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)

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

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.

Study Overview

• Status: Completed
• Conditions: Solid Tumors; Pediatrics
• Intervention / Treatment: Drug: Eribulin Mesylate

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: E7389

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) of Eribulin Mesylate	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.	First dose of study drug (Baseline) up to Cycle 1 Day 21
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	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.	First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38)
Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values		First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38)
Number of Participants With Clinically Significant Vital Sign Values		First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38)
Number of Participants With Clinically Significant Electrocardiogram (EKG)		First dose of study drug (Baseline) up to 30 days after last dose of study drug (Cycle 8 Day 38)
T1/2: Terminal Half-life for Eribulin Mesylate		Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose
Cmax: Maximum Observed Plasma Concentration for Eribulin Mesylate		Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Eribulin Mesylate		Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose
AUC 0-t: Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for Eribulin Mesylate		Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose
AUC 0-inf: Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time for Eribulin Mesylate		Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose
CL: Clearance for Eribulin Mesylate		Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose
Vd: Volume of Distribution for Eribulin Mesylate		Day 1 predose and at 10, 30 minutes, 1, 2, 4, 6, 24, 48, 72, 96 or 120 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Best Overall Response	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.	First dose of study drug (Baseline) up to approximately Cycle 8 (21-days treatment cycle)

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Collaborators: Children's Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2014
• Primary Completion (Actual): January 28, 2016
• Study Completion (Actual): January 28, 2016

Study Registration Dates

• First Submitted: June 18, 2014
• First Submitted That Met QC Criteria: June 20, 2014
• First Posted (Estimate): June 24, 2014

Study Record Updates

• Last Update Posted (Actual): January 15, 2019
• Last Update Submitted That Met QC Criteria: January 2, 2019
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Pediatric; Solid Tumors; Tumors; Lymphomas
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma
• Other Study ID Numbers: E7389-A001-113 (ADVL1314)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No