Study in patients with Non-Small Cell Lung Cancer whose disease has got worse on Osimertinib treatment.

Phase 1

• Conditions: Advanced Non-Small Cell Lung Cancer; MedDRA version: 21.1Level: PTClassification code 10061873Term: Non-small cell lung cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-003974-29-SE
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2019-05-17
• Last Update Posted: 19 August 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 280

Inclusion Criteria

Inclusion criteria applicable to all study treatment modules (Groups A/B):
•NSCLC with the following features:
oLocally advanced or metastatic disease (i.e., advanced NSCLC) not amenable to curative surgery or radiotherapy at study entry.
oHistologically or cytologically confirmed adenocarcinoma of the lung harbouring EGFR mutation(s) known to be associated with EGFR TKI sensitivity at diagnosis.
oReceived only 1 line of therapy, with single-agent osimertinib, for advanced NSCLC, with clinical benefit as judged by investigator discretion.
oEvidence of radiological disease progression on first-line monotherapy with osimertinib 80mg once daily.
•Suitable for a mandatory biopsy defined as having an accessible tumour and a stable clinical condition that will allow the patient to tolerate the procedure. The biopsy should be performed within 60 days prior to the planned first dose of study treatment.
•Patients must have measurable disease per RECIST 1.1.
•World Health Organisation (WHO) performance status 0 or 1 with no deterioration between screening and the first dose of study treatment and a minimum life expectancy of 12 weeks.
•Adequate coagulation parameters, defined as: International Normalisation Ratio (INR) <1.5 × upper limit of normal (ULN) and activated partial thromboplastin time <1.5 × ULN unless patients are receiving therapeutic anti-coagulation which affects these parameters.
•Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin, factor Xa inhibitors or thrombin inhibitors for =2 weeks.
•Willingness to adhere to the study treatment-specific contraception requirements.
Module 1 only:
•NSCLC with confirmed MET amplification or MET exon 14 skipping as determined by Next Generation Sequencing (NGS) testing on tumour tissue collected on or after disease progression on prior monotherapy with osimertinib.
•Adequate liver function defined as:
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 x upper limit of normal (ULN) with TBL =1 x ULN
OR
- TBL > ULN and =1.5 x ULN with ALT and AST =1 x ULN
Module 2 only:
•Possess a mutation at the C797 residue in the EGFR receptor as determined by NGS testing on tumour tissue collected on or after disease progression on prior monotherapy with osimertinib
Module 3:
•For the Group A (biomarker matched) cohort only, must possess at least one of: EGFR gene amplification, a mutation at the L718 or G724 residue or insertion in exon 20 of the EGFR gene, as determined by NGs testing on tumour tissue collected on or after disease progression on prior monotherapy with osimertinib
Module 4 only:
•Body weight >30 kg.
Module 5 only:
•NSCLC with confirmed ALK arrangement as determined by NGS testing on tumour tissue collected on or after disease progression on prior monotherapy with osimertinib.
Observational Cohort (Group C):
•Patients diagnosed with histopathological transformation to SCLC or SCC (squamous cell carcinoma) following progression on first-line osimertinib
•Actionable mutation with potential treatment that is not currently available within ORCHARD
Module 6 only:
•NSCLC with confirmed RET rearrangement as determined by NGS testing on tumour tissue collected on or after disease progression on prior monotherapy with osimertinib.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1

Exclusion Criteria

Exclusion Criteria for modules in Groups A/B:
•Patients whose disease has progressed within the first 3 months of osimertinib treatment
•Must not have experienced a toxicity that led to permanent discontinuation/dose reduction or have any unresolved toxicities from prior osimertinib treatment greater than Common Terminology Criteria for Adverse Event(CTCAE) Grade 1 at the time of starting study treatment
•Must not have discontinued osimertinib>60 days prior to first dose of study treatment
•Prior or concurrent treatment with systemic anticancer therapy for locally advanced/metastatic NSCLC
•Major surgery within 28 days prior to the first dose of study treatment except
•Receipt of live attenuated vaccine within 30 days prior to first dose of study treatment
•Treatment with warfarin/coumarin analogues within 7 days prior to first dose of study treatment
•Diagnosis of small cell lung cancer or squamous cell carcinoma
•Spinal cord compression, symptomatic/unstable brain metastases, except for patients who have completed definitive therapy, are not on steroids, have a stable neurologic status for 2 weeks after completion of the definitive therapy and steroids
•History of another primary malignancy except for:
oMalignancy treated with curative intent and with no active disease for at least 2 years before first dose of study treatment
oAdequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease
oAdequately treated carcinoma in situ without evidence of disease
oLocalised non-invasive primary disease under surveillance
•Active infection, including Hepatitis B/C virus or human immunodeficiency virus(HIV)
•Any of the following cardiac criteria:
oAny clinically important abnormalities of resting ECG
oUnstable atrial fibrillation or cardiac arrhythmia with a ventricular rate>100 bpm on an ECG at rest
oUncontrolled hypertension
oUncontrolled angina or acute coronary syndrome within 6 months prior to screening
oAt risk for brain perfusion/stroke or transient ischemic attack in the last 6 months prior to screening
oSymptomatic heart failure
oSevere valvular heart disease
•Inadequate bone marrow reserve or organ function
•Creatinine clearance<50 mL/min
Module 1,2,3,5&6 only:
•Past history of interstitial lung disease(ILD), drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD.
•Currently receiving medications or herbal supplements known to be strong inducers/inhibitors of CYP3A4(for Module 1, this includes inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic range) within 2 weeks of study treatment(3 weeks for St John’s Wort and Modules 5 & 6)
•Any additional factors that increase the risk of QTc prolongation or arrhythmic events
Module 1 only:
•Mean resting QTcF>470 msec for women and>450 msec for men at screening.
•Acute myocardial infarction currently or within 6 months.
•Active gastrointestinal disease or other condition that will interfere with the absorption, distribution, metabolism, or excretion of oral therapy
Module 2 only:
•Mean resting QTcF >470 msec
Module 3 only:
•Mean QTcF=450msec
Module 4 only:
•Active or prior autoimmune or inflammatory disorders(exceptions do apply)
•Uncontrolled intercurrent illness and active infection
•Any unresolved toxicity National Cancer Institute(NCI) CTCAE Grade=2 from previous anticancer therapy(exceptions do apply)
•Osimertinib therapy within 10 days prior to first dose of study treatment
•Radiother

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified