Study Evaluating the Safety and Efficacy of Eribulin Mesilate in Combination With Irinotecan Hydrochloride in Children With Refractory or Recurrent Solid Tumors

Rhabdomyosarcoma Clinical Trial

Official 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03245450
• Other study ID #: E7389-G000-213
• Secondary ID: 2016-003352-67
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 5, 2018
• Est. completion date: May 17, 2021

Study information

• Verified date: June 2021
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: May 17, 2021
• Est. primary completion date: May 17, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Months to 25 Years

Eligibility

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.

Inclusion Criteria:

• 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.

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.

Related Conditions & MeSH terms

• Ewing Sarcoma
• Non-Rhabdomyosarcoma Soft Tissue Sarcoma
• Recurrence
• Refractory or Recurrent Solid Tumors
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing

Intervention

Drug:
• Eribulin mesilate
IV infusion
• Irinotecan hydrochloride
IV infusion

Locations

Country	Name	City	State
France	Centre Oscar Lambret	Lille	Nord
France	Centre Léon Berard	Lyon	Rhône
France	Hopitaux de La Timone	Marseille	Bouches-du-Rhône
Germany	Eisai Trial Site 1	Aachen	Nordrhein-Westfalen
Germany	Eisai Trial Site 3	Berlin
Germany	Eisai Trial Site 6	Essen
Germany	Eisai Trial Site 2	Frankfurt	Hessen
Germany	Eisai Trial Site 4	Freiburg	Baden-Württemberg
Germany	Eisai Trial Site 5	Gottingen	Niedersachsen
Greece	Aghia Sophia' Children's General Hospital of Athens	Athens	Attiki
Greece	AHEPA University General Hospital of Thessaloniki	Thessaloníki
Italy	Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi	Bologna	Emilia-Romagna
Italy	Azienda Ospedaliera A Meyer	Firenze	Toscana
Italy	Istituto G Gaslini Ospedale Pediatrico IRCCS	Genova	Liguria
Italy	Istituto Nazionale Dei Tumori	Milan
Italy	Azienda Ospedaliera Di Padova	Padova	Veneto
Italy	Fondazione Policlinico Universitario A Gemelli	Roma	Lazio
Italy	Ospedale Pediatrico Bambino Gesù	Roma	Lazio
Italy	Ospedale Infantile Regina Margherita	Torino	Piemonte
Poland	Instytut Pomnik Centrum Zdrowia Dziecka	Warszawa	Mazowieckie
Poland	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu	Wroclaw	Dolnoslaskie
Spain	Hospital Universitario Vall d'Hebron - PPDS	Barcelona	Cataluña
Spain	Hospital Sant Joan de Deu	Esplugues De Llobregat	Cataluña
Spain	Hospital Infantil Universitario Niño Jesus	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitari i Politecnic La Fe de Valencia	Valencia
Switzerland	Kinderspital Zürich - Eleonorenstiftung	Zürich
United Kingdom	Birmingham Children's Hospital	Birmingham	West Midlands
United Kingdom	Addenbrooke's Hospital	Cambridge	Cambridgeshire
United Kingdom	The Leeds Teaching Hospitals Charitable Foundation - Leeds Childrens Hospital (LCH)	Leeds	Yorkshire
United Kingdom	Alder Hey Childrens Hospital	Liverpool	Merseyside
United Kingdom	University College London	London
United Kingdom	Royal Manchester Childrens Hospital	Manchester
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Royal Victoria Infirmary	Newcastle
United Kingdom	John Radcliffe Hospital	Oxford	Oxfordshire
United Kingdom	Southampton General Hospital	Southampton	Hampshire
United Kingdom	Royal Marsden Hospital - Surrey	Sutton	Surrey

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Countries where clinical trial is conducted

France,  Germany,  Greece,  Italy,  Poland,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride	The RP2D was evaluated based on a review of the outcomes of safety (including dose limiting toxicities [DLTs]), tumor assessments, and pharmacokinetic (PK) in Phase 1 by investigators and the study team.	First dose of study drug up to Cycle 1 (Cycle length=21 days)
Primary	Phase 2: Objective Response Rate (ORR)	ORR was defined as the percentage of participants achieving best overall response (BOR) of confirmed partial response (PR) or complete response (CR) determined by investigator assessment per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis less than (<) 10 millimeter (mm). PR was at least a 30 percent (%) decrease in the sum of diameter (SOD) of target lesions, taking as reference the baseline sum diameters.	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	Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment, or reemerged during treatment, having been present at pre-treatment (baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.	From first dose of study drug up to approximately 2 years 4 months
Secondary	Number of Participants With Serious Adverse Event (SAE)	SAE was defined as any untoward medical occurrence at any dose if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect.	Up to approximately 2 years and 4 months
Secondary	Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38		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	Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38		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	Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38	Half-life for irinotecan and metabolite SN-38 could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm as the slope of the terminal phase of the concentration-time profiles could not be determined.	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	Phase 1, Total Clearance (CL) of Eribulin and Irinotecan	CL for irinotecan could not be estimated for phase 1:schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.	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	Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan	Vz for irinotecan could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.	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	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		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	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	AUC(0-inf) for irinotecan and metabolite SN-38 could not be estimated for phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 20 mg/m^2 and phase 1: schedule A, eribulin mesilate 1.4 mg/m^2 + irinotecan 40 mg/m^2 arm because it was not possible to calculate half-life as the slope of the terminal phase of the concentration-time profiles could not be determined.	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	Phase 2: Progression Free Survival (PFS)	PFS was defined as the time from date of first dose to the date of disease progression (PD). PFS was assessed based on the investigators' assessments utilizing RECIST 1.1. PD was defined as at least 20% increase or 5 mm increase in the sum of diameters of target lesions recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method.	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	Phase 2: Clinical Benefit Rate (CBR)	CBR was defined as the percentage of participants with BOR of CR, PR, or durable stable disease (SD) based on RECIST 1.1 (durable SD was defined as SD with duration of greater than [>] 11 weeks). CR was defined as disappearance of all target and non-target lesions. All pathological (whether target or non-target) must have a reduction in their short axis <10 mm. PR was defined as at least 30% decrease in the SOD of target lesions, taking as reference the baseline sum diameters.	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	Model Predicted Apparent Total Body Clearance (CL) of Eribulin	Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. The data presented are the CL parameter estimates, with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.	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	Volume of Distribution Estimates From the Population PK Model for Eribulin	Per the planned PK analysis, PK samples were collected and analyzed using a population PK approach to estimate PK parameters. Eribulin plasma concentration data from this study were pooled from studies (NCT00069264, NCT00069277, NCT00326950, NCT00706095, NCT01000376, NCT01106248, NCT02171260, NCT00413192, NCT01458249, NCT03441360 and NCT01327885), and a population PK model was applied to the pooled dataset. Data presented are the volume of distribution of the central compartment (V1), volume of distribution of the first peripheral compartment (V2), and volume of distribution of the second peripheral compartment (V3) parameter estimates with Measure Type "Number" defining the eribulin PK model. They are population PK model predictions and have been estimated using non-linear mixed effects model.	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)