Horizon Scanning Centre September 2012

Liposomal (Lipoplatin) in combination with gemcitabine for – first line

SUMMARY NIHR HSC ID: 7481

Liposomal cisplatin is intended to be used in combination with gemcitabine as first line therapy for the treatment of unresectable pancreatic cancer. If licensed, it would provide an additional treatment option for this patient group This briefing is who currently have few effective options. Liposomal cisplatin is a new formulation that targets and fuses with human tumour cells allowing for the based on specific delivery of the cytotoxic drug directly into cancer cells. This reduces information the toxicity of cisplatin and helps evade the . available at the time

of research and a Pancreatic cancer is the ninth most common cancer in the UK and the fifth limited literature most common cause of death from cancer. It is often diagnosed at an search. It is not advanced stage and has 1-year and 5-year survival rates of around 12% and intended to be a 3% respectively. The majority of cases occur between 60-80 years of age. In definitive statement 2008, there were 7,179 new diagnoses in England and Wales and 7,065 on the safety, deaths occurred in 2010. efficacy or effectiveness of the For unresectable pancreatic cancer, treatment is palliative. Current options health technology include gemcitabine in combination with capecitabine, FOLFIRINOX, or covered and should monotherapy with gemcitabine or fluorouracil. Liposomal cisplatin is currently not be used for in a phase III clinical trial comparing its effect on one-year survival against commercial treatment with gemcitabine alone. This trial is expected to complete in Q2 purposes or 2014. commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk

NIHR Horizon Scanning Centre

TARGET GROUP

• Pancreatic cancer: unresectable – first line; in combination with gemcitabine.

TECHNOLOGY

DESCRIPTION

Liposomal cisplatin (Lipoplatin) is a new formulation that targets and fuses with human tumour cells allowing for the specific delivery of the cytotoxic drug directly into cancer cells. This reduces the toxicity of cisplatin and helps evade the immune system. Liposomal cisplatin is intended to be used for the treatment of unresectable pancreatic cancer and is administered by intravenous (IV) infusion at 200mg/m2 on days 1, 8 and 15 of a 21 day cycle, in combination with gemcitabine at 1,000mg/m2 on days 1 and 8 of a 21 day cycle for 3 cycles or until disease progression.

Liposomal cisplatin is in phase III clinical trials for non-small cell lung cancer, head and neck cancer and , and in phase II trials for gastric cancer.

INNOVATION and/or ADVANTAGES

If licensed, liposomal cisplatin will provide an additional treatment option for this patient group who currently have few effective options.

DEVELOPER

Regulon Inc.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Pancreatic cancer is the ninth most common cancer in the UK and the fifth most common cause of death from cancer1. It may arise in the head, body or tail of the pancreas and symptoms, which include jaundice, nausea, diarrhoea, weight loss, loss of appetite and severe pain, vary depending on the tumour site2,3. There are three main types described: infiltrating ductal , which account for around 90% of pancreatic cancers, acinar cell carcinoma, and pancreatoblastoma4.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011).

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CLINICAL NEED and BURDEN OF DISEASE

Pancreatic cancer has one of the worst prognoses of all solid tumours, with >95% of those affected dying of their disease4. The high mortality rate is, at least in part, due to the vast majority of patients presenting at an advanced stage3. Patients with unresectable, locally advanced disease have a median survival of 6-11 months, and patients with metastatic disease have a median survival of 2-6 months5. The 1-year survival rate is low, at around 12%, and less than 3% survive to 5 years3. Pancreatic cancer affects both sexes equally, with a lifetime risk of 1 in 77 for men and 1 in 79 for women6. It is rare before the age of 45 years; 80% of cases occur between 60-80 years of age7. In 2008, there were 7,179 new diagnoses in England and Wales6, and 7,065 deaths occurred in 20108. In 2010-11, there were 23,893 hospital admissions due to pancreatic cancer in England, accounting for 30,016 finished consultant episodes and 98,426 bed days9 (ICD C25).

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. The use of gemcitabine for the treatment of pancreatic cancer (TA25). 20013. • NICE interventional procedure guidance in development. IRE for the treatment of pancreatic cancer. Expected winter 201310.

Other Guidance

• ESMO. Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 20104. • Pancreatic Section of the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, and Royal College of Pathologists, Special Interest Group for Gastro-Intestinal Radiology. Guidelines for the management of patients with pancreatic cancer, periampullary and ampullary carcinomas. 20057.

EXISTING COMPARATORS and TREATMENTS

Curative surgery is currently a treatment option for only around 4% of the overall patient population3. As the majority of cases are diagnosed at advanced stages, the aim of treatment is usually palliative; to improve quality of life and relieve symptoms1. Current options include3,5: • – gemcitabine in combination with capecitabine, FOLFIRINOX (fluorouracil, oxaliplatin and irinotecan); or monotherapy with gemcitabine or fluorouracil alone (if combination chemotherapy contraindicated). • Second line therapy may be considered for a small proportion of patients, if fit enough for subsequent treatment – fluoropyrimidines (fluorouracil or capecitabine) or oxaliplatin in combination with gemcitabine. • Concurrent chemo-radiotherapy – for locally advanced disease only. • Palliative surgery and endoscopic placement of biliary drainage stents to control symptoms such as jaundice and gastric outlet obstruction.

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• Palliative radiotherapy for control of symptoms associated with localised disease such as pain.

EFFICACY and SAFETY

Trial EUCTR2011-003601-25-GR, LipoGem- EUCTR2006-005485-40-GR, LipoGem- PII-1L-Pancr; liposomal cisplatin with PII-1L-Pancr; liposomal cisplatin with gemcitabine vs gemcitabine alone; phase gemcitabine; phase II. III. Sponsor Regulon AE. Regulon AE. Status Ongoing. Ongoing. Source of Trial registry11, manufacturer. Trial registry12, manufacturer. information Location EU (inc UK), USA and other countries. Greece. Design Randomised, active-controlled. Non-randomised, single arm. Participants n=328 (planned); adults; pancreatic n=61 (planned); adults aged 18-70 years; cancer; locally advanced or metastatic pancreatic cancer; unresectable, locally ; no prior treatment. advanced or metastatic adenocarcinoma; chemotherapy naïve. Schedule Randomised to: Liposomal cisplatin, IV, 120mg/m2 on Arm 1: Liposomal cisplatin, IV, 200mg/m2, days 1, 8 and 15 of 21 day cycle, with plus gemcitabine, IV, 1,000mg/m2 on days gemcitabine, IV, 1,000mg/m2 on days 1 1 and 8 of 21 day cycle, both for 3 cycles. and 8 of 21 day cycle, both for 3 cycles. Patients without disease progression Patients without disease progression continue for 3 additional cycles. Then, continue with maintenance liposomal patients without disease progression cisplatin, IV, 120mg/m2 and gemcitabine, continue with maintenance liposomal IV, 1,000mg/m2 on days 1 and 15 of 28 cisplatin, IV, 200mg/m2 every 8 weeks. day cycle. Arm 2: gemcitabine, IV, 1,000mg/m2 on days 1, 8 and 15 of a 21 day cycle for 3 cycles. Patients without disease progression continue for 3 further cycles. Follow-up Active treatment period 18 weeks followed Active treatment period 9 weeks followed by maintenance therapy until disease by maintenance therapy until disease progression; follow-up until death. progression; follow-up until death. Primary One year survival; overall survival (OS). Disease control ratea; OS. outcome/s Secondary Progression-free survival (PFS); objective 1 year survival; toxicity; PFS; ORR; QoL; outcome/s response rate (ORR); quality of life (QoL); safety. safety. Expected Q2 2014. Q4 2013. reporting date

COST and IMPACT

ESTIMATED COST

The cost of liposomal cisplatin is not yet known.

a Defined as the sum of complete response, partial response and stable disease at week 9.

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IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services if more  Decreased use of existing services patients suitable for chemotherapy

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion suggests that further research is required to confirm what benefit toxic combination therapies really offer patients, especially triple therapy combinations.

REFERENCES

1 CancerResearchUK. Key facts pancreatic cancer. http://publications.cancerresearchuk.org/downloads/Product/CS_KF_PANCR.pdf Accessed 6 August 2012. 2 CancerResearchUK. Types of pancreatic cancer. http://cancerhelp.cancerresearchuk.org/type/pancreatic-cancer/about/types-of-pancreatic-cancer Accessed 6 August 2012. 3 National Institute for Health and Clinical Excellence. The use of gemcitabine for the treatment of pancreatic cancer. Technology appraisal TA25. London: NICE; May 2001. 4 European Society for Medical Oncology. Pancreatic cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010; 21(suppl5):v55-v58. 5 Cancer Research UK. Pancreatic cancer survival statistics. http://info.cancerresearchuk.org/cancerstats/types/pancreas/survival/ Accessed 8 August 2012. 6 Cancer Research UK. Pancreatic cancer – UK incidence statistics. http://info.cancerresearchuk.org/cancerstats/types/pancreas/incidence/ Accessed 8 August 2012. 7 Pancreatic Section of the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, Royal College of Pathologists, Special Interest Group for Gastro-Intestinal Radiology. Guidelines for the management of patients with pancreatic cancer periampullary and ampullary carcinomas. Gut. 2005;54:1-16. 8 Office for National Statistics. Mortality statistics: deaths registered in England and Wales (Series DR). 2010. www.ons.gov.uk 9 NHS Hospital episode statistics. NHS England 2010-11. HES data 2012. www.hesonline.nhs.uk 10 National Institute for Health and Clinical Excellence. IRE for the treatment of pancreatic cancer. Interventional procedure guidance in development. Expected winter 2013.

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11 EU clinical trials register. Randomised, multicenter phase III clinical study of lipoplatin plus gemcitabine versus gemcitabine as first-line treatment in inoperable, locally advanced or metastatic pancreatic cancer. https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-003601- 25/GR Accessed 6 August 2012. 12 EU clinical trials register. Multicenter phase II/III clinical study of lipoplatin plus gemcitabine as first-line treatment in inoperable, locally advanced or metastatic pancreatic cancer. https://www.clinicaltrialsregister.eu/ctr-search/trial/2006-005485-40/GR Accessed 6 August 2012.

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