A multicentre single-arm phase II trial assessing the safety and efficacy of first-line osimertinib and locally ablative radiotherapy in patients with synchronous oligo-metastatic EGFR-mutant non-small cell lung cancer
- Conditions
- Neoplasms
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 13
7.1.Inclusion criteria
7.1.1. Histologically confirmed, treatment naïve EGFR-mutant NSCLC, with or without T790M resistance mutation.
Presence of the sensitising EGFR-mutation (exon 19 deletion and/or exon 21 L858R) detected by an accredited laboratory.
7.1.2. Synchronous oligo-metastatic stage IV disease (max 5 lesions)
7.1.3. Measurable disease as defined according to RECIST v1.1
7.1.4. All lesions amenable for radical radiotherapy according to local judgment
7.1.5. Age =18 years
7.1.6. ECOG performance status 0-2
7.1.7. Life expectancy =12 months
7.1.8. Adequate haematological function:
– Haemoglobin ?90 g/L
– Absolute neutrophil count (ANC) ?1.5× 109/L
– Platelet count ?100× 109/L
7.1.9. Adequate renal function:
Serum creatinine ?1.5x ULN or creatinine clearance =50 mL/min (calculated according to Cockcroft-Gault, see below). Confirmation of creatinine clearance is only required when serum creatinine is >1.5x ULN.
Cockcroft-Gault formula: mLmin=(140-age[years])×actual body weight [kg]72×Creatinineserum (mgdL)(×0.85 if female)
7.1.10. Adequate liver function:
– ALT and AST ?2.5× ULN. If the patient has liver metastases, ALT and AST must be =5× ULN
– Total serum bilirubin ?1.5× ULN. If the patient has documented Gilbert’s syndrome (unconjugated hyperbilirubinaemia), total serum bilirubin must be ?3× ULN.
7.1.11. Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test within 7 days before enrolment.
7.1.12. Written IC for protocol treatment must be signed and dated by the patient and the investigator prior to any trial-related intervention.
7.2. Exclusion criteria
7.2.1. Prior chemotherapy, immunotherapy, radiotherapy or therapeutical surgery for NSCLC (an exception is the resection and postoperative radiotherapy of the resection cavity of CNS or adrenal metastases)
7.2.2. More than 5 distant oligo-metastases (any second intra-thoracic lesion will count as a distant metastasis; regional nodal metastases will not count towards 5 oligo-metastases) and more than 2 intra-thoracic lesions.
7.2.3. Brain metastases not amenable for radiosurgery or neurosurgery
7.2.4. Presence of leptomeningeal metastases
7.2.5. Symptomatic spinal cord compression
7.2.6. Extracranial metastatic locations not amenable for radical radiotherapy such as malignant ascites, pleural or pericardial effusion, diffuse lymphangiosis of skin or lung, diffuse bone marrow metastasis, metastasis invading the GI tract, abdominal masses/abdominal organomegaly, identified by physical exam that is not measurable by reproducible imaging techniques.
7.2.7. Currently receiving (or unable to stop use prior to enrolment or to receiving the first dose of osimertinib treatment) medications or herbal supplements known to be potent CYP3A4 inducers. Potent CYP3A4 inducers are contraindicated for the duration of the trial.
7.2.8. 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.
Patients 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
? Positive for HBsAg, negative for HBeAg but for >6 months have had transaminases levels below ULN and HBV DNA levels below 2000 IU/mL (i.e., are in an inactive carrier state).
7.2.9. 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.
7.2.10. Any of the following cardiac criteria:
? QTcF >470 msec, using the screening clinic ECG machine derived QTc value (QTcF: corrected QT interval using Fredericia's formula).
? Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block or second degree heart block).
? Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause Torsades de Pointes (TdP).
7.2.11. Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
7.2.12. Idiopathic pulmonary fibrosis which is a contraindication to lung radiation.
7.2.13. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
7.2.14. 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
7.2.15. Women who are pregnant or in the period of lact
Study & Design
- Study Type
- Interventional Study
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Safety;Efficacy
- Secondary Outcome Measures
Name Time Method Overall Survival;Pattern of disease progression;Distant progression-free survival;Objective response rate;Duration of response;Toxicity according to CTCAE v5.0;Symptom-specific and global Quality of life