INTERVENTION:

The study will consist of two parts where participants will be randomly assigned to receive the study treatments in a cross‐over manner. Part 1: The treatments administered to participants in Part 1 of the study will be as follows: Treatment A: Nasogastric administration of 600 mg entrectinib, delivered as a suspension in water on Day 1 following an 8‐hour fast Treatment B: Oral administration of 600 mg entrectinib delivered as a suspension in milk on Day 1 following an 8‐hour fast Treatment C: Oral administration of 600 mg entrectinib capsules on Day 1 following an 8‐hour fast. Part 1 – Sequence

ABC:

Participants will receive three treatments in sequence ABC on Day 1 of Periods 1, 2, and 3 respectively. There will be a 14‐day washout period between each treatment period. Participants will be monitored up to Day 14 after the last dose of the study drug. Part 1 – Sequence

BCA:

Participants will receive three treatments in sequence BCA on Day 1 of Periods 1, 2, and 3 respectively. There will be a 14‐day washout period between each treatment period. Participants will be monitored up to Day 14 after the last dose of the study drug. Part 1 ‐ Sequence

CAB:

Participants will receive treatments in sequence CAB on Day 1 of Periods 1, 2, and 3 respectively. There will be a 14‐day washout period between each treatment period. Participants will be monitored up to Day 14 after the last dose of the study drug. Part 2: The treatments administered to participants in Part 2 of the study will be as follows: Treatment C: Oral administration of 600 mg entrectinib capsules on Day 1 following an 8‐hour fast Treatment D: Oral administration of 600 mg entrectinib delivered as a suspension in water on Day 1 following an 8‐hour fast Treatment E: Oral administration of 30 mg lansoprazol

CONDITION:

Bioavailability of entrectinib in healthy participants ; Not Applicable

PRIMARY OUTCOME:

1. Maximum observed plasma concentration (Cmax) of entrectinib and M5 (its metabolite) measured from blood samples collected at pre‐dose and multiple timepoints up to 96 hours post entrectinib administration in each of the three periods (1, 2 and 3) in both Part 1 and Part 2; 2. Area under the plasma concentration versus time curve from time zero extrapolated to infinity (AUC0‐inf) of entrectinib and M5 (its metabolite) measured from blood samples collected at pre‐dose and multiple timepoints up to 96 hours post entrectinib administration in each of the three periods (1, 2 and 3) in both Part 1 and Part 2

SECONDARY OUTCOME:

1. Time to maximum observed plasma concentration (Tmax) of entrectinib and its metabolite, M5 (as appropriate) measured from blood samples collected at pre‐dose and multiple timepoints up to 96 hours post entrectinib administration in each of the three periods (1, 2 and 3) in both Part 1 and Part 2; 2. Area under the plasma concentration versus time curve from hour zero to the last measurable concentration (AUC0‐t) of entrectinib and its metabolite, M5 (as appropriate) measured from blood samples collected at pre‐dose and multiple timepoints up to 96 hours post entrectinib administration in each of the three periods (1, 2 and 3) in both Part 1 and Part 2 ; 3. Apparent terminal elimination half‐life (t1/2) of entrectinib and its metabolite, M5 (as appropriate) measured from blood samples collected at pre‐dose and multiple timepoints up to 96 hours post entrectinib administration in each of the three periods (1, 2 and 3) in both Part 1 and Part 2; 4. Relative bioavailability for AUCinf (Frel) of entrectinib and its metabolite, M5 (as appropriate) measured from blood samples collected at pre‐dose and multiple timepoints up to 96 hours post entrectinib administration in each of the three periods (1, 2 and 3) in both Part 1 and Part 2; 5. Metabolite (M5) to parent (entrectinib) ratio for AUCinf (MPR) measured from blood samples collected at pre‐dose and multiple timepoints up to 96 hours post entrectinib administration in each of the three periods (1, 2 and 3) in both Part 1 and Part 2; 6. Percentage of participants with adverse events (AEs) and severity of AEs determined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) collected from screening up to 14 days after the final dose of entrectinib (up to approximately 70 days)

INCLUSION CRITERIA:

1. Female of non‐childbearing potential or male, between 18 and 55 years of age, inclusive, at Screening 2. Within body mass inde X(BMI) range of 18.0 to 32.0 kg/m², inclusive, and weighing at least 50 kg at Screening 3. 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 clinical laboratory evaluation results 4. Negative hepatitis panel (hepatitis B surface antigen and hepatitis C virus antibody) and negative human immunodeficiency virus (HIV) antibody screens 5. Females must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at each Check‐in (Day ‐1)

This study will evaluate the bioavailability, palatability, safety and tolerability of entrectinib in healthy volunteers. Part 1 of the study will explore the performance of entrectinib multi‐particle formulation. Part 2 will evaluate the effect of drug substance particle size on entrectinib bioavailability.

Neurotrophic tyrosine receptor kinase genes (NTRK1/2/3) act as oncogenic drivers across a range of tumors. NTRK fusions occur at low frequency (<5%) in all breast cancer types, including >90% of secretory breast carcinomas. Furthermore, up to 30% of patients (pts) with breast cancer will develop central nervous system (CNS) metastases (mets). Entrectinib is a potent, oral TRKA/B/C, ROS1 and ALK inhibitor, specifically selected for its CNS penetration properties. Entrectinib was evaluated in 3 global phase 1/2 clinical trials (ALKA-372-001 [EudraCT 2012-000148- 88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]), where it demonstrated strong and durable systemic and intracranial efficacy in pts with NTRK-fp solid tumors, including those with breast cancer. We present updated data from this integrated analysis (data cut-off: 31 October 2018) focusing on pts with breast cancer. The entrectinib trials were conducted at >150 sites in 15 countries, and enrolled pts with locally advanced/metastatic NTRK-fp tumors (with or without baseline CNS mets) confirmed by nucleic acid-based methods. Tumor assessments were performed at the end of cycle 1 (4 weeks) and every 8 weeks thereafter, and evaluated by blinded independent central review (BICR) using RECIST v1.1. Primary endpoints were objective response rate (ORR) and duration of response (DoR) by BICR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. At clinical cut-off, the overall efficacy-evaluable population included 74 adults from the 3 trials, with 12 different NTRK-fp tumor types and >25 histopathologies. In these pts, ORR by BICR was 63.5% (95% CI 51.5-74.4), including five complete responses (CR) and 42 partial responses (PR). Median (95% CI) DoR, PFS and OS were 12.9 (9.3-not estimable [NE]), 11.2 (8.0-15.7) and 23.9 (16.0-NE) months, respectively. The efficacy-evaluable NTRK-fp breast cancer cohort included 6 pts with a median age of 63 (range 36-67) years; most had an Eastern Cooperative Oncology Group performance status of 0 (3/6; 50%) or 1 (1/6; 17%). Breast cancer tumors were classified as secretory (4/6; 67%; all NTRK3-fp) or non-secretory (2/6; 33%; all NTRK1-fp). Pts had received 0 (3/6; 50%), 1 (1/6; 17%) or ≥4 (2/6; 33%) lines of prior therapy for metastatic disease. At data cut off, the median survival follow-up was 17.4 (range 1.7-23.9) months. ORR was 100% (2 CR, 2 PR; 95% CI 39.8-100.0) in pts with secretory and 50% (1 PR, 1 missing/unevaluable; 95% CI 1.3-98.7) in pts with non-secretory histology. Median (95% CI) DoR, PFS, and OS were 12.9 (4.2-NE), 10.1 (5.1-NE), and 23.9 (5.1-23.9) months, respectively. At baseline, 2 pts had CNS mets per investigator assessment; 1 of these pts had missing response data. CNS mets were confirmed by BICR in the other pt (non-secretory); this pt had received whole brain radiotherapy 2-6 months before starting entrectinib treatment, and had systemic PR and intracranial non-CR/non-progressive disease (non-measurable CNS lesion). The overall integrated safety-evaluable population comprised 504 pts with any gene fusion who received ≥1 dose of entrectinib. Most treatment-related adverse events (TRAEs) were Grade ≤3 (96.1%); the most frequently reported TRAEs were dysgeusia (39.7%) and fatigue (31.5%). Seven breast cancer pts were evaluated for safety, of whom six (85.7%) reported TRAEs; all were Grade ≤3. The most frequently reported TRAEs (each occurring in 3/7 pts; 42.9%) were nausea, anemia, and increased alanine or aspartate aminotransferase. Dose reductions and interruptions due to TRAEs were each reported in 3/7 pts (42.9%); no discontinuations or deaths due to TRAEs were recorded. In this updated integrated analysis, entrectinib induced objective responses in all pts with NTRK-fp breast cancer who had data available, and was generally well tolerated with no discontinuations due to TRAEs.

This is an open-label study in advanced solid tumor patients to determine if entrectinib affects the pharmacokinetics of midazolam and any of its pharmacologically active metabolites.

Single arm study with dose escalation Phase Ib cohort followed by a Phase II cohort. PAC-1 (PO) will be given daily on Days 1 through 21 of each cycle (28-day cycle). Entrectinib (PO) will be given daily on Days 1 through 28 of each cycle. Response will be evaluated after every 2 cycles. Treatment will continue until disease progression based on RECIST criteria or intolerable toxicity.

Entrectinib, a multikinase inhibitor of ROS1 and tropomyosin receptor kinases, is recommended to treat ROS1-positive metastatic non-small cell lung cancer (NSCLC). In a previous study, entrectinib-related cardiotoxicity occurred in 2% of patients; however, lethal arrhythmias remain understudied. We encountered a case of fatal arrhythmia due to drug-induced Brugada syndrome caused by entrectinib. An 81-year-old Japanese male with lung adenocarcinoma harboring ROS1-fusion gene was treated with entrectinib. The patient developed lethal arrhythmias three days after drug initiation, including ventricular tachycardia with Brugada-like electrocardiogram changes. Echocardiography and coronary angiography revealed no evidence of acute coronary syndrome or myocarditis. Following the termination of entrectinib, the electrocardiogram abnormality improved within 12 days. Hence, paying special attention to and monitoring electrocardiogram changes is necessary. In addition, it is also necessary to consider early therapeutic interventions and discontinuation of the drug in cases of drug-induced Brugada syndrome.

BACKGROUND:

ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target ROS1 KD mutations, less is known about bypass signaling in TKI-resistant ROS1+ lung cancers.

METHODS:

Utilizing a primary, patient-derived TPM3-ROS1 cell line (CUTO28), we derived an entrectinib-resistant line (CUTO28-ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a CD74-ROS1 NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK-2 entrectinib trial to determine the prevalence of MET amplification.

RESULTS:

CUTO28-ER cells did not exhibit ROS1 KD mutations. MET TKIs inhibited proliferation and downstream signaling and MET transcription was elevated in CUTO28-ER cells. CUTO28-ER cells displayed extrachromosomal (ecDNA) MET amplification without MET activating mutations, exon 14 skipping, or fusions. The CD74-ROS1 patient samples illustrated MET amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib-resistant ROS1+ NSCLC STARTRK-2 patients with ctDNA analysis at enrollment and disease progression displayed MET amplification.

CONCLUSIONS:

Treatment with ROS1-selective inhibitors may lead to MET-mediated resistance. The discovery of ecDNA MET amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1-selective inhibitors, MET gene testing and treatments targeting MET should be explored to overcome MET-driven resistance.

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

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.

BACKGROUND:

Entrectinib is a tropomyosin receptor kinase inhibitor approved for the treatment of neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumours based on single-arm trials. Traditional randomised clinical trials in rare cancers are not feasible; we conducted an intrapatient analysis to evaluate the clinical benefit of entrectinib versus prior standard-of-care systemic therapies.

METHODS:

Patients with locally advanced/metastatic NTRK fusion-positive tumours enrolled in the global phase II, single-arm STARTRK-2 trial were grouped according to prior systemic therapy and response. The key analysis used growth modulation index [GMI; ratio of progression-free survival (PFS) on entrectinib to time to discontinuation (TTD) on the most recent prior therapy]; ratio ≥1.3 indicated clinically meaningful efficacy. Additional analyses investigated TTD and objective response rate (ORR) for entrectinib and prior therapies.

RESULTS:

Seventy-one patients were included; 51 received prior systemic therapy. In 38 patients who progressed on prior therapy, ORR was 60.5% (23/38) with entrectinib and 15.8% (6/38) with the most recent prior therapy. Median PFS [11.2 months; 95% confidence interval (CI) 6.7-not estimable] for entrectinib exceeded median TTD (2.9 months; 95% CI 2.0-4.9) for most recent prior therapy. From the intrapatient analysis of GMI, 65.8% had a ratio ≥1.3 and median GMI was 2.53. Consistent results were observed at more stringent GMI thresholds; 60.5% of patients had GMI ≥1.5 or ≥1.8 and 57.9% had GMI ≥2.0.

CONCLUSIONS:

ORR was high and PFS was longer on entrectinib versus TTD on prior therapy. Furthermore, 65.8% of patients experienced clinically meaningful benefit based on GMI. This intrapatient analysis demonstrates comparative effectiveness of entrectinib in a rare, heterogeneous adult population.