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Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children (POE14-01)

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ClinicalTrials.gov Identifier: NCT02512926
Recruitment Status : Recruiting
First Posted : July 31, 2015
Last Update Posted : July 12, 2021
Sponsor:
Collaborators:
Amgen
Pediatric Oncology Experimental Therapeutics Investigators' Consortium
Information provided by (Responsible Party):
Jessica Boklan, MD, Phoenix Children's Hospital

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Relapsed Solid Tumors Refractory Solid Tumors Relapsed Leukemia Refractory Leukemia Drug: Carfilzomib Drug: Cyclophosphamide Drug: Etoposide Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Carfilzomib in Combination With Cyclophosphamide and Etoposide for Children With Relapsed and Refractory Solid Tumors and Leukemias
Actual Study Start Date : February 16, 2016
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leukemia

Arm Intervention/treatment
Experimental: Carfilzomib
Carfilzomib in combination with cyclophosphamide and etoposide
Drug: Carfilzomib
Carfilzomib in combination with cyclophosphamide and etoposide for children with relapsed and refractory solid tumors and leukemias

Drug: Cyclophosphamide
Drug: Etoposide



Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. To evaluate toxicities of carfilzomib in the pediatric population when combined with conventional chemotherapy. [ Time Frame: Treatment initiation through 30 days post treatment ]
    Record AEs and SAEs

  2. Determine patient response rate (CR, PR, SD, PD) with this regimen [ Time Frame: Treatment initiation through 30 days post treatment ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 29 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02512926


Contacts
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Contact: Jessica Boklan, MD 602-933-0920 jboklan@phoenixchildrens.com
Contact: Aru Narendran, MD, PhD 403-210-6418 anarendr@ucalgary.ca

Locations
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United States, Arizona
Phoenix Children's Hospital Recruiting
Phoenix, Arizona, United States, 85016
Contact: Christopher Oless    602-933-0188    coless@phoenixchildrens.com   
Contact: Laura Evdokimo    602-933-5004    levdokimo@phoenixchildrens.com   
Principal Investigator: Jessica Boklan, MD         
United States, Arkansas
Arkansas Children's Hospital Recruiting
Little Rock, Arkansas, United States, 72202
Contact: Kevin Bielamowicz, MD    501-364-1494    kjbielamowicz2@uams.edu   
Principal Investigator: Kevin Bielamowicz, MD         
United States, California
Stanford University School of Medicine and Stanford Cancer Institute Recruiting
Palo Alto, California, United States, 94304
Contact: Norman Lacayo, MD    650-723-5533    lacayon@stanford.edu   
Principal Investigator: Norman Lacayo, MD         
United States, Massachusetts
Dana Farber Cancer Institute Active, not recruiting
Boston, Massachusetts, United States, 02215
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Tanya Trippett, MD    212-639-8267    trippet1@mskcc.org   
Principal Investigator: Tanya Trippett, MD         
United States, Pennsylvania
Penn State Hershey Children's Hospital Recruiting
Hershey, Pennsylvania, United States, 17033-0850
Contact: Valerie Brown, MD, PhD    717-531-6012    vbrown1@hmc.psu.edu   
Principal Investigator: Valerie Brown, MD, PhD         
United States, Texas
University of Texas Health Science Center at San Antonio Recruiting
San Antonio, Texas, United States, 78229
Contact: Anne-Marie Langevin, MD    210-567-7460    langevin@uthscsa.edu   
Principal Investigator: Anne-Marie Langevin, MD         
Canada, Alberta
Alberta Children's Hospital Recruiting
Calgary, Alberta, Canada, T3B 6A8
Contact: Aru Narendran, MD, PhD    403-210-6418    anarendr@ucalgary.ca   
Principal Investigator: Aru Narendran, MD, PhD         
Sponsors and Collaborators
Phoenix Children's Hospital
Amgen
Pediatric Oncology Experimental Therapeutics Investigators' Consortium
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Responsible Party: Jessica Boklan, MD, Principal Investigator, Phoenix Children's Hospital
ClinicalTrials.gov Identifier: NCT02512926    
Obsolete Identifiers: NCT03273829
Other Study ID Numbers: POE14-01
First Posted: July 31, 2015    Key Record Dates
Last Update Posted: July 12, 2021
Last Verified: June 2021
Keywords provided by Jessica Boklan, MD, Phoenix Children's Hospital:
Solid Tumors
Leukemia
Relapsed
Refractory
Additional relevant MeSH terms:
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Neoplasms
Leukemia
Neoplasms by Histologic Type
Cyclophosphamide
Etoposide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors