| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non-small cell lung cancer (NSCLC), colorectal carcinoma (CRC), salivary gland cancers, papillary thyroid cancer, melanoma, and sarcomas |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10023774 |
| E.1.2 | Term | Large cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061934 |
| E.1.2 | Term | Salivary gland cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033701 |
| E.1.2 | Term | Papillary thyroid cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039491 |
| E.1.2 | Term | Sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| The primary objectives for this study are to explore the relative bioavailability (level of the study drug present in the blood) of entrectinib from two paediatric formulations and the reference adult capsule formulation under fed conditions (Part 1) and to explore the relative bioavailability of two entrectinib capsule formulations under fasted conditions (Part 2). |
|
| E.2.2 | Secondary objectives of the trial |
The safety objective (secondary study objective) for this study is to explore the safety and tolerability of a single oral dose of entrectinib in healthy volunteers.
An additional objective for this study is to explore the palatability (taste and acceptability) of coated and uncoated multi-particulate formulations. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able and willing to comply with the study restrictions and to give written informed consent before any study procedure.
2. Healthy male or female subjects of non-childbearing potential aged 18 to 60 years, inclusive, at time of signing Informed Consent Form (ICF)
3. A body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive, and weighing ≥50 kg, at screening.
4. Healthy in the opinion of the investigator. Healthy is defined by the absence of evidence of any active disease or clinically significant medical condition based on a detailed medical history, physical examination, vital signs and 12-lead ECG assessment, and laboratory safety test results.
5. Agreement to comply with measures to prevent pregnancy and restrictions on egg and sperm donation.
- Female subjects of non-childbearing potential do not need to use any methods of contraception. Non-childbearing potential is defined as either post-menopausal (at least 12 months without a period [i.e., amenorrhea]; in a woman at least 45 years of age and documented by a serum follicle stimulating hormone (FSH) level consistent with postmenopausal status [e.g., 40 IU/L]), or surgically sterile (e.g., bilateral oophorectomy, bilateral salpingectomy, hysterectomy; note: tubal ligation is not considered an appropriate method of surgical sterilization) for at least 90 days.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom plus an approved method of effective contraception, and agreement to refrain from donating sperm, as defined in the protocol. |
|
| E.4 | Principal exclusion criteria |
1. Women of childbearing potential, women who are pregnant or breastfeeding, or intending to become pregnant during the study or within 14 days after the final dose of entrectinib or have a pregnant partner.
All women must have a negative serum pregnancy test at screening and a negative urine test at every admission.
2. A clinical significant medical history of gastrointestinal surgery (e.g., gastric bypass) or other gastrointestinal disorder (e.g., malabsorption syndrome) that might affect absorption of medicines from the gastrointestinal tract.
3. Presence of a clinically significant disease, illness, medical condition or disorder, or any other medical history determined by the investigator to be clinically significant and relevant. Ongoing chronic disorders which are not considered clinically significant are permissible providing they are stable.
4. A clinically significant abnormality in laboratory test results. In case of borderline or questionable results, tests may be repeated to confirm eligibility. Red blood cell count be lower than the lower limit of normal (RBC<LLN).
5. A clinically significant abnormal physical examination finding.
6. QTcF interval >450 msec or the presence of any other abnormal ECG finding, which, in the investigator’s opinion, is clinically significant.
7. Confirmed by repeat (e.g., 2 consecutive measurements) systolic blood pressure greater than 140 or less than 90 mmHg, or diastolic blood pressure greater than 90 or less than 50 mmHg, or resting pulse rate greater than 90 or less than 40 beats per minute.
8. Clinically significant change in health status, as judged by the investigator, or any major illness within the four weeks before screening, or clinically significant acute infection or febrile illness within the 14 days before screening.
9. Any other ongoing condition or disease, or laboratory test result, that the investigator considers would render the participant unsuitable for the study, place the subject at undue risk, interfere with the ability of the subject to complete the study, or confound interpretation of study data.
10. Use of moderate or potent inhibitors or inducers of CYP P450 3A4 enzyme or P-gp transporter within the 28 days before screening, or use of other prohibited medications within the 7 days before screening.
11. Participation in any other clinical study involving an investigational medicinal product (IMP) or device within 3 months prior to planned dosing day (Day 1).
12. A positive test result for hepatitis B, hepatitis C (HCV), or human immunodeficiency virus (HIV).
13. Recent history of alcoholism, drug abuse, or addiction within the last year prior to screening, or a positive test for alcohol or drugs of abuse at screening or admission for each period.
14. Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units = 125 mL glass of wine, depending on type).
15. Current smokers and those who have smoked within the last 12 months. A confirmed (by repeat) breath carbon monoxide reading of greater than 10 ppm at screening or admission for each period.
16. Current users of e-cigarettes and nicotine replacement products and those who have used these products within the last 12 months
17. Known history of clinically significant hypersensitivity, or severe allergic reaction, to entrectinib or related compounds.
18. Presence or history of clinically significant allergy requiring treatment, as judged by the investigator. Hay fever is allowed unless it is active.
19. Donation or loss of over 400 mL of blood within the three months before screening.
20. Subjects who are study site employees, or immediate family members of a study site or Sponsor employee.
21. Subjects who have previously been enrolled in this study. Subjects who have taken part in Part 1 are not permitted to take part in Part 2.
22. Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator or delegate at screening.
23. Failure to satisfy the investigator of fitness to participate for any other reason. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint:
• The geometric mean ratio and associated 90% confidence intervals (CI) of entrectinib and M5 area under the concentration–time curve from Time 0 to infinity (AUC0-inf) and maximum concentration observed (Cmax) parameters |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Ongoing throughout the study, as defined in the clinical protocol |
|
| E.5.2 | Secondary end point(s) |
• Incidence and severity of adverse events,
• Incidence of abnormalities in laboratory safety tests, physical examinations,12-lead ECGs, vital sign measurements
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Ongoing throughout the study, as defined in the clinical protocol |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Bioavailability, palatability, tolerability |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Bioavailability, palatability, safety and tolerability study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.6 | Cross over | Yes |
| 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 | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| LVLS (Last visit, last subject) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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