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This is a Phase 1 Study of Eribulin Mesylate in Pediatric Participants With Recurrent or Refractory Solid Tumors (Excluding [Central Nervous System] CNS), Including Lymphomas (BOLD 113)

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ClinicalTrials.gov Identifier: NCT02171260
Recruitment Status : Completed
First Posted : June 24, 2014
Results First Posted : December 24, 2018
Last Update Posted : January 15, 2019
Sponsor:
Collaborator:
Children's Oncology Group
Information provided by (Responsible Party):
Eisai Inc.

Brief Summary:
This is a Phase 1 study of eribulin mesylate in pediatric participants with recurrent or refractory solid tumors (excluding CNS), including lymphomas. Eribulin mesylate will be administered intravenously, once per day on Days 1 and 8 of a 21-day cycle. This study aims to determine the maximum tolerated dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of this regimen in Part A1 (participants greater than or equal to [>=] 12 months and less than [<] 18 years). Part A2 will enroll infants (greater than [>] 6 months and <12 months) one dose level behind the dose level at which participants in Part A1 are enrolling, in order to maximize safety for infant participants. Additionally, this study aims to describe the toxicities and the pharmacokinetics of eribulin mesylate when administered to children. In a preliminary manner, the antitumor effect of eribulin mesylate will also be described.

Condition or disease Intervention/treatment Phase
Pediatrics Solid Tumors Drug: Eribulin Mesylate Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Eribulin Mesylate, a Novel Microtubule Targeting Chemotherapeutic Agent in Children With Refractory or Recurrent Solid Tumors (Excluding CNS), Including Lymphomas
Actual Study Start Date : July 31, 2014
Actual Primary Completion Date : January 28, 2016
Actual Study Completion Date : January 28, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Eribulin Mesylate
Eribulin mesylate will be administered intravenously on Days 1 and 8 of each 21-day cycle. A cycle of therapy is considered to be 21 days. The starting dose for eribulin mesylate will be at 1.1 milligram per square meter (mg/m^2) (Dose Level 1), which is approximately 80% of the adult MTD, and will be escalated up to no more than 2.2 mg/m^2.
Drug: Eribulin Mesylate
Eribulin mesylate will be administered intravenously on Days 1 and 8 of each 21-day cycle.
Other Name: E7389




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Eribulin Mesylate [ Time Frame: First dose of study drug (Baseline) up to Cycle 1 Day 21 ]
    MTD: maximum dose at which <one third participants had DLT in Cycle 1. DLT: Grade 3/4 drug-related non hematological toxicity (except Grade 3 nausea, vomiting of <3 days, Grade 3 liver enzyme elevation with alanine transaminase/aspartate transaminase and gamma glutamyl transferase that returned to Grade <=1 or baseline prior to next dose; Grade 3 fever, infection, hypophosphatemia, hypokalemia, hypocalcemia/hypomagnesemia responsive to oral supplementation). Non-hematological toxicity causing >=14 days delay between treatment cycles. Haematological DLTs included: Grade 4 neutropenia/platelets<75,000/mm^3 on Day 8 that does not resolve to absolute neutrophil count >=750/mm^3 and platelets>=75,000/mm^3 by Day 11, neutropenia for >7 days; platelet count <25,000/mm^3, or required platelet transfusion, on 2 separate days within 7-day period;Grade 3 thrombocytopenia complicated by bleeding and/or required platelet transfusion;myelosuppression causing >14 days delay between treatment cycles.

  2. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38) ]
    TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 30 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a participants or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A SAE was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect.

  3. Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values [ Time Frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38) ]
  4. Number of Participants With Clinically Significant Vital Sign Values [ Time Frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38) ]
  5. Number of Participants With Clinically Significant Electrocardiogram (EKG) [ Time Frame: First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38) ]
  6. T1/2: Terminal Half-life for Eribulin Mesylate [ Time Frame: Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose ]
  7. Cmax: Maximum Observed Plasma Concentration for Eribulin Mesylate [ Time Frame: Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose ]
  8. Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Eribulin Mesylate [ Time Frame: Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose ]
  9. AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Eribulin Mesylate [ Time Frame: Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose ]
  10. AUC 0-inf: Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time for Eribulin Mesylate [ Time Frame: Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose ]
  11. CL: Clearance for Eribulin Mesylate [ Time Frame: Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose ]
  12. Vd: Volume of Distribution for Eribulin Mesylate [ Time Frame: Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose ]

Secondary Outcome Measures :
  1. Number of Participants With Best Overall Response [ Time Frame: First dose of study drug (Baseline) up to approximately Cycle 8 (21-days treatment cycle) ]
    Best Overall Response (BOR): best response recorded from start of study treatment until disease progression (PD) or recurrence based on response evaluation criteria in solid tumors (RECIST) version 1.1 for target and non-target lesions. Participants with evaluable disease were also eligible for assessment.



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Participants must be >=12 months and <18 years of age at the time of study enrollment (Part A1).
  • Participants must be >6 months and <12 months of age at the time of study enrollment (Part A2). Participants will enroll one dose level behind the dose level at which participants in Part A1 are enrolling.
  • Participants with refractory or recurrent solid tumors or lymphomas, excluding CNS tumors, are eligible. Participants must have had histologic verification of malignancy at original diagnosis or relapse. Participants with primary CNS tumors, known CNS metastases, or a prior history of CNS metastases are not eligible.
  • Participants must have either measurable or evaluable disease.
  • Participants current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
  • Karnofsky >= 50% for participants >16 years of age and Lansky >=50 for participants less than or equal to (<=)16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  • Participants must have fully recovered from the acute toxic effects of all prior anticancer chemotherapy.

    1. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).
    2. Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (example Neulasta) or 7 days for short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    3. Biologic (anti-neoplastic agent): At least 14 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 14 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
    4. Immunotherapy: At least 42 days after the completion of any type of immunotherapy, example tumor vaccines.
    5. Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody.
    6. X-ray telescope (XRT): At least 14 days after local palliative XRT (small port); At least 150 days must have elapsed if prior total body irradiation(TBI), craniospinal and/or entire spinal XRT or if >=50% radiation of pelvis; At least 42 days must have elapsed if other substantial bone marrow (BM) radiation.
    7. Stem Cell Infusion without TBI: No evidence of active graft versus host disease and at least 84 days must have elapsed after transplant or stem cell infusion.
  • Adequate Bone Marrow Function Defined as:

    1. Peripheral absolute neutrophil count (ANC) >=1000 per cubic millimeter (/mm^3).
    2. Platelet count >=100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
    3. Hemoglobin (Hb) at least 8 gram per deciliter (g/dL) at baseline (blood transfusions are allowed during the screening period to correct Hb values less than 8 g/dL).

All participants enrolled on the study must be evaluable for hematologic toxicity.

  • Adequate Renal Function Defined as:

    1. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >=70 milliliter per minute (ml/min) per (/) 1.73 square meter (m^2) or
    2. A serum creatinine milligram per deciliter (mg/dL) based on age/gender as follows:

      1. 6 months to <1 year: male, 0.5; female, 0.5
      2. 1 to < 2 years: male, 0.6; female, 0.6
      3. 2 to < 6 years: male, 0.8; female, 0.8
      4. 6 to < 10 years: male, 1; female, 1
      5. 10 to < 13 years: male, 1.2; female, 1.2
      6. 13 to < 16 years: male, 1.5; female, 1.4
      7. >=16 years: male, 1.7; female, 1.4

        The threshold creatinine values were derived from the Schwartz formula for estimating GFR (Schwartz et al., 1985) utilizing child length and stature data published by the Centers for Disease Control and Prevention (CDC).

  • Adequate Liver Function Defined as:

    1. Bilirubin (sum of conjugated + unconjugated) <=1.5 * upper limit of normal (ULN) for age
    2. serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase [ALT]) <=110 units per liter (U/L). For the purpose of this study, the ULN for SGPT is 45 U/L.
    3. Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) <= 125 U/L. For the purpose of this study, the ULN for SGOT is 50 U/L.
    4. Serum albumin >= 2 g/dL
  • Adequate Cardiac Function Defined as:

    1. Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by gated radionuclide study
    2. Corrected QT interval (QTc) <= 480 millisecond (msec) Note: Participants with Grade 1 prolonged QTc (450-480 msec) at the time of study enrollment should have correctable causes of prolonged QTc addressed if possible (that is, electrolytes, medications).
  • All participants and/or their participants or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. Participants must be willing to comply with all aspects of the protocol.
  • Participants with known human immunodeficiency virus (HIV) who have CD4+ T cell counts greater than or equal to 500 cells/m^3 and who do not require antiretroviral therapy are eligible.

Exclusion Criteria

  • Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal studies. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective double barrier contraceptive method for the entire period in which they are receiving protocol therapy and up to 6 months after treatment.
  • Concomitant Medications

    • Participants receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible.
    • Participants who are currently receiving another investigational drug are not eligible.
    • Participants who are currently receiving other anticancer agents are not eligible.
    • Participants who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial.
    • Participants who are receiving drugs that prolong the QTc are not eligible.
  • Participants who have received prior therapy with eribulin mesylate are not eligible.
  • Participants with hypersensitivity to excipients of the study drug are not eligible. The excipients are ethanol, hydrochloric acid, sodium hydroxide and water for injection.
  • Participants who have a prior history of viral hepatitis (B or C) as demonstrated by positive serology (presence of antigens) or have an uncontrolled infection requiring treatment are not eligible.
  • Participants with greater than Grade 1 peripheral sensory neuropathy or greater than Grade 1 peripheral motor neuropathy graded according to the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies are not eligible.
  • Cardiac Pathology

    • Participants with known congestive heart failure, symptomatic or left ventricle (LV) ejection fraction 50% or shortening fraction less than 27% are not eligible.
    • Participants with congenital long QT syndrome, bradyarrhythmias, or QTc greater than 480 msec are not eligible.
  • CNS Disease

    • Participants with primary CNS tumors are not eligible.
    • Participants with prior history of or known metastatic CNS disease involvement are not eligible. (Note: CNS imaging for participants without a known history of CNS disease is only required if clinically indicated).
  • Participants who have had or are planning to have the following invasive procedures are not eligible:

    • Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to enrollment.
    • Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 3 days prior to enrollment for external lines (with example, Hickman or Broviac) and at least 7 days prior to enrollment for subcutaneous port.
    • Core biopsy within 7 days prior to enrollment.
    • Fine needle aspirate within 7 days prior to enrollment. NOTE: For purposes of this study, bone marrow aspirate and biopsy are not considered surgical procedures and therefore are permitted within 14 days prior to start of protocol therapy.
  • Participants with known bone marrow involvement are not eligible.
  • Participants who have received a prior solid organ transplantation are not eligible.
  • Participants who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.

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): NCT02171260


Locations
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United States, Alabama
Children's Hospital of Alabama
Birmingham, Alabama, United States, 35233
United States, California
Childrens Hospital of Orange County
Orange, California, United States, 92868
UCSF Medical Center-Parnassus
San Francisco, California, United States, 94143
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Georgia
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia, United States, 30322
United States, Indiana
Riley Hospital for Children
Indianapolis, Indiana, United States, 46202
United States, Michigan
C S Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota Cancer Center-Fairview
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 1914
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15224
United States, Tennessee
St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98145
United States, Wisconsin
Midwest Children's Cancer Center
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Eisai Inc.
Children's Oncology Group

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Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT02171260     History of Changes
Other Study ID Numbers: E7389-A001-113 (ADVL1314)
First Posted: June 24, 2014    Key Record Dates
Results First Posted: December 24, 2018
Last Update Posted: January 15, 2019
Last Verified: June 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eisai Inc.:
Tumors
Lymphomas
Solid Tumors
Pediatric
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases