E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non Small Cell Lung Cancer |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
To evaluate the efficacy of taletrectinib by the objective response rate (ORR) in the patients with advanced or metastatic ROS1 positive NSCLC |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy by duration of response (DOR) 2. To evaluate the efficacy by progression-free survival (PFS) 3. To evaluate the efficacy by time to treatment failure(TTF) 4. To evaluate the efficacy by time to response(TTR) 5. To evaluate the efficacy endpoints (ORR,DOR and PFS) assessed by investigators 6. To evaluate the intracranial efficacy of taletrectinib 7. To evaluate the efficacy by overall survival (OS) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥18 years (or ≥20 years as required by local regulations) 2. Histologically or cytologically confirmed diagnosis of locally advanced (including inoperable Stage IIIA or IIIB NSCLC) or metastatic NSCLC (cohorts 1-3, 5-6) or other solid tumors including NSCLC patients ineligible for other cohorts (cohort 4). 3. Evidence of ROS1 fusion by a validated assay as performed in Clinical Laboratory Improvement Amendments (CLIA)-certified or locally equivalent diagnostic laboratories. The molecular assays (i.e., Reverse Transcription Polymerase Chain Reaction [RT-PCR], Next-generation Sequencing [NGS]) are highly recommended. 4. Sufficient tumor tissue is required for patients in Cohort 1 and for TKInaïve patients in Cohort 5 in order to perform confirmatory ROS1 fusion testing at the designated central laboratories. For patients in cohort 1 and for TKI-naïve patients in Cohort 5, an archival tumor tissue specimen should be available and collected prior to enrollment. If archival tumor tissue is unavailable, then a fresh biopsy must be performed. Tumor tissue for patients in other cohorts is highly recommended and tumor tissue obtained after progression on the most recent prior ROS1 TKI therapy in these cohorts is preferred. Cytology samples (e.g., pleural effusion cell pellets) may be acceptable for patients in cohorts 2-4. Cohort 6, and patients in Cohort 5 that received prior treatment with TKI(s) having ROS1 activity. 5. Patients with central nervous system (CNS) involvement, including leptomeningeal carcinomatosis, which is stable (either asymptomatic or previously treated and controlled), are allowed: • Seizure prophylaxis is permitted with non-enzyme inducing antiepileptic drugs (non-EIAEDs). • Corticosteroid treatment at a stable or decreasing dose of ≤10 mg prednisone or equivalent if required within 7 days prior to the first dose of taletrectinib. • Local therapy including but not limited to whole brain radiation or gamma knife irradiation treatment must be completed at least 14 days before enrollment and the patient clinically stable (e.g., no corticosteroids or anticonvulsant treatment) for 7 days prior to first dose of taletrectinib (for patients with neurological symptoms or signs due to CNS metastasis at screening). 6. The patient is either ROS1 TKI treatment naïve, or treated with prior ROS1 TKI(s): • Cohort 1: Patients with locally advanced or metastatic ROS1-positive NSCLC. Systemic chemotherapy naïve or pretreated with 1 prior line of chemotherapy, but never treated with any ROS1 TKI. • Cohort 2: Patients with locally advanced or metastatic ROS1-positive NSCLC. Prior treatment with 1 approved ROS1 TKI (crizotinib or entrectinib) and disease progression. The patient can be either chemotherapy naïve or has received 1 line of systemic chemotherapy for the locally advanced or metastatic ROS1 positive NSCLC. • Cohort 3: Patients with locally advanced or metastatic ROS1-positive NSCLC. Prior treatment with ≥2 TKIs with ROS1 activity and disease progression. The patient can be either chemotherapy naïve or has received 1 line of systemic chemotherapy for locally advanced or metastatic ROS1-positive NSCLC, patients with known ROS1 resistant mutations are preferred. • Cohort 4: Patients with other ROS1-positive solid tumors, or NSCLC patients ineligible for Cohorts 1-3. Prior treatment with ≤3 TKIs with ROS1 activity. The patient can be either chemotherapy naïve or has received ≤ 2 lines of systemic chemotherapy for locally advanced or metastatic solid tumors. Cohort 5: Patients with locally advanced or metastatic ROS1-positive NSCLC. The patient can be either chemotherapy naïve or has received ≤2 lines of systemic chemotherapy line of systemic chemotherapy for locally advanced or metastatic ROS1-positive SCLC. ROS1-TKI-naïve or pretreated with TKI(s) having ROS1 activity. • Cohort 6: Patients with locally advanced or metastatic ROS1-positive NSCLC. Previously treated with ≥1 TKI having ROS1 activity. Prior adjuvant platinum-based chemotherapy and platinum-based chemotherapy for advanced or metastatic disease is allowed if completed >12 months from the study treatment start date with one exception: a patient may be eligible if started on chemotherapy, provided that no more than 2 cycles of chemotherapy were administered and no evidence of disease progression. 7. At least 1 measurable disease per RECIST 1.1 assessed by investigator. 8. Eastern Cooperative Oncology Group Performance Status: 0 or 1.9. Patient with a life expectancy ≥12 weeks based on the judgment of investigator. 10. Patients with adequate organ function meeting the following criteria: a) Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT): ≤ 3.0 × upper limit of normal (ULN) (or ≤ 5.0 × ULN, for patients with concurrent liver metastases) For full list of Inclusion criteria please see section 5.1 in Protocol |
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E.4 | Principal exclusion criteria |
1. Treatment with small molecule anticancer therapy including other investigational agents or cytotoxic systemic anticancer therapy (with exceptions as noted in Inclusion Criterion 6 which requires at least 3 weeks washout), within 2 weeks (or 5 half-lives of the compound, whichever is shorter) prior to the first dose of taletrectinib; or treatment with monoclonal antibodies including immune checkpoint inhibitors, within 4 weeks before the first dose of taletrectinib. 2. Major surgical procedure, open biopsy, or significant traumatic injury ≤4 weeks before the first dose of taletrectinib or anticipation of need for major surgical procedure during the study. • Placement of vascular access device is not considered major surgery. Other minor surgical procedures, such as catheter placement or minimally invasive biopsy, are allowed. 3. Radiotherapy within 14 days before study treatment. Stereotactic radiosurgery (SRS), stereotactic radiation therapy (SRT), and palliative radiation outside the chest and brain are allowed but must be completed 1 week before starting study treatment. 4. Have been diagnosed with another primary malignancy other than NSCLC except for adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively treated non-metastatic prostate cancer; or patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since initial diagnosis of the other malignancy. Note: This criterion does not apply to patients to be enrolled in Cohort 4. 5. Adverse events due to prior therapy are unresolved to ≤ CTCAE Grade 1 or has not returned to baseline, at the time of the first dose of taletrectinib except for AEs not constituting a safety risk to the patient based on the judgment of investigators. 6. Patients with untreated spinal cord compression caused by tumor and/or cancerous meningitis. 7. History or evidence of interstitial fibrosis, interstitial lung disease or drug-induced pneumonitis (Excluding clinically insignificant or asymptomatic post-radiation pneumonitis). 8. Any gastrointestinal disorders that may affect absorption of oral medications. 9. Active and clinically significant bacterial, fungal, or viral infection including hepatitis B virus (HBV), hepatitis C virus (HCV), or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Note that the following are permitted: • Patients treated for hepatitis C (HCV) or HIV with no detectable viral load; for at least 1 month prior to the first dose of taletrectinib. Note: caution with drug-drug interactions of concomitant anti-HIV agents and CYP3A substrates. • Patients with known hepatitis B (HBV) infections: - With past or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of hepatitis B surface antigen [HBsAg]); or - With inactive HBV carrier state (defined as HBsAg-positive, with normal ALT, and HBV DNA <2,000 IU/mL or <10,000 copies/mL). Note: Please consider that for patients in an inactive HBV carrier state or with a resolved HBV infection, there may be a risk of HBV reactivation and anti-HBV prophylaxis should be considered. 10. Clinically significant cardiovascular diseases within 3 months prior to the first dose of taletrectinib: myocardial infarction, severe/unstable angina, coronary/peripheral endovascular treatment, heart failure or cerebrovascular disorder including transient ischemic attack. 11. Ongoing cardiac dysrhythmias of ≥ CTCAE Grade 2, uncontrolled atrial fibrillation of any grade, or QT interval corrected for heart rate by Fredericia's formula (QTcF) >470 milliseconds, or symptomatic bradycardia <45 beats per minute; patient has family or medical history of long QT syndrome. 12. Pregnancy or lactation/breastfeeding. 13. Use of food or drugs that are known potent cytochrome P450 3A4/5 (CYP3A4/5) inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment. 14. Administration of agents with potential QT interval prolonging effect within 14 days prior to first dose of study treatment and while on treatment. 15. Patients with other severe medical or mental diseases in whom the risk is increased by the participation to the study or treatment with study treatment in the opinion of the Investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Confirmed ORR according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by IRC for cohorts 1-2.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the entire study period. |
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E.5.2 | Secondary end point(s) |
1. DOR according to RECIST 1.1 assessed by IRC (cohorts 1-2) 2. PFS according to RECIST 1.1 assessed by IRC (cohorts 1-2) 3. TTF according to RECIST 1.1 assessed by IRC(cohorts 1-2) 4. TTR according to RECIST 1.1 assessed by IRC(cohorts 1-2) 5. ORR, DOR and PFS according to RECIST 1.1 assessed by investigators (cohorts 1-2) 6. Confirmed intracranial (IC)-ORR, IC-DOR, IC-PFS and time to intracranial progression(TTiP) according to mRECIST 1.1 assessed by IRC (cohorts 1-2) 7. OS (cohorts 1-2) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Efficacy: Throughout the entire study period.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Ukraine |
Canada |
China |
Japan |
Korea, Republic of |
United States |
France |
Italy |
Poland |
Spain |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |