| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Anaplastic lymphoma kinase positive non-small cell lung cancer (ALK+ NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer |
|
| 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Comparison of the efficacy of brigatinib in the 1st-line use to that of any other 2nd-generation TKI (PFS 1st-line treatment) |
|
| E.2.2 | Secondary objectives of the trial |
· PFS 2nd-line treatment
· Comparison of the efficacy of brigatinib in the 1st-line use to that of any other TKI as evidenced by TNT 1st line (TNT 1st line, defined as the time from begin of 1st-line treatment until begin of 2nd-line treatment)
· Comparison of the efficacy of brigatinib in the 1st-line use to that of any other TKI as evidenced by TNT 2nd line (TNT2, defined as time from begin of 2nd line until begin of 3rd-line treatment)
· Comparison of the efficacy of brigatinib in the 1st-line use to that of any other TKI as evidenced by TNT1/2 (defined as time from begin of 1st-line treatment until begin of 3rd-line treatment)
· Overall survival (OS)
· Efficacy in the CNS (“brain control”)
o intracranial ORR (iORR)
o intracranial DOR (iDOR)
o time to intracranial progression (TTiP)
· QoL with SF-12 and EORTC-QLQ-BN20
· Safety and tolerability of brigatinib in the 1st-line use to that of any other TK
· Biomarker analyses
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Fully informed written consent and any locally-required authorization (EU Data Privacy Directive) given by the patient
2. Male or female ≥ 18 years of age
NOTE: There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
3. Histologically confirmed, locally advanced (stage III) and not suitable for curative treatment, i.e. R0 operation or definitive chemo-/radiation, or metastatic (stage IV) ALK+ NSCLC
NOTE: Documentation of ALK rearrangement by a positive result of any ALK assay approved in Germany [i.e. positivity for at least one of the three: immunohistochemistry (IHC), NGS, fluorescence in situ hybridisation (FISH)] must be available at baseline. Treatment can already be started based on a local ALK+ test result, but subsequent central testing of the baseline biopsy for molecular profiling incl. determination of ALK variant and TP53 status should be made possible for all patients.
4. No prior therapy for metastatic ALK+ NSCLC including therapy with ALK inhibitors. However, 1 or 2 cycles of chemotherapy, chemo-immunotherapy or immunotherapy as well as cerebral irradiation before inclusion in the study will be allowed.
5. At least 1 measurable (i.e., target) lesion per RECIST v1.1 or otherwise evaluable lesion (e.g. brain lesion with at least 5 mm of longest diameter if measured by high-resolution cMRT e.g. using 1 mm slices thickness and not planned for irradiation before the first response assessment)
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
7. Have adequate organ function, as determined by:
• Total bilirubin ≤1.5x the upper limit of the normal range (ULN)
(< 3x the ULN if Gilbert’s disease is present)
• Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2
(calculated by MDRD or any other validated formula, see Appendix 13.4)
• Alanine aminotransferase/aspartate aminotransferase ≤2.5x ULN
NOTE: ≤5x ULN is acceptable if liver metastases are present.
• Serum lipase or serum amylase ≤1.5x ULN
• Platelet count ≥75x 109/L
• Hemoglobin ≥9 g/dL
• Absolute neutrophil count ≥1.5x 109/L
8. Willingness and ability to comply with scheduled visit and study procedures
9. Patient willing to participate in accompanying research program
10. Collection of current biopsy during screening must be feasible
NOTE: For each patient a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block must be available for biomarker evaluation. Excisional, incisional or core needle biopsies are appropriate, while fine needle aspirations are insufficient.
11. Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days prior to randomization. Women must not be breastfeeding.
12. Female patients who
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or
- Agree to completely abstain from heterosexual intercourse.
|
|
| E.4 | Principal exclusion criteria |
1. History or presence at baseline of pulmonary interstitial disease, drug-related pneumonitis, or radiation pneumonitis
2. Uncontrolled hypertension, defined as hypertension treated* with anti-hypertensive drugs AND blood pressure ≥ 160 mmHg (systolic) or ≥ 100 mmHg (diastolic) in repeated measurements. Untreated elevated blood pressure is not an exclusion criterion and should receive adequate anti-hypertensive adjustment.
*Please note: In case of treatment, at least 3 anti-hypertensive drugs should have been used with the intention to control hypertensive disease
3. Systemic treatment with strong cytochrome P-450 (CYP) 3A inhibitors, strong CYP3A inducers, or moderate CYP3A inducers or treatment with any investigational systemic anticancer agents, chemotherapy or radiation therapy (except for stereotactic radiosurgery or stereotactic radiation therapy) or palliative radiotherapy within 14 days of randomization
4. Treatment with antineoplastic monoclonal antibodies within 30 days of randomization
5. Major surgery within 30 days of randomization. Minor surgical procedures, such as catheter placement or minimally invasive biopsies, are allowed.
6. Current symptomatic spinal cord compression as confirmed by radiographic imaging. Patients with leptomeningeal disease without symptomatic cord compression are allowed.
7. Significant or uncontrolled cardiovascular disease, specifically including, but not restricted to the following:
• If an acute coronary syndrome has ensued in the past 6 months, successful reperfusion has to be documented and the patient has to be free of symptoms.
• New York Heart Association Class III or IV heart failure within 6 months prior to randomization
• Any history of clinically significant ventricular arrhythmia
8. Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose of study drug
9. Malabsorption syndrome or other gastrointestinal illness or condition that could affect oral absorption of the study drug
10. Active severe or uncontrolled chronic infection, including but not limited to, the requirement for intravenous antibiotics for longer than 2 weeks
11. History of HIV infection. Testing is not required in the absence of history.
12. Chronic hepatitis B (surface antigen-positive) or chronic active hepatitis C infection. Testing is not required in the absence of history.
13. Any serious medical condition or psychiatric illness that could, in the investigator’s opinion, potentially compromise patient safety or interfere with the completion of treatment according to this protocol
14. Known or suspected hypersensitivity to brigatinib or other TKI or their excipients
15. Life-threatening illness unrelated to cancer
16. Involvement in the planning and/or conduct of the study (applies to both Takeda staff and/or staff of sponsor and study site)
17. Patient who might be dependent on the sponsor, site or the investigator
18. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities [§ 40 Abs. 1 S. 3 Nr. 4 AMG]
19. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG]
20. Legal incapacity or limited legal capacity
21. Females who are pregnant or breastfeeding
22. Patients who have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring an increasing dose of corticosteroids to control symptoms within 7 days prior to randomization.
23. Rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS 1st-line treatment is defined as the time from the first dosing date of any study medication to the date of the first objectively documented tumor progression, as determined by investigators (per RECIST v1.1), or death due to any cause. Subjects who did not progress or die will be censored on the date of their last tumor assessment. Subjects who did not have any on study tumor assessments and did not die will be censored on the first dosing date of study medication. Subjects who started 2nd-line treatment or any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After LPLV, approx. Q3 / 2025 |
|
| E.5.2 | Secondary end point(s) |
· PFS 2nd-line treatment (RECIST v1.1) is defined as the time from the first dosing date of any 2nd-line TKI to the date of the objectively documented tumor progression, as determined by investigators (per RECIST v1.1), or death due to any cause. Subjects who did not progress or die will be censored on the date of their last tumor assessment. Subjects who did not have any on study tumor assessments and did not die will be censored on the first dosing date of study medication. Subjects who started 2nd-line treatment or any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent anti-cancer therapy.
· TNT 1st line (TNT1, i.e. time-to-next treatment for the 1st line, defined as the time from begin of 1st-line treatment until begin of 2nd-line treatment)
· TNT 2nd line (TNT2, i.e. time-to-next treatment for the 2nd line, defined as time from begin of 2nd line until begin of 3rd-line treatment)
· TNT1/2 (time-to-next treatmemt for the 1st and 2nd line together, defined as time from begin of 1st-line treatment until begin of 3rd-line treatment)
· Overall survival (OS), defined as the time from treatment start in the 1st line to the date of death (due to any cause). Subjects without death events will be censored at the last date known alive.
· Efficacy in the CNS (“brain control”) of 1st- and 2nd-line treatment assessed by applying RECIST v1.1 criteria
o intracranial ORR (iORR), defined as the percentage of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Best overall response (BOR) is defined as the best response designation, recorded between the date of first dose and the date of the initial objectively documented intracranial tumor progression per RECIST criteria or the date of subsequent therapy or death, whichever occurs first. For participants without documented progression or subsequent therapy, all available response designations will contribute to the BOR determination.
o intracranial DOR (iDOR), defined as the time from documentation of CR or PR according to RECIST v1.1 (whichever is first recorded) until the first date that the intracranial PD is objectively documented or until death (whichever occurs first).
o time to intracranial progression (TTiP), defined as the time from start of 1st-line treatment until the occurrence of a new CNS lesion or progression of pre-existing CNS lesions (adjusted for the two competing events “death” and “extracranial progression inducing a change in ALK inhibitor treatment")
· QoL assessed with SF-12 and EORTC-QLQ-BN20
(EORTC-QLQ-BN20 in case of brain metastases, only)
· Safety and tolerability including type, incidence and severity of AEs, SAEs
Exploratory Endpoints:
· Capturing ALK fusion variants, TP53 mutation status and „acquired resistance“ mutations via standardized NGS-based multiplex analysis
· Efficacy of treatment according to ALK fusion variant and TP53 status
· Molecular resistance patterns after 1st-line failure
· Impact of 2nd-line treatment after failure of 1st line as defined
· Clinical utility of cerebrospinal fluid ctDNA analysis in “brain-only” progression
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| After LPLV, approx. Q3 / 2025 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
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