STUDY 15 - Comparing Gemcitabine/Carboplatin and Hydroxychloroquine Versus Carboplatin/Etoposide Therapy Alone in Small Cell Lung Cancer (SCLC)

Study Overview
=================
Brief Summary
-----------------
To determine whether the combination of gemcitabine/carboplatin with hydroxychloroquine (HCQ) is associated with an improved clinical outcome (progression free and overall survival) compared with chemotherapy alone in patients with small cell lung cancer (SCLC)

Detailed Description
-----------------
This is a multicentre, randomised, phase II trial which aims to compare the combination of hydroxychloroquine and gemcitabine/carboplatin versus standard carboplatin/etoposide chemotherapy, as first line treat in patients with stage IV disease. The standard first line chemotherapy treatment remains a platinum-based chemotherapy and this has been unchanged for 20 years. Novel active treatment approaches are urgently needed to improve survival in SCLC. Patients are randomised to one of two treatment arms; carboplatin/etoposide or gemcitabine/carboplatin/hydroxychloroquine.

Official Title
-----------------
A Phase II, Multicentre, Randomised Trial Comparing Combination Gemcitabine/Carboplatin and Hydroxychloroquine Versus Carboplatin/Etoposide Therapy Alone in Small Cell Lung Cancer (SCLC)

Conditions
-----------------
Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Gemcitabine
* Drug: Carboplatin
* Drug: Etoposide
* Drug: Hydroxychloroquine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or cytologically confirmed SCLC Stage IV disease Performance status ECOG 0-2 Life expectancy >8 weeks Age 18 or over Willing and able to give informed consent Patient considered able to tolerate chemotherapy Adequate renal function - defined by GFR ≥50mL/min as measured by EDTA or C&G Adequate bone marrow reserve: Absolute neutrophil count ≥1.5 x 109/L, haemoglobin ≥90 g/L, platelet count ≥100 x 109/L Negative pregnancy test for WCBP Highly effective contraception is mandatory for all patients of reproductive potential At least one site of measurable disease (target lesion) for RECIST 1.1 evaluation Hypersensitivity or history of severe allergic reaction to any of the IMPs Able to swallow medication Exclusion Criteria: Mixed cell histology (i.e. NSCLC and SCLC) Prior macular degeneration or diabetic retinopathy History of glaucoma Patients with abnormal LFTs (ALP, ALT/AST*) that are ≥3 x ULN (≥5 x ULN for patients with liver metastases) Patients with abnormal bilirubin levels that are ≥1.5 x ULN Prior treatment for this disease e.g. chemotherapy, surgery, radiotherapy (except palliative radiotherapy to bone metastases) Documented side effects to chloroquine or related agents Treatment with chloroquine or related agents within the last year prior to randomisation Evidence of significant medical condition or laboratory finding which, in the opinion of the investigator, makes it undesirable for the patient to participate in the trial Previous medical history of prolonged QT interval A history of prior malignant tumour, unless the patient has been without evidence of disease for at least 3 years or the tumour was a non-melanoma skin tumour or early cervical cancer Patients with symptomatic brain metastases Women who are breastfeeding Concurrent cytochrome P450 enzyme-inducing anticonvulsant drugs e.g. phenytoin, carbamazepine, phenobarbital, primidone or oxcarbazepine Patients who are unable to have their digoxin levels regularly monitored if both ALT and AST performed then both need to be recorded

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control Arm<br>IV carboplatin AUC5 (area under curve) on Day1 IV etoposide 120mg/m2 Day 1, followed by oral etoposide 100mg BD (twice daily) on Day 2 and Day 3 | Drug: Carboplatin<br>* Chemotherapy<br>Drug: Etoposide<br>* Chemotherapy<br>|
| Experimental: Investigational Arm<br>IV gemcitabine 1200mg/m2 on Day 1 and Day 8 IV carboplatin AUC5 on Day 1 Oral HCQ will be taken at a dose of 400mg BD from day 1 of cycle 1 (maximum of 30 months) | Drug: Gemcitabine<br>* Chemotherapy<br>Drug: Carboplatin<br>* Chemotherapy<br>Drug: Hydroxychloroquine<br>* Maintenance Agent<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  | Defined as the time from randomisation to first progression/death (whichever came first), assessed up to 41 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | From date of randomisation to death due to any cause, assessed up to 41 months | 
| Objective response as measured by Response Evaluation Criteria in Solid Tumours (RECIST) v.1.1 | Complete Response (CR)/ Partial Response (PR)/ Progressive Disease (PD)/ Stable Disease (SD) | From first tumour assessment to progression/trial end (whichever is first), assessed up to 41 months | 
| Adverse events | Including ophthalmologic and treatment specific toxicities | From date of consent to 30 days after final trial treatment | 
| Quality of life as measured by EQ-5D | The questionnaire is a standardised questionnaire | From baseline to progression/trial end (whichever is first), assessed up to 41 months | 
| Quality of life as measured by QLQC-30 | The questionnaire is a standardised questionnaire | From baseline to progression/trial end (whichever is first), assessed up to 41 months | 
| Quality of life as measured by QLQ-LC-13 | The questionnaire is a standardised questionnaire | From baseline to progression/trial end (whicenver is first), assessed up to 41 months | 
| Compliance measured by dose intensity | Capturing dose delays, modifications and omissions | From first date of trial treatment to progression/trial end (whichever is first), assessed up to 41 months | 
| Compliance measured by dose exposure | Capturing dose delays, modifications and omissions | From first date of trial treatment to progression/trial end (whichever is first), assessed up to 41 months |