A RANDOMIZED, OPEN-LABEL, TWO PART STUDY TO EXPLORE THE PERFORMANCE OF ENTRECTINIB PROTOTYPE MINI-TABLET FORMULATIONS AND THE EFFECT OF DRUG SUBSTANCE PARTICLE SIZE ON ENTRECTINIB BIOAVAILABILITY IN HEALTHY VOLUNTEERS

INTERVENTION:

Product Name: ENTRECTINIB (Ro 710‐2122/F15) FILM‐COATED TABLETS, 50 mg (20 x 2.5 mg) Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Entrectinib CAS Number: 1108743‐60‐7 Current Sponsor code: RO710122 Other descriptive name: RXDX‐101 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Product Name: ENTRECTINIB (Ro 710‐2122/F16) FILM‐COATED TABLETS, 50 mg (20 x 2.5 mg) Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

Entrectinib CAS Number: 1108743‐60‐7 Current Sponsor code: RO710122 Other descriptive name: RXDX‐101 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ Product Name: Entrectinib (RXDX‐101) F06 hard capsules, 200 mg (Ro 710 2122/F04) Pharmaceutical Form: Capsule, hard INN or Proposed

INN:

Entrectinib CAS Number: 1108743‐60‐7 Current Sponsor code: RO710122 Other descriptive name: RXDX‐101 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ Product Name: Entrectinib F06 HPMC Capsules (unmilled/coarse API), 200 mg Pharmaceutical Form: Capsule INN or Proposed

INN:

Entrectinib CAS Number: 1108743‐60‐7 Current Sponsor code: RO710122 Other descriptive name: RXDX‐101 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐

CONDITION:

non‐small cell lung cancer (NSCLC), colorectal carcinoma (CRC), salivary gland cancers, papillary thyroid cancer, melanoma, and sarcomas ; MedDRA version: 21.1 Level: PT Classification code 10023774 Term: Large cell lung cancer System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 21.0 Level: PT Classification code 10061451 Term: Colorectal cancer System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 20.0 Level: PT Classification code 10061934 Term: Salivary gland cancer System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 21.1 Level: PT Classification code 10033701 Term: Papillary thyroid cancer System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 21.1 Level: LLT Classification code 10053571 Term: Melanoma System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) ; MedDRA version: 20.0 Level: PT Classification code 10039491 Term: Sarcoma System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04]

SECONDARY OUTCOME:

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; Timepoint(s) of evaluation of this end point: Ongoing throughout the study, as defined in the clinical protocol

PRIMARY OUTCOME:

Main Objective: 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). 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 Secondary Objective: 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. Timepoint(s) of evaluation of this end point: Ongoing throughout the study, as defined in the clinical protocol

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 perio