recruiting
Phase:
DFCI Protocol ID: 15-588

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.

Conducting Institutions:

Dana-Farber Cancer Institute

Overall PI:

Steven Dubois MD, Dana Farber Cancer Institute

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

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.

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