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

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ClinicalTrials.gov Identifier: NCT02856893
Recruitment Status : Recruiting
First Posted : August 5, 2016
Last Update Posted : September 20, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
NSCLC Drug: Osimertinib Drug: Gefitinib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 159 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients
Actual Study Start Date : October 10, 2017
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : December 2027

Resource links provided by the National Library of Medicine


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 Name: 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 Name: AZD9291, Tagrisso

Drug: Gefitinib
Gefitinib 250mg daily until progression
Other Name: 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 Name: AZD9291, Tagrisso

Drug: Gefitinib
Gefitinib 250mg daily until progression
Other Name: Iressa




Primary Outcome Measures :
  1. PFS Rate at 18 months [ Time Frame: 24 months after first patient in ]

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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02856893


Contacts
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Contact: Nuria Renard +32 2 774 16 96 1613@eortc.org

Locations
Show Show 22 study locations
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
AstraZeneca
Investigators
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Principal Investigator: Rafal Dziadziuszko, MD PhD Mecical University of Gdansk, Poland
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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT02856893    
Other Study ID Numbers: EORTC-1613
ESR-15-11406 ( Other Identifier: Astra Zeneca )
First Posted: August 5, 2016    Key Record Dates
Last Update Posted: September 20, 2019
Last Verified: September 2019

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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
Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
AZD9291
Osimertinib
Gefitinib
NSCLC
liquid biopsy
ctDNA
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Gefitinib
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action