Safety Study of CPX-351 in Children With Relapsed Leukemia or Lymphoma
Primary Purpose
Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Burkitt Lymphoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CPX-351
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring Relapsed acute myeloid leukemia, non-therapy related acute myeloid leukemia, Refractory acute myeloid leukemia, Untreated acute myeloid leukemia, Lymphoma, Leukemia
Eligibility Criteria
Inclusion Criteria:
Age
- 12 months to 21 years at time of enrollment into dose exploration phase
- 12 months to 30 years at time of enrollment into expanded phase
- Diagnosis: Patients must have a diagnosis of a hematologic malignancy (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or aggressive lymphoma.
Disease Status
- Acute myeloid leukemia - patients with non-therapy related AML must be in first or greater relapse or have refractory disease to at least two courses of induction therapy.
- Acute lymphoid leukemia - patients with ALL must be in second or greater relapse or have relapsed disease refractory to re-induction therapy.
- Aggressive Lymphoma - patients must have relapsed or refractory disease for which there is no known curative therapy available. Patients must have measurable disease by CT scan.
- Performance status: Karnofsky > or = to 50% or Lansky > or = to 50.
Prior therapy: Patients must have fully recovered from acute toxicities of prior therapy.
- Hematopoetic Stem cell transplant (HSCT): Patients who relapsed after HSCT, are eligible provided they have no evidence of active graft versus host disease (GVHD) and are at least 2 months post-transplant.
- Anthracycline exposure: Patients who have not previously had TBI (total body irradiation) must have a total previous cumulative anthracycline exposure ≤ 450 mg/m2 daunorubicin equivalents. Patients who have had prior TBI or radiation to the mediastinum must have a previous cumulative anthracycline exposure e ≤ 300 mg/m2 daunorubicin equivalents.
Cytotoxic therapy:
- AML and Lymphoma: at least 14 days must have elapsed since the completion of systemic cytotoxic therapy, with the exception of hydroxyurea.
- ALL: patients who relapsed while receiving standard maintenance therapy do not have a waiting period. At least 14 days must have elapsed since receiving systemic cytarabine or an anthracycline/anthracenedione.
- Intrathecal cytotoxic therapy: no waiting period is required for patients receiving intrathecal cytarabine, methotrexate and/or hydrocortisone. At least 14 days must have elapsed since receiving liposomal cytarabine in intrathecal injection.
Organ function requirements
- Adequate bone marrow function - platelet count >/= 20,000/uL (may receive platelet transfusions; Hemoglobin >/= 8 g/dL (may receive red blood cell transfusions)
- Adequate Renal function - a maximum serum creatinine is based on age/gender. Subjects that do not meet eligibility criteria based upon serum creatinine may meet eligibility criteria based upon a 24 hour creatinine clearance or radioisotope determined GFR >/= 70 mL/min/1.73 m2.
- Adequate liver function - Direct bilirubin </= 1.5 x upper limit of normal (ULN) for age and SGPT (ALT) < 5.0 x upper limit of normal (ULN) for age and institution (unless elevation is related to leukemia involvement).
- Adequate cardiac function - Shortening fraction of >/= 27% by echocardiogram, or Ejection fraction of >/= 50% by gated radionuclide study or echocardiogram.
- Central Nervous system function - patients with seizure disorder may be enrolled if on anticonvulsants and well controlled and CNS toxicity </= Grade 2.
Exclusion Criteria:
- Patients with the following diagnosis are not eligible: acute promyelocytic leukemia (APML), Down Syndrome, Fanconi Anemia, acute lymphoblastic leukemia with central nervous system leukemia (CNS status 3), Wilson's disease
- Pregnant or breast-feeding women. Males and females of reproductive potential may not participate unless they have agreed to use an effective method of contraception.
Concomitant medications
- Growth factors- growth factors that support platelet or white cell number or function must not be administered within 7 days prior to enrollment.
- Investigational drugs - patients currently receiving another investigational drug are not eligible.
- Anti-cancer agents- patients who are currently receiving other anti-cancer agents are not eligible with the exception of intrathecal cytarabine and oral hydroxyurea. Hydroxyurea must be discontinued 24 hours prior to initiation of protocol therapy.
- Infection: Patients who have an uncontrolled infection are not eligible.
- Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
- History of Wilson's disease or other copper-metabolism disorder
- Major surgery within 4 weeks of enrollment.
- Greater than 13.6 Gy prior radiation to the mediastinum
Sites / Locations
- Cincinnati Children's Hospital Medical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
CPX-351
Arm Description
CPX-351 is made up of two chemotherapy drugs that patients may have already received called cytarabine and daunorubicin that are now packaged together. Subjects will receive a single course of CPX-351 administered on Days 1, 3, and 5.
Outcomes
Primary Outcome Measures
Determine rate of dose limiting toxicities
Any Grade 3 or greater adverse event that can be possible/probably/or definitely attributable to CPX-351 that occurs between Day 1 and Day 56.
Number of participants with dose limiting toxicities to determine maximum tolerated dose.
If 2 or more participants have dose limiting toxicities at a given dose level, the maximum tolerated dose will have been exceeded.
Pharmacokinetics: Serum concentration of CPX-351 components (cytarabine and daunorubicin) and metabolites.
Blood samples will be collected on Day 5 (prior to CPX-351 infusion, 45 minutes (mid infusion), 90 minutes (immediately post-infusion), 2 hr, 5 hr, 8 hr, 12 hrs, Day 6, Day 8, and Day 10. Serum will be analyzed for drug and metabolite concentrations.
Secondary Outcome Measures
Tumor measurement by bone marrow biopsy, blood counts, and/or PET/CT scan
Tumor measurements will be used to assess disease response per standard response criteria for acute myeloid leukemia, acute lymphoid leukemia and lymphoma.
Serum levels of biomarkers (troponin-1, troponin-T, and B-type natriuretic) of cardiac injury.
Full Information
NCT ID
NCT01943682
First Posted
September 12, 2013
Last Updated
November 6, 2020
Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Jazz Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT01943682
Brief Title
Safety Study of CPX-351 in Children With Relapsed Leukemia or Lymphoma
Official Title
A Phase I/Pilot Study of CPX-351 for Children, Adolescents and Young Adults With Recurrent or Refractory Hematologic Malignancies
Study Type
Interventional
2. Study Status
Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
September 2013 (undefined)
Primary Completion Date
March 2019 (Actual)
Study Completion Date
April 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital Medical Center, Cincinnati
Collaborators
Jazz Pharmaceuticals
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to test the safety of a study drug called CPX-351. This drug has been tested in adults but not yet in children and adolescents. This study tests different doses of the drug to see which dose is safer in children and adolescents.
Patients who have blood cancer are being asked to take part in this study . Blood cancers may include leukemia and lymphoma. Patients able to be in this study have already been treated with standard chemotherapy for their disease and the disease is still growing or has come back.
CPX-351 is a drug that is not yet approved by the United States Food and Drug Administration (FDA) and is only used in research studies like this one. CPX-351 is made up of two chemotherapy drugs that patients may have already received called cytarabine and daunorubicin that are now packaged together.
Another purpose of this study is to collect blood samples for special research studies. Researchers want to study how much of the CPX-351 is in the body over time. These studies are call pharmacokinetic studies or PK studies for short. PK studies require the collection of several blood samples before and after participants are given the study drug.
Detailed Description
Cytarabine in combination with an anthracycline is a frequently used chemotherapy platform for both newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) and other hematologic malignancies. Synergistic antitumor activity has been demonstrated between cytarabine and daunorubicin that is dependent upon the ratio of the drugs with the best therapeutic effect observed with a cytarabine to daunorubicin ratio of 5:1 in in vitro and in vivo models. CPX-351 is a liposomal preparation of cytarabine and daunorubicin that maintains this therapeutic drug ratio 24 hours post infusion. The altered biodistribution from encapsulation may result in a greater therapeutic effect in patients with relapsed hematologic malignancies and demonstrate greater tolerability than non-liposomal cytarabine and daunorubicin.
This is a single institution phase-I pilot study that aims to assess the pharmacokinetics, toxicity and tolerability of CPX-351 in pediatric and young adults with relapsed/refractory hematologic malignancies. Subjects will receive a single course of CPX-351 administered on Days 1, 3, and 5. The study will first open to children in a dose exploration phase, and then be available to an expanded cohort, which will be open to children and young adults once a tolerable dose has been determined.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Burkitt Lymphoma, Diffuse Large Cell Lymphoma, Gray Zone Lymphoma, Lymphoblastic Lymphoma, Anaplastic Large Cell Lymphoma, Hodgkin Lymphoma
Keywords
Relapsed acute myeloid leukemia, non-therapy related acute myeloid leukemia, Refractory acute myeloid leukemia, Untreated acute myeloid leukemia, Lymphoma, Leukemia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
27 (Actual)
8. Arms, Groups, and Interventions
Arm Title
CPX-351
Arm Type
Experimental
Arm Description
CPX-351 is made up of two chemotherapy drugs that patients may have already received called cytarabine and daunorubicin that are now packaged together. Subjects will receive a single course of CPX-351 administered on Days 1, 3, and 5.
Intervention Type
Drug
Intervention Name(s)
CPX-351
Intervention Description
Comparison of Different doses of drug
Primary Outcome Measure Information:
Title
Determine rate of dose limiting toxicities
Description
Any Grade 3 or greater adverse event that can be possible/probably/or definitely attributable to CPX-351 that occurs between Day 1 and Day 56.
Time Frame
56 days
Title
Number of participants with dose limiting toxicities to determine maximum tolerated dose.
Description
If 2 or more participants have dose limiting toxicities at a given dose level, the maximum tolerated dose will have been exceeded.
Time Frame
56 Days
Title
Pharmacokinetics: Serum concentration of CPX-351 components (cytarabine and daunorubicin) and metabolites.
Description
Blood samples will be collected on Day 5 (prior to CPX-351 infusion, 45 minutes (mid infusion), 90 minutes (immediately post-infusion), 2 hr, 5 hr, 8 hr, 12 hrs, Day 6, Day 8, and Day 10. Serum will be analyzed for drug and metabolite concentrations.
Time Frame
10 Days
Secondary Outcome Measure Information:
Title
Tumor measurement by bone marrow biopsy, blood counts, and/or PET/CT scan
Description
Tumor measurements will be used to assess disease response per standard response criteria for acute myeloid leukemia, acute lymphoid leukemia and lymphoma.
Time Frame
28 days
Title
Serum levels of biomarkers (troponin-1, troponin-T, and B-type natriuretic) of cardiac injury.
Time Frame
30 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age
12 months to 21 years at time of enrollment into dose exploration phase
12 months to 30 years at time of enrollment into expanded phase
Diagnosis: Patients must have a diagnosis of a hematologic malignancy (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or aggressive lymphoma.
Disease Status
Acute myeloid leukemia - patients with non-therapy related AML must be in first or greater relapse or have refractory disease to at least two courses of induction therapy.
Acute lymphoid leukemia - patients with ALL must be in second or greater relapse or have relapsed disease refractory to re-induction therapy.
Aggressive Lymphoma - patients must have relapsed or refractory disease for which there is no known curative therapy available. Patients must have measurable disease by CT scan.
Performance status: Karnofsky > or = to 50% or Lansky > or = to 50.
Prior therapy: Patients must have fully recovered from acute toxicities of prior therapy.
Hematopoetic Stem cell transplant (HSCT): Patients who relapsed after HSCT, are eligible provided they have no evidence of active graft versus host disease (GVHD) and are at least 2 months post-transplant.
Anthracycline exposure: Patients who have not previously had TBI (total body irradiation) must have a total previous cumulative anthracycline exposure ≤ 450 mg/m2 daunorubicin equivalents. Patients who have had prior TBI or radiation to the mediastinum must have a previous cumulative anthracycline exposure e ≤ 300 mg/m2 daunorubicin equivalents.
Cytotoxic therapy:
AML and Lymphoma: at least 14 days must have elapsed since the completion of systemic cytotoxic therapy, with the exception of hydroxyurea.
ALL: patients who relapsed while receiving standard maintenance therapy do not have a waiting period. At least 14 days must have elapsed since receiving systemic cytarabine or an anthracycline/anthracenedione.
Intrathecal cytotoxic therapy: no waiting period is required for patients receiving intrathecal cytarabine, methotrexate and/or hydrocortisone. At least 14 days must have elapsed since receiving liposomal cytarabine in intrathecal injection.
Organ function requirements
Adequate bone marrow function - platelet count >/= 20,000/uL (may receive platelet transfusions; Hemoglobin >/= 8 g/dL (may receive red blood cell transfusions)
Adequate Renal function - a maximum serum creatinine is based on age/gender. Subjects that do not meet eligibility criteria based upon serum creatinine may meet eligibility criteria based upon a 24 hour creatinine clearance or radioisotope determined GFR >/= 70 mL/min/1.73 m2.
Adequate liver function - Direct bilirubin </= 1.5 x upper limit of normal (ULN) for age and SGPT (ALT) < 5.0 x upper limit of normal (ULN) for age and institution (unless elevation is related to leukemia involvement).
Adequate cardiac function - Shortening fraction of >/= 27% by echocardiogram, or Ejection fraction of >/= 50% by gated radionuclide study or echocardiogram.
Central Nervous system function - patients with seizure disorder may be enrolled if on anticonvulsants and well controlled and CNS toxicity </= Grade 2.
Exclusion Criteria:
Patients with the following diagnosis are not eligible: acute promyelocytic leukemia (APML), Down Syndrome, Fanconi Anemia, acute lymphoblastic leukemia with central nervous system leukemia (CNS status 3), Wilson's disease
Pregnant or breast-feeding women. Males and females of reproductive potential may not participate unless they have agreed to use an effective method of contraception.
Concomitant medications
Growth factors- growth factors that support platelet or white cell number or function must not be administered within 7 days prior to enrollment.
Investigational drugs - patients currently receiving another investigational drug are not eligible.
Anti-cancer agents- patients who are currently receiving other anti-cancer agents are not eligible with the exception of intrathecal cytarabine and oral hydroxyurea. Hydroxyurea must be discontinued 24 hours prior to initiation of protocol therapy.
Infection: Patients who have an uncontrolled infection are not eligible.
Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
History of Wilson's disease or other copper-metabolism disorder
Major surgery within 4 weeks of enrollment.
Greater than 13.6 Gy prior radiation to the mediastinum
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Perentesis, MD
Organizational Affiliation
Children's Hospital Medical Center, Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
12. IPD Sharing Statement
Links:
URL
http://www.cincinnatichildrens.org/research/divisions/c/cbdi/default/
Description
Cincinnati Children's Cancer and Blood Diseases Institute
URL
http://www.cincinnatichildrens.org/research/divisions/o/oncology/default/
Description
Cincinnati Children's Hospital Oncology Division
URL
http://www.cincinnatichildrens.org/service/l/leukemia-lymphoma/clinical-trials/
Description
Leukemia and Lymphoma Program
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Safety Study of CPX-351 in Children With Relapsed Leukemia or Lymphoma
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