| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Soft tissue sarcoma (STS) |
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| E.1.1.1 | Medical condition in easily understood language |
Cancers of the supporting tissues of the body, including the muscles, nerves, fat, blood vessels and deep skin tissues
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10041299 |
| E.1.2 | Term | Soft tissue sarcomas |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare overall survival (OS) in subjects with advanced soft tissue sarcoma ([STS], one of two subtypes: adipocytic [ADI] or leiomyosarcoma [LMS]) when treated with eribulin (Arm A) or dacarbazine (Arm B). |
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| E.2.2 | Secondary objectives of the trial |
(1)To compare progression-free survival (PFS) between Arm A and Arm B.
(2)To compare progression-free rate at Week 12 (PFR12wks) between Arm A and Arm B.
(3)To compare the clinical benefit rate ([CBR], complete response (CR) or partial response (PR) or durable stable disease ([dSD] duration of stable disease (SD) ≥ 11 weeks) between Arm A and Arm B.
(4)To compare the safety and tolerability between Arm A and Arm B.
(5)To characterize the population pharmacokinetics (PK) of eribulin in subjects with STS.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
(1) Histologically confirmed diagnosis of soft tissue sarcoma of high or intermediate grade with one of the following histological subtypes:
(1a) Adipocytic sarcoma, including:
i. Dedifferentiated
ii. Myxoid
iii. Round Cell
iv. Pleomorphic.
(1b). Leiomyosarcoma.
(2) Documented evidence of advanced (locally recurrent, locally advanced and/or metastatic) adipocytic (restricted to subtypes listed in Inclusion 1) or leiomyosarcoma, incurable by surgery and/or radiotherapy.
(3) Subjects should have received at least two standard systemic regimens for advanced soft tissue sarcoma one of which must have included an anthracycline (unless contraindicated)
(4) Radiographic evidence of disease progression by RECIST criteria on or after the last anti-cancer therapy within the 6 months prior to randomization.
(5) Presence of measurable disease meeting the following criteria:
(5a) At least one lesion of ≥ 1.0 cm in long-axis diameter for non lymph nodes or ≥ 1.5 cm in short-axis diameter for lymph nodes which is serially measurable according to RECIST 1.1 using either computerized tomography or magnetic resonance imaging or panoramic and close-up color photography. If there is only one target lesion and it s a non-lymph node, it should have a long-axis diameter of at least 1.5 cm.
(5b) Lesions that have had radiotherapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion.
(6) Eastern Cooperative Oncology Group performance status of 0, 1 or 2.
(7) Adequate renal function defined as calculated creatinine clearance ≥ 50 mL/min per the Cockroft and Gault formula.
(8) Adequate bone marrow function, defined as:
(8a) ANC ≥ 1,500/mm3 or ≥ 1.5 x 10^9/L.
(8b) Platelet count ≥ 100,000/mm3 or ≥ 100 x 10^9/L.
(8c) Hemoglobin (Hb) ≥ 10g/dL at baseline (blood transfusions, hematopoietic growth factors and hematinics are allowed during the Prerandomization Phase to correct Hb values < 10g/dL).
(9) Adequate liver function, defined as:
(9a) Bilirubin ≤ 1.5 times the ULN except for unconjugated hyperbilirubinemia of Gilbert’s syndrome.
(9b) ALP and AST ≤ 3 times ULN. For total ALP >3 times ULN, the ALP liver isoenzyme must be ≤ 3 times ULN.
(10) Female subjects of child-bearing potential must agree to use two forms of highly effective contraception from the last menstrual period prior to randomization (or use a double barrier method until they are on two forms of highly effective contraception for at least one menstrual cycle), during the study treatment, and for 3 months after the final dose of study treatment.
(11) Male subjects and their female partner who are of child-bearing potential (as defined in Inclusion 10), and are not practicing total abstinence, must agree to use two forms of highly effective contraception from the last menstrual period of their female partner prior to randomization (or use a double barrier method until they are on two forms of highly effective contraception for at least one menstrual cycle), during study treatment, and for 3 months (or 6 months if they received dacarbazine) after the final dose of study treatment.
(12) Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
(13) Males or females aged ≥ 18 years at the time of informed consent.
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| E.4 | Principal exclusion criteria |
(1) Subjects who have received any anti-cancer therapy, including surgery or intratumoral therapy, radiotherapy, chemotherapy, hormonal, biological (including humanized antibodies) immunotherpay and targeted agents within 21 days, or five half-lives of the drug (whichever ist longer) prior to randomization.
(2) Subjects who have not recovered from acute toxicities as a result of prior anti-cancer therapy to ≤ Grade 1, according to Common Terminology Criteria for Adverse Events (CTCAE), except for peripheral neuropathy and alopecia.
(3) Subjects that have previously been treated with dacarbazine or its analogue temozolomide, or eribulin.
(4) Major surgery within 21 days prior to randomization.
(5) Pre-existing peripheral neuropathy > CTCAE Grade 2.
(6) Significant cardiovascular impairment, defined as:
(6a) Cardiac failure > New York Heart Association (NYHA) Class II according to the NYHA Functional Classification,
(6b) Unstable angina or myocardial infarction within 6 months of enrolment,
(6c) Serious and potentially life-threatening arrythmia.
(7) Subjects with a high probability of Long QT syndrome, or QTc interval prolongation of more than or equal to 501 msec on at least two separate ECGs, following correction of any electrolyte imbalance.
(8) Subjects with known central nervous system metastases.
(9) Any serious concomitant illness or infectious disease requiring treatment, or infectious disease not requiring treatment, but with significant risks for myelosuppressive complications associated with chemotherapy.
(10) Any malignancy that required treatment, or has shown evidence of recurrence (except for soft tissue sarcoma, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ) during the 5 years prior to randomization.
(11) Female subjects must not be pregnant as documented by a negative beta-human chorionic gonadotropin (ß-hCG) test with a minimum sensitivity 25 IU/L or equivalent unit of ß-hCG at Screening and Baseline, or breastfeeding.
(12) Hypersensitivity to the active substance or any of the excipients of the eribulin drug product, or dacarbine (please refer to the dacarbazine prescribing information).
(13) Any medical or other condition which, in the opinion of the PI or designee, will preclude participation in a clinical trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival, measured from the date of randomization until date of death from any cause. Subjects who are lost to follow-up and the subjects who are alive at the date of data cut-off will be censored at the date the subject was last known alive. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| When the target number of events (estimated to be 353 deaths) has been observed |
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| E.5.2 | Secondary end point(s) |
(1)Progression-free survival, defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death (whichever occurs first). Progression free survival censoring rules will apply, and will be defined in the SAP.
(2)Progression-free rate at Week 12, defined as the proportion of subjects alive and progression-free at 12 weeks from the date of randomization.
(3)Clinical Benefit Rate, the proportion of subjects who have best overall response of CR or PR or dSD. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| When the target number of events (estimated to be 353 deaths) has been observed |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Romania |
| Russian Federation |
| Singapore |
| Spain |
| Thailand |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study will be when the last subject has died, unless the Sponsor decides to terminate survival follow-up for all subjects in the Extension Phase, once all subjects have discontinued study treatment. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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