Clinical trial NCT00969306: Chloroquine as an Anti-Autophagy Drug in Stage IV Small Cell Lung Cancer (SCLC) Patients
Official title: Chloroquine as an Anti-autophagy Drug in Stage IV Small Cell Lung Cancer (SCLC) Patients: A Phase 1 Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Small Cell Lung Cancer
Lead sponsor: Maastricht Radiation Oncology
Sponsor class: OTHER
Collaborators: name: Maastricht University Medical Center
name: National Cancer Institute (NCI)
First posted: 2009-09-01
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 6 years
Secondary outcomes:
measure: Tumor response (according to RECIST)
timeFrame: 6 years
measure: Overall survival
timeFrame: 6 years
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: NKI/AvL
city: Amsterdam
country: Netherlands
facility: VU Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht Radiation Oncology
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
Study officials:
affiliation: Maastricht Radiation Oncology
name: Philippe Lambin, DM, PhD
role: PRINCIPAL_INVESTIGATOR
References: