Ewing Sarcoma, Non-Rhabdomyosarcoma Soft Tissue Sarcoma, Refractory or Recurrent Solid Tumors, Rhabdomyosarcoma
Conditions
Keywords
eribulin mesilate, irinotecan, combination therapy, children
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).
Interventions
IV infusion
DRUGIrinotecan hydrochloride
IV infusion
Sponsors
Eisai Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 25 Years
Healthy volunteers
No
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. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride | First dose of study drug up to Cycle 1 (Cycle length=21 days) | 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. |
| Phase 2: Objective Response Rate (ORR) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | — |
| 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) | — |
| Phase 1, T1/2: Half-life 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) | 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. |
| Phase 1, Total Clearance (CL) of Eribulin and Irinotecan | 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) | 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. |
| Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan | 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) | 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. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug up to approximately 2 years 4 months | 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. |
| 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 | 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) | 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. |
| Phase 2: Progression Free Survival (PFS) | 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 | 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. |
| Phase 2: Clinical Benefit Rate (CBR) | 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 | 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. |
| Model Predicted Apparent Total Body Clearance (CL) of Eribulin | 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) | 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. |
| Volume of Distribution Estimates From the Population PK Model for Eribulin | 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) | 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. |
| 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) | — |
| Number of Participants With Serious Adverse Event (SAE) | Up to approximately 2 years and 4 months | 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. |
Countries
France, Germany, Greece, Italy, Poland, Spain, Switzerland, United Kingdom
Participant flow
Recruitment details
Participants took part in the study at 22 investigative sites in France, Germany, Greece, Italy, Poland, Spain and United Kingdom from 05 March 2018 to 17 May 2021.
Pre-assignment details
A total of 46 participants were screened, out of which 13 participants were treated in the Phase 1 and 27 participants were treated in Phase 2 (9 participants each in the relapsed/refractory rhabdomyosarcoma \[RMS\], non-rhabdomyosarcoma soft tissue sarcoma \[NRSTS\], and Ewing sarcoma \[EWS\] cohorts).
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2 Participants received eribulin mesilate 1.4 mg/m\^2 intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 20 mg/m\^2, intravenous infusion on Days 1 to 5 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent. | 3 |
| Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 Participants received eribulin mesilate 1.4 mg/m\^2, intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 40 mg/m\^2, intravenous infusion on Days 1 to 5 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent. | 4 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2 Participants received eribulin mesilate 1.4 mg/m\^2 and irinotecan hydrochloride 100 mg/m\^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent. | 3 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 Participants received eribulin mesilate 1.4 mg/m\^2 and irinotecan hydrochloride 125 mg/m\^2 intravenous infusion on Days 1 and 8 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent. | 3 |
| Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 Participants with RMS received eribulin mesilate 1.4 mg/m\^2, intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 40 mg/m\^2, intravenous infusion on Days 1 to 5 in every 21 days treatment cycle until disease progression, development of intolerable toxicity or withdrawal of consent. | 9 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 Participants with NRSTS received eribulin mesilate 1.4 mg/m\^2, intravenous infusion on Days 1 and 8 and irinotecan hydrochloride 40 mg/m\^2, intravenous infusion on Days 1 to 5 in every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent. | 9 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 Participants with EWS received eribulin mesilate 1.4 mg/m\^2, intravenous infusion on Days 1 and 8 and Irinotecan hydrochloride 40 mg/m\^2, intravenous infusion on Days 1 to 5 in every 21 days treatment cycle until disease progression, development of unacceptable toxicity or withdrawal of consent. | 9 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 2 |
| Overall Study | Clinical disease progression | 0 | 0 | 1 | 0 | 0 | 2 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 1 | 1 | 1 | 1 |
| Overall Study | Radiological disease progression | 3 | 3 | 2 | 2 | 7 | 6 | 6 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Total | Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 100 mg/m^2 | Phase 1: Schedule A, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 20 mg/m^2 | Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous Phase 1 | 7.33 years STANDARD_DEVIATION 2.54 | 9.87 years STANDARD_DEVIATION 4.842 | 8.06 years STANDARD_DEVIATION 4.997 | 13.97 years STANDARD_DEVIATION 4.231 | 10.94 years STANDARD_DEVIATION 6.583 | — | — | — |
| Age, Continuous Phase 2 | — | 11.78 years STANDARD_DEVIATION 3.899 | — | — | — | 11.59 years STANDARD_DEVIATION 3.753 | 11.05 years STANDARD_DEVIATION 3.845 | 12.71 years STANDARD_DEVIATION 4.348 |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 20 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants | 6 Participants |
| Age, Customized Children (2-11 years) | 4 Participants | 20 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 38 Participants | 3 Participants | 3 Participants | 3 Participants | 9 Participants | 9 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 4 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 33 Participants | 3 Participants | 2 Participants | 3 Participants | 8 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Female | 1 Participants | 19 Participants | 2 Participants | 2 Participants | 2 Participants | 5 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 21 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 4 | 1 / 3 | 1 / 3 | 4 / 9 | 3 / 9 | 3 / 9 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 3 / 3 | 3 / 3 | 9 / 9 | 9 / 9 | 9 / 9 |
| serious Total, serious adverse events | 1 / 3 | 3 / 4 | 0 / 3 | 1 / 3 | 5 / 9 | 4 / 9 | 3 / 9 |
Outcome results
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.
Time frame: First dose of study drug up to Cycle 1 (Cycle length=21 days)
Population: The Dose Evaluable Set (DES) for Phase 1 included all the participants who completed Cycle 1 treatment and were evaluated for DLTs and those who discontinued treatment during Cycle 1 due to DLTs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants | Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride | Eribulin Mesilate | 1.4 mg/m^2 |
| Phase 1: All Participants | Phase 1: Recommended Phase 2 Dose (RP2D) of Eribulin Mesilate in Combination With Irinotecan Hydrochloride | Irinotecan Hydrochloride | 40 mg/m^2 |
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.
Time frame: 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
Population: Full analysis set included all participants who received at least 1 dose of either study drug.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | Phase 2: Objective Response Rate (ORR) | 11.1 percentage of participants | 90% Confidence Interval 0.6 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: Objective Response Rate (ORR) | 11.1 percentage of participants | 90% Confidence Interval 0.6 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: Objective Response Rate (ORR) | 11.1 percentage of participants | 90% Confidence Interval 0.6 |
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.
Time frame: 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)
Population: PK analysis set included all participants who had documented dosing history had at least one postdosing quantifiable drug concentration. Analysis population for this outcome measure included participants from current study E7389-G000-213 and from studies (NCT00069264,NCT00069277,NCT00326950,NCT00706095,NCT01000376,NCT01106248,NCT02171260, NCT00413192,NCT01458249,NCT03441360,NCT01327885).Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: All Participants | Model Predicted Apparent Total Body Clearance (CL) of Eribulin | 2.89 L/hr |
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.
Time frame: Up to approximately 2 years and 4 months
Population: Safety analysis set included all participants who received at least 1 dose of either study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: All Participants | Number of Participants With Serious Adverse Event (SAE) | 1 Participants |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Serious Adverse Event (SAE) | 3 Participants |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Serious Adverse Event (SAE) | 0 Participants |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Number of Participants With Serious Adverse Event (SAE) | 1 Participants |
| Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Serious Adverse Event (SAE) | 5 Participants |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Serious Adverse Event (SAE) | 4 Participants |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Serious Adverse Event (SAE) | 3 Participants |
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.
Time frame: From first dose of study drug up to approximately 2 years 4 months
Population: Safety analysis set included all participants who received at least 1 dose of either study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: All Participants | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 4 Participants |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 2: RMS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 9 Participants |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 9 Participants |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 9 Participants |
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.
Time frame: 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)
Population: PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants | 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 | Eribulin | 438.1 h*ng/mL | Geometric Coefficient of Variation 39 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Eribulin | 506.0 h*ng/mL | Geometric Coefficient of Variation 16.6 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Irinotecan | 5036.1 h*ng/mL | Geometric Coefficient of Variation 70.9 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Eribulin | 666.9 h*ng/mL | Geometric Coefficient of Variation 69 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Metabolite SN-38 | 169.0 h*ng/mL | Geometric Coefficient of Variation 51.4 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | 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 | Irinotecan | 3698.5 h*ng/mL | Geometric Coefficient of Variation 39.2 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | 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 | Metabolite SN-38 | 149.4 h*ng/mL | Geometric Coefficient of Variation 4.3 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | 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 | Eribulin | 576.9 h*ng/mL | Geometric Coefficient of Variation 133.6 |
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
Time frame: 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)
Population: PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants | 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 | Metabolite SN-38 | 68.00 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 19.7 |
| Phase 1: All Participants | 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 | Eribulin | 422.5 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 40 |
| Phase 1: All Participants | 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 | Irinotecan | 1812.6 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 13.5 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Irinotecan | 3686.1 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 36.4 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Eribulin | 403.7 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.1 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Metabolite SN-38 | 145.04 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 11.6 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Metabolite SN-38 | 138.22 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 42.2 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Eribulin | 616.9 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 66.1 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | 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 | Irinotecan | 4693.9 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 66.1 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | 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 | Irinotecan | 3633.7 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 38.9 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | 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 | Eribulin | 603.5 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 87.3 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | 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 | Metabolite SN-38 | 65.47 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 153.2 |
Secondary
Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38
Time frame: 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)
Population: PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 369.3 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 58 |
| Phase 1: All Participants | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 6.518 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 9.4 |
| Phase 1: All Participants | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 538.8 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 165.9 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 179.4 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 136.1 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 17.170 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 39.7 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 399.5 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 19.1 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 1168.1 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 39.8 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 348.7 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 25 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 25.409 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 51.6 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 323.3 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 20.6 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 18.614 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 74.3 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Cmax: Maximum Observed Plasma Concentration of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 1555.4 nanogram/milliliter (ng/mL) | Geometric Coefficient of Variation 39.5 |
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.
Time frame: 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)
Population: PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: All Participants | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 27.50 hours |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 34.70 hours |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 5.140 hours |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 30.00 hours |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Metabolite SN-38 | 12.000 hours |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 4.430 hours |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Metabolite SN-38 | 10.390 hours |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, T1/2: Half-life of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 25.30 hours |
Secondary
Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38
Time frame: 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)
Population: PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 0.250 hours | Full Range 0.07 |
| Phase 1: All Participants | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 0.420 hours | Full Range 0.25 |
| Phase 1: All Participants | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 0.080 hours | Full Range 0.03 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 0.305 hours | Full Range 0 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 0.305 hours | Full Range 0 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 0.135 hours | Full Range 0.03 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 0.080 hours | Full Range 0 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 0.300 hours | Full Range 0.03 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 0.330 hours | Full Range 0.3 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Irinotecan | 0.170 hours | Full Range 0.13 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Eribulin | 0.050 hours | Full Range 0.01 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) of Eribulin, Irinotecan and Its Active Metabolite SN-38 | Active Metabolite SN-38 | 0.250 hours | Full Range 0.13 |
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.
Time frame: 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)
Population: PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants | Phase 1, Total Clearance (CL) of Eribulin and Irinotecan | Eribulin | 3.1781 liter per hour (L/h) | Geometric Coefficient of Variation 43.9 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Total Clearance (CL) of Eribulin and Irinotecan | Eribulin | 2.4581 liter per hour (L/h) | Geometric Coefficient of Variation 8 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Total Clearance (CL) of Eribulin and Irinotecan | Eribulin | 2.9060 liter per hour (L/h) | Geometric Coefficient of Variation 32.8 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Total Clearance (CL) of Eribulin and Irinotecan | Irinotecan | 27.27 liter per hour (L/h) | Geometric Coefficient of Variation 23.2 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Total Clearance (CL) of Eribulin and Irinotecan | Eribulin | 1.7521 liter per hour (L/h) | Geometric Coefficient of Variation 136.6 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Total Clearance (CL) of Eribulin and Irinotecan | Irinotecan | 30.30 liter per hour (L/h) | Geometric Coefficient of Variation 60.7 |
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.
Time frame: 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)
Population: PK analysis set included participants who had documented dosing history and at least one post-dosing quantifiable drug concentration. Here 'N' (overall number of participants analyzed) included all participants who were evaluable for this outcome measure and 'n' (number analyzed) included all participants who were evaluable for each category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: All Participants | Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan | Eribulin | 124.70 liter | Geometric Coefficient of Variation 41.5 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan | Eribulin | 126.96 liter | Geometric Coefficient of Variation 18.1 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan | Eribulin | 130.78 liter | Geometric Coefficient of Variation 35.9 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan | Irinotecan | 248.5 liter | Geometric Coefficient of Variation 16.1 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan | Eribulin | 63.35 liter | Geometric Coefficient of Variation 101.8 |
| Phase 1: Schedule B, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 125 mg/m^2 | Phase 1, Volume of Distribution (Vz) of Eribulin and Irinotecan | Irinotecan | 195.1 liter | Geometric Coefficient of Variation 69 |
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.
Time frame: 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
Population: Full analysis set included all participants who received at least 1 dose of either study drug.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | Phase 2: Clinical Benefit Rate (CBR) | 55.6 percentage of participants | 90% Confidence Interval 25.1 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: Clinical Benefit Rate (CBR) | 33.3 percentage of participants | 90% Confidence Interval 9.8 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: Clinical Benefit Rate (CBR) | 55.6 percentage of participants | 90% Confidence Interval 25.1 |
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.
Time frame: 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
Population: Full analysis set included all participants who received at least 1 dose of either study drug.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1: All Participants | Phase 2: Progression Free Survival (PFS) | 2.69 months | 90% Confidence Interval 1.28 |
| Phase 2: NRSTS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: Progression Free Survival (PFS) | 1.35 months | 90% Confidence Interval 1.15 |
| Phase 2: EWS Cohort, Eribulin Mesilate 1.4 mg/m^2 + Irinotecan 40 mg/m^2 | Phase 2: Progression Free Survival (PFS) | 6.70 months | 90% Confidence Interval 1.38 |
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.
Time frame: 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)
Population: PK analysis set included all participants who had documented dosing history had at least one postdosing quantifiable drug concentration. Analysis population for this outcome measure included participants from current study E7389-G000-213 and from studies (NCT00069264,NCT00069277,NCT00326950,NCT00706095,NCT01000376,NCT01106248,NCT02171260, NCT00413192,NCT01458249,NCT03441360,NCT01327885).Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: All Participants | Volume of Distribution Estimates From the Population PK Model for Eribulin | V1 | 4.08 liter |
| Phase 1: All Participants | Volume of Distribution Estimates From the Population PK Model for Eribulin | V2 | 2.03 liter |
| Phase 1: All Participants | Volume of Distribution Estimates From the Population PK Model for Eribulin | V3 | 106 liter |