Chloroquine as an Anti-Autophagy Drug in Stage IV Small Cell Lung Cancer (SCLC) Patients

Study Overview
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Brief Summary
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Chloroquine might very well be able to increase overall survival in small cell lung cancer by sensitizing cells resistant to chemotherapy and radiotherapy.

Detailed Description
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Tumor hypoxia is a well-known factor negatively influencing outcome in many solid tumors, including small cell lung cancer. Hypoxic cells are more radio-resistant, more chemo-resistant and more prone to develop distant metastases than normoxic cells. One of the mechanisms responsible for survival of these therapy-resistant hypoxic cells is (macro-)autophagy: a phenomenon in which cells provide themselves with energy (ATP) by digesting their own cell-organelles. Chloroquine is a potent blocker of autophagy and has been demonstrated in a lab setting to dramatically enhance tumor response to radiotherapy, chemotherapy and even anti-hormonal therapy. Thus, chloroquine might very well be able to increase overall survival in small cell lung cancer by sensitizing cells resistant to chemotherapy and radiotherapy.

Official Title
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Chloroquine as an Anti-autophagy Drug in Stage IV Small Cell Lung Cancer (SCLC) Patients: A Phase 1 Trial

Conditions
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Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Chloroquine, A-CQ 100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed ''extensive disease'' (Stage T0-4 N0-3 M1) small cell lung cancer At least one measurable disease site, defined as lesion of ≥ 1 cm unidimensionally on CT-scan. WHO performance status 0-2 Absolute neutrophil count at least 1800/µl and platelets at least 100000/µl and hemoglobin at least 6.2 mmol/l. Calculated creatinine clearance at least 60 ml/min Adequate hepatic function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; ALT, AST, and alkaline phosphatase ≤ 2.5 x ULN for the institution (in case of liver metastases ≤ 5 x ULN for the institution) No previous platinum chemotherapy or topo-isomerase-inhibitors for SCLC. Life expectancy more than 6 months 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 mixed pathology, e.g. non-small cell plus small cell cancer No recent (< 3 months) severe cardiac disease (NYHA class >1) (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: 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 QTc 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 prolongating the QT-interval are excluded if the QT-interval is > 460 msec (Appendix, table 2). Medication that might cause QT-prolongation or Torsades de pointes tachycardia is not allowed (Appendix, Table 1). Drugs with a risk of prolongating the QT-interval that cannot be discontinued are allowed, however, under close monitoring by the treating physician (Appendix, table 2). No uncontrolled infectious disease No other active malignancy No major surgery (excluding diagnostic procedures like e.g., mediastinoscopy) in previous 4 weeks No treatment with investigational drugs in 4 weeks prior to or during this study No chronic systemic immune therapy No known G6PD deficiency Exclusion Criteria: The opposite of the above

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chloroquine<br>Patients receive Chloroquine | Drug: Chloroquine, A-CQ 100<br>* Administration: Orally Timing: Once daily Tablets of 100 mg During or after meals In case of missed dose: intake of the missed dose is still possible up until 12 hours before the next dose. Patients should always note date and time of intake on the chloroquine monitoring form.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the toxicity of adding chloroquine in escalating doses in SCLC patients: to standard dose cisplatin-etoposide in extensive disease SCLC; to standard dose concurrent radiotherapy and cisplatin-etoposide in limited disease SCLC |  | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response (according to RECIST) |  | 6 years | 
| Overall survival |  | 6 years |