Rozlytrek

Entrectinib.

Rozlytrek 100 mg hard capsule: Each 100 mg hard capsule contains 100 mg entrectinib.
Rozlytrek 200 mg hard capsule: Each 200 mg hard capsule contains 200 mg entrectinib.
Excipients/Inactive Ingredients: Anhydrous lactose, Microcrystalline cellulose, Tartaric acid, Hypromellose, Crospovidone, Magnesium stearate and Colloidal silicon dioxide.

Pharmacotherapeutic Group: Antineoplastic agent, other protein kinase inhibitors. ATC Code: L01EX14.
PHARMACOLOGY: Pharmacodynamics: Mechanism of Action: Entrectinib is a potent inhibitor of receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1; encoded by the gene ROS1), and anaplastic lymphoma kinase (ALK; encoded by the gene ALK). The major active metabolite of entrectinib, M5, showed similar in vitro potency and activity.
Fusion proteins that include TRK, ROS1 or ALK kinase domains drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Entrectinib potently inhibits the TRK kinases, ROS1 and ALK, leading to inhibition of downstream signaling pathways, cell proliferation and induction of tumor cell apoptosis. Entrectinib demonstrates potent inhibition of cancer cell lines harboring NTRK, ROS1 and ALK fusion genes, irrespective of tumor type. Entrectinib has anti-tumor potency in NTRK and ROS1 fusion-driven tumor models, driving tumor regressions across multiple tumor types, including sarcomas, head and neck carcinoma, non-small cell lung carcinoma (NSCLC), colorectal cancer (CRC), acute myeloid leukemia (AML), and gliomas.
Entrectinib is a CNS penetrant molecule that showed brain-to-plasma concentration ratios of 0.4-2.2 in multiple animal species (mice, rats and dogs). It has demonstrated potent anti-tumor activity in three TRKA-driven intracranial tumor models and one ALK-driven intracranial tumor model. These data are consistent with entrectinib dosing resulting in sufficient brain exposure achieving target pharmacological activities at steady-state and at clinically relevant systemic exposures.
Clinical/Efficacy Studies: NTRK fusion-positive solid tumors: Efficacy in Adult patients: The efficacy of ROZLYTREK in the treatment of NTRK fusion-positive solid tumors in adult patients was evaluated by combining the results from 3 single-arm, open label clinical trials (ALKA, STARTRK-1 and STARTRK-2) through a pre-specified integrated analysis.
Study ALKA was a Phase I single arm, open-label study in patients ≥ 18 years of age with solid tumors with NTRK1/2/3, ROS1, or ALK molecular alterations to determine the maximum tolerated dose. Study STARTRK-1 was a Phase I multi-center single arm, open label study in patients ≥ 18 years of age with solid tumors with NTRK1/2/3, ROS1, or ALK molecular alterations. The study included a dose escalation segment and a dose expansion segment. In the dose expansion segment, patients received 600 mg daily in repeated 4-week cycles and the primary objective was to evaluate the recommended Phase 2 dose. Study STARTRK-2 was a multicenter, international Phase II single-arm basket study in patients with solid tumors with NTRK1/2/3, ROS1, or ALK gene rearrangements. Patients received 600 mg ROZLYTREK once daily in 4-week cycles.
The primary efficacy outcome measures in the integrated analyses were objective response rate (ORR) and duration of response (DOR) as evaluated by Blinded Independent Central Review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary efficacy outcome measures included clinical benefit rate (CBR), progression-free survival (PFS), time to central nervous system (CNS) progression, overall survival (OS), and in patients presenting with CNS metastases at baseline - intracranial (IC) ORR, IC-DOR, and IC-PFS (also evaluated by BICR using RECIST v1.1).
The efficacy evaluable analyses set comprised a total of 74 adult patients with confirmed NTRK fusion-positive solid tumors treated with ROZLYTREK, not previously treated with a TRK inhibitor, presenting with measurable disease at baseline as assessed by investigator, and with ≥ 6 months of follow up. NTRK fusion-positive status was determined by a validated nucleic acid-based test performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalently accredited laboratory, prior to enrollment in the study.
The baseline demographic and disease characteristics of the efficacy evaluable population were: 47.3% males, median age of 57 years (range: 21 to 83 years), 70.0% white Caucasian, 17.6% Asian, 5.5% Hispanic or Latino and 59.7% never smokers. The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 (40.5%), 1 (45.9%), or 2 (13.5%). Most patients (97.3%) had metastatic disease [most common sites being lung (60.8%), lymph nodes (52.7%) and brain (25.7%)], 2.7% patients had locally advanced disease, and 27% patients had no prior systemic therapies. The overall median duration of follow-up was 14.2 months.
Efficacy results from patients with NTRK-fusion positive solid tumors are summarized in Table 1. (See Table 1.)

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As shown in Figure 1, most adult patients with NTRK-fusion positive solid tumors experienced tumor shrinkage, as assessed by BICR according to RECIST 1.1. (See Figure 1.)

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Of the 74 adult patients with NTRK-fusion positive solid tumors in the efficacy evaluable analysis set, 19 patients were identified by the Investigator to have CNS metastases at baseline. Efficacy results by BICR according to RECIST v1.1 in this subgroup of patients with CNS metastases at baseline are summarized in Table 2. (See Table 2.)

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Objective response rate by tumor type in all efficacy evaluable adult patients with NTRK-fusion positive solid tumors is presented in Table 3. (See Table 3.)

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Intracranial Response: Of the 74 adult patients with NTRK-fusion positive solid tumors in the efficacy evaluable analysis set, 16 patients had CNS metastases at baseline as assessed by BICR, including 8 patients with measurable CNS lesions. Intracranial ORR, DOR, and PFS assessed by BICR according to RECIST version 1.1 in this subgroup of patients with measurable CNS lesions at baseline are summarized in Table 4. (See Table 4.)

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Primary CNS tumors: Across the three trials, seven adult patients with CNS primary tumors were treated with ROZLYTREK with a minimum of 6 months of follow-up. IC-ORR, DOR and PFS were assessed by BICR according to Response Assessment in Neuro-Oncology Criteria (RANO). One patient had an objective response with a DOR of 2.79 months and PFS of 6.34 months.
Patient Reported Outcomes: Study STARTRK-2 evaluated patient-reported outcomes (PRO) of the treatment impact on symptoms, functioning and health-related quality of life (HRQoL) based on the EORTC Core Quality of Life Questionnaire (QLQ-C30), Lung Cancer Module (QLQ-LC13), and the Colorectal Cancer Module (QLQ-CR29).
Most safety evaluable patients indicated that the symptoms commonly associated with ROZLYTREK treatment (lack of appetite, nausea, diarrhea and vomiting) were of low severity, if present. Efficacy evaluable patients with NTRK-fusion positive NSCLC (n=12) reported moderate lung-related symptoms at baseline with qualitative trends towards improvement while receiving Rozlytrek. Patients with mCRC (n=7) reported low abdominal symptoms burden at baseline, which generally remained low over time. Qualitative trends towards improvements in functioning (moderate to high at baseline) and maintenance of HRQoL (high at baseline) were observed for patients with NTRK fusion-positive solid tumors while receiving ROZLYTREK as measured by the Physical function, the Role function and the Global Health Status from the EORTC QLQ-C30.
Efficacy in Pediatric patients: The efficacy of ROZLYTREK in pediatric patients with NTRK fusion-positive solid tumors was evaluated in study STARTRK-NG (ST-NG). This study is a multi-center Phase I/II open-label dose-escalation and expansion study in pediatric patients with relapsed or refractory solid tumors, including primary CNS tumors, with or without NTRK, ROS1 or ALK molecular alterations. Patients received 250 mg/m² to 750 mg/m² once daily of ROZLYTREK in 4-week cycles. The range of survival follow up was 6.9 months to 18.0 months.
Table 5 summarizes the efficacy of ROZLYTREK in 7 pediatric patients (less than 18 years of age) with NTRK fusion-positive solid tumors as assessed by the Investigator according to RECIST version 1.1 for extra-cranial tumors and according to RANO for CNS primary tumors. Efficacy data in pediatric patients with NTRK fusion-positive solid tumors is further supported by extrapolation from results in the respective adult populations. (See Table 5.)

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ROS1-positive NSCLC: The efficacy of ROZLYTREK in the treatment of ROS1 positive locally advanced or metastatic NSCLC was evaluated by combining the results from 3 single-arm, open label clinical trials (ALKA, STARTRK-1 and STARTRK-2) described previously, through a pre-specified integrated analysis.
The primary efficacy outcome measures in the integrated analyses were ORR and DOR, as evaluated by BICR according to RECIST v1.1. The secondary efficacy outcome measures included CBR, PFS, time to CNS progression, OS, and in patients presenting with CNS metastases at baseline - IC-ORR, IC-DOR, and IC-PFS (also evaluated by BICR using RECIST v1.1).
The efficacy evaluable analyses set comprised a total of 94 patients with histologically confirmed ROS1-positive NSCLC treated with ROZLYTREK, not previously treated with a ROS1-inhibitor, presenting with measurable disease at baseline as assessed by the investigator, and with ≥12 months of follow up. ROS1-positive status was determined by a validated nucleic acid-based test performed at a CLIA-certified or equivalently accredited laboratory, prior to enrollment in the study.
The baseline demographic and disease characteristics of the efficacy evaluable population were: 36.2% males, median age of 53 years (range: 27 to 86 years), 79.8% patients <65 years of age, 48.9% white Caucasian, 43.6% Asian, 5.3% Black, 2.4% Hispanic or Latino and 59.6% never smokers. The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was 0 (37.2%), 1 (51.1%), or 2 (11.7%). Most patients (98.9%) had metastatic disease with 42.6% having brain metastases [other common sites were lung (57.4%) and lymph nodes (75.5%)], 1.1% patients had locally advanced disease, and 33% patients had no prior systemic therapies. The overall median duration of follow-up was 20.9 months.
Efficacy results from patients with ROS1-positive NSCLC are summarized in Table 6. (See Table 6.)

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Most ROS1-positive NSCLC patients treated with ROZLYTREK experienced tumor shrinkage of their defined target lesions, as assessed by BICR according to RECIST 1.1. (See Figure 2.)

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Of the 94 patients with ROS1-positive NSCLC in the efficacy evaluable analysis set, 40 patients were identified by the Investigator to have CNS metastases at baseline. Efficacy results by BICR according to RECIST v1.1 in this subgroup of patients with CNS metastases at baseline are summarized in Table 7. (See Table 7.)

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Intracranial Response: Of the 94 patients with ROS-1 positive NSCLC in the efficacy evaluable analysis set, 34 patients had CNS metastases at baseline as assessed by BICR, including 18 patients with measurable CNS lesions. Intracranial ORR, DOR, and PFS assessed by BICR according to RECIST version 1.1 in this subgroup of patients with measurable CNS lesions at baseline are summarized in Table 8 and Figure 3 as follows. (See Table 8 and Figure 3.)

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Patient Reported Outcomes: Patients with ROS1-positive NSCLC reported rapid and durable clinically meaningful improvement (change from baseline of ≥10 points on a 0-100 scale) in lung-cancer symptoms (cough, dyspnea, chest pain) as measured by the EORTC QLQ LC13. Patients maintained their day-to-day function resulting in an improvement in HRQoL while on ROZLYTREK treatment (evaluated by the Physical function, Role function and Global Health Status from the EORTC QLQ-C30). In addition, most patients, indicated that the symptoms commonly associated with ROZLYTREK treatment (lack of appetite, nausea, diarrhea and vomiting) were of low severity, if present.
Immunogenicity: Not applicable.
Pharmacokinetics: The pharmacokinetic parameters for entrectinib and its major active metabolite (M5) have been characterized in patients with NTRK-positive solid tumors and ROS1-positive NSCLC, and healthy subjects.
Following administration of a single 600 mg dose of entrectinib, the estimated entrectinib mean (± SD) C_max was 1990 (± 1050) nM and AUC_0,24 33900 (± 15800) nM*h and for M5 C_max was 765 (± 598) nM and AUC_0,24 13300 (± 10200) nM*h. At steady-state the estimated entrectinib mean C_max was 3490 (± 1600) nM and AUC_0,24 62800 (±29100) nM*h and for M5 C_max was 1340 (± 934) nM and AUC_0,24 25500 (±29100) nM*h.
The population PK model estimated mean accumulation at steady-state following 600 mg once daily administration of entrectinib was 1.89 (±0.381) and 2.01 (± 0.437) for M5.
Absorption: Following a single 600 mg oral administration of ROZLYTREK to patients with NTRK-fusion positive and ROS1 positive NSCLC under fed conditions, entrectinib was rapidly absorbed reaching time-to-maximum plasma concentration (T_max) after approximately 4 - 6 hours. Based on population pharmacokinetic analysis, steady-state was achieved within 5 days for entrectinib with 600 mg once daily dosing.
The estimated absolute bioavailability of entrectinib based on physiologically based pharmacokinetic (PBPK) modeling was 55%.
No clinically significant effect of food on entrectinib bioavailability was observed. Following a single 600 mg oral administration of ROZLYTREK to healthy subjects under fasting conditions and following a high fat, high calorie meal, the GMR under fed/fasted condition for AUC_inf (90%CI) was 115% (107, 124) and for C_max (90%CI) was 106% (98.9, 115). Entrectinib can be administered with or without food (see Dosage & Administration).
Distribution: Entrectinib and its major active metabolite M5 are highly bound to human plasma proteins independent of drug concentrations. In human plasma, entrectinib and M5 had similar protein binding with >99% bound at a clinically relevant concentration.
After a single oral dose of [¹⁴C]-labeled entrectinib, the geometric mean volume of distribution (Vz/F) was 860 L, suggesting extensive distribution into tissues. Population pharmacokinetic analysis estimated volume of distribution of 551 L and 81.1 L for entrectinib and M5, respectively.
Metabolism: Entrectinib is metabolized predominantly by CYP3A4 (~76%). Minor contributions from several other CYPs and UGT1A4 were estimated at <25% in total. The active metabolite M5 (formed by CYP3A4) and the direct N-glucuronide conjugate, M11 (formed by UGT1A4), are the two major circulating metabolites identified.
Elimination: Following administration of a single dose of [¹⁴C]-labeled entrectinib administered orally to healthy subjects, the majority of radioactivity was excreted in feces (82.9%) with minimal excretion in urine (3.06%). In feces, 35.7% and 22.1% of the dose was excreted as unchanged entrectinib and M5, respectively, indicating hepatic clearance is the major route of elimination.
Entrectinib and M5 account for approximately 73% of radioactivity in systemic circulation at C_max, and approximately half of total radioactivity AUC_inf.
Population PK analysis estimated a CL/F of 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively.
Pharmacokinetics in Special Populations: Pediatric Population: Non-compartmental analysis and population pharmacokinetic modeling approaches demonstrated that the pharmacokinetics of entrectinib and M5 were comparable in adults and children allowing extrapolation of data in adults to pediatric patients.
Data obtained from population pharmacokinetic analyses show that a dose of 300 mg/m² of ROZLYTREK once daily in pediatric patients results in a similar systemic exposure attained in adults treated with 600 mg of ROZLYTREK, once daily. Population pharmacokinetic analysis data support dosing of pediatric patients with BSA ≥ 1.51 m² with 600 mg of ROZLYTREK once daily.
Geriatric Population: No differences in entrectinib exposure were noted in patients older than 65 years and younger adults based on pharmacokinetic analysis.
Renal impairment: Negligible amounts of entrectinib and the active metabolite M5 are excreted unchanged in urine (~3% of the dose) indicating renal clearance plays a minor role in the elimination of entrectinib. Population pharmacokinetic data obtained in patients with mild and moderate impairment show that pharmacokinetics of entrectinib are not significantly affected in renal impairment. No formal pharmacokinetic study has been conducted and no population pharmacokinetic data was collected in patients with severe renal impairment. However, since entrectinib elimination via the kidney is negligible, no dose adjustment is required in patients with renal impairment.
Hepatic impairment: The pharmacokinetics of entrectinib were studied in subjects with hepatic impairment due to cirrhosis and subjects with normal hepatic function. Following administration of a single oral dose of 100 mg entrectinib, the AUC_inf GMRs (90%CI) of entrectinib were 1.57 (1.03, 2.41) for the mild (Child-Pugh A), 1.54 (1.06, 2.24) for the moderate (Child-Pugh B), and 1.80 (1.22, 2.66) for the severe (Child-Pugh C) hepatic impaired groups compared to the normal hepatic function group. The combined AUC_last of entrectinib and M5 showed no relevant change in the hepatic impaired groups compared to the normal hepatic function group. The AUC_last GMRs (90%CI) were 1.30 (0.889, 1.89) for the mild, 1.24 (0.886, 1.73) for the moderate, and 1.39 (0.988, 1.95) for the severe hepatic impaired groups compared to the normal hepatic function group.
In addition to the modest increases in entrectinib exposure observed, the variability in systemic exposure was high and observed exposures overlapped across all the study groups.
No dose adjustment is required in patients with underlying mild, moderate or severe hepatic impairment.
Ethnicity: Following a single oral dose of ROZLYTREK in Japanese and Caucasian healthy volunteers, no clinically relevant differences in the exposure of ROZLYTREK were observed. Based on population pharmacokinetics analysis, there was no relationship between systemic exposure of entrectinib and race/ethinicity (Asian, Japanese, white and other ethnicities). No dose adjustment is required for patients of different race/ethnicities. See Special Dosage Instructions under Dosage & Administration.
Toxicology: Preclinical safety data: Carcinogenicity: No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.
Genotoxicity: Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. Entrectinib was not clastogenic in the in vivo micronucleus assay in rats and did not induce DNA-damage in a comet assay in rats. A potential for abnormal chromosome segregation (aneugenicity) has been detected under in vitro conditions in cultured human peripheral blood lymphocytes (HPBL) but was not detected in the in vivo micronucleus assay in rats.
Impairment of Fertility: No fertility studies in animals have been performed to evaluate the effect of entrectinib. With the exception of dose dependent decreases in prostate weight in male dogs, no effects of entrectinib on reproductive organs were observed in the repeat-dose toxicology studies in rats and dogs at approximately 2.4-fold and 0.6-fold, respectively, the human exposure by AUC at the recommended human dose.
Reproductive toxicity: In an embryo-fetal developmental study in rats, maternal toxicity (decreased body weight gain and food consumption) and fetal malformations (including body closure defects and malformations of the vertebrae and ribs), were observed at 200 mg/kg/day of entrectinib, which represents approximately 2-fold the human exposure by AUC at the recommended dose. Lower fetal weights and reduced skeletal ossification were observed at exposures equivalent to 0.7 times the human exposure by AUC at the recommended dose.
Other: In a 13-week juvenile rat toxicology study from post-natal day 7 to day 97 (approximately equivalent to neonate to 16 years of age in humans), effects on growth and development were observed in the dosing and recovery phases including decreased body weight gain and delayed sexual maturation (at ≥ 4 mg/kg/day, approximately 0.1 times the human exposure by AUC at the recommended dose), deficits in neurobehavioral assessments including functional observational battery and learning and memory (at ≥ 8 mg/kg/day, approximately 0.2 times the human exposure by AUC at the recommended dose) and decreased femur length (at 16 mg/kg/day, approximately 0.3 times the human exposure by AUC at the recommended dose).
Entrectinib penetrates the CNS with brain-to-plasma concentration ratios of ~0.4 in mice, 0.6-1.5 in rats and 1.4-2.2 in dogs following repeated oral daily dosing. Consistent with being a weak P-gp substrate, entrectinib demonstrated high retention in the CNS following IV infusion in rats, achieving sufficient steady-state concentrations in the brain to cover target pharmacological activity at clinically relevant systemic exposure. M5 was also detected in a brain homogenate in rats following a single oral dose or an IV infusion of entrectinib for 5-6 hours, but the exposures of M5 were lower than entrectinib in both plasma and brain in rats.

Solid tumors: ROZLYTREK is indicated for the treatment of adult and pediatric patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive locally advanced or metastatic solid tumors, who have progressed following prior therapies, or as initial therapy when there are no acceptable standard therapies.
Non-small cell lung cancer (NSCLC): ROZLYTREK is indicated for the treatment of patients with ROS1-positive, locally advanced or metastatic NSCLC.

General: Patient Selection: Solid Tumors: A validated assay is required for the selection of patients with NTRK fusion-positive locally advanced or metastatic solid tumors. NTRK fusion-positive status should be established prior to initiation of ROZLYTREK therapy.
NSCLC: A validated assay is required for the selection of patients with ROS1-positive locally advanced or metastatic NSCLC. ROS1-positive status should be established prior to initiation of ROZLYTREK therapy.
Dosage: ROZLYTREK hard capsules can be taken with or without food, swallowed whole and must not be opened or dissolved.
Adults: The recommended dose of ROZLYTREK for adults is 600 mg given orally, once daily (see PHARMACOLOGY: Pharmacokinetics under Actions).
Pediatric patients: The recommended dose of ROZLYTREK for pediatric patients who have the ability to swallow capsules is 300 mg/m² orally, once daily (see Table 9). (See PHARMACOLOGY: Pharmacokinetics under Actions.) (See Table 9.)

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Duration of Treatment: It is recommended that patients are treated with ROZLYTREK until disease progression or unacceptable toxicity.
Delayed or Missed Doses: If a planned dose of ROZLYTREK is missed, patients can make up that dose unless the next dose is due within 12 hours. If vomiting occurs immediately after taking a dose of ROZLYTREK, patients may repeat that dose.
Dose Modifications: Management of adverse events may require temporary interruption, dose reduction, or discontinuation of treatment with ROZLYTREK, based on the prescriber's assessment of the patient's safety or tolerability.
Adults: For adults, the dose of ROZLYTREK may be reduced up to 2 times, based on tolerability. Table 10 provides general dose reduction advice for adult patients. ROZLYTREK treatment should be permanently discontinued if patients are unable to tolerate a dose of 200 mg once daily. (See Table 10.)

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Pediatric Patients: Table 11 provides specific dose reduction advice for pediatric patients. For pediatric patients, the dose of ROZLYTREK may be reduced up to 2 times, based on tolerability.
For some patients an intermittent dosing schedule is required to achieve the recommended reduced total weekly pediatric dose. ROZLYTREK treatment should be permanently discontinued if patients are unable to tolerate the lowest reduced dose. (See Table 11.)

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Dose Modifications for Specific Adverse Reactions: Recommendations for ROZLYTREK dose modifications for adults and pediatric patients for specific adverse reactions are provided in Table 12. (See Precautions and Adverse Reactions.) (See Table 12.)

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Dose Modifications for Specific Drug Interactions: Concomitant strong or moderate CYP3A inhibitors: Adults: The concomitant use of strong or moderate CYP3A inhibitors and ROZLYTREK in adults should be avoided or limited to 14 days or less. If concomitant use of strong or moderate CYP3A inhibitors cannot be avoided, ROZLYTREK dose should be reduced to 100 mg once daily for use with strong CYP3A inhibitors and to 200 mg once daily for use with moderate CYP3A inhibitors.
After discontinuation of the concomitant strong or moderate CYP3A inhibitors, ROZLYTREK dose that was taken prior to initiating the strong or moderate CYP3A inhibitor can be resumed. A wash out period may be required for CYP3A4 inhibitors with long half-life. (See Interactions.)
Pediatric patients: The concomitant use of strong or moderate CYP3A inhibitors in pediatric patients should be avoided. (See Interactions.)
Concomitant CYP3A inducers: Co-administration of ROZLYTREK with CYP3A inducers in adult and pediatric patients should be avoided. (See Interactions.)
Special Dosage Instructions: Pediatric use: Pediatric patients must have the ability to swallow whole ROZLYTREK capsules. Dosage for patients is based on body surface area (mg/m²) with a maximum daily dose of 600 mg (see Table 9 as previously shown for pediatric dosing).
Geriatric use: No dose adjustment of ROZLYTREK is required in patients ≥ 65 years of age. (See PHARMACOLOGY: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.)
Renal Impairment: No dose adjustment is required in patients with mild or moderate renal impairment. The safety and efficacy of ROZLYTREK have not been studied in patients with severe renal impairment. However, since entrectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment. (See Precautions and PHARMACOLOGY: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.)
Hepatic Impairment: No dose adjustment is required in patients with underlying mild, moderate or severe hepatic impairment based on a study in subjects with hepatic impairment. (See Precautions and PHARMACOLOGY: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.)
Other Special Patient Populations: Ethnicity: No dose adjustment is necessary for patients of different ethnicities (see PHARMACOLOGY: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).

There is no experience with overdose in clinical trials with ROZLYTREK. Patients who experience overdose should be closely supervised and supportive care instituted. There are no known antidotes for ROZLYTREK.

ROZLYTREK is contraindicated in patients with a known hypersensitivity to entrectinib or any of the excipients.

General: Congestive Heart Failure: Congestive heart failure (CHF) has been reported across clinical trials with ROZLYTREK (see Table 13 under Adverse Reactions). These reactions were observed in patients with or without a history of cardiac disease and resolved upon treatment with diuretics and/or dose reduction/interruption of ROZLYTREK.
For patients with symptoms or known risk factors of CHF, left ventricular ejection fraction (LVEF) should be assessed prior to initiation of Rozlytrek treatment. Patients receiving ROZLYTREK should be carefully monitored and those with clinical signs and symptoms of CHF, including shortness of breath or edema, should be evaluated and treated as clinically appropriate.
Based on the severity of CHF, ROZLYTREK treatment should be modified as described in Table 12 in Dosage & Administration.
Cognitive Disorders: Cognitive disorders, including confusion, mental status changes, memory impairment, and hallucinations, were reported in clinical trials with ROZLYTREK, (see Adverse Reactions for description of events). Patients should be monitored for signs of cognitive changes.
Based on the severity of the cognitive disorder, ROZLYTREK treatment should be modified as described in Table 12 in Dosage & Administration.
Patients should be counseled on the potential for cognitive changes with ROZLYTREK treatment. Patients should be instructed not to drive or use machines until symptoms resolve, if they experience symptoms of cognitive disorders. (See Effects on ability to drive and use machine as follows.)
Fractures: Rozlytrek increases the risk of fractures (see Description of selected adverse drug reactions under Adverse Reactions). Patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures should be evaluated promptly. In adult patients, some fractures occurred in the setting of a fall or other trauma to the affected area, while in pediatric patients fractures occurred in patients with minimal or no trauma. There are no data on the effects of Rozlytrek on healing of known fractures and the risk of occurrence of future fractures. In the majority of pediatric patients treatment was continued with Rozlytrek and the fracture healed.
QTc Interval Prolongation: QT interval prolongation has been observed in patients treated with ROZLYTREK in clinical trials (see Adverse Reactions).
Use of ROZLYTREK should be avoided in patients with congenital long QT syndrome and in patients taking medications that are known to prolong QT interval. Assessment of ECG at baseline and periodic monitoring of ECGs and electrolytes are recommended.
Based on the severity of QTc prolongation, ROZLYTREK treatment should be modified as described in Table 12 in Dosage & Administration.
Central Nervous System Effects: A broad spectrum of central nervous system (CNS) adverse reactions occurred in patients receiving ROZLYTREK, including cognitive impairment, mood disorders, dizziness, and sleep disturbances.
Advise patients and caregivers of these risks with ROZLYTREK. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue ROZLYTREK based on severity.
Hepatotoxicity: Increased AST or ALT has been reported across clinical trials with ROZLYTREK (see Adverse Reactions).
Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Withhold or permanently discontinue ROZLYTREK based on the severity. If withheld, resume ROZLYTREK at the same or reduced dose.
Hyperuricemia: Hyperuricemia has been reported across clinical trials with ROZLYTREK (see Adverse Reactions).
Assess serum uric acid levels prior to initiating ROZLYTREK and periodically during treatment. Monitor patients for signs and symptoms of hyperuricemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold ROZLYTREK for signs and symptoms of hyperuricemia. Resume ROZLYTREK at same or reduced dose upon improvement of signs or symptoms based on severity.
Vision Disorders: Vision disorders has been observed in patients treated with ROZLYTREK in clinical trials (see Adverse Reactions).
For patients with new visual changes or changes that interfere with activities of daily living, withhold ROZLYTREK until improvement or stabilization and conduct an ophthalmological evaluation as clinically appropriate. Upon improvement or stabilization, resume ROZLYTREK at same or reduced dose.
Drug Abuse and Dependence: Not applicable.
Renal Impairment: No dose adjustment is required in patients with mild or moderate renal impairment based on population pharmacokinetic analysis. The safety and efficacy of ROZLYTREK in patients with severe renal impairment have not been studied. See Special Dosage Instructions: Renal Impairment under Dosage & Administration and PHARMACOLOGY: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration and PHARMACOLOGY: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Effects on ability to drive and use machine: ROZLYTREK may influence the ability to drive and use machines. Patients should be instructed not to drive or use machines until the symptoms resolve, if they experience cognitive adverse reactions, syncope, blurred vision, or dizziness, during treatment with ROZLYTREK. (See previous text and Adverse Reactions).
Use in Pregnancy: Embryo-fetal toxicity: Based on the findings in animal studies, ROZLYTREK may cause fetal harm when administered to a pregnant woman. When administrated to pregnant rats, ROZLYTREK caused maternal toxicity and developmental toxicities at exposures 2.3-fold the human exposure by AUC at the recommended dose. (See PHARMACOLOGY: Toxicology: Preclinical safety data: Reproductive toxicity under Actions.)
Female patients receiving ROZLYTREK should be advised of the potential harm to the fetus. Female patients of reproductive potential, must use highly effective contraceptive methods during treatment and for 5 weeks following the last dose of ROZLYTREK. (See Females and Males of Reproductive Potential under Use in Pregnancy & Lactation.)
Use in Children: The safety and efficacy of ROZLYTREK have been studied in pediatric patients. See previous text, Clinical Trials under Adverse Reactions and PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies under Actions. In addition, use of ROZLYTREK in pediatric patients is supported by extrapolation of evidence from clinical trials in adults to pediatric population, based on population pharmacokinetic data demonstrating similar drug exposure in adults and pediatric patients. See Special Dosage Instructions under Dosage & Administration, and PHARMACOLOGY: Pharmacodynamics: Clinical/Efficacy Studies and Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Rozlytrek was associated with a higher incidence of skeletal fractures in the pediatric patients compared to adult patients. See previous text and Clinical Trials under Adverse Reactions.
Use in the Elderly: No differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients. No dose adjustment is required in patients ≥ 65 years of age. See Special Dosage Instructions under Dosage & Administration and PHARMACOLOGY: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.

Females and Males of Reproductive Potential: Fertility: See PHARMACOLOGY: Toxicology: Preclinical safety data: Impairment of Fertility under Actions.
Pregnancy testing: Female patients of reproductive potential should have medically supervised pregnancy testing prior to initiating ROZLYTREK therapy.
Contraception: Female patients of reproductive potential, must use highly effective contraceptive methods during treatment and for 5 weeks following the last dose of ROZLYTREK.
Based on the potential for genotoxicity, male patients with female partners of child-bearing potential must use highly effective contraceptive methods during treatment and for 3 months following the last dose of ROZLYTREK (See PHARMACOLOGY: Toxicology: Preclinical safety data: Genotoxicity under Actions).
Pregnancy: Female patients of reproductive potential must be advised to avoid pregnancy while receiving ROZLYTREK (see Precautions). There is no available data on the use of ROZLYTREK in pregnant women. Based on animal studies with entrectinib (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions) and its mechanism of action, ROZLYTREK may cause fetal harm when administered to a pregnant woman. Patients receiving ROZLYTREK should be advised of the potential harm to the fetus. Female patients should be advised to contact the doctor, should pregnancy occur.
Labor and Delivery: The safe use of ROZLYTREK during labor and delivery has not been established.
Lactation: It is not known whether entrectinib or its metabolites are excreted in human breast milk. No studies have been conducted to assess the effects of ROZLYTREK on milk production or its presence in breast milk. As the potential for harm to the nursing infant is unknown, mothers should be advised to discontinue breast-feeding during treatment with ROZLYTREK.

Clinical Trials: Summary of the safety profile: For the clinical development program of ROZLYTREK, a total of 504 patients have received ROZLYTREK in 4 clinical trials (ALKA, STARTRK-1, STARTRK-2 and STARTRK-NG). The safety of ROZLYTREK was evaluated as integrated analyses of these 4 clinical trials. The median duration of exposure to ROZLYTREK was 5.5 months.
The safety of ROZLYTREK in adult patients has been evaluated in a total of 475 patients with NTRK-fusion positive, ROS1-positive or ALK-positive solid tumors, in studies ALKA, STARTRK-1, and STARTRK-2.
The safety of ROZLYTREK has been evaluated in 29 pediatric patients with solid tumors (27 patients enrolled in STARTRK-NG, and 2 patients enrolled in STARTRK-2). Of these, 1 patient was less than 1 year old, 21 patients were 2 to 11 years old, 7 patients were 12 to 17 years old.
Tabulated summary of adverse drug reactions from clinical trials: Table 13 summarizes the adverse drug reactions (ADRs) occurring in adult and pediatric patients treated with ROZLYTREK. Adverse drug reactions from clinical trials are listed by MedDRA system organ class. The following categories of frequency have been used: very common ≥1/10, common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to < 1/1000), very rare (<1/10,000). (See Table 13.)

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Description of selected adverse drug reactions: Cognitive disorders: A variety of cognitive symptoms were reported across clinical trials (see General under Precautions). These included events reported as cognitive disorders (6.3%), confusional state (7.3%), disturbance in attention (3.8%), memory impairment (4.2%), amnesia (2.8%), mental status changes (1.2%), hallucination (1.0%), delirium (0.8%), hallucination visual (0.4%) and mental disorder (0.2%). Grade 3 events were reported in 4.4% of patients. In the pediatric population, 3.4% (1/29) pediatric patients experienced disturbance in attention of Grade 1 severity. Patients who had brain metastases at baseline had a higher frequency of these events (29.7%) compared to those without brain metastases (23.1%).
Fractures: Fractures were experienced by 5.3% (N=475) of adult patients and 20.7% (N=29) of pediatric patients. In general, there was inadequate assessment for tumour involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumour involvement were reported in some patients. In both adult and pediatric patients, most fractures were hip or other lower extremity fractures (e.g., femoral or tibial shaft). In 2 pediatric patients, bilateral femoral neck fractures occurred. No patients discontinued Rozlytrek due to fractures.
In adult patients, some fractures occurred in the setting of a fall or other trauma to the affected area. The median time to fracture was 3.42 months (range: 0.26 months to 18.5 months) in adults. Rozlytrek was interrupted due to fractures in 36.0% of adult patients that experienced fractures.
In pediatric patients, all fractures occurred in patients with minimal or no trauma. The median time to fracture was 3.38 months (range: 1.77 months to 7.39 months) in pediatric patients. Rozlytrek was interrupted due to fractures in 33.3% of pediatric patients that experienced fractures.
Ataxia: Ataxia (including events of ataxia, balance disorder, and gait disturbances) was reported in 15.7% of patients. The median time to onset for ataxia was 0.36 months (range: 0.03 months to 28.19 months) and the median duration was 0.66 months (range: 0.03 months to 11.99 months). The majority of patients (67.1%) recovered from ataxia. Ataxia related adverse events were observed more frequently in elderly patients (23.8%) compared to patients below 65 years of age (12.8%).
Syncope: Syncope events were reported in 4.6% of patients. In some patients, syncope was reported with concurrent hypotension, dehydration, or QTc prolongation and in other patients no other concurrent related conditions were reported.
QTc interval prolongation: Among the 504 patients who received entrectinib across clinical trials, 17 (4.0%) patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of > 60 ms after starting entrectinib, and 12 (2.8%) patients had a QTcF interval of ≥500 ms.
Peripheral sensory neuropathy: Peripheral sensory neuropathy was reported in 15.7% of patients. The median time to onset was 0.49 months (range 0.03 months to 20.93 months) and the median duration was 0.76 months (range: 0.07 months to 6.01 months). The majority of patients (55.7%) recovered from peripheral neuropathy.
Eye Disorders: Eye disorders reported across clinical trials included events of vision blurred (8.5%), diplopia (2.6%), and visual impairment (1.6%). The median time to onset for eye disorders was 1.87 months (range: 0.03 months to 21.59 months). The median duration of eye disorders was 1.02 months (range 0.03 months to 14.49 months). The majority of patients (61.7%) recovered from the eye disorder events.
Laboratory Abnormalities: The following table provides treatment-emergent shifts from baseline in laboratory abnormalities occurring in patients treated with ROZLYTREK across the 4 clinical trials. (See Table 14.)

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Postmarketing Experience: Not applicable.

Effects of entrectinib on others drugs: CYP substrates: Based on the in vitro studies in human liver microsomes, entrectinib exhibits inhibitory potential toward CYP3A.
In vitro studies indicate that entrectinib and its major active metabolite, M5, do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP2D6 at clinically relevant concentrations.
In vitro results indicate entrectinib has weak induction potential toward CYP3A and CYP2C8/9.
In a clinical study, co-administration of multiple doses of entrectinib and midazolam, a sensitive CYP3A substrate, increased the systemic exposure of midazolam by approximately 50% indicating a weak inhibitory effect of entrectinib on the metabolism of midazolam (Geometric mean ratio (GMR) with/without entrectinib for AUCinf (90% CI) was 150% (129%, 173%)).
Therefore, no dose adjustment is required when ROZLYTREK is co-administered with CYP3A substrates.
P-gp substrates: In vitro data suggest that entrectinib has inhibitory potential towards P-gp.
In a clinical study, co-administration of a single oral dose of entrectinib with a sensitive P-gp substrate, digoxin, increased the digoxin C_max by approximately 28% and overall exposure by approximately 18% (GMR with/without entrectinib for C_max (90% CI) was 128% (98.2%, 167%) and AUC_inf (90% CI) was 118% (106%, 132%)). The renal clearance of digoxin was similar between treatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect of entrectinib on renal clearance of digoxin.
These results indicate that entrectinib is a weak P-gp inhibitor and that no clinically significant interaction exists between digoxin, as a P-gp substrate, and entrectinib. Therefore, no dose adjustment is required when ROZLYTREK is co-administered with P-gp substrates.
BCRP substrates: As with P-gp, a mild inhibition of BCRP was observed in in vitro studies. Given that no clinically significant interaction was observed with the P-gp substrate digoxin, an interaction with BCRP is not predicted. No dose adjustment is required when ROZLYTREK is co-administered with BCRP substrates.
Other transporter substrates: In vitro data indicate that entrectinib has weak inhibitory potential toward organic anion-transporting polypeptide (OATP) 1B1 and multidrug and toxin extrusion protein 1 (MATE1).
Oral Contraceptive: Physiologically-based pharmacokinetic simulation of the effects of co-administration of multiple oral doses of entrectinib with ethinyl estradiol, an oral contraceptive, predicted no drug-drug interaction. GMR with/without entrectinib for AUC_inf (90% CI) of 112% (111%, 113%) and C_max (90% CI) was 112% (111%, 113%).
Therefore, ROZLYTREK can be co-administered with an oral contraceptive.
Effects of other drugs on entrectinib: Based on in vitro data, CYP3A4 is the predominant enzyme mediating the metabolism of entrectinib and formation of its major active metabolite M5.
CYP3A inducers: Co-administration of multiple oral doses of rifampin, a strong CYP3A inducer, with a single oral dose of entrectinib reduced the systemic exposure of entrectinib by 77%. GMR with/without rifampin for AUC_inf (90% CI) was 23.3% (18.4%, 29.5%) and C_max (90% CI) was 44.4% (35.3%, 55.9%).
Co-administration of ROZLYTREK with CYP3A inducers should be avoided (see Dosage & Administration).
CYP3A inhibitors: Co-administration of a single oral dose of entrectinib with multiple oral doses of itraconazole, a strong CYP3A4 inhibitor, increased the systemic exposure of entrectinib by 500%. GMR with/without itraconazole for AUC_inf (90% CI) was 604% (454%, 804%) and C_max (90% CI) was 173% (137%, 218%).
Co-administration of strong and moderate CYP3A inhibitors (including, but not limited to, anti-fungal agents, anti-retroviral agents) with ROZLYTREK should be avoided or limited to 14 days. If concurrent use is unavoidable, dose adjustment of ROZLYTREK is required as described in Dosage & Administration.
Medicinal products that increase gastric pH: The aqueous solubility of entrectinib in vitro is pH dependent. In a clinical study, administration of entrectinib with lansoprazole (a proton pump inhibitor (PPI)), resulted in a 25% decrease in entrectinib systemic exposure which is not clinically relevant. GMR with/without lansoprazole for AUC_inf (90% CI) was 74.5% (64.7%, 85.9%) and C_max (90% CI) was 76.5% (67.6%, 86.6%).
Therefore, no dose adjustments are required when ROZLYTREK is co-administered with PPIs or other drugs that raise gastric pH (e.g., H2 receptor antagonists or antacids).
Effect of transporters on Entrectinib disposition: Based on the in vivo brain-to-plasma concentration ratio (≥0.6) at steady-state in rats and dogs as well as lack of sensitivity to a P-gp inhibitor in vitro in a P-gp expressing cell assay, entrectinib is considered a poor substrate of P-gp. M5 is a substrate of P-gp.
Entrectinib is not a substrate of BCRP but M5 is a substrate of BCRP. Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.

Incompatibilities: Not applicable.
Special Instructions for Use, Handling and Disposal: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store above 30°C.
Store in the original package and keep the bottle tightly closed in order to protect from moisture.
Shelf-life: 36 months.

Targeted Cancer Therapy

L01EX14 - entrectinib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.

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