Osimertinib Treatment on EGFR T790M Plasma Positive NSCLC Patients (APPLE) (APPLE)

APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients

The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC patients. Finally, the trial will also explore the mechanisms of acquired resistance to Osimertinib based on the results of an optional biopsy upon progression.

Study Overview

• Status: Active, not recruiting
• Conditions: NSCLC
• Intervention / Treatment: Drug: Osimertinib; Drug: Gefitinib

Detailed Description

Primary objective To evaluate the best strategy for delivering Osimertinib (AZD9291) in NSCLC patients with EGFR mutation. The objective is assessed by Progression Free Survival rate at 18 months (PFS-18).

Secondary objectives

• To evaluate PFS on Osimertinib measured from randomization by RECIST criteria 1.1 [Ref 33].
• To evaluate PFS measured from switching to Osimertinib by RECIST criteria 1.1 [Ref 33].
• To determine the proportion of patients receiving Osimertinib based on the determination of cfDNA T790M mutation positive.
• To evaluate time to symptomatic brain metastases in patients with presence of brain metastases at study entry.
• To evaluate PFS-2 (defined as the sum of the PFS to Gefitinib and the PFS to Osimertinib treatment).
• To evaluate Overall Response Rate (ORR) to Osimertinib.
• To evaluate the Treatment duration.
• To evaluate Time to progression (TTP) on Osimertinib (measured from switching to osimertinib).
• To evaluate Overall Survival (OS).
• To evaluate time to brain progression (TTBP).
• Safety.

• Study Type: Interventional
• Enrollment (Anticipated): 156
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France
    • Institut Bergonié
  • Brest, France
    • CHU de Brest
  • Caen, France
    • Centre François Baclesse
  • Créteil, France
    • Centre Hopitalier Intercommunal De Creteil
  • Marseille, France
    • Institut Paoli-Calmettes
  • Marseille, France
    • Assistance Publique - Hopitaux de Marseille - Hopital Nord
  • Strasbourg, France
    • Centre Paul Strauss
  • Toulouse, France
    • CHU Toulouse - Hopital Larrey
  • Vandœuvre-lès-Nancy, France
    • Institut de Cancérologie de Lorraine
  • Villejuif, France
    • Gustave Roussy
• Jordan
  • Amman, Jordan
    • King Hussein Cancer Center
• Poland
  • Gdansk, Poland
    • Medical University of Gdansk
• Slovenia
  • Golnik, Slovenia
    • University Clinic Golnik
  • Ljubljana, Slovenia
    • The Institute Of Oncology
• Spain
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Vall d'Hebron Institut d'Oncologia
  • Barcelona, Spain
    • Hospital Clinic Universitari de Barcelona
  • Coruna, Spain
    • University Hospital A Coruna-Hospital Teresa Herrera
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario Ramon Y Cajal
  • Mataró, Spain
    • Institut Catala d'Oncologia - ICO Badalona - Hospital De Mataro
  • Sevilla, Spain
    • Virgen del Rocio University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion:

Registration:

• Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory;
• Stage IV NSCLC;
• Blood sample available for cfDNA EGFR T790M central testing;
• Age ≥18 years;
• EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI;
• Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration;
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

Randomization:

• Report of adequacy sample for cfDNA EGFR T790M test by central laboratory;
• Prior palliative radiotherapy or surgery are allowed if completed at least 4 weeks before the randomization;
• Patients with brain metastases are allowed provided they are stable (i.e. without evidence of progression by imaging for at least two weeks prior to the first dose of trial treatment and without deterioration of any neurologic symptoms), and have not received steroids for at least 7 days before randomization; Baseline tumor assessment scans are done within 21 days before randomization;
• Evaluable disease as defined below;
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis of ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.
• WHO Performance Status 0-2, with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks;
• Adequate bone marrow, renal, hepatic and liver function within 21 days from randomization and defined as follows:
• Absolute neutrophil count ≥1.5 x 109/L;
• Platelet count ≥100 x 109/L;
• Haemoglobin ≥9 g/dL;
• Alanine aminotransferase (ALT) ≤2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
• Aspartate aminotransferase (AST) ≤2.5xULN if no demonstrable liver metastases or ≤5xULN in the presence of liver metastases;
• Total bilirubin ≤1.5xULN if no liver metastases or ≤3xULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases;
• Serum creatinine ≤1.5xULN concurrent with creatinine clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault equation);
• No significant comorbidity that according to the investigator would hamper the participation on the trial;
• Female patients should be using adequate contraceptive measures, should not be breastfeeding, until 12 months after the last dose, and must have a negative pregnancy test (serum or urine) prior to first dose of study drug (within 72 hours); or female patients must have an 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 amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
• Women under 50 years old would be consider 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, bilateraloophorectomy, or bilateral salpingectomy but not tubal ligation.

• Male patients should be willing to use barrier contraception, i.e., condoms

  o Male patients will be advised to arrange for the freezing of sperm samples prior to the start of the study should they wish to father children, and not to donate sperm until 6 months after discontinuation of study treatment." (as per Investigator Brochure, IB)

• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion:

• Treatment with any of the following:
• Prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic NSCLC including chemotherapy, biologic therapy, immunotherapy, or any investigational drug;
• Prior treatment with an EGFR-TKI;
• Major surgery (excluding placement of vascular access) within 4 weeks before randomization;
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks before randomization
• Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study drug) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4;
• Other anti-cancer therapies and alternative medications such as homeopathic treatment, etc;
• Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known;
• Leptomeningeal carcinomatosis; spinal cord compression;
• Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than CTCAE grade 2 at the time of randomization;
• Patients will not be eligible if they have evidence of active malignancy (other than non-melanoma skin cancer or localized cervical cancer or localised and presumed cured prostatic cancer) within 2 years before randomization and are not receiving specific treatment for these malignancies at baseline assessment;
• 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 including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Active infection will include any patients receiving intravenous treatment for infection; active hepatitis B infection will, at a minimum, include all patients who are Hepatitis B surface antigen positive (HbsAg positive) based on serology assessment. Screening for chronic conditions is not required;
• 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 or Gefitinib;
• Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs using local clinic ECG machine-derived QTcF value
• 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, PR interval >250 msec or history of episodes of bradycardia (<50 BPM);
• 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.
• Abnormal cardiac function: LVEF < 50% (assessed by MUGA or ECHO)
• Past medical history of ILD (Interstitial Lung Disease), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Osimertinib till progression; Osimertinib until PD according to RECIST 1.1	Drug: Osimertinib; Osimertinib 60 or 40 mg daily until progression; Other Names: AZD9291, Tagrisso
Experimental: Gefitinib till + blood test/progression than Osimertinib; Gefitinib until emergence of positive T790M status ("cfDNA T790M positive progression") followed by Osimertinib until second PD according to RECIST 1.1	Drug: Osimertinib; Osimertinib 60 or 40 mg daily until progression; Other Names: AZD9291, Tagrisso; Drug: Gefitinib; Gefitinib 250mg daily until progression; Other Names: Iressa
Active Comparator: Gefitinib till progression than Osimertinib; Gefitinib until PD according to RECIST 1.1 followed by Osimertinib until PD according to RECIST 1.1	Drug: Osimertinib; Osimertinib 60 or 40 mg daily until progression; Other Names: AZD9291, Tagrisso; Drug: Gefitinib; Gefitinib 250mg daily until progression; Other Names: Iressa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
PFS Rate at 18 months	24 months after first patient in

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS measured from switching to Osimertinib by RECIST criteria 1.1		24 months after first patient in
Proportion of patients receiving Osimertinib based on the determination of cfDNA T790M mutation positive		24 months after first patient in
Time to progression on Osimertinib		through study completion
Time to symptomatic brain metastases in patients with presence of brain metastases at study entry		24 months after first patient in
Overall Response Rate (ORR) to Osimertinib		24 months after first patient in
Treatment duration		24 months after first patient in
Overall Survival (OS)		24 months after first patient in
Time to brain progression (TTBP)		24 months after first patient in
Safety	Number of participants with treatment-related adverse events by CTCAE version 4.0. Adverse events, serious adverse events and adverse reactions will be monitored.	24 months after first patient in

Collaborators and Investigators

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Rafal Dziadziuszko, MD PhD, Mecical University of Gdansk, Poland

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2017
• Primary Completion (Anticipated): February 1, 2023
• Study Completion (Anticipated): December 1, 2027

Study Registration Dates

• First Submitted: July 11, 2016
• First Submitted That Met QC Criteria: August 4, 2016
• First Posted (Estimate): August 5, 2016

Study Record Updates

• Last Update Posted (Actual): September 15, 2022
• Last Update Submitted That Met QC Criteria: September 13, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: NSCLC; Osimertinib; ctDNA; liquid biopsy; Gefitinib; AZD9291
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Gefitinib; Osimertinib
• Other Study ID Numbers: EORTC-1613; ESR-15-11406 (Other Identifier: Astra Zeneca)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes