Phase III Study to Determine Efficacy of Durvalumab in Stage II-III Non-small Cell Lung Cancer (NSCLC) After Curative Intent Therapy.

Study Overview
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Brief Summary
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This is a Phase III double-blind, placebo-controlled study of Durvalumab versus Placebo in patients with stage II-III NSCLC who are MRD-positive following curative intent therapy.

Detailed Description
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This is a Phase III, randomized, multicenter, double-blind, placebo-controlled, study to evaluate the efficacy and safety of durvalumab adjuvant therapy compared to placebo in patients with completely resected stage II-III NSCLC who have undergone curative intent therapy (complete resection ± neoadjuvant and/or adjuvant therapy), who have no evidence of Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1-defined disease recurrence, and who become MRD+ during surveillance period.

Official Title
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A Phase III, Randomized, Multicenter, Double-blind, Placebo-controlled Study of Durvalumab for the Treatment of Stage II-III NSCLC Patients With Minimal Residual Disease Following Surgery and Curative Intent Therapy.

Conditions
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Carcinoma, Non- Small Cell Lung

Intervention / Treatment
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* Drug: Durvalumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICFs and in the protocol. Provision of signed and dated, written informed consent form prior to any mandatory study-specific procedures, sampling, and analyses. Provision of signed and dated written optional genetic informed consent prior to collection of the optional sample for genetic analysis. This consent should be signed at the time of second screening. This optional sample and analyses are separate from the mandatory genetic testing consent included in ICF1. The following criteria must have been met at the time of surgery or at the time of the curative intent therapy (first screening): Age ≥18 years at the time of screening (ICF1); Male and/or female Histologically confirmed NSCLC with resectable stage II-III disease who have undergone curative intent therapy (complete resection of the primary tumor ± neoadjuvant and/or adjuvant therapy) per SoC. Select stage IIIB (ie, T3N2 or T4N2) patients will be eligible, provided they are upstaged to T3N2 or T4N2 based on confirmed pathology after surgery. Patients who are staged as T3N2 or T4N2 prior to surgery are not eligible. A contrast-enhanced CT/MRI scan of the chest and abdomen (including liver and adrenal glands) along with brain MRI (preferred) or brain CT with IV contrast must have been done for surgical planning prior to surgery. It is recommended that patients undergo combined FDG-PET (18F-Fluoro-deoxyglucose positron emission tomography) and CT scan (computerized tomography) within the 6 weeks prior to surgery in order to rule out detectable extrathoracic, extracranial metastasis and to assess for potential mediastinal lymph node involvement prior to surgery. If the positron emission tomography (PET) scan was not performed, or data from a PET is not available, patients may still be enrolled into the study provided appropriate imaging (CT/MRI) is performed prior to randomization. Complete resection of the primary NSCLC is mandatory. Invasive (pre-operative or intra-operative) exploration of hilar and mediastinal lymph nodes must have been performed to confirm primary tumor nodal status (prior to or after surgery). Surgical resection of the primary NSCLC can occur by open thoracotomy or by video-assisted thoracic surgery (VATs) and resection can be achieved by segmentectomy, lobectomy, sleeve resection, bilobectomy or pneumonectomy. Patients undergoing wedge resection are not eligible for this study. Criteria for prior systemic chemotherapy/radiotherapy: Patients should have completed (or be undergoing) curative intent therapy (surgery ± neoadjuvant and/or adjuvant therapy; adjuvant therapy can include PORT) with exceptions noted below: Patients who discontinue chemotherapy and/or PORT for toxicity prior to completion of all planned therapy are eligible. Patients who have not received any neoadjuvant and/or adjuvant chemotherapy, and meet all other eligibility criteria, may be eligible under the following circumstances: All patients who are eligible for adjuvant chemotherapy MUST be offered adjuvant chemotherapy. The patient has declined adjuvant chemotherapy, and in the opinion of the Investigator, this is the patient's final decision after receiving appropriate information and adequate time to make the decision. The patient's refusal of adjuvant chemotherapy must be documented. If in the view of the Investigator, adjuvant chemotherapy is contraindicated due to an underlying intercurrent illness/laboratory abnormality, which is not considered reversible within a reasonable timeframe for the patient to be eligible for adjuvant therapy, which must be documented. Criteria assessed prior to and at the start of surveillance: Confirmation of suitable biosamples for WES and central PD-L1 testing. Resected tumor tissue and whole blood samples must be provided to the diagnostic laboratory for WES of tumor and germline DNA, respectively as soon as possible following pathology confirmation. Samples must be sent no later than 1-2 weeks after completion of adjuvant therapy or 3-5 weeks after surgery (if no adjuvant therapy is given) for development of the Sponsor-approved personalized panel for MRD detection at a central reference laboratory. Germline sequencing of whole blood is mandatory. Resected tumor tissue must also be provided for PD-L1 testing at a central reference laboratory (see inclusion criteria 15). Post-adjuvant therapy or post-surgery (if no adjuvant therapy is given) CT scan of the chest and abdomen (including liver and adrenal glands) and brain MRI [preferred] or brain CT with IV contrast should be available to confirm no evidence of metastasis. If scans were not performed post-curative intent therapy, additional scans must be done prior to start of surveillance. Consents to be accessible for q6w±3d plasma sample collection for MRD evaluation and for q12w±1w CT scans during the 96-week surveillance period. The plasma sample that marks the start of surveillance must be collected 8±1 weeks after completion of adjuvant therapy (if administered) or 12±1 weeks after surgery (where adjuvant therapy is not given). A patient who is determined to be MRD- based on analysis of this plasma sample (ie, MRD- at the start of surveillance) may continue in surveillance provided all other eligibility criteria are met. A patient who is determined to be MRD+ based on analysis of this plasma sample (ie, MRD+ at the start of surveillance) may be eligible for immediate randomization provided all other eligibility criteria are met. A patient who becomes MRD+ during surveillance is eligible to enter the second screening period and may be randomized in the study if all other eligibility criteria are met. Criteria for second screening prior to randomization to treatment: CT scan of the chest and abdomen (including liver and adrenal glands) and brain MRI [preferred] or brain CT with IV contrast performed within the 28 days ± 7 days prior to randomization to confirm no evidence of RECIST 1.1-defined disease recurrence and/or metastasis. Known tumor PD-L1 status determined at a central reference laboratory testing service using a validated Ventana SP263 PD-L1 immunohistochemistry (IHC) assay prior randomization. Patients with unknown PD-L1 status are not eligible for the study. WHO/Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Complete post-operative wound healing must have occurred prior to randomization; patients must have recovered from all acute, reversible toxic effects from prior treatments (excluding alopecia) that could potentially adversely impact further administration of durvalumab/placebo according to the Investigator's judgment. Must have recovered from all acute, reversible toxic effects from chemotherapy that could potentially adversely impact further administration of durvalumab or placebo according to the Investigator's judgment Adequate organ and marrow function as described in the protocol. Must have a life expectancy of at least 12 weeks Weight Body weight >30 kg Inclusion criteria assessed prior to entering the observation period No evidence of RECIST 1.1-defined disease recurrence or metastasis confirmed by CT scan of the chest and abdomen (including liver and adrenal glands) and a brain MRI (preferred) or brain CT with IV contrast. MRD- status, as determined by testing the last plasma sample collected during the 96-week surveillance period. Exclusion Criteria: Diagnostics assessments: EGFR and/or ALK mutant as assessed either from the tumor biopsy taken prior to surgery or the resected tumor tissue. Testing must be performed using a wellvalidated, local regulatory-approved test. EGFR/ALK may be tested centrally if local testing is unavailable. Mixed small cell and NSCLC histology. Require re-resection or are deemed to have unresectable NSCLC by amultidisciplinary evaluation that must include a thoracic surgeon who performs lung cancer surgery as a significant part of their practice. Baseline imaging demonstrating unequivocal evidence of RECIST 1.1-defined disease recurrence or evidence of clinical recurrence outside of imaging prior to randomization. In the event of lymphadenopathy on imaging that would lead to exclusion, histopathological confirmation of lymph node metastasis should be obtained prior to excluding a patient from the study. If pathological confirmation of lymph node metastasis is not technically feasible and imaging appearance are deemed unequivocal for relapse, the patient will be excluded. Medical conditions History of allogeneic organ or bone marrow transplantation. Non-leukocyte-depleted whole blood transfusion in 120 days of genetic sample collection Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: Patients with vitiligo or alopecia Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement Any chronic skin condition that does not require systemic therapy Patients without active disease in the last 5 years may be included but only after consultation with the Study Physician Patients with celiac disease controlled by diet alone Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic gastrointestinal conditions associated with diarrhea, 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. History of another primary malignancy except for Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP 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 History of active primary immunodeficiency 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 virus (HBV) (known positive HBV surface antigen (HBsAg) result), hepatitis C virus (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Known allergy or hypersensitivity to any of the IPs or any of the IP excipients Prior/concomitant therapy Received any IO therapy in the adjuvant setting or any prior exposure to durvalumab. Received any radiotherapy in the neoadjuvant setting. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of IP. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last dose of IP. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Current or prior use of immunosuppressive medication within 14 days before the first dose of IP. The following are exceptions to this criterion: Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular injection) Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) Prior/concurrent clinical study experience Previous IP assignment in the present study Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment. Other exclusions Female patients who are pregnant or breastfeeding. - Female patients who become pregnant during the study will be withdrawn from surveillance and are not eligible for randomization. Male or female patients of reproductive potential who are not willing to employ effective birth control at the time of entry into second screening (initiated with the signing of ICF2a) until 90 days after the last dose of IP (See Appendix H). Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab<br>Intravenous administration of Durvalumab | Drug: Durvalumab<br>* Intravenous administration of Durvalumab<br>* Other names: Medi4736;|
| Placebo Comparator: Placebo<br>Intravenous administration of placebo | Other: Placebo<br>* Placebo Comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the efficacy of durvalumab compared to placebo as measured by DFS in all randomized patients. Outcomes measures were adjusted to align with the previous version of the protocol except for the changes according to the protocol amendment. | DFS in FAS (using Investigator assessments according to RECIST 1.1). | Approximately 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the safety and tolerability profile of durvalumab monotherapy compared with placebo. Outcomes measures were adjusted to align with the previous version of the protocol except for the changes according to the protocol amendment. | Safety measures will be described as exploratory manner. | Approximately 2 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-L1, NCSLC, Double-blind, MEDI4736, Durvalumab, DFS, OS, MRD+, Lung cancer