Hydroxychloroquine as an anti-autophagy and chromatin modulating drug in combination with erlotinib in non-small cell lung cancer (NSCLC) patients: a single-center single arm open-label phase II trial

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 136

Inclusion Criteria

* Histologically confirmed stage IV non-squamous NSCLC patients.
* Patients:
with an activating EGFR mutation who progressed on erlotinib or gefitinib monotherapy.
OR
who failed after at least one line of platinum based doublet chemotherapy and who are EGFR TKI naïve.
* At least one measurable disease site, defined as a lesion of * 1 cm in at least one dimension on CT-scan.
* WHO performance status 0-2.
* No symptomatic brain metastases.
* Absolute neutrophil count of at least 1500/*l, platelet count of at least 100000/*l and hemoglobin level at least 6 mmol/l.
* Calculated creatinine clearance of at least 60 ml/min.
* Adequate hepatic function: Total bilirubin * 1.5 x upper limit of normal (ULN); ALT, AST, and alkaline phosphatase * 2.5 x ULN (in case of liver metastases * 5 x ULN).
* Willing and able to comply with the study prescriptions
* 18 years or older.
* Not pregnant or breast feeding and willing to take adequate contraceptive measures during the study.
* Ability to give and having given written informed consent before patient registration.
* No recent (< 3 months) severe (NYHA class >1) cardiac disease (congestive heart failure, infarction). No history of cardiac arrythmia (multifocal premature ventricular contractions, uncontrolled atrial fibrillation, bigeminy, trigeminy, ventricular tachycardia) which is symptomatic and requiring treatment (CTC AE 4.0), or asymptomatic sustained ventricular tachycardia. Asymptomatic atrial fibrillation controlled on medication is allowed.
* No cardiac conduction disturbances or medication potentially causing them: congenital long QT-syndrome or unexplained sudden death of first degree relative under 40 years of age, QT interval > 480 msec (note: when this is the case on screening ECG, the ECG may be repeated twice. If the average QT-interval of these 3 measurements remains below 480 msec, patient is eligible). Patients on medication potentially prolonging the QT-interval are excluded if the QT-interval is > 460 msec. Medication that might cause QT-prolongation or Torsades de pointes tachycardia is not allowed. Drugs with a risk of prolonging the QT-interval that cannot be discontinued are allowed, however, under close monitoring by the treating physician.
* No uncontrolled infectious disease.
* No clinically significant gastrointestinal abnormalities.
* No other active malignancy.
* No major surgery (excluding diagnostic procedures like e.g. mediastinoscopy or VATS biopsy) in the previous 4 weeks.
* No treatment with investigational drugs in the 4 weeks prior to or during this study that are thought or known to interact with autophagy or the EGFR axis.
* No known G6PD deficiency.
* No psoriasis or porphyria.
* No known hypersensitivity to 4-aminoquinoline compound.
* No retinal or visual field changes from prior 4-aminoquinoline compound use.
* No known prior hypersensitivity to erlotinib, HCQ or any of their components.

Exclusion Criteria

We refer to the inclusion criteria

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The difference in metabolic activity of the tumor after one week of treatment<br /><br>as compared to the baseline value, measured with 18F-FDG PET using predefined<br /><br>PET response criteria.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>* To assess the disease control rate (DCR) according to the response evaluation<br /><br>criteria in solid tumors (RECIST v1.1) with CT-Thorax, performance free<br /><br>survival (PFS) after six months of treatment and overall survival (OS) after<br /><br>one year of treatment.<br /><br>* To assess the level of autophagy at baseline and the inhibition of autophagy<br /><br>during treatment in peripheral blood and tumor samples.<br /><br>* Upon progression, a rebiopsy will be taken to analyse EGFR mutation and<br /><br>autophagy status and to analyse mechanisms of secondary resistance to<br /><br>erlotinib/hydroxychloroquine treatment.</p><br>