An Open-label, Multicenter, Multiple Dose, Phase 1 Study to Establish the Maximum Tolerated Dose of E7389 Liposomal Formulation in Patients With Solid Tumors

NCT01945710 | Completed Phase 1 Results

• 2 other identifiers: E7389-E044-1122012-001184-69
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 4

Brief Summary

Study E7389-E044-112 is a Phase 1 study designed to assess the safety, tolerability and preliminary efficacy of eribulin-liposomal formulation (E7389-LF) in patients with solid tumors. This dose-escalation study will determine the maximum tolerated dose, dosing schedules tested, the dose schedule regimen with a more favorable tolerability profile, and a preliminary indication of efficacy.

Conditions

Solid Tumors

Keywords

Tumors

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of Eribulin-LF

  The MTD was defined as the highest dose level at which no more than 1/6 participants experienced a dose limiting toxicity (DLTs), with the next higher dose having at least 2 of 3 or 2 of 6 participants experiencing DLTs. MTD was determined by summarizing the number and percentage of participants with DLTs for the first cycle, by study dosing schedule, initial dosing level and overall for the dose escalation part. For participants who continued to Cycle 2, the DLTs which occurred from 1st dose up to the day before Day 1 of Cycle 2 were counted. For participants who discontinued before Cycle 2, the DLTs which occurred from 1st dose up to Day 21 (Schedule 1) or Day 28 (Schedule 2) of Cycle 1 were counted. DLTs were evaluated and graded based on the National Cancer Institutes (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

  Schedule 1: Cycle 1 (21 days); Schedule 2: Cycle 1 (28 days)

• Dose Limiting Toxicities at the Indicated Dose Levels, as an Assessment of Dosing Frequency

  DLTs were evaluated for both Schedule 1 and Schedule 2. DLTs were defined as neutropenia grade 4 that lasted more than 5 days, neutropenia grade 3 or 4 complicated by fever and/or infection (absolute neutrophil count (ANC) less than 1.0 x 10\^9/liter, fever greater than or equal to 38.5 degrees Celsius), thrombocytopenia grade 4 of any duration, thrombocytopenia grade 3 complicated by bleeding and/or requiring platelet or blood transfusion, hypersensitivity reaction grade 3 or 4 including allergy reactions or anaphylaxis; symptomatic bronchospasm requiring parenteral medication(s) with our without urticarial; allergy-related edema/angioedema, or other grade 3 or 4 clinically significant non-hematologic toxicities (except for inadequately treated nausea and /or vomiting) considered related to study drug. Participants with two or more adverse events in the same system organ class (or with the same preferred term) was counted only once for that system organ class (or preferred term).

  Cycle 1 of Dose Escalation part in Schedule 1 and Schedule 2

Secondary Outcomes (16)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) as a Measure of Safety and Tolerability of Eribulin-LF

  From date of first dose until 30 days after the final dose of study drug, up to approximately 3 years 6 months

• Maximum Plasma Concentration (Cmax) of Eribulin-LF

  Schedule 1: Cycle 1/Day 1 and Cycle 3/Day 1; Schedule 2: Cycle 1/Day 1 and Day 15 and Cycle 3/Day 1 and Day 15

• Time to Maximum Plasma Concentration (Tmax) of Eribulin-LF

  Schedule 1: Cycle 1/Day 1 and Cycle 3/Day 1; Schedule 2: Cycle 1/Day 1 and Day 15 and Cycle 3/Day 1 and Day 15

• Plasma Half-life (t1/2) of Eribulin-LF

  Schedule 1: Cycle 1/Day 1 and Cycle 3/Day 1; Schedule 2: Cycle 1/Day 1 and Day 15 and Cycle 3/Day 1 and Day 15

• Area Under the Plasma Concentration-Time Curve From Time 0 Time of Last Quantifiable Concentration (AUC(0-t) ) of Eribulin-LF

  Schedule 1: Cycle 1/Day 1 and Cycle 3/Day 1; Schedule 2: Cycle 1/Day 1 and Day 15 and Cycle 3/Day 1 and Day 15

Study Arms (2)

Eribulin-LF Schedule 1

EXPERIMENTAL

Schedule 1: Eribulin-LF administered as IV infusion on Day 1 of a 21-day cycle starting at 1 mg/m\^2 escalating up to 3.5 mg/m\^2. Schedule 1a: Eribulin-LF administered as IV infusion on Day 1 of a 28-day cycle starting at 1 mg/m\^2 escalating up to 3.5 mg/m\^2 (only to be investigated in the event that a 21-day cycle is considered inappropriate).

Drug: Eribulin-LF

Eribulin-LF Schedule 2

EXPERIMENTAL

Schedule 2: Eribulin-LF administered as IV infusion on Day 1 and Day 15 of a 28-day cycle starting at 1 mg/m\^2 escalating up to 3.5 mg/m\^2 (only to be investigated in the event that a 21-day cycle is considered appropriate).

Drug: Eribulin-LF

Interventions

Eribulin-LF DRUG

Also known as: E7389-liposomal formulation (E7389-LF), Eribulin mesylate, Eribulin mesilate

Eribulin-LF Schedule 1; Eribulin-LF Schedule 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 years or older.
• Histological or cytological evidence of an unresectable or refractory solid tumor.
• Participants who have at least one measurable lesion (long axis in non-lymph node: greater than or equal to 10 millimeters (mm); short axis in lymph node: greater than or equal to 15 mm) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the Expansion Part.
• Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limits of normal (ULN) and alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases less than or equal to 5 x ULN). In case ALP is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND participant also is known to have bone metastases, the liver specific ALP must be separated from the total and used to assess the liver function instead of the total ALP.
• Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 milligrams/deciliter (mg/dL) (177 micromole/liter (umol/L)) or calculated creatinine clearance greater than or equal to 40 milliliter/minute (mL/min) per the Cockcroft and Gault formula.
• Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9/liter (L), hemoglobin greater than or equal to 9 grams/deciliter (g/dL) (5.5 millimol/liter (mmol/L)) and platelet count greater than or equal to 100 x 10\^9/L.
• Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin \[B-hCG\]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least one month before dosing).
• Females of childbearing potential must not have had unprotected sexual intercourse within 30 days before study entry and must agree to use two highly effective methods of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method \[condom and occlusive cap - diaphragm or cervical/vault caps - with spermicidal foam/gel/film/cream/suppository\], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the participant must agree to use a double barrier method with spermicide as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation.
• Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation.
• Provide written informed consent.
• Willing and able to comply with all aspects of the protocol.

You may not qualify if:

• Females who are pregnant (positive B-hCG \[or hCG\] test) or breastfeeding.
• Participants who have received any anticancer therapy within 21 days prior to study entry for cytotoxic agents (42 days for mitomycin C and nitrosoureas), radiotherapy, hormonal, biological (including humanized antibodies) and targeted agents, or within 30 days for an investigational agent.
• Participants who have not recovered from acute toxicities as a result of prior anti-cancer therapy to less than Grade 2, according to Common Terminology Criteria for Adverse Events (CTCAE), except alopecia.
• Participants who have previously been treated with eribulin-LF.
• Radiation therapy encompassing greater than 30% of the bone marrow.
• Major surgery within 21 days prior to enrollment.
• Pre-existing peripheral neuropathy greater than CTCAE Grade 1.
• Significant cardiovascular impairment, defined as:
• Congestive heart failure greater than Class II according to the New York Heart Association.
• Unstable angina or myocardial infarction within 6 months of enrollment, or cardiac arrhythmia requiring treatment.
• A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT/QTc interval (e.g., a repeated demonstration of a QTc interval greater than 500 milliseconds (ms)).
• A history of risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT Syndrome) or the use of concomitant medications that prolonged the QT/QTc interval.
• Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments.
• Diagnosed with meningeal carcinomatosis.
• Participants with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks prior to enrollment. Any symptom(s) attributed to brain metastases must be stable for at least 4 weeks prior to enrollment, and radiographic stability should be confirmed by comparing a brain scan (CT with contrast or MRI with and without contrast) performed during the Screening Period to a brain scan performed at least 4 weeks earlier using the same modality.

Sponsors & Collaborators

• Eisai Limited: lead

Study Sites (4)

Royal Marsden Hospital

Sutton, Surrey, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, United Kingdom

Location

UCL Cancer Institute

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

MeSH Terms

Conditions

Neoplasms

Interventions

eribulin

Results Point of Contact

• Title: Eisai Medical Information
• Organization: Eisai Inc.

esi_medinfo@eisai.com

1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 16, 2013
• First Posted: September 18, 2013
• Study Start: December 11, 2012
• Primary Completion: October 1, 2015
• Study Completion: May 17, 2016
• Last Updated: July 23, 2019
• Results First Posted: July 23, 2019

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will share

Locations

GB (4)