Description:
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.
Title
- Brief Title: Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children
- Official Title: Phase I Study of Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children With Relapsed and Refractory Solid Tumors and Leukemias
Clinical Trial IDs
- ORG STUDY ID:
POE14-01
- NCT ID:
NCT02512926
- NCT ALIAS:
NCT03273829
Conditions
- Relapsed Solid Tumors
- Refractory Solid Tumors
- Relapsed Leukemia
- Refractory Leukemia
Interventions
Drug | Synonyms | Arms |
---|
Carfilzomib | | Carfilzomib |
Cyclophosphamide | | Carfilzomib |
Etoposide | | Carfilzomib |
Purpose
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.
Detailed Description
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Carfilzomib | Experimental | Carfilzomib in combination with cyclophosphamide and etoposide | - Carfilzomib
- Cyclophosphamide
- Etoposide
|
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.
Maximum Eligible Age: | 29 Years |
Minimum Eligible Age: | 6 Months |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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 |
Time Frame: | 30 Days post treatment initiation |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | To evaluate toxicities of carfilzomib in the pediatric population when combined with conventional chemotherapy. |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | Record AEs and SAEs |
Measure: | Determine patient response rate (CR, PR, SD, PD) with this regimen |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | |
Measure: | To measure if circulating plasma proteosome (cProt) levels post treatment correlate with response to therapy and overall survival. |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | |
Measure: | To measure if the levels of proteasome activity and resistance to carfilzomib correlates with toxicity and/or response to treatment |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | |
Measure: | To measure if inhibition of proteasome activity by carfilzomib results in alteration in a number of autophagy and apoptosis related proteins, providing means to evaluate correlates of activity of carfilzomib |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | |
Measure: | To measure the level of proteosome inhibition in patient PBMCs before and during treatment by determination of the level of protein ubiquitination |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | |
Measure: | To determine in vitro sensitivity of patient leukemias and solid tumors to carfilzomib alone and in combination with study chemotherapeutic agents in order to generate a predictive model of drug sensitivity |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | |
Measure: | To perform whole exome sequencing (WES) and RNA seq on patient leukemia and solid tumor samples and WES on germ line DNA in order to determine potential mechanisms of drug sensitivity or resistance |
Time Frame: | Treatment initiation through 30 days post treatment |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Phoenix Children's Hospital |
Trial Keywords
- Solid Tumors
- Leukemia
- Relapsed
- Refractory
Last Updated
July 12, 2021