Clinical trial NCT03441360: 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)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsed/Refractory Rhabdomyosarcoma
Non-rhabdomyosarcoma Soft Tissue Sarcoma
Ewing Sarcoma
Keywords: eribulin mesylate
pediatric
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2018-02-22
Enrollment: 23
Sex: ALL
Minimum age (years): 12
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


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 who are unable to walk because of paralysis and/or previous surgeries, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.
* 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.
  * Monoclonal 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. The duration of this interval must be discussed with the sponsor.
  * 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) Note: 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 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 commenced/adjusted/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 3 months after study drug discontinuation). No sperm donation is allowed during the study period or for 3 months 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 Post-transplant: Participants who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant
* Strong CYP3A4 inducers/inhibitors

  * 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%
  * Participants with congenital long QT syndrome, bradyarrhythmias, or QTc \>480 millisecond (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

Primary outcomes:
measure: Percentage of Participants With Objective Response
timeFrame: From date of randomization up to first documentation of disease progression (PD) or date of death, whichever occurred first (approximately 32 months)
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: From the time from the first dose date to the date of disease progression (PD) or date of death, whichever occurred first (up to approximately 32 months)
measure: Number of Participants With Any Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From date of administration of first dose up to 28 days after the last dose, or until resolution, whichever came first (up to approximately 45 months)
measure: Number of Participants With a Shift From Baseline to Worst Post-Baseline Common Terminology Criteria for Adverse Events (CTCAE) Grade in Laboratory Value
timeFrame: From first dose of study drug up to approximately 32 months
measure: Number of Participants With Clinically Significant Change From Baseline in Electrocardiogram (ECG) Values
timeFrame: From first dose of study drug up to approximately 32 months
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs Values
timeFrame: From first dose of study drug up to approximately 32 months
measure: Number of Participants With Shift From Baseline to Worst Post-baseline for Lansky Play-performance Scale
timeFrame: Baseline up to approximately 32 months
measure: Number of Participants With Shift From Baseline to Worst Post-baseline for Karnofsky Performance Status Scores
timeFrame: Baseline up to approximately 32 months
measure: Duration of Response (DOR)
timeFrame: From day of first documentation of PR or CR to the day of disease progression or death (up to approximately 32 months)
measure: Overall Survival (OS)
timeFrame: From the day of first dose to the day of death, up to approximately 45 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Cancer Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital- San Diego
state: California
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Wilmington
country: United States
facility: Nemours / A.I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children - Indiana University
state: Indiana
city: Des Moines
country: United States
facility: Blank Children's Hospital
state: Iowa
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: CS Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital and Clinics
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers cancer Institute of NJ
state: New Jersey
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Randall Children's Hospital at Legacy Emanuel
state: Oregon
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Health Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: Norfolk
country: United States
facility: Children's Hosptial of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
References: