Clinical Trials /

Study to Assess Safety and Preliminary Activity of Eribulin Mesylate in Pediatric Participants With Relapsed/Refractory Rhabdomyosarcoma (RMS), Non-rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) and Ewing Sarcoma (EWS)

NCT03441360

Description:

This study will be conducted as an assessment of the safety and preliminary activity of eribulin mesylate in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), or Ewing sarcoma (EWS) to determine whether each cohort warrants further investigation.

Related Conditions:
  • Ewing Sarcoma
  • Rhabdomyosarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study to Assess Safety and Preliminary Activity of Eribulin Mesylate in Pediatric Subjects With Relapsed/Refractory Rhabdomyosarcoma (RMS), Non-rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) and Ewing Sarcoma (EWS)
  • Official Title: A Phase 2, Multicenter, Open-label Study to Assess Safety and Preliminary Activity of Eribulin Mesylate in Pediatric Subjects With Relapsed/Refractory Rhabdomyosarcoma (RMS), Non-rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS) and Ewing Sarcoma (EWS)

Clinical Trial IDs

  • ORG STUDY ID: E7389-G000-223
  • NCT ID: NCT03441360

Conditions

  • Relapsed/Refractory Rhabdomyosarcoma
  • Non-rhabdomyosarcoma Soft Tissue Sarcoma
  • Ewing Sarcoma

Interventions

DrugSynonymsArms
Eribulin mesylateEribulin mesylate 1.4 mg/m^2: RMS

Purpose

This study will be conducted as an assessment of the safety and preliminary activity of eribulin mesylate in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), or Ewing sarcoma (EWS) to determine whether each cohort warrants further investigation.

Trial Arms

NameTypeDescriptionInterventions
Eribulin mesylate 1.4 mg/m^2: RMSExperimentalPediatric participants with relapsed/refractory rhabdomyosarcoma (RMS) will receive eribulin mesylate administered as an intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle at a dose of 1.4 milligrams per meters squared (mg/m^2). Participants will continue study therapy until progression of disease (per Response Evaluation Criteria In Solid Tumors [RECIST] 1.1), intolerable toxicity, or withdrawal of consent.
  • Eribulin mesylate
Eribulin mesylate 1.4 mg/m^2: NRSTSExperimentalPediatric participants with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) will receive eribulin mesylate administered as an IV infusion on Days 1 and 8 of each 21-day cycle at a dose of 1.4 mg/m^2. Participants will continue study therapy until progression of disease (per RECIST 1.1), intolerable toxicity, or withdrawal of consent.
  • Eribulin mesylate
Eribulin mesylate 1.4 mg/m^2: EWSExperimentalPediatric participants with Ewing sarcoma (EWS) will receive eribulin mesylate administered as an IV infusion on Days 1 and 8 of each 21-day cycle at a dose of 1.4 mg/m^2. Participants will continue study therapy until progression of disease (per RECIST 1.1), intolerable toxicity, or withdrawal of consent.
  • Eribulin mesylate

Eligibility Criteria

        Inclusion Criteria:

          -  Age: ≥12 months to <18 years old at the time of informed consent

          -  Diagnosis: Histologically confirmed rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft
             tissue sarcoma (NRSTS) (Grade 2 or 3), or Ewing sarcoma (EWS) which is relapsed or
             refractory (failed front line therapy)

          -  The presence of measurable disease meeting the following criteria:

               -  At least 1 lesion of ≥1.0 centimeter (cm) in the longest diameter for a non-lymph
                  node or ≥1.5 cm in the short-axis diameter for a lymph node that is serially
                  measurable according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
                  using computerized tomography/magnetic resonance imaging (CT/MRI).

               -  Lesions that have had radiotherapy must show subsequent radiographic evidence of
                  increase in size by at least 20% to be deemed a target lesion.

          -  Therapeutic options: Participant's 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.

          -  Performance level: Performance score ≥50%. Karnofsky (for participants >16 years of
             age) or Lansky (for participants ≤16 years of age)

          -  Participants must have fully recovered from the acute toxic effects of all prior
             anticancer therapy and must meet the following minimum duration from prior anticancer
             directed therapy prior to study drug administration. If, after the required time
             frame, the numerical eligibility criteria are met, eg, blood count criteria, the
             participant is considered to have recovered adequately:

               -  Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21
                  days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days
                  if prior nitrosourea).

               -  Anticancer agents not known to be myelosuppressive (eg, not associated with
                  reduced platelet or absolute neutrophil count [ANC] counts): ≥7 days after the
                  last dose of agent.

               -  Antibodies: 3 half-lives must have elapsed from infusion of last dose of antibody
                  (including checkpoint inhibitors), and toxicity related to prior antibody therapy
                  must be recovered to Grade ≤1.

               -  Hematopoietic growth factors: ≥14 days after the last dose of a long-acting
                  growth factor (eg, Neulasta) or 7 days for a short-acting growth factor. For
                  agents that have known adverse events (AEs) occurring beyond 7 days after
                  administration, this period must be extended beyond the time during which AEs are
                  known to occur.

               -  Interleukins, interferons, and cytokines (other than hematopoietic growth
                  factors): ≥21 days after the completion of interleukins, interferons, or
                  cytokines (other than hematopoietic growth factors)

               -  Stem cell infusions (with or without total body irradiation [TBI]): ≥84 days

               -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell
                  infusion including donor lymphocyte infusion or boost infusion: ≥84 days after
                  infusion and no evidence of graft versus host disease (GVHD)

               -  Autologous stem cell infusion including boost infusion: ≥42 days

               -  Cellular therapy: ≥42 days after the completion of any type of cellular therapy
                  (eg, modified T-cells, natural killer cells, dendritic cells, etc)

               -  Radiation therapy (XRT)/External Beam Irradiation including Protons: ≥14 days
                  after local XRT, ≥150 days after TBI, craniospinal XRT or if radiation to ≥50% of
                  the pelvis, ≥42 days if other substantial BM radiation

               -  Radiopharmaceutical therapy (eg, radiolabeled antibody,
                  131I-metaiodobenzylguanidine): ≥42 days after systemically administered
                  radiopharmaceutical therapy.

          -  Adequate bone marrow function, defined as:

               -  ANC ≥1.0 × 10^9/Liter (L)

               -  Platelet count ≥100 × 10^9/L (transfusion independent, defined as not receiving
                  platelet transfusions within a 7-day period prior to study drug administration)

               -  Hemoglobin at least 8.0 grams per deciliter (g/dL) at Baseline (blood
                  transfusions are allowed during the screening period to correct hemoglobin values
                  less than 8.0 g/dL) As blood transfusions are permitted to meet the hemoglobin
                  criteria, participants requiring transfusion must not be known to be refractory
                  to red blood cell or platelet transfusions.

          -  Adequate renal function, defined as:

               -  A serum creatinine based on age/gender, derived from the Schwartz formula for
                  estimating glomerular filtration rate (GFR)

               -  Or creatinine clearance or radioisotope GFR ≥50 milliliters per minute
                  (mL/min)/1.73 meters squared (m^2) based on a 12 or 24 hour urine creatinine
                  collection

          -  Adequate liver function, defined as:

               -  Bilirubin (sum of conjugated + unconjugated) ≤1.5 × upper limit of normal (ULN)
                  for age

               -  Alanine aminotransferase (ALT) ≤110 units per Liter (U/L). For the purpose of
                  this study, the ULN for ALT is 45 U/L

               -  Serum albumin ≥2 g/dL

          -  Informed consent: All participants and/or their parents 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.

        Exclusion Criteria:

          -  Pregnancy, breastfeeding, contraception: Females who are breastfeeding or pregnant at
             Screening or Baseline (as documented by a positive beta-human chorionic [β-hCG] or
             human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 International
             Units per Liter [IU/L] or equivalent units of β-hCG [or hCG]). A separate baseline
             assessment is required if a negative screening pregnancy test was obtained more than
             72 hours before the first dose of study drug.

               -  Females of childbearing potential (all post pubertal females will be considered
                  to be of childbearing potential unless they have early menopause [amenorrheic for
                  at least 12 consecutive months, in the appropriate age group, and without other
                  known or suspected cause] or have been sterilized surgically [ie, bilateral tubal
                  ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at
                  least 1 month before dosing]) who:

               -  Do not agree to use a highly effective method of contraception for the entire
                  study period and for 6 months after study drug discontinuation, ie:

               -  Total abstinence (if it is their preferred and usual lifestyle);

               -  An intrauterine device (IUD) or intrauterine system (IUS);

               -  A contraceptive implant;

               -  An oral contraceptive (must be on a stable dose of the same oral hormonal
                  contraceptive product for at least 4 weeks before dosing with study drug and for
                  the duration of the study and for 6 months after study drug discontinuation); or

               -  Do not have a vasectomized partner with confirmed azoospermia.

        For sites outside of the European Union (EU), it is permissible that if a highly effective
        method of contraception is not appropriate or acceptable to the participant, or the
        participant has changed oral hormonal contraceptive product/dose within 4 weeks prior to
        study drug administration, then the participant must agree to use a medically acceptable
        method of contraception, ie, double barrier methods of contraception such as condoms plus
        diaphragm or cervical/vault cap with spermicide.

          -  Males who have not had a successful vasectomy (confirmed azoospermia) or if they and
             their female partners do not meet the criteria above (ie, not of childbearing
             potential or practicing highly effective contraception throughout the study period or
             for 28 days after study drug discontinuation). No sperm donation is allowed during the
             study period or for 28 days after study drug discontinuation.

             - Concomitant medications:

          -  Corticosteroids: Participants receiving corticosteroids who have not been on a stable
             or decreasing dose of corticosteroid for at least 7 days prior to study drug
             administration (except when indicated for Central Nervous System [CNS] metastases,
             then participants must not have received corticosteroids for at least 28 days)

          -  Anticancer Agents: participants who are currently receiving other anticancer agents

          -  Anti-GVHD agents posttransplant

          -  Participants who are receiving cyclosporine, tacrolimus or other agents to prevent
             graft-versus-host disease post bone marrow transplant

               -  Received prior therapy with eribulin mesylate

               -  Any other malignancy that required treatment (except for non-melanoma skin
                  cancer, or histologically confirmed complete excision of carcinoma in situ),
                  within 2 years prior to study drug administration

               -  Has hypersensitivity to eribulin or any of the excipients

               -  Has a prior history of viral hepatitis (B or C) as demonstrated by positive
                  serology (presence of antigens) or have an uncontrolled infection requiring
                  treatment. Participants with a known prior history of hepatitis B or C may be
                  eligible pending agreement with the sponsor.

               -  Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor
                  neuropathy graded according to the Modified ("Balis") Pediatric Scale of
                  Peripheral Neuropathies

               -  Has cardiac pathology: Participants with known congestive heart failure,
                  symptomatic or left ventricular (LV) ejection fraction <50% or shortening
                  fraction <27% and participants with congenital long QT syndrome,
                  bradyarrhythmias, or QTc >480 msec on at least 2 separate electrocardiograms
                  (ECGs).

               -  Has CNS Disease: Participants with brain or subdural metastases are not eligible
                  unless the metastases are asymptomatic and do not require treatment or have been
                  adequately treated by local therapy (eg, surgery or radiotherapy) and have
                  discontinued the use of corticosteroids for this indication for at least 4 weeks
                  prior to study drug administration. Confirmation of radiographic stability must
                  be done by comparing the brain scan (CT or MRI) performed during the Screening
                  Period, using the same imaging modality, to a brain scan performed earlier (and
                  following local therapy where applicable). Participants must be clinically
                  stable. It is not the intention of this protocol to treat participants with
                  active brain metastases.

        Note: CNS imaging is required to confirm eligibility for participants with a known history
        of CNS disease.

          -  Have had or are planning to have the following invasive procedures:

               -  Major surgical procedure or significant traumatic injury within 28 days prior to
                  study drug administration

               -  Laparoscopic procedure or open biopsy within 7 days prior to study drug
                  administration

               -  Central line placement or subcutaneous port placement is not considered major
                  surgery but must be placed at least 2 days prior to study drug administration

               -  Core biopsy, including bone marrow biopsy, within 2 days prior to study drug
                  administration

               -  Fine needle aspirate within 3 days prior to study drug administration

          -  Has any serious concomitant illness that in the opinion of the investigator(s) could
             affect the participant's safety or interfere with the study assessments

          -  Participants with known human immunodeficiency virus (HIV); due to lack of available
             safety data for eribulin therapy in HIV-infected participants
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response
Time Frame:up to 36 months
Safety Issue:
Description:Number of participants achieving a best objective response of partial response (PR) or complete response (CR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, by up to 24 weeks after all participants have completed response assessment. Response assessment will be as determined by investigator. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in the short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:up to 36 months
Safety Issue:
Description:PFS is defined as the time from the first dose date to the date of disease progression (PD) or date of death (whichever occurs first). PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Measure:Number of participants with any treatment-emergent (TE) serious adverse event (SAE)
Time Frame:up to 36 months
Safety Issue:
Description:An SAE is any untoward medical occurrence that at any dose: results in death; is life threatening (ie, the participant was at immediate risk of death from the adverse event as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during treatment, having been absent at pretreatment (Baseline) or (1) reemerges during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
Measure:Number of participants with any TE non-serious adverse event
Time Frame:up to 36 months
Safety Issue:
Description:An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with the medicinal product. A TEAE is defined as an AE that emerges during treatment, having been absent at pretreatment (Baseline) or (1) reemerges during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or (2) worsens in severity during treatment relative to the pretreatment state, when the AE is continuous.
Measure:Number of participants with any abnormal, clinically significant clinical laboratory value
Time Frame:up to 36 months
Safety Issue:
Description:Clinical significance will be assessed by the investigator.
Measure:Number of participants with any abnormal, clinically significant electrocardiogram (ECG) value
Time Frame:up to 36 months
Safety Issue:
Description:Clinical significance will be assessed by the investigator.
Measure:Number of participants with any abnormal, clinically significant vital sign value
Time Frame:up to 36 months
Safety Issue:
Description:Clinical significance will be assessed by the investigator.
Measure:Change from Baseline in scores on the Lansky Play-Performance Scale
Time Frame:Baseline; up to 36 months
Safety Issue:
Description:The Lansky Play-Performance Scale can be used to rate a child's activity level. Parents will be asked to rate their child's activity level over the past week. Scores on the Lansky Play-Performance Scale range from 0 (unresponsive) to 100 (fully active, normal).
Measure:Change from Baseline in Karnofsky Performance Status Scores
Time Frame:Baseline; up to 36 months
Safety Issue:
Description:The Karnofsky Performance scale allows physicians to classify participants based on functional impairment. Physicians will assign a performance score for participants, ranging from 0 (dead) to 100 (normal, no complaints).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Eisai Inc.

Trial Keywords

  • eribulin mesylate
  • pediatric

Last Updated

February 26, 2018