| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Resectable, Early-stage (II to IIIB) Non-small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 10029519 |
| E.1.2 | Term | Non-small cell lung cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029518 |
| E.1.2 | Term | Non-small cell lung cancer stage II |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029520 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIA |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| 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 |
- To assess the antitumour activity of neoadjuvant treatment administered prior to surgery in terms of pCR
- To assess the safety and tolerability of neoadjuvant and adjuvant treatment |
|
| E.2.2 | Secondary objectives of the trial |
To assess the efficacy of neoadjuvant treatment administered prior to surgery followed by adjuvant treatment post-surgery in terms of EFS and DFS
To assess the feasibility of receiving the planned surgical tumour resection in patients receiving neoadjuvant treatment
To assess the antitumour activity of neoadjuvant treatment administered prior surgery in terms of mPR
To assess the efficacy of neoadjuvant treatment administered prior to surgery in terms of ORR
To assess the efficacy of neoadjuvant and adjuvant treatment in terms of OS
To describe the PK of study drugs in patients receiving neoadjuvant/adjuvant treatment
To assess the immunogenicity of study drugs in patients receiving neoadjuvant/adjuvant treatment
To investigate baseline PD-L1 expression in patients treated with neoadjuvant and adjuvant treatment, and associations with clinical endpoints
To evaluate changes in ctDNA during neoadjuvant treatment in patients with evaluable ctDNA and associations with clinical endpoints |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
2) Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses.
3) Provision of signed and dated written ICF prior to collection of sample sfor genetic analysis.
4) Patients must be ≥ 18 years at the time of screening.
5) Newly diagnosed NSCLC patients with resectable Stage IIA to IIIB disease.
6) WHO or ECOG performance status of 0 or 1 at enrolment.
7) Adequate organ and marrow function as defined in protocol.
8) Must have a life expectancy of at least 12 weeks.
9) Body WT > 35 kg.
10) Male and/or female.
Females of childbearing potential should agree to use an acceptable method of contraception from the time of screening throughout the total duration of the study and for following period after receiving the last dose of study interventions:
- Durvalumab or volrustomig: 90 days
- Oleclumab or monalizumab: 180 days
Female patients must not donate, bank or retrieve for their own use, ova during this same time period.
11) Negative pregnancy test (serum) for women of childbearing potential.
12) Provision of tumour samples to confirm Programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR), or anaplastic lymphoma (ALK) status.
13) Provision of tumour appropriate for exploratory biomarker analyses.
Please refer to protocol for a complete list. |
|
| E.4 | Principal exclusion criteria |
1) Patients with sensitising EGFR mutations or ALK translocations.
2) History of allogeneic organ transplantation.
3) Active or prior documented autoimmune or inflammatory disorders. Exceptions to this criterion are defined in protocol.
4) Uncontrolled intercurrent illness including uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active bleeding diseases, active ILD, serious chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirements.
5) History of another primary malignancy, with exceptions as defined in protocol.
6) Patients with small-cell lung cancer or mixed small-cell lung cancer.
7) History of active primary immunodeficiency.
8) Past or current history of ILD, or suspected ILD that cannot be ruled out by imaging.
9) Evidence of the infections as defined in protocol (including active tuberculosis, HIV that is not well controlled, hepatitis B or A and HCV.)
10) Patients who have preoperative radiotherapy treatment as part of their care plan.
11) Patients who require or may require pneumonectomy, segmentectomies, or wedge resections, as assessed by their surgeon, at baseline, to obtain potentially curative resection of primary tumour.
12) QTcF interval ≥ 470 ms.
13) Known allergy or hypersensitivity to any of the study interventions.
14) Any medical contraindication to treatment with chemotherapy as listed in the local labelling.
15) Patients with moderate or severe cardiovascular disease as defined in protocol.
16) Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment.
17) Receipt of live attenuated vaccine within 30 days prior to the first dose of study interventions.
18) Major surgical procedure (as defined by the Investigator) within 30 days prior to the first dose of study interventions.
19) Prior exposure to approved or investigational immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies. Patients who received agents targeting the adenosine pathway are also excluded.
20) Current or prior use of immunosuppressive medication within 14 days before the first dose of study interventions, with some exceptions as defined in the protocol.
21) Participation in another clinical study with an investigational product administered within 30 days prior to enrolment.
22) Previous study interventions (durvalumab, oleclumab, monalizumab, volrustomig) assignment in the present study.
Please refer to protocol for a complete list. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
pCR is defined as lack of any viable tumour cells after complete evaluation in the resected lung cancer specimen and all sampled regional lymph nodes as determined by central BIPR and described by IASLC 2020.
The measure of interest is the proportion of patients with 0% residual viable tumour cells within all resected tissue as assessed by the central blinded pathologist.
Safety and tolerability will be evaluated in terms of AEs, vital signs, and clinical laboratory parameters. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study design at various timepoints. |
|
| E.5.2 | Secondary end point(s) |
• EFS is defined as the time from randomisation to the first of the following: local or distant disease recurrence, progressive disease that precludes surgery or prevents completion of surgery, or death due to any cause.
•DFS is defined as the time from surgery until the first of the following: local or distant disease recurrence or date of death due to any cause.
• Feasibility to surgery is defined as having the planned surgical resection within 40 days from the end of the last dose of neoadjuvant study interventions.
The measure of interest is the proportion of patients that have intended surgery within 40 days from the end of last dose of neoadjuvant study interventions.
• mPR is defined as ≤ 10% viable tumour cells in resected tumour after complete evaluation in the resected lung cancer specimen as determined by central BIPR as described by IASLC 2020. The measure of interest is the proportion of patients with ≤ 10% residual viable tumour cells within all resected tissue as assessed by the central blinded pathologist.
• ORR is defined as the proportion of patients who have a CR or PR as determined by Investigator using RECIST 1.1.
Patients who go off therapy prior to surgery, without a response, receive a subsequent therapy prior to surgery, and then respond will not be included as responders in the ORR.
The measure of interest is the proportion of patients with OR.
• OS is defined as the time from randomisation until the date of death due to any cause.
The measure of interest is the landmark OS at 12 months and 24 months, and other clinically relevant timepoints if feasible. If reached by the end of the study, the median OS will also be of interest.
• Concentration of study interventions in plasma or serum.
• Presence of ADA for study interventions.
• Baseline PD-L1 expression.
• ctDNA clearance on-treatment prior to surgery. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study design at various timepoints. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| 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 |
| Taiwan |
| Canada |
| Korea, Republic of |
| United States |
| Belgium |
| France |
| Hungary |
| Ireland |
| Italy |
| Portugal |
| Spain |
| Türkiye |
|
| 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
|
| The end of study is defined as the last expected visit/contact of the last patient completing the study (SoA, Table 2 in protocol). The sponsor has the option to end enrolment in a treatment arm or the entire study per recommendation of the SRC or business decision. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
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