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ID
Source
Brief title
Health condition
histologically confirmed stage IV non-squamous NSCLC patients who are eligible to start with EGFR targeted therapy;
1. patients who progressed on erlotinib or gefitinib monotherapy after having experienced an initial response.
2. patients who failed chemotherapy after at least one line of platinum based doublet chemotherapy and who are EGFR TKI naïve
Dutch:
Histologisch bewezen stadium IV non-squamous NSCLC patienten.
• Patienten:
• met een activerende EGFR mutatie die progressief zijn onder erlotinib of gefitinib monotherapie.
OF
• welke progressieve ziekte hebben na eerdere
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the efficacy of HCQ and erlotinib treatment, as measured by a decrease in tumor 18F-FDG uptake after one week in two cohorts of NSCLC patients that are eligible for erlotinib therapy.
Secondary outcome
1. To assess the disease control rate (DCR) according to the response evaluation criteria in solid tumors (RECIST v1.1) with CT-Thorax, the performance free survival (PFS) at six months and the overall survival (OS) at one year;
2. To assess the level of autophagy at baseline and to detect autophagy inhibition during treatment in peripheral blood and tumor samples (section 11);
3. To analyze the relation between EGFR mutation status and response to hydroxychloroquine and erlotinib treatment;
4. To assess toxicity of hydroxychloroquine according to CTC AE 4.0.
Background summary
Background:
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 enautophagy inhibition by HCQ seem to be the responsible mechanisms that cause (re)sensitization of tumor cells for erlotinib.
Objective of the study:
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.
Study population:
Histologically confirmed stage IV non-squamous NSCLC patients who are eligible to start with EGFR targeted therapy:
1. Patients who progressed on erlotinib or gefitinib monotherapy after having experienced an initial response;
2. Patients who failed chemotherapy after at least one line of platinum based doublet chemotherapy and who are EGFR TKI naive.
Intervention:
Erlotinib 150 mg once daily and HCQ 1000 mg once daily.
Primary study parameters/outcome of the study:
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.
Secundary study parameters/outcome of the study:
1. 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;
2. To assess the level of autophagy at baseline and the inhibition of autophagy during treatment in peripheral blood and tumor samples;
3. 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.
Study objective
HCQ causes both autophagy inhibition and chromatin modification, thereby (re)sensitizing tumor cells to EGFR TKIs, hypothetically increasing response rates after one week.
Study design
Before treatment initiation:
1. Medical history;
2. CTC-AE 4.0;
3. Check concomitant medication (ask);
4. Clinical examination (blood pressure, heart rate, WHO performance status, weight, length);
5. Standard lab tests: Hemoglobin, white blood cell count, white blood cell differentiation, platelet count, serum creatinin, blood urea, liver function (bilirubin, LDH, gamma-GT, ALAT, ASAT, Alkaline Phosphatase), ions (Na, K, Cl, Ca, Mg), TSH, pregnancy-test (if indicated);
6. Blood sample for detecting autophagy;
7. 18F-FDG PET-CT (within 10 days from treatment start);
8. ECG;
9. Lung function (FEV-1, DLCO);
10. Ophtalmologic examination: Retinal examination, visual acuity;
11. Tumor biopsy (lesion is selected based upon a trade of between the lowest complication risk and the highest success rate).
After one week:
1. Check intake of chloroquine and concomitant medication (ask);
2. CTC-AE 4.0;
3. Clinical examination (blood pressure, heart rate, WHO performance status, weight);
4. Standard lab tests (same as baseline);
5. Blood sample for detecting autophagy;
6. Blood sample to measure the concentration of HCQ in plasma;
7. 18F-FDG PET-CT;
8. Tumor biopsy (lesion is selected based upon a trade of between the lowest complication risk and the highest success rate).
Every visit (3-weekly):
1. Check intake of chloroquine and concomitant medication (ask);
2. CTC-AE 4.0;
3. Clinical examination (blood pressure, heart rate, WHO performance status, weight);
4. Standard lab tests (same as baseline).
Every 6 weeks:
CT Thorax.
At disease progression:
1. Tumor biopsy (lesion is selected based upon a trade of between the lowest complication risk and the highest success rate);
2. Blood sample for detecting autophagy.
Twice a year:
Opthalmologic control visit.
Intervention
Erlotinib 150 mg once daily and HCQ 1000 mg once daily. This medication will be given until progression.
VU University Medical Centre<br>
PO Box 7057
E.F. Smit
Amsterdam 1007 MB
The Netherlands
+31 (0)20 4444782
ef.smit@vumc.nl
VU University Medical Centre<br>
PO Box 7057
E.F. Smit
Amsterdam 1007 MB
The Netherlands
+31 (0)20 4444782
ef.smit@vumc.nl
Inclusion criteria
1. Histologically confirmed stage IV non-squamous NSCLC patients;
2. Patients:
A. With an activating EGFR mutation who progressed on erlotinib or gefitinib monotherapy, OR;
B. Who failed after at least one line of platinum based doublet chemotherapy and who are EGFR TKI naïve.
3. At least one measurable disease site, defined as a lesion of ≥ 1 cm in at least one dimension on CT-scan;
4. WHO performance status 0-2;
5. No symptomatic brain metastases;
6. Absolute neutrophil count of at least 1500/μl, platelet count of at least 100000/μl and hemoglobin level of at least 6 mmol/l;
7. Calculated creatinine clearance of at least 60 ml/min;
8. 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);
9. Willing and able to comply with the study prescriptions;
10. 18 years or older;
11. Not pregnant or breast feeding and willing to take adequate contraceptive measures during the study;
12. Ability to give and having given written informed consent before patient registration;
13. No recent (< 3 months) severe 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;
14. No cardiac conduction disturbances or medication potentially causing them: QTc interval prolongation with other medications that required discontinuation of the treatment, 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;
15. No uncontrolled infectious disease;
16. No other active malignancy;
17. No major surgery (excluding diagnostic procedures like e.g. mediastinoscopy or VATS biopsy) in the previous 4 weeks;
18. No treatment with investigational drugs that are thought or known to interact with autophagy in the 4 weeks prior to or during the current trial;
19. No known G6PD deficiency;
20. No psoriasis or porphyria;
21. No known hypersensitivity to 4-aminoquinoline compound;
22. No visual field changes from prior 4-aminoquinoline compound use;
23. No known prior hypersensitivity to erlotinib, HCQ or any of their components.
Exclusion criteria
See inclusion criteria.
Design
Recruitment
Followed up by the following (possibly more current) registration
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL3209 |
| NTR-old | NTR3360 |
| CCMO | NL38376.029.12 |
| ISRCTN | ISRCTN wordt niet meer aangevraagd. |
| OMON | NL-OMON37508 |