Horizon Scanning Centre March 2015

Evofosfamide for locally advanced, unresectable or metastatic – first line in combination with

SUMMARY NIHR HSC ID: 7060

Evofosfamide is intended to be used as a first line treatment option for patients with locally advanced, unresectable or metastatic (late stage) This briefing is pancreatic cancer. Evofosfamide is an intravenously administered, cytotoxic, hypoxia-activated prodrug (HAP), it is a nitromidazole-linked prodrug of based on dibromo isophoramide mustard, a potent DNA alkylator. Evofosfamide is information essentially inactive under normal oxygen levels. The trigger molecule keeps available at the time the toxin inactive until it is in the hypoxic region of the tumour so as to of research and a prevent general toxicity and it is activated by the low oxygen concentrations limited literature thus killing cells in its vicinity. Evofosfamide is administered at 340mg/m2 in search. It is not combination with 1,000mg/m2 gemcitabine, both via intravenous (IV) infusion intended to be a over 30 minutes on days 1, 8 and 15 of every 28 day cycle. definitive statement on the safety, Pancreatic cancer affects both sexes equally, with a lifetime risk of I in 77 for efficacy or men and 1 in 79 for women. In the UK, around 8,800 people were effectiveness of the diagnosed with pancreatic cancer in 2011. Pancreatic cancer has one of the health technology worst prognoses of all solid tumours with >95% of those affected dying of covered and should their disease. not be used for commercial As the majority of pancreatic cancer is diagnosed at an advanced stage, the purposes or aim of treatment is usually palliative; to improve quality of life and relieve commissioning symptoms. Surgery with the intention of a cure is only possible in around without additional one-fifth of new cases. Evofosfamide is currently in two phase III clinical trials information. in combination with gemcitabine comparing its effects on survival vs gemcitabine alone. These trials are expected to complete in 2014 and 2017.

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: locally advanced, unresectable or metastatic (late stage) – first line; in combination with gemcitabine.

TECHNOLOGY

DESCRIPTION

Evofosfamide (TH-302, HAP-302) is a cytotoxic, hypoxia-activated prodrug (HAP) for the treatment of cancer. It is a nitroimidazole-linked prodrug of dibromo isophoramide mustard, a potent DNA alkylator. To prevent general toxicity, the trigger molecule keeps the toxin inactive until the prodrug is in the hypoxic region of the tumour, where it is then activated by the low oxygen concentration, thus killing cells in its vicinity. Evofosfamide is essentially inactive under normal oxygen levels, however in areas of hypoxia, evofosfamide becomes activated and converts to an alkylating cytotoxic agent resulting in DNA cross-linking. This renders cells unable to replicate their DNA and divide, leading to apoptosis1. Evofosfamide is used in combination with gemcitabine, a cytotoxic drug which has poor tissue penetration but targets the regions of tumours that are located in proximity to the tumour blood vessels. Combining gemcitabine with evofosfamide may enable the targeting of both the normoxic and hypoxic regions of tumoursa.

In phase III clinical trials, patients received 340mg/m2 evofosfamide, in combination with 1,000mg/m2 gemcitabine, both via intravenous (IV) infusion over 30 minutes on days 1, 8 and 15 of every 28 day cycle2.

Evofosfamide in combination with is also in phase III clinical trials for the first line treatment of locally advanced, unresectable, or metastatic soft tissue sarcoma. Evofosfamide in combination with pemetrexed is in phase II trials for advanced non- squamous non-small cell lung cancer and evofosfamide monotherapy phase II trials for advanced melanoma.

INNOVATION and/or ADVANTAGES

If licenced, evofosfamide will provide an additional treatment option for patients with locally advanced, unresectable or metastatic pancreatic cancer.

DEVELOPER

Merck KGaA.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

a Company provided information.

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PATIENT GROUP

BACKGROUND

Pancreatic cancer is the tenth most common cancer in the UK and the fifth most common cause of death from cancer3. Pancreatic cancer 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 site4,5. There are three main types of pancreatic cancer: infiltrating ductal adenocarcinoma, which account for around 90% of cancers, acincar cell carcinoma, and pancreablastoma6.

NHS or GOVERNMENT PRIORITY AREA

• NHS England. 2013/14 NHS Standard Contract for Cancer: Pancreatic (Adult). A02/S/b. • NHS England. 2013/14 NHS Standard Contract for Cancer: (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Children, Teenagers and Young Adults). B12/S/b. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a.

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 disease6. The high mortality rate is due in part to the majority of patients (approximately 80%7) presenting at an advanced stage8. Even with early diagnosis the prognosis for pancreatic cancer is still poor; of all adults with pancreatic cancer, about 19% live for at least 1 year after they are diagnosed, about 4% live for 5 years after diagnosis and only about 3% live for at least 10 years after diagnosis. For pancreatic cancer that has spread to other parts of the body, the average life expectancy is only a few months9.

Pancreatic cancer affects both sexes equally, with a lifetime risk of 1 in 77 for men and 1 in 79 for women10. Around 8,800 people were diagnosed with pancreatic cancer in 2011 in the UK11. In 2013, 7,549 deaths were registered in England and Wales12. In 2013-2014, there were 11,759 admissions due to pancreatic cancer (ICD-10 C25) in England, resulting in 15,050 bed days and 11,548 finished consultant episodes13.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Pancreatic cancer (locally advanced, metastatic) – masitinib [ID566]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Pancreatic cancer (metastatic) – nimotuzumab (1st line) [ID513]. Expected date of issue to be confirmed. • NICE technology appraisal in development. Pancreatic cancer – capectitabine [ID389]. Expected date of issue to be confirmed.

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• NICE technology appraisal in development. Pancreatic adenocarcinoma (untreated, metastatic) – paclitaxel albumin-bound nanoparticles (with gemcitabine) [ID680]. Expected date of issue to be confirmed. • NICE technology appraisal. Guidance on the use of gemcitabine for the treatment of pancreatic cancer (TA25). May 2001. • NICE interventional procedures guidance in development. Arterial reconstruction for locally advanced pancreatic cancer. Expected date of issue to be confirmed. • NICE interventional procedures guidance. Endoscopic bipolar radiofrequency ablation for treating biliary obstruction caused by cholangiocarcinoma or pancreatic adenocarcinoma (IPG464). September 2013. • NICE interventional procedures guidance. Irreversible electroporation for treating pancreatic cancer (IPG442). February 2013. • NICE interventional procedures guidance. Autologous pancreatic islet cell transplantation for improved glycaemic control after pancreatectomy (IPG274). September 2008. • NICE interventional procedures guidance. Laparoscopic distal pancreatectomy (IPG204). January 2007.

Other Guidance

• European Society for Medical Oncology and European Society of Digestive Oncology. Pancreatic adenocarcinoma: ESMO-ESDO clinical practice. Guidelines for diagnosis, treatment and follow-up. 201214. • ESMO. Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 20106.

CURRENT TREATMENT OPTIONS

Surgery with the intention of a cure is only possible in around one-fifth (20%) of new cases15. As the majority of cases are diagnosed at an advanced stage, the aim of treatment is usually palliative; to improve quality of life and relieve symptoms5. Current treatment options include5,6,16: • Chemotherapy: - FOLFIRINOX (5-FU, oxaliplatin and irinotecan). - Gemcitabine monotherapy. - Gemcitabine in combination with capecitabine. - Gemcitabine in combination with nab-paclitaxel. - Second line therapy may be considered for a small proportion of patients, if they are fit enough for further treatment. - Fluoropyramidines (5-FU 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. • Palliative radiotherapy for control of symptoms associated with localised disease, such as pain.

EFFICACY and SAFETY

Trial NCT01144455; evofosfamide with MAESTRO, NCT01746979; evofosfamide gemcitabine vs gemcitabine alone; phase with gemcitabine vs gemcitabine alone; II. phase III. Sponsor Threshold Pharmaceuticals. EMD Serono and Threshold Pharmaceuticals.

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Status Complete but unpublished. Ongoing.

Source of Trial Registry17. Trial Registry18. information Location USA. USA and Germany. Design Randomised. Randomised. Participants n=165 (planned); aged ≥18 years; locally n=660 (planned); aged ≥18 years; locally advanced unresectable or metastatic advanced unresectable or metastatic pancreatic ductal adenocarcinoma pancreatic ductal adenocarcinoma proven either by histology or cytology; proven either by histology or cytology; previously untreated with chemotherapy previously untreated with chemotherapy or systemic therapy other than: or systemic therapy other than: radiosensitising doses of 5-fluorouracil or radiosensitising doses of 5-fluorouracil or gemcitabine, neoadjuvant chemotherapy gemcitabine, neoadjuvant chemotherapy if relapse occurred at least 6 months after if relapse occurred at least 6 months after surgical resection, or adjuvant surgical resection or adjuvant chemotherapy if relapse occurred at least chemotherapy if relapse occurred at least 6 months after completion of adjuvant 6 months after completion of adjuvant chemotherapy; measurable disease by chemotherapy; measurable or non- RECIST 1.1 criteria; life expectancy of at measurable disease by RECIST 1.1 least 3 months; acceptable liver and criteria; documentation of disease renal function; acceptable haematological progression since any prior therapy; status. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; life expectancy of at least 3 months; acceptable liver and renal function; acceptable haematological status. Schedule Randomised to evofosfamide 240mg/m2 Randomised to evofosfamide 340mg/m2 IV with 1,000mg/m2 gemcitabine IV, both with 1,000mg/m2 gemcitabine IV over 30 over 30 minutes on day 1, 8 and 15 of minutes day 1, 8 and 15 of each 28 day each 28 day cycle; or gemcitabine cycle; or gemcitabine alone 1,000mg/m2 1,000mg/m2 IV over 30 minutes on day 1, IV over 30 minutes day 1, 8 and 15 of 8 and 15 of each 28 day cycle. each 28 day cycle. Follow-up Tumour assessment performed locally Follow up every 2 months for a minimum every 8 weeks. of 18 months from first dose, until death, loss to follow-up or end of trial. Primary Progression free survival (PFS). OS. outcome/s Secondary Objective response rate (confirmed and PFS; overall response rate; overall outcome/s unconfirmed); duration of response; survival rate; overall disease control stable disease rate; overall survival (OS) according to RESIST 1.1; quality of life including 6 and 12 month survival; event EuroQuol-5D health outcome free survival; serum CA 19-9 response; questionnaire; quality of life assessment change in pain intensity as measured by European Organisation for the Research Visual Analogue Sore (VAS); change in and Treatment of Cancer (EORTC) performance status. quality of life questionnaire core 30. Expected Study completion date reported as Study completion date reported as reporting January 2014. February 2017. date

ESTIMATED COST and IMPACT

COST

The cost of evofosfamide is not yet known, however the cost of selected comparator treatments for pancreatic cancer are summarised as follows19:

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Drug Dose Cost for 3 monthsb Gemcitabine 1,000mg/m2 once weekly infusion for 7 weeks of an 8 week cycle, £3,240 (initial 3 followed by 3 weekly infusions in 4 week cycles. months treatment) 5-fluorouracil 12mg/kg for three days, then 6mg/kg on alternate days for a further £172 3 doses. Repeated every 4 weeks

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

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

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs: additional  Reduced drug treatment costs treatment

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

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 Pento JT, “TH-302” DNA alkylating agent, hypoxia-activated cytotoxic prodrug, Oncolytic; Drugs of the Future.2001;36:9:663-66. 2 ClinicalTrials.gov. Clinical trial testing TH-302 in combination with gemcitabine in previously untreated subjects with metastatic or locally advanced unresectable pancreatic adenocarcinoma (MAESTRO). https://clinicaltrials.gov/ct2/show/NCT01746979?term=NCT01746979&rank=1 Accessed 18 February 2015. 3 CancerResearchUK. Key facts pancreatic cancer. http://publications.cancerresearchuk.org/downloads/product/CS_KF_PANCREAS.pdf. Accessed 18 February 2015. 4 CancerResearchUK. Types of pancreatic cancer. http://www.cancerresearchuk.org/about- cancer/type/pancreatic-cancer/about/types-of-pancreatic-cancer. Accessed 18 February 2015. 5 National Institute for Health and Clinical Excellence. The use of gemcitabine for the treatment of pancreatic cancer. Technology appraisal TA25. London: NICE; May 2001. 6 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. 7 El Kamar F, Grossbard L and Kozuch P. Metastatic pancreatic cancer: emerging strategies in chemotherapy and palliative care. The Oncologist. 2003;8:18-34. b Costing based on average adult body weight of 77.9kg and average surface area of 1.88m2. Assumes wastage.

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8 Pancreatic Cancer UK. Pancreatic cancer survival statistics. http://www.pancreaticcancer.org.uk/media/86664/study-for-surivial-report-final.pdf Accessed 18 February 2015. 9 Cancer Research UK. Statistics and outlook for pancreatic cancer. http://www.cancerresearchuk.org/about-cancer/type/pancreatic-cancer/treatment/statistics-and- outlook-for-pancreatic-cancer. Accessed 18 February 2015. 10 Cancer Research UK. Pancreatic cancer – UK incidence statistics. http://info.cancerresearchuk.org/cancerstats/types/pancreas/incidence/ Accessed 18 February 2015. 11 Cancer Research UK. Publications, Pancreatic cancer key stats. http://publications.cancerresearchuk.org/downloads/product/CS_KF_PANCREAS.pdf Accessed 18 February 2015 12 Office for National Statistics. Mortality statistics: deaths registered in England and Wales (Series DR). 2013. http://www.ons.gov.uk 13 Health and Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2013-2014. www.hesonline.nhs.uk 14 Cascinu S, Falconi M, Valentini V et al. Pancreatic cancer: ESMO-ESDO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012;23(7):33-40. 15 Bond-Smith G, Banga N, Hammond TM et al. "Pancreatic adenocarcinoma". BMJ (Clinical research ed.) 2012;344:e2476.doi:10.1136/bmj.e2476.PMID 22592847. 16 Cancer Research UK. Types of treatment for pancreatic cancer. http://www.cancerresearchuk.org/about-cancer/type/pancreatic-cancer/treatment/which- treatment-for-pancreatic-cancer Accessed 19 February 2015. 17 ClinicalTrials.gov. Study of the safety and efficacy of TH-302 in combination with gemcitabine compared with gemcitabine alone in previously untreated patients with pancreatic adenocarcinoma. https://clinicaltrials.gov/ct2/show/study/NCT01144455?term=NCT01144455&rank=1#locn Accessed 19 February 2015. 18 ClinicalTrials.gov. Clinical trial testing TH-302 in combination with gemcitabine in previously untreated subjects with metastatic or locally advanced unresectable pancreatic adenocarcinoma (MAESTRO). https://clinicaltrials.gov/ct2/show/NCT01746979?term=NCT01746979&rank=1 Accessed 19 February 2015. 19 The Royal Pharmaceutical Society. British National Formulary. BNF March 2015. https://www.medicinescomplete.com/mc/bnf/current/

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