To evaluate the efficacy of the drug combination. Translational work is aimed to explore pharmacodynamic, predictive and surrogate endpoint biomarkers in tumor tissue and blood.
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The difference in metabolic activity of the tumor after one week of treatment
as compared to the baseline value, measured with 18F-FDG PET using predefined
PET response criteria.
Secondary outcome
* To assess the disease control rate (DCR) according to the response evaluation
criteria in solid tumors (RECIST v1.1) with CT-Thorax, performance free
survival (PFS) after six months of treatment and overall survival (OS) after
one year of treatment.
* To assess the level of autophagy at baseline and the inhibition of autophagy
during treatment in peripheral blood and tumor samples.
* Upon progression, a rebiopsy will be taken to analyse EGFR mutation and
autophagy status and to analyse mechanisms of secondary resistance to
erlotinib/hydroxychloroquine treatment.
Background summary
Less than 30% of patients with metastatic NSCLC respond to standard
platinum-based doublet chemotherapy. In addition, the side-effect profile of
this treatment is far from satisfactory.
EGFR TKI (epidermal growth factor receptor tyrosine kinase inhibitor) treatment
is associated with a favorable side-effect profile. However, patients either
possess primary resistance to EGFR-TKIs or develop secondary resistance during
the course of anti-EGFR treatment. Preclinical work has shown that the
combination of hydroxychloroquine (HCQ) and erlotinib has the ability to
overcome primary and secondary resistance to EGFR TKIs. Chromatin modulation en
autophagy inhibition by HCQ seem to be the responsible mechanisms that cause
(re)sensitization of tumor cells for erlotinib.
Study objective
To evaluate the efficacy of the drug combination. Translational work is aimed
to explore pharmacodynamic, predictive and surrogate endpoint biomarkers in
tumor tissue and blood.
Study design
Single-center single arm open-label phase II study.
Intervention
Erlotinib 150 mg once daily and HCQ 1000 mg once daily.
Study burden and risks
Wide experience exists with the prescription of both drugs and both drugs have
been found to be save when prescribed. A recent Phase I study showed that the
combination ican be given safely with an acceptable toxicity profile. Patients
accrued to the study will have to visit the outpatient department 3-weekly,
where a case record form (CRF) will be filled out and blood will be drawn. A
PET-CT scan and tumor biopsy will be performed at baseline and after one week
of treatment. The amount and schedule of investigations are not different from
routine clinical practice, except for the two PET-CT scans and the tumor biopsy
after one week of treatment.
Postbus 7057
1007 MB Amsterdam
NL
Postbus 7057
1007 MB Amsterdam
NL
Listed location countries
Age
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004903-20-NL |
| CCMO | NL38376.029.12 |
| OMON | NL-OMON21406 |