OSIMERTINIB for Non-small cell lung cancer (unresectable, stage III)

Inclusion criteria

• {"criterion_text":"- Patients must be 18 or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent form.\n- Availability of the EGFRm test results confirming that the tumour harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including de novo T790M\n- WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline at screening and prior to first dose.\n- Minimum life expectancy of > 12 weeks at Day 1.\n- Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative\n- At least one lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements.\n- Male and/or female. Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies and/or SoC CRT\n- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.\n- Patients with histologically documented NSCLC of predominantly non-squamous, squamous, and adenosquamous pathology who present with locally advanced, unresectable (Stage III) disease (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology). It is recommended but not required that except for overt cT4 disease, nodal status N2, or N3 should have been proven by biopsy, via endobronchial ultrasound, mediastinoscopy, thoracoscopy, or in absence of biopsy, should have been confirmed with whole body 18FDG PET plus contrast-enhanced CT in addition to or in combination with PET.\n- Patient who are eligible for and - planning to undergo CCRT or SCRT treatment.\n- Patients who had recurred from Stage I/II/III after complete surgery or had gross incomplete resections can be included if they didn’t receive treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents.\n- Patients with HBV are only eligible for inclusion if they meet all the following criteria: •Demonstrate absence of HCV co-infection or history of HCV co-infection •Demonstrate absence of HIV co-infection •Patients with active HBV infection are eligible if they are: ▪Receiving anti-viral treatment for at least 6 weeks prior to study treatment, HBV DNA is suppressed to <100 IU/mL and transaminase levels are below ULN. Participants with a resolved or chronic HBV infection are eligible if they are: ▪Negative for HBsAg and positive for hepatitis B core antibody [anti-HBc IgG or total anti-HBc Ab]. In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment or ▪Positive for HBsAg, but for > 6 months have had transaminases levels below ULN and HBV DNA levels below <100 IU/mL (i.e., are in an inactive carrier state). In addition, patients must be receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment.\n- Patients with HIV are only eligible for inclusion if they meet all the following criteria: •Demonstrate absence of HBV/ HCV co-infection •Undetectable viral RNA load for 6 months •CD4+ count of >350 cells/μL •No history of AIDS-defining opportunistic infection within the past 12 months •Stable for at least 4 weeks on the same anti-HIV medications"}

Exclusion criteria

• {"criterion_text":"- Any presence of small cell and mixed small-cell and non-small cell histology.\n- Previous enrolment in the present study. Rescreening of individuals who were screen failures is allowed.\n- For females only: Currently pregnant (confirmed with positive pregnancy test) or breastfeeding.\n- Past medical history of ILD/pneumonitis, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD/pneumonitis.\n- Patients should refrain from breastfeeding from enrolment throughout the study and until 6 weeks after last dose of study intervention\n- In addition, the following are considered criteria for exclusion from the exploratory genetic research: Prior allogeneic bone marrow transplant. Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.\n- Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included after consultation with the AstraZeneca medical monitor (eg, hearing loss).\n- Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection (eg, patients receiving treatment for infection, including HCV, HIV, and tuberculosis) or active uncontrolled HBV infection.\n- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.\n- History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease. Patients who have received RT with overlapping fields (eg, cured breast cancer) should be excluded.\n- Patient meets any of the following cardiac criteria: a.\tMean resting QTc > 470 msec, obtained from 3 ECGs, using the screening clinic ECG machine–derived QTc value. b.\tAny clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block and second-degree heart block. Patients with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgement with cardiologist consultation recommended. c.\tHistory of QT prolongation associated with other medications that required discontinuation of that medication.\n- Prior treatment with any chemotherapy, radiation therapy, immunotherapy or investigational agents for locally advanced, unresectable Stage III NSCLC. Prior surgical resection (ie, Stage I, II, or III) with no systemic treatment with residual disease or a recurrence is permitted.\n- Congenital long QT syndrome, family history of long QT syndrome, unexplained sudden death under 40 years of age in first-degree relatives or patients with any factors that increase the risk of QTc prolongation/arrhythmic events such as electrolyte abnormalities, heart failure or any concomitant medication known to prolong the QT interval and cause TdP.\n- Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4 (at least 3-week prior to dosing). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.\n- Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: -Absolute neutrophil count <1.5 × 109/L -Platelet count <100 × 109/L -Haemoglobin <90 g/L -Alanine transferase >2.5 times the upper limit of normal (ULN) -Aspartate transferase >2.5 times ULN -Total bilirubin >1.5 times ULN or >3 times ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) -Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault formula); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN.\n- Prior exposure to EGFR-TKI therapy\n- Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.\n- Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks (unless the safety profile is known prior to first dose of study intervention), or concurrent enrolment in another clinical study (unless the study is observational [noninterventional], or the patient is in the followup period of an interventional study).\n- History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.\n- History of hypersensitivity to active or inactive excipients of the chemotherapy regimen of choice (pemetrexed or paclitaxel; cisplatin or carboplatin) or RT or drugs with a similar chemical structure or class to the chemotherapy.\n- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).\n- 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."}

Primary endpoints

• {"endpoint_text":"- Outcome measure: PFS PFS is defined as the time from date of first dose until progression per RECIST 1.1 as assessed by the investigator at the local site, or death due to any cause. The analysis will include all dosed patients. The primary measure of interest is the proportion of patients alive and progression free at 12 months.","definition_or_measurement_approach":"PFS is defined as the time from date of first dose until progression per RECIST 1.1 as assessed by the investigator at the local site, or death due to any cause. The analysis will include all dosed patients. Primary measure: proportion of patients alive and progression free at 12 months."}

Secondary endpoints

• {"endpoint_text":"- Outcome measure: ORR ORR is defined as the proportion of patients who have a CR or PR, as determined by the investigator at local site per RECIST 1.1. The analysis will include all dosed patients with measurable disease at baseline. The measure of interest is the estimate of ORR at end of induction phase after the 8 week scan.","definition_or_measurement_approach":"ORR = proportion of patients with CR or PR per RECIST 1.1 by investigator at local site; analysis includes all dosed patients with measurable disease at baseline; measure of interest = ORR estimate at end of induction after 8-week scan."}
• {"endpoint_text":"- Outcome measure: DCR DCR is defined as the percentage of subjects who have a best overall response of CR or PR or SD (at 8 weeks) as determined by the investigator at the local site per RECIST 1.1. Data obtained from first dose until end of induction phase will be included in the assessment of DCR, regardless of whether a patient withdraws from therapy. The measure of interest is the estimate of DCR at the end of induction phase after the 8 week scan.","definition_or_measurement_approach":"DCR = percentage with best overall response CR, PR or SD at 8 weeks per RECIST 1.1 by investigator; data from first dose until end of induction included; measure = DCR estimate at end of induction after 8-week scan."}
• {"endpoint_text":"- Outcome measure: OS OS is defined as time from date of first dose until the date of death due to any cause. The analysis will include all dosed patients. All deaths will be included, regardless of whether the patient withdraws from therapy or receives another anticancer therapy. The measure of interest is the OS rate at 12 and 24 months.","definition_or_measurement_approach":"OS = time from first dose to death due to any cause; analysis includes all dosed patients; measure = OS rate at 12 and 24 months."}
• {"endpoint_text":"- Outcome measure: EFS EFS is defined as time from date of first dose until any of the following events: progression of disease that precludes CRT or completion of CRT, progression during or after CRT, or death due to any cause. The analysis will include all dosed patients. All events will be included, regardless of whether the patient withdraws from therapy or receives another anticancer therapy. The measure of interest is the EFS rate at 12 months.","definition_or_measurement_approach":"EFS = time from first dose until event (progression precluding CRT/completion of CRT, progression during/after CRT, or death); analysis includes all dosed patients; measure = EFS rate at 12 months."}
• {"endpoint_text":"- Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory testing, ECG, LVEF, and WHO performance status","definition_or_measurement_approach":"Safety/tolerability assessed by adverse events, vital signs, clinical labs, ECG, left ventricular ejection fraction (LVEF), and WHO performance status."}

Spain

Earliest CTIS Part Ii Submission Date

05-02-2024

Latest Decision Or Authorization Date

10-10-2024

Processing Time Days

248

Number Of Sites

8

Number Of Participants

16

Primary sponsor

Full Name

Astrazeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Fortrea Inc.

Responsibilities

Vendor management, Site Start Up, Clinical Ancillary Supplies Services, Patient Recruitment, Clinical Monitoring, Xcellerate Services, CTMS/eTMF, Meetings

Name

Signant Health Global LLC

Name

Labcorp Central Laboratory Services S.a.r.l.

Name

Perceptive Informatics Inc.

Responsibilities

Imaging

Third parties

• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"Vendor management, Site Start Up, Clinical Ancillary Supplies Services, Patient Recruitment, Clinical Monitoring, Xcellerate Services, CTMS/eTMF, Meetings","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Center For Information And Study On Clinical Research Participation Inc.","duties_or_roles":"Lay Language Summary of study results","organisation_type":"Patient organisation/association"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services S.a.r.l.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"Imaging","organisation_type":"Pharmaceutical company"}