| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Phase 1: paediatric subjects with relapsed/refractory solid tumors (excluding CNS)
Phase 2: paediatric subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS) |
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| E.1.1.1 | Medical condition in easily understood language |
Different types of cancer that are not responding to treatment or have
reappeared following an initial recovery |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• Phase 1: To determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with weekly and daily irinotecan hydrochloride in paediatric subjects with relapsed/refractory solid tumors (excluding CNS)
• Phase 2: To assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and Ewing sarcoma (EWS)
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| E.2.2 | Secondary objectives of the trial |
Phase 1:
• To assess the safety and tolerability of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects
• To determine the optimal schedule of irinotecan hydrochloride when administered with standard schedule (Days 1 and 8) of eribulin mesilate in paediatric subjects
Phase 2:
• To assess Progression Free Survival (PFS) of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects.
• To assess the Clinical Benefit Rate (CBR) at 12 weeks of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects
Phase 1&2:
• To evaluate the pharmacokinetic (PK) profile of eribulin, irinotecan and its active metabolite and compare to appropriate historical data.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. a) Age: ≥12 months to ≤25 years old at the time of consent (no more than 25% of subjects between the ages of 18 and 25 years will be enrolled in this study). b) >6 months and <12 months at the times of consent (Phase 1 and Schedule A only) subjects will be enrolled one dose level behind he dose level at which the ≥12 months to <18 years old group are enrolled.
2. Diagnosis:
Phase 1: Histologically confirmed solid tumor, excluding CNS tumor, which is relapsed or refractory, and for which there are no currently available therapies.
Phase 2: Histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory having received at least 1 prior therapy), including primary treatment.
3. 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 computed 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.
4. Therapeutic options: Subject’s current disease state must be one for which there is no known curative therapy.
5. Performance level: Performance score ≥50% Karnofsky (for subjects >16 years of age) or Lansky (for subjects ≤16 years of age).
6. Subjects must have fully recovered from the acute toxic effects of all prior anticancer treatments prior to study drug administration:
• Myelosuppressive chemotherapy: Must not have received within 21 days to study drug administration (42 days if prior nitrosourea).
• Hematopoietic growth factors: Must not have received a long-acting growth factor (eg, Neulasta) within 14 days or a short-acting factor within 7 days. For agents that have known 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.
• Targeted therapy (antineoplastic agent eg, tyrosine kinase inhibitor): Must not have received an antineoplastic targeted therapy within 14 days. For agents that have known AEs occurring beyond 14 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.
• Immunotherapy: Must not have received immunotherapy, e.g. tumor vaccines, within 42 days.
• Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody.
• Radiotherapy (XRT): Must not have received within 14 days prior to study drug administration (small field) or 42 days for craniospinal XRT, or if ≥50% radiation of pelvis.
• Autologous Stem cell infusion: At least 84 days must have elapsed after stem cell infusion prior to study drug administration.
• Allogeneic bone marrow transplant, including mini-transplant: No evidence of active Graft vs. Host disease and at least 100 days must have elapsed after transplant or stem cell infusion prior to study drug administration.
7. Adequate bone marrow function, defined as:
• Peripheral absolute neutrophil count (ANC) ≥1 × 109/L.
• Platelet count ≥100 × 109/L (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to study drug administration).
• Hemoglobin (Hb) at least 8.0 g/dL at baseline (blood transfusions are allowed during the screening period to correct Hb values less than 8.0 g/dL).
As blood transfusions are permitted to meet the hemoglobin criteria, subjects must not be known to be refractory to red blood cell or platelet transfusions.
8. Adequate renal function, defined as:
• A serum creatinine based on age/gender, derived from the Schwartz formula for estimating GFR. Refer to table in protocol.
• Or serum creatinine clearance or GFR ≥50ml/min/1.73m2, based on a 12 or 24h urine creatinine collection.
9. Adequate liver function, defined as:
• Bilirubin (sum of conjugated + unconjugated) ≤1.5 times the ULN for age.
• Alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN (in the case of liver metastases ≤5 × ULN), unless there are bone metastases, in which case liver-specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase.
• Serum albumin ≥2 g/dL.
10. Informed consent: All subjects and/or their parents or legally authorized representatives 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.
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| E.4 | Principal exclusion criteria |
1. 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 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* 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** OR
◦ Do not have a vasectomized partner with confirmed azoospermia.
*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).
**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.
2. 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.
◦ Strong CYP3A4 inducers/inhibitors, including traditional medicinal products (eg. St. John's Wort).
3.Prior Therapies:
◦ Phase 1: Received prior therapy with eribulin mesilate within 6 months prior to study drug administration.
◦ Phase 2: Received prior therapies with eribulin mesilate or irinotecan
hydrochloride (IH) (for prior IH subjects can be included if there was no tumor progression during IH therapy).
4.Any 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.
5.Has hypersensitivity to either study drug or any of the excipients.
6.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 (*
Subjects with a known prior history of hepatitis B or C may be eligible pending
agreement with the sponsor).
7.Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor neuropathy graded according to the Modified (“Balis”) Pediatric Scale of Peripheral Neuropathies.
8.Has cardiac pathology, defined as:
◦ Subjects with known congestive heart failure, symptomatic or LV ejection fraction
<50% or shortening fraction <27% and subjects with congenital long QT syndrome,
bradyarrhythmias, or QTc >480 msec on at least 2 separate ECGs.
9.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 (eg, surgery or radiotherapy) and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration. Subjects must be clinically stable. It is not the intention of this protocol to treat subjects with active brain metastases.
10.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.
Central line placement or subcutaneous port placement is not considered major surgery.
◦ Laparoscopic procedure or open biopsy within 7 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.
11.Subjects with known human immunodeficiency virus (HIV); due to lack of available safety data for eribulin therapy in HIV infected patients.
12.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 including active or severe chronic inflammatory bowel disease or bowel obstruction.
13. Has received a live-virus vaccination within 30 days of planned start of study therapy. Seasonal flu vaccines that do not contain live virus are permitted. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Phase 1: The MTD/RP2D of eribulin mesilate in combination with irinotecan hydrochloride in paediatric subjects with relapsed/refractory extra-cranial solid tumors, excluding CNS tumors. Note: Subjects <12 months will not contribute to the determination of MTD/RP2D and data is for descriptive purposes only.
• Phase 2: Objective response rate (ORR): defined as the proportion of subjects achieving a best overall response of confirmed partial or complete response, as determined by investigator assessment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Phase 1: DLTs to establish the MTD are assessed during the first cycle for each subject on each dose level.
• Phase 2: Tumour assessments are performed every 6 weeks until Week 12 and then and then the frequency of assessments may decrease to every 9 weeks (or sooner if clinically indicated). |
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| E.5.2 | Secondary end point(s) |
Phase 1 & 2 Endpoints:
• Safety and tolerability: adverse events (AEs), serious adverse events, clinical laboratory values, ECG parameters, vital sign measurements and physical examinations
Timepoint of evaluation:
Following provision of informed consent/assent and through out the study until 28 days after the last dose of study drug.
• The pharmacokinetic profile of eribulin, irinotecan and its active metabolite.
Timepoint of evaluation:
Phase 1 (Cycle 1): For subjects ≥12 months and >10 kg (Irinotecan, its metablite and eribulin will be assayed).
Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first),
and at the end of the eribulin infusion, then at 1, 2, 4, 6 and 24 hours post-eribulin
infusion. Both irinotecan (and its metabolite, SN-38) and eribulin will be assayed. At 72 and 120 hours post eribulin infusion, eribulin only will be assayed.
For subjects <12 months as well as those ≥12 months and < or equal to 10 kg (subjects under 6 kg will not have PK samples taken) (Irinotecan, its metablite and eribulin will be assayed).
Cycle 1, Day 1: At the end of the irinotecan infusion (irinotecan is administered first) and then immediately after the end of the eribulin infusion (ie 10 ± 5 minutes from the start of the eribulin infusion).
Cycle 1, Day 4 or 5: During the collection of the first twice weekly CBC sample.
Cycle 1, Day 8: Before the eribulin infusion and then immediately after the end of the eribulin infusion (ie 10 ± 5 minutes from the start of the eribulin infusion).
Phase 2 Endpoints:
• Progression-free survival (PFS): defined as the time from the first dose date to the date of disease progression as determined by investigator review, or death
Timepoint of evaluation:
Progression-free survival, defined as the time from the date of first dose to the date of first documentation of disease progression, or date of death (whichever occurs first).
• The Clinical Benefit Rate (CBR) at 12 weeks: defined as the proportion of subjects with best overall response (BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD >11 weeks)
Timepoint of evaluation:
Clinical Benefit Rate, defined as the proportion of subjects with best overall response (BOR) of CR, PR or durable SD based on RECIST 1.1 (durable SD >11 weeks). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As detailed under Secondary endpoint (above). Not possible to detail in full in this field due to limit on number of characters. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Greece |
| Italy |
| Poland |
| Spain |
| Switzerland |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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