Etoposide and Cisplatin or Carboplatin as First-Line Chemotherapy With or Without Pravastatin in Treating Patients With Small Cell Lung Cancer

A Multicentre Phase III Randomized Double Blind Placebo Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Patients With Small Lung Cancer

RATIONALE: Drugs used in chemotherapy, such as etoposide, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pravastatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by making tumor cells more sensitive to chemotherapy. It is not yet known whether etoposide and cisplatin or carboplatin are more effective with or without pravastatin in treating small cell lung cancer.

PURPOSE: This randomized phase III trial is studying etoposide and cisplatin or carboplatin to see how well they work when given as first-line chemotherapy together with pravastatin compared with first-line chemotherapy and a placebo in treating patients with small cell lung cancer.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: carboplatin; Drug: cisplatin; Drug: etoposide phosphate; Drug: pravastatin sodium

Detailed Description

OBJECTIVES:

Primary

• Compare the survival of patients with small cell lung cancer treated with etoposide phosphate in combination with cisplatin or carboplatin as first-line chemotherapy with vs without pravastatin.

Secondary

• Compare the progression-free survival of patients treated with these regimens.
• Compare the local progression-free survival (local control) of these patients.
• Compare the response rate in these patients.
• Compare the toxicity of these regimens in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease stage (limited stage vs extensive stage), ECOG performance status (0 or 1 vs 2 or 3), and participating site. Patients are randomized to 1 of 2 treatment arms.

All patients receive chemotherapy comprising cisplatin IV or carboplatin IV on day 1 and etoposide phosphate IV on days 1-3 or orally twice daily on days 2 and 3. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

• Arm I: Patients receive oral pravastatin daily beginning on day 1 of chemotherapy and continuing for up to 24 months.
• Arm II: Patients receive oral placebo daily beginning on day 1 of chemotherapy and continuing for up to 24 months.

Some patients may undergo blood and urine sample collection at baseline and periodically during and after study treatment. Samples are examined by genetic analysis, metabonomics and proteomics (to detect expression of RAS proteins, phospho-Erk, and other signals downstream of RAS), and cholesterol measurements.

After completion of study treatment, patients are followed every 2 months for 1 year and every 3 months thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

PROJECTED ACCRUAL: A total of 842 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 846
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • Ashford-Kent, England, United Kingdom, TN24 0LZ
      • William Harvey Hospital
    • Aylesbury-Buckinghamshire, England, United Kingdom, HP21 8AL
      • Stoke Mandeville Hospital
    • Barnstaple, England, United Kingdom, EX31 4JB
      • North Devon District Hospital
    • Bath, England, United Kingdom, BA1 3NG
      • Royal United Hospital
    • Birmingham, England, United Kingdom, B18 7QH
      • City Hospital - Birmingham
    • Birmingham, England, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital
    • Birmingham, England, United Kingdom, B75 7RR
      • Good Hope Hospital
    • Birmingham, England, United Kingdom, B71 4HJ
      • Sandwell General Hospital
    • Bournemouth, England, United Kingdom, BH7 7DW
      • Royal Bournemouth Hospital
    • Bradford, England, United Kingdom, BD9 6RJ
      • Bradford Royal Infirmary
    • Brighton, England, United Kingdom, BN2 5BE
      • Sussex Cancer Centre at Royal Sussex County Hospital
    • Burton-upon-Trent, England, United Kingdom, DE13 0RB
      • Queen's Hospital
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital
    • Canterbury, England, United Kingdom, CT1 3NG
      • Kent and Canterbury Hospital
    • Chelmsford, England, United Kingdom, CM1 7ET
      • Broomfield Hospital
    • Cheltenham, England, United Kingdom, GL53 7AN
      • Gloucestershire Oncology Centre at Cheltenham General Hospital
    • Colchester, England, United Kingdom, C03 3NB
      • Essex County Hospital
    • Cosham, England, United Kingdom, PO6 3LY
      • Queen Alexandra Hospital
    • Dartford Kent, England, United Kingdom, DA2 8DA
      • Darent Valley Hospital
    • Derby, England, United Kingdom, DE22 3NE
      • Royal Derby Hospital
    • Dorchester, England, United Kingdom, DT1 2JY
      • Dorset County Hospital
    • Durham, England, United Kingdom, DH1 5TW
      • University Hospital of North Durham
    • Essex, England, United Kingdom, CM20 1QX
      • Princess Alexandra Hospital
    • Exeter, England, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Gloucester, England, United Kingdom, GL1 3NN
      • Gloucestershire Royal Hospital
    • Grimsby, England, United Kingdom, DN33 2BA
      • Diana Princess of Wales Hospital
    • Guildford, England, United Kingdom, GU2 7XX
      • St. Luke's Cancer Centre at Royal Surrey County Hospital
    • Harrogate, England, United Kingdom, HG2 7SX
      • Harrogate District Hospital
    • Hereford, England, United Kingdom, HR1 2ER
      • Hereford Hospitals
    • High Wycombe, England, United Kingdom
      • Wycombe General Hospital
    • Huddersfield, West Yorks, England, United Kingdom, HD3 3EA
      • Huddersfield Royal Infirmary
    • Hull, England, United Kingdom, HU16 5JQ
      • Castle Hill Hospital
    • Ipswich, England, United Kingdom, IP4 5PD
      • Ipswich Hospital
    • Keighley, England, United Kingdom, BD20 6TD
      • Airedale General Hospital
    • King's Lynn, England, United Kingdom, PE30 4ET
      • Queen Elizabeth Hospital
    • Leeds, England, United Kingdom, LS16 6QB
      • Cancer Research UK Clinical Centre at St. James's University Hospital
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • London, England, United Kingdom, SW17 0QT
      • St. George's Hospital
    • London, England, United Kingdom, W6 8RF
      • Charing Cross Hospital
    • London, England, United Kingdom, SE1 9RT
      • Guy's Hospital
    • London, England, United Kingdom, SE18 4QH
      • Queen Elizabeth Hospital - Woolwich
    • London, England, United Kingdom, NW1 2BU
      • University College Hospital
    • Luton, England, United Kingdom, LU4 0DZ
      • Luton and Dunstable Hospital
    • Maidstone, England, United Kingdom, ME16 9QQ
      • Maidstone Hospital
    • Manchester, England, United Kingdom, M23 9LJ
      • Wythenshawe Hospital
    • Manchester, England, United Kingdom, M20 4BX
      • Christie Hospital
    • Margate, England, United Kingdom, CT9 4AN
      • Queen Elizabeth the Queen Mother Hospital
    • Middlesbrough, England, United Kingdom, TS4 3BW
      • James Cook University Hospital
    • Milton Keynes, England, United Kingdom, MK6 5LD
      • Milton Keynes General Hospital
    • Newcastle-Upon-Tyne, England, United Kingdom, NE7 7DN
      • Freeman Hospital
    • Newport, England, United Kingdom, PO30 5TG
      • St. Mary's Hospital
    • North Yorkshire, England, United Kingdom, DL6 1JG
      • Friarage Hospital
    • Northwood, England, United Kingdom, HA6 2RN
      • Mount Vernon Cancer Centre at Mount Vernon Hospital
    • Nottingham, England, United Kingdom, NG5 1PB
      • Nottingham City Hospital
    • Nottingham, England, United Kingdom, NG5 1PB
      • Northampton General Hospital
    • Nottinghamshire, England, United Kingdom, NG17 4JL
      • King's Mills Hospital
    • Orpington, Kent, England, United Kingdom, BR6 8ND
      • Princess Royal University Hospital
    • Peterborough, England, United Kingdom, PE3 6DA
      • Peterborough Hospitals Trust
    • Plymouth, England, United Kingdom, PL6 8DH
      • Derriford Hospital
    • Poole Dorset, England, United Kingdom, BH15 2JB
      • Dorset Cancer Centre
    • Reading, England, United Kingdom, RG1 5AN
      • Berkshire Cancer Centre at Royal Berkshire Hospital
    • Salisbury, England, United Kingdom, SP2 8BJ
      • Salisbury District Hospital
    • Scarborough, England, United Kingdom, YO12 6QL
      • Scarborough General Hospital
    • Scunthorpe, England, United Kingdom, DN15 7BH
      • Scunthorpe General Hospital
    • Shrewsbury, England, United Kingdom, SY3 8XQ
      • Royal Shrewsbury Hospital
    • Slough, Berkshire, England, United Kingdom, SL2 4HL
      • Wexham Park Hospital
    • South Shields, England, United Kingdom, NE34 0PL
      • South Tyneside District Hospital
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton General Hospital
    • Stevenage, England, United Kingdom, SG1 4AB
      • Lister Hospital
    • Torquay, England, United Kingdom, TQ2 7AA
      • Torbay Hospital
    • Walsall, England, United Kingdom, WS2 9PS
      • Walsall Manor Hospital
    • Weston-super-Mare, England, United Kingdom, BS23 4TQ
      • Weston General Hospital
    • Wolverhampton, England, United Kingdom, WV10 0QP
      • New Cross Hospital
    • Worcester, England, United Kingdom, WR5 1AN
      • Worcestershire Royal Hospital
    • Worthing, England, United Kingdom, BN11 2DH
      • Worthing Hospital
    • Yeovil, England, United Kingdom, BA21 4AT
      • Yeovil District Hospital
    • York, England, United Kingdom, Y031 8HE
      • Cancer Care Centre at York Hospital
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary
    • Falkirk, Scotland, United Kingdom, FK1 5QE
      • Falkirk and District Royal Infirmary
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Center at Velindre Hospital
    • Cardiff, Wales, United Kingdom, CF64 2XX
      • LLandough Hospital
    • Gwent, Wales, United Kingdom
      • Nevill Hall Hospital
    • Haverfordwest, Wales, United Kingdom, SA61 2PZ
      • Withybush General Hospital
    • Newport Gwent, Wales, United Kingdom, NP9 2UB
      • Royal Gwent Hospital
    • Rhyl, Denbighshire, Wales, United Kingdom, LL 18 5UJ
      • Glan Clwyd Hospital
    • Swansea, Wales, United Kingdom, SA2 8QA
      • Singleton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed small cell lung cancer

  • Limited stage or extensive stage disease
• No mixed cell histology
• No symptomatic brain metastases that require immediate radiotherapy

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3
• Life expectancy > 8 weeks
• Platelet count > 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count > 1,500/mm^3
• Glomerular filtration rate ≥ 50 mL/min
• Creatine kinase ≤ 5 times upper limit of normal (ULN)
• Liver function tests (ALP, ALT/AST, and bilirubin) < 3 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 1 year after completion of chemotherapy/radiotherapy and for an additional 28 days after completion of pravastatin sodium
• Able to tolerate chemotherapy
• No evidence of significant medical condition or laboratory finding that, in the opinion of the investigator, would preclude study participation
• No family history of hypercholesterolemia
• No history of malignant tumor unless the patient has been without evidence of disease for ≥ 3 years or tumor was a nonmelanoma skin tumor or early cervical cancer

PRIOR CONCURRENT THERAPY:

• More than 12 months since prior statin
• More than 4 weeks since prior fibrates (e.g., bezofibrate, gemfibrozil, or fenofibrate)
• No prior chemotherapy for this cancer
• No prior radiotherapy for this cancer unless to distant metastases (i.e., not within the thorax or thoracic/cervical spine area)
• No concurrent cyclosporine
• Concurrent radiotherapy allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carboplatin/cisplatin and Etoposide with Pravastatin	Drug: carboplatin; Should be given according to local practice but suggested doses and schedules are provided in the protocol.; Drug: cisplatin; Should be given according to local practice but suggested doses and schedules are provided in the protocol.; Drug: etoposide phosphate; Day 1: given by IV, days 2 and 3 given by IV or oral. Dose should be given according to local practice but suggested doses and schedules are provided in the protocol.; Drug: pravastatin sodium; 40mg daily oral tablet taken for a maximum of 2 years
Placebo Comparator: Carboplatin/cisplatin and Etoposide with Placebo	Drug: carboplatin; Should be given according to local practice but suggested doses and schedules are provided in the protocol.; Drug: cisplatin; Should be given according to local practice but suggested doses and schedules are provided in the protocol.; Drug: etoposide phosphate; Day 1: given by IV, days 2 and 3 given by IV or oral. Dose should be given according to local practice but suggested doses and schedules are provided in the protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Survival	Reported at death.

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	Time until the date of disease progression
Local progression-free survival (local control)	Time until the date of disease progression
Response rate as measured by RECIST criteria after course 3	Post chemo cycle 3
Toxicity as measured by CTCAE version 3.0	At every clinic visit or if serious, an SAE form shoudl be submitted

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Study Chair: Michael J. Seckl, MD, PhD, Charing Cross Hospital

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: February 8, 2007
• First Submitted That Met QC Criteria: February 8, 2007
• First Posted (Estimate): February 12, 2007

Study Record Updates

• Last Update Posted (Estimate): December 3, 2014
• Last Update Submitted That Met QC Criteria: December 1, 2014
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: extensive stage small cell lung cancer; limited stage small cell lung cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Carboplatin; Etoposide; Etoposide phosphate; Cisplatin; Pravastatin
• Other Study ID Numbers: CDR0000531141; CRUK-LUNGSTAR; EU-20649; ISRCTN56306957; EUDRACT-2005-005821-71; UCL-BRD/05/129; MREC-06-MRE10-28; CTA-20363-0215-001; CTAAC-C1312-A5335; CTAAC-C1312-A12462