Eribulinmesilat

Phase 1 (open)

Phase 1 will determine the maximal tolerated dose (MTD) and the recommanded Phase 2 dose (RP2D) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric subjects with relapsed/refractory extra-cranial solid tumors.

Phase 2 (still closed, 02/2018)

Will evaluate the safety and efficacy (objective Response rate) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric subjects with relapsed/refractory RMS and NRSTS, using the combination dose and schedule determined in Phase 1.

Phase 1:
Phase 1: Will determine the MTD/RP2D of eribulin mesilate in combination with irinotecan hydrochloride in pediatric subjects with relapsed/refractory extra-cranial solid tumors.
Eribulin mesilate will be administered as an intravenous (IV) infusion on Days 1 and 8 of each 21 day cycle, at the RP2D determined in the single-agent dose finding study E7389-A001-113 (1.4 mg/m2).
Irinotecan hydrochloride will be administered as an IV infusion using 2 different dose schedules:
- Days 1-5 of a 21 day cycle at the following doses; 20 mg/m2 and 40 mg/m2
And
-Days 1 and 8 of a 21 day cycle at the following doses; 100 mg/m2 and 125 mg/m2

Pre-study Phase:
Day -14 to -1, computerized tomography (CT) / magnetic resonance imaging (MRI) scans must be performed within 14 days prior to study drug administration. All clinical and laboratory test results to determine eligibility must be performed within 7 days prior to study drug administration, unless otherwise indicated.
Treatment Phase:
The Treatment Phase will start on Day 1 (D1) of Cycle 1 (C1). Subjects will receive eribulin mesilate by IV infusion on Days 1 and 8 of a 21-day cycle together with IV irinotecan hydrochloride administered on either:
-Days 1-5
-Days 1 and 8 of a 21-day cycle (See Study Design of Phase 1).
The most appropriate schedule will be taken forward to Phase 2 and will represent the RP2D (See Study Design of Phase 2).
Subjects in both Phase 1 and Phase 2 will remain on treatment if they are receiving clinical benefit, as outlined in the Duration of Treatment.

• Age: ≥12 months to <18 years old at the time of consent.
• Diagnosis: Phase 1: Histologically confirmed extra-cranial solid tumor, which is relapsed or refractory, and for which there are no currently available therapies. Phase 2: Histologically confirmed RMS or NRSTS which is relapsed or refractory having received at least 1 prior systemic therapy, including primary treatment.
• Disease status: Phase 1: Subjects must have either measurable or evaluable disease as per RECIST 1.1. Phase 2: Subjects must have measurable disease as per RECIST 1.1.
• Measurable disease is defined as meeting the following criteria: a. At least 1 lesion of ≥1.0 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 RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI). b. 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: Subject’s current disease state must be one for which there is no known curative therapy..
• Performance level: Performance score ≥50% Karnofsky (for subjects >16 years of age) or Lansky (for subjects ≤16 years of age)
• Subjects must have fully recovered from the acute toxic effects of all prior anticancer Treatments prior to study drug administration:
• Adequate bone marrow function
• Adequate renal function
• Adequate liver function
• Informed consent: All subjects and/or their parents or guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. Subjects must be willing to comply with all aspects of the protocol.

• Females who are breastfeeding or pregnant at Screening or Baseline
• Females of childbearing potential 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
• Concomitant Medications: Corticosteroids: Subjects receiving corticosteroids who have not been on a stable dose for at least 7 days prior to study drug administration. Anticancer agents: Subjects who are currently receiving other anticancer agents. Anti-GVHD agents post-transplant: Subjects who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant.
• Participant has a known prior history of viral hepatitis (B or C) as demonstrated by positive serology (presence of antigens) or have an uncontrolled infection requiring Treatment
• Participant has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor neuropathy
• Participant has cardiac pathology
• Participant has CNS disease: Subjects 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
• 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.
• HIV Infection
• Participant has any serious concomitant illness that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments.