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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03245450




Registration number
NCT03245450
Ethics application status
Date submitted
8/08/2017
Date registered
10/08/2017
Date last updated
28/06/2022

Titles & IDs
Public title
Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors
Scientific title
A Phase 1/2 Single-arm Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan in Children With Refractory or Recurrent Solid Tumors
Secondary ID [1] 0 0
2016-003352-67
Secondary ID [2] 0 0
E7389-G000-213
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Condition category
Condition code
Cancer 0 0 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 0 0 0 0
Bone
Cancer 0 0 0 0
Children's - Other
Other 0 0 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Eribulin mesilate
Treatment: Drugs - Irinotecan hydrochloride

Experimental: Eribulin mesilate plus irinotecan hydrochloride - In Schedules A and B, eribulin mesilate at the dose of 1.4 milligrams per meters squared (mg/m^2) will be administered as an intravenous (IV) infusion on Days 1 and 8 of each 21-day cycle. In Schedule A, irinotecan hydrochloride at the doses of 20 mg/m^2 or 40 mg/m^2 will be administered as an IV infusion on Days 1 to 5 of a 21-day cycle. In Schedule B, irinotecan hydrochloride at the doses of 100 mg/m^2 or 125 mg/m^2 will be administered as an IV infusion on Days 1 and 8 of a 21-day cycle.


Treatment: Drugs: Eribulin mesilate
IV infusion

Treatment: Drugs: Irinotecan hydrochloride
IV infusion
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride
Timepoint [1] 0 0
First dose of study drug up to Cycle 1 (Cycle length=21 days)
Primary outcome [2] 0 0
Phase 2: Objective Response Rate (ORR)
Timepoint [2] 0 0
From date of first dose of study drug until disease progression, development of unacceptable toxicity, withdrawal of consent, or up to approximately 2 years 4 months
Secondary outcome [1] 0 0
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Timepoint [1] 0 0
From first dose of study drug up to approximately 2 years 4 months
Secondary outcome [2] 0 0
Number of Participants With Serious Adverse Event (SAE)
Timepoint [2] 0 0
Up to approximately 2 years and 4 months
Secondary outcome [3] 0 0
Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38
Timepoint [3] 0 0
For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Secondary outcome [4] 0 0
Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38
Timepoint [4] 0 0
For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Secondary outcome [5] 0 0
Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38
Timepoint [5] 0 0
For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Secondary outcome [6] 0 0
Phase 1, Total Clearance (CL) of Eribulin and Irinotecan
Timepoint [6] 0 0
For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Secondary outcome [7] 0 0
Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan
Timepoint [7] 0 0
For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Secondary outcome [8] 0 0
Phase 1, AUC(0-t): Area Under the Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38
Timepoint [8] 0 0
For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Secondary outcome [9] 0 0
Phase 1, AUC(0-inf): Area Under the Concentration-time Curve From Zero (Pre-dose) Extrapolated to Infinite Time of Eribulin, Irinotecan and Its Active Metabolite SN-38
Timepoint [9] 0 0
For eribulin, Cycle 1 Day 1: 0-120 hours post-eribulin infusion; For irinotecan and its metabolite, Cycle 1 Day 1: 0-24 hours post-irinotecan infusion (cycle length=21 days)
Secondary outcome [10] 0 0
Phase 2: Progression Free Survival (PFS)
Timepoint [10] 0 0
From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months
Secondary outcome [11] 0 0
Phase 2: Clinical Benefit Rate (CBR)
Timepoint [11] 0 0
From the date of first dose to the date of first documentation of PD, or date of death, whichever occurred first up to approximately 2 years 4 months
Secondary outcome [12] 0 0
Model Predicted Apparent Total Body Clearance (CL) of Eribulin
Timepoint [12] 0 0
Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)
Secondary outcome [13] 0 0
Volume of Distribution Estimates From the Population PK Model for Eribulin
Timepoint [13] 0 0
Cycle 1 Day 1: 0.5-120 hours after eribulin infusion; Cycle 1 Day 8: pre-dose and at the end of the eribulin infusion (cycle length=21 days)

Eligibility
Key inclusion criteria
Participants must be

* >=12 months to less than or equal to (<=) 25 years old at the time of consent [no more than 25 percent (%) of participants between the ages of 18 and 25 years will be enrolled in this study].
* In Phase 1, >6 months and <12 months at the time of consent (Schedule A only) participants will be enrolled one dose level behind the >=12 months participant in order to maximize safety for infant participants. In Phase 2, participants aged >6 months and <12 months at the time of consent will be enrolled to Schedule A with a modified dose of eribulin with the irinotecan dose maintained in order to maximize safety for infant participants.



* Phase 1: Participants must be diagnosed with histologically confirmed solid tumors (excluding CNS tumors), which is relapsed or refractory, and for which there are no currently available therapies.
* Phase 2: Participants must be diagnosed with histologically confirmed RMS, NRSTS or EWS which is relapsed or refractory having received at least 1 prior therapy, including primary treatment.
* Phase 1: Participants must have either measurable or evaluable disease as per RECIST 1.1.
* Phase 2: Participants must have measurable disease as per RECIST 1.1.
* Participant's current disease state must be one for which there is no known curative therapy.
* Participant's performance score must be >=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 the performance score.
* Participants must have fully recovered from the acute toxic effects of all prior anticancer treatments prior to study drug administration:

* Must not have received myelosuppressive chemotherapy within 21 days prior to study drug administration (42 days if prior nitrosourea).
* Must not have received a long-acting growth factor (example, Neulasta) within 14 days or a short-acting growth factor within 7 days.
* Must not have received an antineoplastic targeted therapy within 14 days.
* Must not have received immunotherapy, example, tumor vaccines, within 42 days.
* Must not have received monoclonal antibodies within at least 3 half-lives of the antibody after its last dose.
* Must not have received radiotherapy (XRT) within 14 days prior to study drug administration (small field) or 42 days for craniospinal XRT, or if >=50% radiation of pelvis.
* At least 84 days must have elapsed after stem cell infusion prior to study drug administration
* No evidence of active graft-versus-host disease (GVHD) and at least 100 days must have elapsed after allogeneic bone marrow transplant or stem cell infusion prior to study drug administration
* Participants must have adequate bone marrow function, defined as:

* Peripheral absolute neutrophil count (ANC) >=1.0*10^9/liter (L).
* Platelet count >=100*10^9/L (not receiving platelet transfusions within a 7-day period prior to study drug administration).
* Hemoglobin (Hb) at least 8.0 grams per deciliter (g/dL) at baseline (blood transfusions are allowed during the screening period to correct Hb values <8.0 g/dL).
* Participants must have adequate renal function, defined as:

* A serum creatinine based on age/gender, derived from the Schwartz formula for estimating glomerular filtration rate (GFR), per protocol-specified criteria.
* Serum creatinine clearance or GFR >=50 milliliters/minute/1.73 m^2, based on a 12 or 24 hours (h) urine creatinine collection.
* Participants must have adequate liver function, defined as:

* Bilirubin (sum of conjugated + unconjugated) <=1.5 times the upper limit of normal (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.
* All participants and/or their parents or guardians must sign a written informed consent.
* Participants must be willing to comply with all aspects of the protocol.
Minimum age
6 Months
Maximum age
25 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 h 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, that is:
* 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.
* Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (that is, 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:

* Participants receiving corticosteroids who have not been on a stable dose for at least 7 days prior to study drug administration.
* Participants who are currently receiving other anticancer agents.
* Participants who are receiving cyclosporine, tacrolimus or other agents to prevent GVHD post bone marrow transplant.
* Participants who are receiving strong cytochrome P450 3A4 (CYP3A4) inhibitors and inducers including traditional herbal medicinal products (example, St. John's Wort).
* 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 (for prior irinotecan hydrochloride, participants can be included if there was no tumor progression during irinotecan therapy).
* Any other malignancy that required treatment (except non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ), within 2 years prior to study drug administration.
* Has hypersensitivity to either study drug or any of the excipients.
* 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
* 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, defined as:

* 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 QT interval (QTc)>480 milliseconds 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 and have discontinued the use of corticosteroids for this indication for at least 28 days prior to study drug administration. Participants must be clinically stable. It is not the intention of this protocol to treat participants with active brain metastases.

Note: Screening CNS imaging for participants with a known history of CNS disease is required.

* 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.
* 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.
* Participants with known human immunodeficiency virus (HIV); due to lack of available safety data for eribulin therapy in HIV infected participants.
* 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 (including active or severe chronic inflammatory bowel disease or bowel obstruction).
* 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
5/03/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
17/05/2021
Sample size
Target
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
France
State/province [1] 0 0
Bouches-du-Rhône
Country [2] 0 0
France
State/province [2] 0 0
Nord
Country [3] 0 0
France
State/province [3] 0 0
Rhône
Country [4] 0 0
Germany
State/province [4] 0 0
Baden-Württemberg
Country [5] 0 0
Germany
State/province [5] 0 0
Hessen
Country [6] 0 0
Germany
State/province [6] 0 0
Niedersachsen
Country [7] 0 0
Germany
State/province [7] 0 0
Nordrhein-Westfalen
Country [8] 0 0
Germany
State/province [8] 0 0
Berlin
Country [9] 0 0
Germany
State/province [9] 0 0
Essen
Country [10] 0 0
Greece
State/province [10] 0 0
Attiki
Country [11] 0 0
Greece
State/province [11] 0 0
Thessaloníki
Country [12] 0 0
Italy
State/province [12] 0 0
Emilia-Romagna
Country [13] 0 0
Italy
State/province [13] 0 0
Lazio
Country [14] 0 0
Italy
State/province [14] 0 0
Liguria
Country [15] 0 0
Italy
State/province [15] 0 0
Piemonte
Country [16] 0 0
Italy
State/province [16] 0 0
Toscana
Country [17] 0 0
Italy
State/province [17] 0 0
Veneto
Country [18] 0 0
Italy
State/province [18] 0 0
Milan
Country [19] 0 0
Poland
State/province [19] 0 0
Dolnoslaskie
Country [20] 0 0
Poland
State/province [20] 0 0
Mazowieckie
Country [21] 0 0
Spain
State/province [21] 0 0
Cataluña
Country [22] 0 0
Spain
State/province [22] 0 0
Madrid
Country [23] 0 0
Spain
State/province [23] 0 0
Sevilla
Country [24] 0 0
Spain
State/province [24] 0 0
Valencia
Country [25] 0 0
Switzerland
State/province [25] 0 0
Zürich
Country [26] 0 0
United Kingdom
State/province [26] 0 0
Cambridgeshire
Country [27] 0 0
United Kingdom
State/province [27] 0 0
Hampshire
Country [28] 0 0
United Kingdom
State/province [28] 0 0
Merseyside
Country [29] 0 0
United Kingdom
State/province [29] 0 0
Oxfordshire
Country [30] 0 0
United Kingdom
State/province [30] 0 0
Surrey
Country [31] 0 0
United Kingdom
State/province [31] 0 0
West Midlands
Country [32] 0 0
United Kingdom
State/province [32] 0 0
Yorkshire
Country [33] 0 0
United Kingdom
State/province [33] 0 0
London
Country [34] 0 0
United Kingdom
State/province [34] 0 0
Manchester
Country [35] 0 0
United Kingdom
State/province [35] 0 0
Newcastle

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Eisai Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The Phase 1 part of the study is conducted to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory solid tumors (excluding central nervous system \[CNS\] tumors).

The Phase 2 part of the study is conducted to assess the objective response rate (ORR) and duration of response (DOR) of eribulin mesilate in combination with irinotecan hydrochloride in pediatric participants with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and ewing sarcoma (EWS).
Trial website
https://clinicaltrials.gov/study/NCT03245450
Trial related presentations / publications
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT03245450