Liquid Biopsy as a Tool to Evaluate Resistance to First and Third (AZD9291) (EGFR) (TKIs) in (EGFR) Mutant NSCLC

Phase 2

• Conditions: Non Small Cell Lung Cancer
• Interventions: Drug: AZD9291

• Registration Number: NCT02771314
• Lead Sponsor: Hellenic Oncology Research Group

Brief Summary

Based on the possibilities that both plasma and circulating tumor cells (CTCs) (the "liquid biopsy") may offer, we consider that it could be feasible to longitudinally monitor the genetic evolution and the biologic characteristics of CTCs, by using Circulating tumor DNA (ctDNA) and CTCs as a source of biologic material. This approach could provide information regarding the genetic/molecular changes associated with primary and acquired resistance to AZD9291 and, thus, to facilitate to more appropriately adapt the tailored treatment in this particular group of NSCLC patients. It has been recently reported that the detection of resistant clones, based on the tumor-associated genetic aberrations in the blood, can identify treatment resistance up to 10 months earlier than the radiological methods providing, thus, the potential for an early switch to a non cross-resistant therapy in order to improve patients' outcome.

Detailed Description

Lung cancer is among the most common tumor types representing 13% of the newly diagnosed cancers worldwide. Both the absolute and relative frequency of lung cancer has risen dramatically. Unfortunately, lung cancer remains by far the leading cause of cancer-related deaths, accounting for 18% of the total number of deaths. Non Small Lung Cancer (NSCLC) accounts for 85% of all cases of lung cancer and is further classified in several subtypes based on various molecular and histological features.

The initial dose of 80 mg AZD9291 administered once daily orally in the fasted state can be reduced to 40 mg AZD9291 once daily under circumstances

Single arm, open-label, phase II, multicenter study. NSCLC patients with activating EGFR mutations, who are under front line treatment with first generation EGFR TKIs according to the physicians' choice and present disease progression, will be treated with single agent AZD9291. The patients will be followed every 3 months for the detection of mutations (T790M), (C797S), (L858R), del 19 EGFR mutations as well as the mutations \[(KRAS)/(NRAS), (BRAF), (PI3K)\] in the serum/plasma, the determination of the serum levels of Hepatocyte Growth Factor (HGF), the presence of T790M (+) and C797S(+) CTCs as well as the molecular (c-MET) and (HER2 amplification) and phenotypic characterization of CTCs using the filtration platform (ISET). The elimination or the emergence of each of these circulating tumor biomarkers will be correlated with patients' clinical outcome \[objective response to treatment (ORR), (PFS) and (OS)\].

There is no specific control group in this study. Biomarkers profile at baseline will be used as internal control for each patient to monitor changes throughout treatment.

Study Timeline

• Study First Submitted: 2016-04-12
• Study First Submitted QC: 2016-05-11
• Study First Posted: 2016-05-13
• Study Start: 2016-08-02
• Status Verified: 2019-02
• Last Update Submitted: 2019-02-20
• Last Update Posted: 2019-02-22
• Primary Completion: 2020-06
• Study Completion: 2020-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

1. Age >18 years
2. Both sexes
3. Histologically or cytologically documented NSCLC
4. Stage 3b (IIIb) not amenable to radical therapy or stage IV
5. Presence of EGFR activating mutations (exon 19 deletion or L858R in exon 21)
6. First or second line treatment with EGFR TKIs
7. Performance status (ECOG): 0-1
8. Measurable or evaluable disease
9. Adequate organ function tests (Hb>=10g/dL, white blood cell (WBC) >=3.0 x 10^9/L, neutrophils count >=1.5 x 10^9/L, platelets≥100 x 10^9/L, Creatinine clearance >=50 mL/min, Total bilirubin=<1.5 X UNL, aspartate aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline phosphatase (ALP) =<2.5 x UNL)
10. Normal QT interval in ECG
11. Central nervous system (CNS) metastases are allowed provided that they have been irradiated and the patient is clinically stable
12. Women of child bearing potential and all men will be required to use adequate contraceptive measures
13. Life expectancy of at least 3 months
14. Written informed consent

Exclusion Criteria

1. History of serious drug allergy

2. Refractory nausea, vomiting and chronic gastrointestinal diseases

3. Any of the following cardiac criteria:

   • Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
   • Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG.
   • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.

4. Severe or uncontrolled systemic liver disease, including those with known hepatitis B, hepatitis C, and Human Immunodeficiency virus (HIV) infection

5. Interstitial lung disease or pulmonary fibrosis

6. Pregnancy, lactation or other concomitant serious medical condition

7. Other concurrent active malignancy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
AZD9291	AZD9291	AZD9291

Primary Outcome Measures

Name	Time	Method
Biomarkers of resistance to first and third (AZD9291) generation EGFR TKIs, explored by studying baseline serial serum or plasma DNA specimens and baseline Circulating Tumor Cells (CTCs)	Up to 2.5 years

Secondary Outcome Measures

Name	Time	Method
Response rate, assessed using RECIST 1.1	Up to 2.5 years
Progression free survival (PFS)	Up to 2.5 years
Overall Survival	Up to 2.5 years

Trial Locations

Locations (13)

University Hospital of Heraklion Crete; 🇬🇷 Heraklion, Crete, Greece

Anticancer Hospital of Athens "Agios Savvas"; 🇬🇷 Athens, Greece

IASO General Hospital; 🇬🇷 Athens, Greece

General Oncology Hospital of Athens "Ag. Anargiroi"; 🇬🇷 Athens, Greece

Universtiy Hospital of Athens "Attikon"; 🇬🇷 Athens, Greece

Diabalkaniko General Hospital of Thessaloniki; 🇬🇷 Thessaloniki, Greece

251 Air Forces Military Hospital of Athens; 🇬🇷 Athens, Greece

Athens Hospital "Mitera" Hygia Polis; 🇬🇷 Athens, Greece

General Hospital of Athens "Evangelismos"; 🇬🇷 Athens, Greece

General Hospital of Athens "Aretaieio"; 🇬🇷 Athens, Greece

University Hospital of Patra-Rio; 🇬🇷 Río, Greece

Thessaloniki Bioclinic; 🇬🇷 Thessaloniki, Greece

General Hospital of Thesaloniki "G. Papanikolaou"; 🇬🇷 Thessaloníki, Greece