| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Non-Small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare overall survival (OS) in subjects with advanced non-small cell lung cancer (NSCLC) when treated with eribulin (Arm A) and treatment of physician’s choice ([TPC] Arm B). |
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| E.2.2 | Secondary objectives of the trial |
To compare progression-free survival (PFS) between Arm A and Arm B.
To compare the objective response rate (ORR) between Arm A and Arm B.
To compare safety and tolerability between Arm A and Arm B.
To characterize the population pharmacokinetics (PK) of eribulin in subjects with advanced NSCLC. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed diagnosis of NSCLC.
2. Documented evidence of advanced NSCLC not amenable to surgery or radiotherapy.
3. Confirmation of the presence or absence of EGFR mutations prior to study enrolment in all subjects. Subjects with unknown EGFR mutational status and who have received prior treatment with an EGFR TKI can be enrolled, but an archived tumor sample, or if unavailable, a tumor sample obtained prior to randomisation, where feasible, must be made available to perform EGFR mutational analysis.
4. Subjects must have received at least two prior regimens for advanced NSCLC, which should have included a platinum-based regimen and, in all subjects with tumors harbouring EGFR mutations, an EGFR TKI.
5. Radiographic evidence of disease progression on, or after, the last anti-cancer regimen prior to study entry.
6. Presence of measurable disease meeting the following criteria:
a. At least one lesion of at least 1.0 cm in the long-axis diameter for a non-lymph node or at least 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using either CT or MRI. If there is only one target lesion and it is a non-lymph node, it should have a longest diameter of at least 1.5 cm.
b. Lesions previously treated with radiotherapy must show radiographic evidence of disease progression to be deemed a target lesion.
7. ECOG performance status of 0, 1, or 2.
8. Adequate renal function, defined as calculated creatinine clearance greater than or equal to 50 mL/min, using the Cockcroft and Gault formula.
9. Adequate bone marrow function, defined as:
a. Absolute Neutrophil Count of at least 1500/mm3 or at least 1.5 x 10[9]/L
b. Platelet count at least 100,000/mm3 or at least 100 x 10[9]/L
c. Hb at least 10 g/dL at Baseline (blood transfusions, hematopoietic growth factors and hematinics are allowed during the Pre-randomization Phase to correct Hb values less than 10 g/dL).
10. Adequate liver function, defined as:
a. Bilirubin less than or equal to 1.5 times the upper limit of normal, except for unconjugated hyperbilirubinemia of Gilbert’s syndrome
b. ALP, ALT, and AST less than or equal to 3 times the upper limit of normal. For total ALP values greater than 3 times the upper limit of normal, the ALP liver isoenzyme must be less than or equal to 3 times the upper limit of normal.
11. Female subjects of child-bearing potential must agree to use two forms of highly effective contraception from the last menstrual period prior to randomization, during the Treatment Cycles, and for 3 months after the final dose of study treatment.
Female subjects exempt from this requirement are subjects who practice total abstinence.
12. Male subjects and their female partners who are of child-bearing potential as defined in Inclusion 11, and who 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, during the Treatment Cycles, and for 3 months after the final dose of study treatment. If currently abstinent, must agree to use a double barrier method of contraception if they become sexually active during the Treatment Cycles, and for 3 months after the final dose of study treatment or use two forms of highly effective contraception.
13. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.
14. Males or females aged at least 18 years at 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 tumor embolization, chemotherapy, targeted, biological (including humanized antibodies), investigational, immunotherapy, hormonal, or radiotherapy, within 14 days, or five half-lives of the drug (whichever is longer), prior to randomization.
2. Subjects who have not recovered from toxicities as a result of prior anti-cancer therapy to less than Grade 2, according to the CTCAE, except for peripheral neuropathy (see Exclusion 4) and alopecia.
3. Subjects who have previously been treated, or participated in a study with eribulin, whether treated with eribulin or not. The TPC option must not include the same agent which the subject received in a prior regimen.
4. Peripheral neuropathy more than CTCAE Grade 2.
5. Significant cardiovascular impairment, defined as:
a. Congestive heart failure greater than Class II according to the New York Heart Association Cardiac Disease Classification
b. Unstable angina or myocardial infarction within 6 months of enrolment, or
c. Serious cardiac arrhythmia or cardiac arrhythmia requiring treatment.
6. Subjects with a high probability of Long QT Syndrome or QTc interval >500 ms on at least two separate ECGs.
7. Subjects 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 to the affected area of the brain (e.g. stereotactic radiosurgery), and have discontinued the use of corticosteroids for this indication for at least 4 weeks prior to study entry and have confirmed radiographic stability. Confirmation of radiographic stability will be done by comparing the brain scan (CT or MRI) performed during the Screening Period to a brain scan performed at least 4 weeks earlier (and following local therapy where applicable) using the same imaging modality as during the Screening Period. It is not the intention of this protocol to treat subjects with active brain metastasis.
8. Any serious concomitant illness.
9. Known HIV positive, or have an infection requiring treatment.
10. Any malignancy that required treatment, or has shown evidence of recurrence (except for NSCLC, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) during the 5 years prior to study entry.
11. Female subjects must not be pregnant, as documented by a negative β-hCG test with a minimum sensitivity 25 IU/L or equivalent unit of β-hCG, and must not be breastfeeding.
12. Hypersensitivity to either HalB or HalB chemical derivatives or both, or to any of the excipients of the eribulin formulation. Selection of the TPC option prior to randomization will be made exclusive of an option to which the subject has known allergies or contra-indications (please refer to the Prescribing Information of the TPC option).
13. Any medical or other condition which, in the opinion of the investigator, will preclude participation in a clinical trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is Overall Survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall Survival is measured from the date of randomization until date of death from any cause. In absence of confirmation of death, subjects will be censored either at the date that the subject was last known to be alive or the date of study cut-off, whichever comes earlier. |
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| E.5.2 | Secondary end point(s) |
Progression-Free Survival
Objective Response Rate |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression-Free Survival is 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 be defined in the SAP and follow FDA guidance.
Objective Response Rate is defined as the proportion of subjects who have best overall response of Complete Response or Partial Response. |
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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 |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Treatment of Physician's Choice: Vinorelbine, Gemcitabine, Docetaxel or Pemetrexed |
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| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| France |
| Italy |
| Japan |
| Australia |
| Germany |
| Hong Kong |
| Korea, Republic of |
| Malaysia |
| Spain |
| Poland |
| Russian Federation |
| Singapore |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
The definition for the end of the study is when the last subject has died, unless the Sponsor decides to terminate survival follow-up of all subjects in the Extension Phase after the completion of the primary analysis, and when all subjects have discontinued study treatment.
|
|
| 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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