| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer |
|
| 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 | 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 | 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 | 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.1.3 | 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 antitumor activity of neoadjuvant treatment administered
prior to surgery in terms of pathological Complete Response (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
Event-Free Survival (EFS).
-To assess the efficacy of neoadjuvant treatment administered prior to surgery followed by adjuvant treatment post-surgery in terms of Disease Free Survival (DFS) (event from surgery onwards)
-To assess the feasibility of receiving the planned surgical tumor resection in patients receiving neoadjuvant treatment.
-To assess the antitumor activity of neoadjuvant treatment administered prior to surgery in terms of major Pathological Response (mPR)
-To assess the efficacy of neoadjuvant treatment administered prior to surgery in terms of Objective Response Rate (ORR)
-To assess the efficacy of neoadjuvant and adjuvant treatment in terms of Overall Survival (OS).
-To describe the PK of IPH5201 in combination with durvalumab +/-
chemotherapy, in patients receiving neoadjuvant and adjuvant treatment. |
|
| 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 Informed Consent Form (ICF) and in this protocol.
2.Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses – including collection of samples for genetic analysis, if applicable.
3.Patients must be ≥ 18 years at the time of screening.
4.Newly diagnosed and previously untreated patients with histologically or cytologically documented NSCLC. Patients should have resectable (Stage IIA to Stage IIIA) disease (according to Version 8 of IASLC Staging Manual in Thoracic Oncology 2016. For patients with N2 disease, only those with 1 single nodal station ≤ 3 cm are eligible) and be candidate for lobectomy, sleeve resection, or bilobectomy at the time of screening.
5. WHO PS or ECOG PS of 0 or 1 at enrolment.
6. Adequate organ and marrow function as defined below:
• Haemoglobin ≥ 9.0 g/dL.
• Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
• Platelet count ≥ 100 × 109/L.
• Serum bilirubin ≤ 1.5 × Upper limit of normal (ULN). This will not apply to patients with
confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
• Measured creatinine clearance (CrCL) > 40 mL/min or calculated CrCL > 40 mL/min as
determined by Cockcroft-Gault formula using actual body weight (Cockroft and Gault, 1976)
(https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc).
7. Must have a life expectancy of at least 12 weeks.
8. Body Weight > 35 kg.
9. Male and/or female.
10. Negative pregnancy test (serum or urine) for women of
childbearing potential.
11. Provision of tumor samples (newly acquired [preferred] or archival tumor tissue [≤ 6 months old]) to confirm PD-L1 status, EGFR, or ALK status where required during screening and prior to nC1D1.
Provision of tumor samples appropriate for exploratory biomarker analyses.
13. Patients will be suitable for inclusion if the planned surgery to be performed will be lobectomy, sleeve
resection, or bilobectomy, as determined by the attending surgeon based on the baseline findings.
Patients whose planned surgery at enrolment includes pneumonectomy, segmentectomies, or
wedge resections are not eligible for this study.
14. A pre- or post-bronchodilator FEV1 of 1.0 L and DLCO > 40% postoperative predicted value. Use of these cut-off values to assess candidacy for resection should be guided by the results of
cardiopulmonary exercise testing as outlined in the ESMO guidelines on pre-treatment risk assessment. Both an FEV1 and a DLCO test are required for assessing lung function at screening. |
|
| E.4 | Principal exclusion criteria |
1.Patients with sensitizing EGFR mutations or ALK translocations.
2.History of allogeneic organ transplantation.
3.Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic
lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [e.g., granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, or uveitis]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia.
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone
replacement.
• Any chronic skin condition that does not require systemic therapy.
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• Patients without active disease in the last 5 years may be included but only after consultation
with the Study Physician/Medical Scientist.
• Patients with celiac disease controlled by diet alone.
4. Uncontrolled intercurrent illness, including but not limited to, uncontrolled hypertension, unstable
angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease (ILD), serious
chronic gastrointestinal conditions associated with diarrhoea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or
compromise the ability of the patient to give written informed consent.
5. History of any grade of venous or arterial thromboembolic events including cerebrovascular accident, transient ischemic attack, or unstable angina pectoris within 6 months prior to enrollment.
6. History of another primary malignancy, except for the following:
• Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drugs and of low potential risk for recurrence.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated carcinoma in-situ without evidence of disease.
6. Patients with small-cell lung cancer or mixed small-cell lung cancer.
7. History of active primary immunodeficiency.
8. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis
B (known positive HBsAg result) and HCV. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible. Patients positive
for HCV antibody are eligible only if PCR is negative for HCV RNA.
9. Patients who have preoperative radiotherapy treatment as part of their care plan.
10. Patients who require or may require pneumonectomy, segmentectomies, or wedge resections, as
assessed by their surgeon, to obtain potentially curative resection of primary tumor.
11. QTc interval ≥ 470 ms (NOTE: If prolonged, then 2 additional ECGs should be obtained and the average QTcF interval should be used to determine eligibility).
12. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
13. Any medical contraindication to treatment with chemotherapy as listed in the local labelling.
14. Patients with moderate or severe cardiovascular disease:
• Presence of cardiac disease, including myocardial infarction or unstable angina pectoris within
6 months prior to study entry.
• NYHA Class 3 or 4 congestive heart failure, or uncontrolled hypertension.
• History of hypertensive crisis/hypertensive encephalopathy within the past 6 months prior to the scheduled first dose of study treatment.
15. Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.
16. Receipt of live attenuated vaccine within 30 days prior to the first dose of study drugs. Note: Patients, if enrolled, should not receive live vaccine while receiving study drugs and up to 30 days after the
last dose of study drugs.
17. Major surgical procedure (as defined by the Investigator) within 30 days prior to the first dose of study drugs.
18. Prior exposure to 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 (e.g., anti-CD73, A2AR inhibitors, anti-CD39) are also excluded.
19. Current or prior use of immunosuppressive medication within 14 days before the first dose of study drugs. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
• Systemic corticosteroids ≤ 12 mg/day of prednisone or its equivalent.
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-pCR is defined as lack of any viable tumor cells after complete evaluation in the resected lung cancer specimen and all sampled regional lymph nodes as determined by central independent pathological review and described by IASLC 20201.
-Safety and tolerability will be evaluated in terms of Adverse
Events (AEs), vital signs, and clinical laboratory. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-The measure of interest is the proportion of patients with 0% residual viable tumor cells within all resected tissue as assessed by the central pathologist.
-Trough over the study |
|
| E.5.2 | Secondary end point(s) |
-EFS is defined as time from neoadjuvant C1D1 to the first
of the following: Documented local or distant recurrence of lung cancer as determined by Investigator using RECIST 1.1
assessment.
Death due to any cause (event date is date of death).
PD that precludes surgery (event date is the date of this
determination) or PD discovered and reported by the
Investigator upon attempting surgery (event date is the
date of the first attempt at surgery).
-DFS is defined as the time from the date of surgery until the first date of disease recurrence as determined by Investigator using RECIST 1.1 assessment (local or distant), or date of death due to any cause, whichever occurs first. Pathological confirmation from biopsied lesions will also be taken into consideration (as applicable). A new primary malignancy confirmed by pathology is not
considered a DFS event.
-Feasibility to surgery is defined as having the planned surgical resection within 40 days from the end of the last dose of neoadjuvant treatment.
-mPR is defined as ≤ 10% viable tumor cells in resected tumor after complete evaluation in the resected lung cancer specimen as determined by central independent pathological review as described by IASLC 2020 1.
-OS is defined as the time from neoadjuvant C1D1 until the date of death due to any cause. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-The measure of interest is the median of EFS and landmark EFS at 12 months.
-The measure of interest is the median of DFS and landmark DFS at 12 months.
-The measure of interest is the proportion of patients that have intended surgery within 40 days from the end of last dose of neoadjuvant treatment.
-The measure of interest is the proportion of patients with
≤ 10% residual viable tumor cells within all resected tissue as assessed by the central pathologist.
-The measure of interest is the median of the overall OS and landmark OS at 12 months.
|
|
| 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 | 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 | 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| United States |
| France |
| Poland |
| Greece |
| Hungary |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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