ew targeted therapy in relapsed EGFR-mutated lung cancer previously treated with EGFR-inhibitors

Phase 1

• Conditions: ocally advanced or metastatic non-small cell lung cancer where disease has progressed with previous epidermal growth factor receptor tyrosine kinase inhibitor therapy; MedDRA version: 20.0Level: PTClassification code 10029522Term: Non-small cell lung cancer stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10029521Term: Non-small cell lung cancer stage IIIBSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10059515Term: Non-small cell lung cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: 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: EUCTR2015-000307-10-LT
• Lead Sponsor: Oslo University Hospital

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-12-22
• Last Update Posted: 3 July 2017

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Provision of signed and dated, written informed consent.
2. Age > 18 years.
3. Histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiotherapy.
4. Radiological disease progression following at least one prior EGFR TKI.
5. Documented EGFR mutation known to be associated with EGFR TKI sensitivity (also including T790M).
6. ECOG status 0-2 and a minimum life expectancy of 12 weeks.
7. At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline according to RECIST 1.1.
8. Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at
screening:
* Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
* Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels in the post-menopausal range for the institution
* Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation.
9. Male subjects must be willing to use barrier contraception.
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 135
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 65

Exclusion Criteria

1. Treatment with an EGFR-TKI within 8 days or approximately 5x half-life, whichever is the longer, of the first dose of study treatment.
2. Treatment with cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days or approximately 5x half-life, whichever is the longer, of the first dose of study treatment.
3. Previous treatment with osimertinib, or another EGFR TKI with similar profile, e.g. CO-1686
4. Major surgery within 4 weeks of inclusion
5. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of inclusion
6. Subjects currently receiving (or unable to stop using) potent inhibitors or inducers of CYP3A4
7. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the exception of
alopecia grade 2) at the time of starting study treatment.
8. Spinal cord compression or brain metastases unless asymptomatic and on stable steroid dosage
for at least 2 weeks prior to start of study treatment.
9. Any evidence of severe or uncontrolled systemic diseases which in the investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
10. Gastrointestinal conditions incompatible with swallowing or precluding absorption of osimertinib.
11. Exclude based on any of the following cardiac criteria:
* Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec
* Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, 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
12. Current or previous significant interstitial lung disease or radiation pneumonitis
13. Absolute neutrophil count < 1.5 x 109/L
14. Platelet count < 100 x 109/L
15. Haemoglobin < 80 g/L
16. Alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
17. Aspartate aminotransferase (AST) > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases
18. Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) or liver metastases
19. Creatinine >1.5 times ULN concurrent with creatinine clearance < 50 ml/min (measured or calculated by Cockcroft and Gault equation),
20. History of hypersensitivity of osimertinib (or drugs with a similar chemical structure or class.
21. Women who are pregnant or breast-feeding, or have a positive (urine or serum) pregnancy test prior to study entry
22. Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.

Study & Design

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

Primary Outcome Measures

Name	Time	Method
Main Objective: Efficacy evaluation of osimertinib;Secondary Objective: Safety evaluation and translational aspects;Primary end point(s): Objective response rate assessed by RECIST 1.1;Timepoint(s) of evaluation of this end point: At baseline and every 8 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): PFS, DoR, DCR and OS<br>Safety endpoints (CTCAE v4);Timepoint(s) of evaluation of this end point: At baseline and every 8 weeks