ENTRECTINIB for Locally advanced or metastatic solid tumors with NTRK1/2/3, ROS1 or ALK gene rearrangements

Inclusion criteria

• {"criterion_text":"- Histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor that harbors an NTRK1/2/3, ROS1, or ALK gene rearrangement that is predicted to translate into a fusion protein with a functional TrkA/B/C, ROS1, or ALK kinase domain, respectively, without a concomitant second oncodriver (e.g., EGFR, KRAS), as determined by Foundation Medicine, Inc. or by any nucleic acid-based diagnostic testing method (please refer to Section 5.1) performed at a local CLIA-certified or equivalently-accredited diagnostic laboratory. These are patients for whom no alternative effective standard therapy is available or for whom standard therapy is considered unsuitable or intolerable. Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest are no longer eligible.\n- For patients enrolled via local molecular testing, an archival or fresh tumor tissue (unless medically contraindicated) is required to be submitted for independent central molecular testing at Foundation Medicine, Inc. 1. or to the alternative, approved central laboratory for that region.\n- Measurable disease as assessed locally using RECIST v1.1. Note: Patients with non-measurable disease (evaluable disease only) will be eligible for enrollment in the \"non-evaluable for the primary endpoint\" basket and will mainly contribute to assessment of safety, PK, and other secondary endpoints.\n- Patients with CNS involvement, including leptomeningeal carcinomatosis, which is either asymptomatic or previouslytreated and controlled, are allowed. The use of seizure prophylaxis is allowed as long as patients are taking non-enzyme-inducing anti-epileptic drugs (non-EIAEDs).\n- Prior anticancer therapy is allowed (excluding approved or investigational Trk, ROS1, or ALK (non-NSCLC patients only) inhibitors in patients who have tumors that harbor those respective gene rearrangements). Note: The ALK basket is closed to enrolment.\n- At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed after prior chemotherapy or small molecule targeted therapy, respectively, at the time of the start of entrectinib treatment. Note: For targeted therapies, there must be no signs of disease flare or accelerated disease progression after treatment discontinuation.\n- At least 4 weeks must have elapsed since completion of antibody-directed therapy at the time of the start of Entrectinib treatment.\n- Prior radiotherapy is allowed if more than 14 days have elapsed since the end of treatment. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment.\n- Age ≥ 18 years\n- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of at least 4 weeks.\n- Adequate liver function as defined by the following criteria: -Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase (SGOT)) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase (SGPT)) ≤ 3.0 × upper limit of normal (ULN); ≤ 5.0 × ULN if liver metastases are present -Total serum bilirubin ≤ 2.0 × ULN; patients with a known history of Gilbert's syndrome and/or isolated elevations of indirect bilirubin are eligible\n- Women patients of childbearing potential: • Must have a negative serum pregnancy test during screening and must not be breastfeeding or intending to become pregnant during the study • Must agree to remain abstinent or use single or combined contraception methods that result in a failure rate of < 1% per year prior to entering into the study and for 5 weeks following the last dose of study drug • Allowance for locally recognized adequate methods of contraception • Must agree to refrain from donating eggs during the same period -Oral contraceptives and intrauterine hormone releasing systems (IUSs) used by female patients must be combined with a barrier method. Male patients with female partners of childbearing potential: • Must agree to use highly effective contraception during the study and for 3 months following the last dose of study drug. • Requirement for male patients to abstain from donating sperm during the study and for 3 months after study.\n- Ability to swallow entrectinib intact without chewing, crushing, or opening the capsules. Please refer to the Section 5.2.2. of the Protocol for the complete list of the Inclusion criteria\n- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and minimum life expectancy of at least 4 weeks."}

Exclusion criteria

• {"criterion_text":"- Current participation in another therapeutic clinical trial.\n- Prior treatment with approved or investigational Trk, ROS1, or ALK inhibitors in patients who have tumors that harbor those respective gene rearrangements. Note: In cases where the patient was intolerant to prior Trk, ROS1, or ALK inhibitors, please discuss with the Sponsor. In addition, prior treatment with crizotinib is permitted ONLY in ALK- or ROS1-rearranged NSCLC patients presenting with CNS-only progression. Other ALK or ROS1 inhibitors are prohibited in that scenario.\n- History of other previous cancer that would interfere with the determination of safety or efficacy of entrectinib with respect to the qualifying solid tumor malignancy. Note: Patients presenting with dual primary cancers may enroll in the \"non-evaluable for the primary endpoint\" basket if at least one of the cancers harbor an NTRK1/2/3, ROS1, or ALK gene rearrangement as per Inclusion Criterion 1.\n- Familial or personal history of congenital bone disorders or bone metabolism alterations\n- Incomplete recovery from any surgery prior to the start of entrectinib treatment that would interfere with the determination of safety or efficacy of entrectinib.\n- Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of entrectinib: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication.\n- History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction 50% observed during screening for the study\n- History of non-pharmacologically induced prolonged QTc interval (e.g., repeated demonstration of a QTc interval > 450 milliseconds from ECGs performed at least 24 hours apart).\n- History of additional risk factors for torsades de pointes (e.g., family history of long QT syndrome).\n- Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis. Note: Radiation-induced lung disorders are not included in this exclusion criterion.\n- Active gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would reasonably impact drug absorption.\n- Known active infections that would interfere with the assessment of safety or efficacy of entrectinib (bacterial, fungal, or viral) with the exceptions of human Immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections, as noted below: – HIV positivity, only if patients meet any of the following criteria: Patients with a CD4+ T-cell count of <350 cells/μL Patients with a detectable HIV viral load Patients with a history of an opportunistic infection within the past 12 months Patients who are on stable antiretroviral therapy for < 4 weeks – Active HBV infection (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test), with the following exception: Patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) if they are negative for HBV DNA – HCV antibody (HCV Ab) positivity, with the following exceptions: Patients who are HCV Ab-positive but HCV RNA-negative due to prior treatment or natural resolution are eligible Patients with untreated HCV if the HCV is stable, the patient is not at risk for hepatic decompensation, and the intended treatment is not expected to exacerbate the HCV infection Patients on concurrent HCV treatment if they have HCV below the limit of quantification\n- Peripheral sensory neuropathy Grade ≥ 2."}

Primary endpoints

• {"endpoint_text":"- Objective Response Rate (ORR), defined as the proportion of patients with complete response (CR) or partial response (PR)","definition_or_measurement_approach":"Defined as the proportion of patients with complete response (CR) or partial response (PR); objective response rate to be determined per the protocol and main objective states assessment by BICR (Blinded Independent Central Review) in each patient population basket."}

Secondary endpoints

• {"endpoint_text":"- Duration of Response (DOR)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Time to Response (TTR)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Clinical Benefit Rate (CBR)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Intracranial tumor response in patients with measurable brain metastases, as determined by BICR using RANO or RANO-BM as applicable","definition_or_measurement_approach":"Determined by Blinded Independent Central Review (BICR) using RANO or RANO-BM criteria as applicable."}
• {"endpoint_text":"- CNS Progression-Free Survival (CNS-PFS) in patients with measurable CNS disease,","definition_or_measurement_approach":""}
• {"endpoint_text":"- Progression-Free Survival (PFS)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Overall Survival (OS)","definition_or_measurement_approach":""}
• {"endpoint_text":"- Type, incidence, severity, timing, seriousness, and relatedness of adverse events and laboratory abnormalities","definition_or_measurement_approach":""}
• {"endpoint_text":"- Population PK","definition_or_measurement_approach":"Population pharmacokinetics (PK) assessment of entrectinib."}
• {"endpoint_text":"- Ventricular repolarization","definition_or_measurement_approach":""}
• {"endpoint_text":"- Quality-of-life and health status to examine biological markers of bone formation and resorption and markers of calcium metabolism","definition_or_measurement_approach":""}
• {"endpoint_text":"- Assessment of bone mineral density (BMD) via dual X-ray absorptiometry (DXA) scans","definition_or_measurement_approach":"Assessment of BMD by dual X-ray absorptiometry (DXA) scans."}

France

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

09-04-2025

Processing Time Days

322

Number Of Sites

8

Number Of Participants

45

Germany

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

08-04-2025

Processing Time Days

321

Number Of Sites

5

Number Of Participants

16

Italy

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

09-04-2025

Processing Time Days

322

Number Of Sites

5

Number Of Participants

27

Spain

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

07-04-2025

Processing Time Days

320

Number Of Sites

4

Number Of Participants

21

Netherlands

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

14-04-2025

Processing Time Days

327

Number Of Sites

1

Number Of Participants

7

Poland

Earliest CTIS Part Ii Submission Date

22-05-2024

Latest Decision Or Authorization Date

09-04-2025

Processing Time Days

322

Number Of Sites

3

Number Of Participants

15

Primary sponsor

Full Name

F. Hoffmann-La Roche AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

IQVIA Limited

Responsibilities

Codes: 1,10,11,12,15 (investigator payment),5,6,7,8,9

Name

Signant Health Global LLC

Responsibilities

Collection of patient quality of life questionnaire data via TrialSlate ePRO tablet

Third parties

• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"Collection of patient quality of life questionnaire data via TrialSlate ePRO tablet","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Codes: 1,10,11,12,15 (investigator payment),5,6,7,8,9","organisation_type":"Pharmaceutical company"}