| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer (NSCLC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Lung cancer is cancer that starts in the windpipe, main airway or lungs, where there is uncontrolled growth of abnormal cells and NSCLC is one of the major types of lung cancer. |
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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 | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084713 |
| E.1.2 | Term | Tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 study treatment (alectinib or entrectinib or pralsetinib) compared with durvalumab in patients with biomarker-selected, locally advanced, unresectable, Stage III NSCLC who have received concurrent chemoradiotherapy (cCRT) or sequential chemoradiotherapy (sCRT) and have not had radiographic disease progression |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the health-related quality of life of patients with biomarker-selected locally advanced, unresectable, Stage III NSCLC who have received cCRT or sCRT and have not had radiographic disease progression in the study treatment arm compared with in the durvalumab arm
To evaluate the safety and tolerability of study treatment compared with durvalumab in patients with biomarker selected, locally advanced, unresectable, Stage III NSCLC who have received cCRT or sCRT and have not had radiographic disease progression
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age >=18 years
Body weight >=30 kg
Whole-body positron emission tomography/computed tomography scan (PET/CT) performed prior and within 42 days of the first dose of cCRT or sCRT
Histologically or cytologically documented locally advanced, unresectable Stage III NSCLC of either squamous or non-squamous histology (Version 8, American Joint Committee on Cancer/Union for International Cancer Control NSCLC staging system (Amin et al. 2017).
Prior receipt of at least two prior cycles of platinum-based chemotherapy given concurrently with radiotherapy (cCRT); or at least two prior cycles of platinum-based chemotherapy given prior to radiotherapy (sCRT)
The RT component in the cCRT or sCRT must have been at a total dose of radiation of 60 (± 10%) Gy (54 Gy to 66 Gy) administered by intensity-modulated radiotherapy (preferred) or three dimension (3D)-conforming technique
No disease progression during or following platinum-based cCRT or sCRT
Life expectancy ≥ 12 weeks
Documented tumor PD-L1 status
Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2
• Adequate hematologic and end-organ function
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, during the treatment period and for at least 90 days after the final dose of alectinib or durvalumab (Cohort A1 only)
For women of childbearing potential: Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, during the treatment period, and for at least 35 days after the final dose of entrectinib, or 90 days after the final dose of durvalumab (Cohort A2 only)
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs, during the treatment period, and for at least 14 days after the final dose of pralsetinib, or at least 90 days after the final dose of durvalumab (Cohort A3 only)
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm during the treatment period and for least 90 days after the final dose of alectinib or durvalumab (Cohort A1 only)
For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom plus an additional contraception method, and agreement to refrain from donating sperms, during the treatment period and for at least 3 months after the final dose of entrectinib or final dose of durvalumab Cohort A2 only)
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, during the treatment period and for at least 7 days after the final dose of pralsetinib and at least 90 days after the final dose of durvalumab (Cohort A3 only)
Ability to swallow entrectinib intact, without chewing, crushing, or opening the capsules (Cohort A2 only)
Confirmed availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumor specimen
Documented ALK fusion positivity (Cohort A1 only)
Documented ROS1 fusion positivity (Cohort A2 only)
Documented RET fusion positivity (Cohort A3 only
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| E.4 | Principal exclusion criteria |
Any history of previous NSCLC and/or any history of prior treatment for NSCLC
Any evidence of Stage IV disease
If pleural effusion is present the following criteria must be met to exclude malignant involvement (T4 disease):
When pleural fluid is visible on both the computed tomography scan & chest X-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative.
Patients with exudative pleural effusions are excluded regardless of cytology.
Patients with effusions that are minimal (ie not visible on chest X-ray) that are too small to safely tap are eligible
NSCLC known to have one or more of the following ALK point mutations, as identified by site local testing or Sponsor central testing: I1171X (where X is any other amino acid), V1180L, G1202R (Cohort A1)
NSCLC known to have a known or likely oncogenic-driver mutation in the EGFR gene as identified by site local testing or Sponsor central testing
Liver disease
Positive hepatitis B surface antigen test at screening
Patients known to be positive for hepatitis C virus antibody
HIV infection, patients are excluded if HIV is not adequately controlled(specific criteria apply)
Known active tuberculosis
Presence of clinically symptomatic interstitial lung disease or interstitial pneumonitis, including radiation pneumonitis (Cohorts A1, A3)
Grade ≥ 2 pneumonitis from prior cCRT or sCRT
Symptomatic bradycardia(Cohort A1,A2)
Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
Left ventricular ejection fraction less than or equal to 50% observed during the screening for the study (Cohort A2)
Any gastrointestinal (GI) disorder that may affect absorption of oral medications
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
Active or history of autoimmune disease or immune deficiency
History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest CT scan
History of malignancy other than NSCLC within 5 years prior to screening
Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
Major surgical procedure, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
Treatment with systemic immunostimulatory agents
Treatment with live, attenuated vaccine
Treatment with investigational therapy within 28 days prior to initiation of study treatment
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
Treatment with systemic immunosuppressive medication
Prior treatment with ALK inhibitors (Cohort A1)
Prior treatment with ROS1 inhibitors (Cohort A2)
Prior treatment with RET inhibitors (Cohort A3)
Prior treatment with CD137 agonists or immune checkpoint blockade therapies
Prior allogeneic stem cell or solid organ transplantation
History of hypersensitivity to alectinib, durvalumab, or any of their excipients (Cohort A1)
History of hypersensitivity to entrectinib, durvalumab, and their excipients (Cohort A2)
History of hypersensitivity to pralsetinib, durvalumab, or any of their excipients (Cohort A3)
Any prior Grade ≥ 3 immune-mediated adverse event or any unresolved Grade > 1 immune mediated adverse event while receiving any previous immunotherapy agent other than immune checkpoint blockade agents
Any Grade >2 unresolved toxicity from prior cCRT or sCRT
Grade ≥ 2 peripheral neuropathy (Cohort A2)
Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study
Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results
Known hereditary problems of galactose intolerance, a congenital lactase deficiency, or glucose-galactose malabsorption
Pregnancy or breastfeeding or intending to become pregnant during the study treatment or within 90 days after the final dose of alectinib or durvalumab(Cohort A1)
Pregnancy or intention of becoming pregnant during study treatment within 35 days after the final dose of entrectinib, or within 90 days after the final dose of durvalumab(Cohort A2)
Pregnancy or breastfeeding or intention of becoming pregnant during study treatment or within 2 weeks after the final dose of pralsetinib or 3 months after the final dose of durvalumab(Cohort A3)
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1.Progression-free survival (PFS), as determined by Blinded independent central review (BICR) per RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 5 years |
|
| E.5.2 | Secondary end point(s) |
1. PFS, defined as the time from randomization to the first documented disease progression, as determined by the investigator per RECIST v1.1, or death from any cause, whichever occurs first
2. Time to central nervous system (CNS) progression, as determined by BICR and investigator per RECIST v1.1
3. Distant metastasis-free survival (DMFS), s determined by BICR per RECIST v1.1
4. Objective response rate (ORR), as determined by BICR and investigator per RECIST v1.1
5. Duration of response (DOR), as determined by BICR and investigator per RECIST v1.1
6. Overall survival (OS)
7. Time-to-confirmed deterioration (TTCD), in the following patient-reported scales and lung cancer symptoms: Physical functioning, Role functioning, Cough, Chest pain, Dyspnea
8. Change from baseline score as measured through the use of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at 5, 11, and 17 months in the following patient-reported scales and lung cancer symptoms: Physical functioning, Role functioning, Cough, Chest pain, Dyspnea
9. Incidence, type, and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
10. Changes in vital signs, physical findings, and clinical laboratory results during and following administration of protocol-specified investigational medicinal products (IMPs)
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-7. Up to approximately 5 years
8. Baseline to 5 years
9. Up to approximately 5 years
10. Baseline to 5 years
|
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability of study treatment will be assessed in all cohorts. |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Chile |
| Colombia |
| Costa Rica |
| New Zealand |
| Singapore |
| Hong Kong |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| Serbia |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 11 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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