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
Condition: Pediatrics; Solid Tumors
MeSH terms: Lymphoma
Intervention: Eribulin Mesylate
Intervention description: Eribulin mesylate will be administered intravenously on Days 1 and 8 of each 21-day cycle.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 6 Months
Maximum age: 17 Years
Healthy volunteers: No
Keywords: Tumors; Lymphomas; Solid Tumors; Pediatric

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.
    

Eligibility 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.