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This is a Phase 1 Study of Eribulin Mesylate in Pediatric Patients With Recurrent or Refractory Solid Tumors (Excluding CNS), Including Lymphomas. (BOLD 113)

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ClinicalTrials.gov Identifier: NCT02171260
Recruitment Status : Completed
First Posted : June 24, 2014
Last Update Posted : April 17, 2018
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 patients 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 MTD and/or the RP2D of this regimen in Part A1 (patients greater than or equal to 12 months and less than 18 years). Part A2 will enroll infants (greater than 6 months and less than 12 months) one dose level behind the dose level at which patients in Part A1 are enrolling, in order to maximize safety for infant subjects. 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 Mesilate Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Actual Study Start Date : July 31, 2014
Actual Primary Completion Date : April 17, 2015
Actual Study Completion Date : January 28, 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: E7389
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 mg/m2 (Dose Level 1), which is approximately 80% of the adult maximum tolerated dose (MTD), and will be escalated up to no more than 2.2 mg/m2.
Drug: Eribulin Mesilate
Eribulin mesylate will be administered intravenously on Days 1 and 8 of each 21-day cycle.




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of eribulin mesylate administered as an intravenous infusion [ Time Frame: Days 1 and 8 of a 21-day cycle ]
  2. Number of Adverse events as assessed by CTCAE version 4.0, as a measure of safety and tolerability [ Time Frame: Up to 30 days after the last dose of study drug (up to approximately 5 years) ]
    All adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All graded adverse events will be routinely reported throughout the study. Analysis will determine the maximum tolerable dose, and the describe the toxicity profile for the pediatric solid tumor patients.

  3. Pharmacokinetics of eribulin mesylate in Cycle 1: Cmax [ Time Frame: Days 1-8.Days 1-6: predose; 10 (± 5) minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), 96 hours (Day 5), 120 hours (Day 6) post-infusion. Day 8: predose; 10 (± 5) minutes post-infusion. ]
    For subjects greater than or equal to 12 months and less than 18 years of age, Cmax will be determined after the first dose of eribulin. Additionally, after the second dose of eribulin, C0.083 hr will be determined and descriptively compared to the first dose Cmax (and first dose C0.083 hr).

  4. Pharmacokinetics of eribulin mesylate in Cycle 1: tmax [ Time Frame: Days 1-8. Days 1-6: predose; 10 (± 5) minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), 96 hours (Day 5), 120 hours (Day 6) post-infusion. Day 8: predose; 10 (± 5) minutes post-infusion. ]
    For subjects greater than or equal to 12 months and less than 18 years of age, tmax will be determined after the first dose of eribulin.

  5. Pharmacokinetics of eribulin mesylate in Cycle 1: AUC [ Time Frame: Days 1-8. Days 1-6: predose; 10 (± 5) minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 24 hours (Day 2), 48 hours (Day 3), 72 hours (Day 4), 96 hours (Day 5), 120 hours (Day 6) post-infusion. Day 8: predose; 10 (± 5) minutes post-infusion. ]
    For subjects greater than or equal to 12 months and less than 18 years of age, AUC will be determined after the first dose of eribulin.


Secondary Outcome Measures :
  1. Evaluation of disease response to preliminarily define the antitumor activity of eribulin [ Time Frame: Up to 5 days ]
    Patients will have tumor disease evaluations performed at the end of cycles 1, 3, and 5 and then every 3 cycles. Disease response will be assessed according to RECIST 1.1 criteria for patients with solid tumors and will be reported descriptively. Analyses will be descriptive and exploratory and hypotheses generating in nature.

  2. Pharmacokinetics of eribulin mesylate in Cycle 1 in infants with refractory or recurrent cancer: Cmax [ Time Frame: Days 1-8. Day 1: predose; 10 (± 5) minutes post-infusion. Day 4 or Day 5. Day 8: predose; 10 (± 5) minutes post-infusion. ]
    For subjects greater than 6 months but less than 12 months of age, Cmax will be determined after the first dose of eribulin. Additionally, after the second dose of eribulin, C0.083 hr will be determined and descriptively compared to the first dose Cmax (and first dose C0.083 hr).

  3. Pharmacokinetics of eribulin mesylate in Cycle 1 in infants with refractory or recurrent cancer: tmax [ Time Frame: Days 1-8. Day 1: predose; 10 (± 5) minutes post-infusion. Day 4 or Day 5. Day 8: predose; 10 (± 5) minutes post-infusion. ]
    For subjects greater than 6 months but less than 12 months of age, tmax will be determined after the first dose of eribulin.

  4. Pharmacokinetics of eribulin mesylate in Cycle 1 in infants with refractory or recurrent cancer: AUC [ Time Frame: Days 1-8. Day 1: predose; 10 (± 5) minutes post-infusion. Day 4 or Day 5. Day 8: predose; 10 (± 5) minutes post-infusion. ]
    For subjects greater than 6 months but less than 12 months of age, AUC will be determined after the first dose of eribulin.



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 greater than or equal to 12 months and less than 18 years of age at the time of study enrollment (Part A1).
  • Participants must be greater than 6 months and less than 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 central nervous system (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 greater than or equal to 50% for participants greater than 16 years of age and Lansky greater than or equal to 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 (e.g., 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, e.g. 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 traumatic brain injury (TBI), craniospinal and/or entire spinal XRT or if greater than or equal to 50% radiation of pelvis; At least 42 days must have elapsed if other substantial 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) greater than or equal to 1000/millimeters cubed (mm^3)
    2. Platelet count greater than or equal to 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 grams 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) greater than or equal to 70 milliliters per minute (ml/min)/1.73 meters squared (m^2) or
    2. A serum creatinine (milligrams [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 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 x 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. QTc ≤ 480 milliseconds (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 (i.e., 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/mm^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 (e.g., 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


  Hide Study Locations
Locations
United States, Alabama
Birmingham, Alabama, United States
United States, California
Orange, California, United States
San Francisco, California, United States
United States, District of Columbia
Washington, District of Columbia, United States
United States, Georgia
Atlanta, Georgia, United States
United States, Illinois
Chicago, Illinois, United States
United States, Indiana
Indianapolis, Indiana, United States
United States, Maryland
Bethesda, Maryland, United States
United States, Michigan
Ann Arbor, Michigan, United States
United States, Minnesota
Minneapolis, Minnesota, United States
United States, Missouri
Saint Louis, Missouri, United States
United States, New York
New York, New York, United States
United States, Ohio
Cincinnati, Ohio, United States
United States, Oregon
Portland, Oregon, United States
United States, Pennsylvania
Philadelphia, Pennsylvania, United States
Pittsburgh, Pennsylvania, United States
United States, Tennessee
Memphis, Tennessee, United States
United States, Texas
Houston, Texas, United States
United States, Washington
Seattle, Washington, United States
United States, Wisconsin
Milwaukee, Wisconsin, United States
Canada, Ontario
Toronto, Ontario, Canada
Sponsors and Collaborators
Eisai Inc.
Children's Oncology Group

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
Last Update Posted: April 17, 2018
Last Verified: April 2018

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