Horizon Scanning Research June 2016 & Intelligence Centre

Sapacitabine for patients with acute myeloid leukaemia who are not eligible for intensive treatment – first line

LAY SUMMARY

Acute myeloid leukaemia is a rare type of cancer that affects the way This briefing is based on blood cells develop, so that they do not work properly. This leads to an information increased risk of infection, as well as symptoms such as anaemia and available at the time bruising, and is quickly fatal if not treated. Acute myeloid leukaemia of research and a can affect people at any age, but is more common in people over 65. limited literature search. It is not drugs can be very effective in the treatment of acute intended to be a myeloid leukaemia. In some situations, these drugs are combined with definitive statement stem cell or ‘bone marrow’ transplant to improve the chances of curing on the safety, the leukaemia. However, some patients, especially the elderly, cannot efficacy or tolerate intensive chemotherapy and treatments with fewer side effects effectiveness of the are offered instead. health technology covered and should Sapacitabine is a new product aimed at patients aged 70 years or not be used for older that is given as a tablet. If sapacitabine is licensed for use in the commercial UK, it could be a new treatment option for patients with acute myeloid purposes or leukaemia. A current trial is looking to see whether sapacitabine can commissioning improve survival compared to an existing treatment and whether it is without additional safe to use. information.

NIHR HSRIC ID: 3042

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 Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Acute myeloid leukaemia (AML): patients ≥70 years of age; unfit for, or refused standard intensive therapy - first line.

TECHNOLOGY

DESCRIPTION

Sapacitabine (CS-682; CYC-682) is a small molecule of 2’-cyano-2’- deoxyarabinofuranosylcytosine (CNDAC). After conversion in the body into CNDAC, sapacitabine interferes with DNA synthesis by causing single-strand breaks, which subsequently cause double-strand breaks that induce arrest at the and cell death. This DNA damage is repaired by the homologous recombination (HR) pathway and is therefore intended to be used in cancers that have defects in this HR pathway. In the phase III , sapacitabine is administered in alternating cycles with decitabine1.

Sapacitabine does not currently have Marketing Authorisation in the EU for any indication.

Sapacitabine is also currently in phase II development for the treatment of chronic lymphocytic leukaemia, myelodysplastic syndromes and non-small cell lung cancer.

INNOVATION and/or ADVANTAGES

If licensed, sapacitabine will offer an additional treatment option for older patients with AML who are not candidates for standard intensive treatment due to age, frailty or another limitation.

DEVELOPER

Cyclacel Ltd.

AVAILABILITY, LAUNCH OR MARKETING

Sapacitabine is a designated orphan drug in the EU and USA.

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

AML is a heterogeneous disease characterised by uncontrolled clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues2,3. Due to the activation of abnormal genes through chromosomal translocations and other genetic abnormalities, there is maturation arrest of bone marrow cells in the early stages of development4. The immature cells occupy space in the marrow required for normal haematopoiesis, resulting in reduced number of neutrophils, platelets and erythrocytes4,5. The percentage of blast cells in the bone marrow is a practical tool for categorising myeloid neoplasms into AML or myelodysplastic syndromes (MDS) respectively, where myeloid neoplasms with more than

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20% blasts in the peripheral blood or bone marrow are considered AML, either arising de novo or having evolved from a pre-existing MDS6.

The accumulation of cells at various stages of incomplete maturation and the reduced production of healthy haemopoietic elements cause symptoms of anaemia (fatigue and dyspnoea), neutropenia (infections) and thrombocytopenia (haemorrhage), which greatly reduce patient quality of life7. Other symptoms include fever, shortness of breath, gum swelling, swollen lymph glands and bone pain4,8. Whilst the cause of AML is uncertain, known risk factors include exposure to high levels of radiation and exposure to benzene (a chemical used in manufacturing that is also found in cigarettes)4,9.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a. • NHS England. 2013/14 NHS Standard Contract for Haematopoietic stem cell transplantation (Adult). B04/S/a. • NHS England. Clinical Commissioning Policy: Haematopoietic Stem Cell Transplantation. NHSCB/B04/P/a. April 2013.

CLINICAL NEED and BURDEN OF DISEASE

AML is the most common acute leukaemia in adults, accounting for 0.8% of all new cancer cases in the UK and 32% of all leukaemia types combined10,11. In 2013, 2,307 people were diagnosed with AML (ICD-10 C92.0) in England, which equates to an age-standardised rate of 9.5 and 5.6 per 100,000 population for males and females, respectively. Approximately 57% of new cases occur in people aged 70 years and over12.

While the prognosis for younger patients with AML has improved in recent decades, the same cannot be said for older patients, who continue to have a median overall survival in the order of months, with few long-term survivors13. During 2014, 2,212 deaths from AML were registered in England and Wales14. In 2014-15, there were 40,475 hospital admissions due to AML in England, accounting for 43,022 finished consultant episodes and 119,582 bed days15.

The proportion of patients with AML who are able to tolerate and thereby receive intensive chemotherapy could not be established from searches of routine, publicly available data sources and therefore the population eligible to receive sapacitabine could not readily be established. However, it has been suggested that approximately one third of patients above the age of 65 would be eligible for less intensive treatments5.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia (TA218). March 2011.

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• NICE cancer service guidance. Improving outcomes in haemato-oncology cancer (CSGHO). October 2003.

Other Guidance

• National Comprehensive Cancer Network. Clinical practice guidelines in oncology: acute myeloid leukaemia. 201516. • European Society for Medical Oncology. Acute myeloblastic leukaemias in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 20136.

CURRENT TREATMENT OPTIONS

Treatment of AML may be classified as either intensive or non-intensive; intensive chemotherapy is divided into an induction phase, followed by two courses of consolidation and (rarely) a maintenance phase6. Potential candidates for allogeneic haematopoietic stem cell transplant (alloHSCT) should be identified early at diagnosis or during induction chemotherapy. AlloHSCT as a post-remission strategy is associated with the lowest rates of relapse17.

The incidence of AML increases with advancing age and the prognosis for patients with AML worsens substantially with increasing age2. Many older patients are ineligible for intensive treatment and require other therapeutic approaches to optimize clinical outcome2. They should receive best supportive care (BSC) or palliative systemic treatment, which may incorporate either low-dose or a demethylating agent such as or azacitidine6. Guidelines recommend that the treatment of AML should be planned with curative intent whenever possible6. Azacitidine is currently available for the treatment of adult patients with AML with 20-30% blasts and multi-lineage dysplasia, who are not eligible for alloHSCT according to the World Health Organization (WHO) criteria. It is also licensed for the treatment of AML patients (aged ≥65 years) with >30% marrow blasts who are not suitable for HSCT18. Treatment of infections due to neutropenia and transfusions to cover anaemia or thrombocytopenia are important additional measures. In severely neutropenic patients, haematopoietic growth factors may be considered when neutropenic fever or infections are a problem5,6.

EFFICACY and SAFETY

Trial SEAMLESS, Burnett et al. 2015; NCT00590187, CYC682- NCT01303796, CYC682- sapacitabine vs cytarabine; 06; pts aged ≥70 years; 12; pts aged ≥70 years; phase II/III. sapacitabine; phase II. sapacitabine alternating with decitabine vs decitabine alone; phase III. Sponsor Cyclacel Ltd. Cardiff University. Cyclacel Ltd. Status Complete but unpublished. Complete and published. Complete and published. 19 20 Source of Trial registry1. Publication . Publication , trial information registry21. Location EU (incl UK) and USA. UK. USA. Design Randomised, active- Randomised, active- Randomised, uncontrolled. controlled. controlled.

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Participants n=486 (planned); aged 70 n=143; aged 60 yrs and n=105; aged 70 yrs and yrs and older; newly older; AML or high risk older; AML; previously diagnosed AML; Eastern ; untreated by systemic Cooperative Oncology no previous cytotoxic therapy, or in first relapse Group (ECOG) chemotherapy for AML; no after achieving a complete performance status 0-2; no myocardial infarction within remission to initial acute promyelocytic 12 months; no blast induction; no acute leukaemia or transformation of chronic promyelocytic leukaemia; extramedullary myeloid myeloid leukaemia. received no more than one tumour without bone induction systemic therapy marrow involvement; no for AML; no known central systemic anti-cancer nervous system therapy for AML or involvement. treatment with hypomethylating agents or cytotoxic chemotherapy; no known or suspected central nervous system involvement; no known hypersensitivity to decitabine. Schedule Randomised to Randomised to Randomised to sapacitabine administered sapacitabine 300mg oral sapacitabine 200mg oral in alternating cycles with twice daily for 3 twice daily for 7 decitabine; or decitabine consecutive days in wks 1 consecutive days every 3-4 alone. The dose and and 2 of a 6 wk cycle for 6 wks; or sapacitabine frequency of administration cycles; or cytarabine 20mg 300mg oral twice daily for 7 have not been reported. subcutaneous twice daily consecutive days every 3-4 for 10 days, for 4 cycles. wks; or sapacitabine 400mg oral twice daily for 3 consecutive days per week for 2 wks every 3-4 weeks. Follow-up Follow-up 42 mths. Follow-up 2 yrs. Follow-up 1 yr. Primary Overall survival (OS). Complete remission (CR); OS. outcomes OS. Secondary Complete remission 2 yr survival; 2 yr relapse- Rate and duration of outcomes duration; complete free survival. complete remission; remission with incomplete complete remission without platelet count recovery and blood count recovery; duration; partial remission transfusion requirements; with duration; hospitalised days; safety. haematological improvement with duration; stable disease with duration; number of units of blood product transfused; hospitalised days; 1 yr survival. Key results - For sapacitabine vs OS at 1 yr was 35% (95% cytarabine groups, CI 16-59). respectively: percentage of pts achieving CR, 13% vs 21% (p=0.2, 95% CI 0.75 to 4.12); percentage of pts surviving at 2 yrs, 11% vs 12% (p=0.2, 95% CI 0.86 to 1.78); percentage of pts achieving 2 yr relapse-free

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survival, 14% vs 10% (p=0.4, 95% CI 0.33 to 1.61). Adverse - The most common grade The most common grade effects 3-4 adverse events for the 3-4 adverse events were (AEs) sapacitabine group were thrombocytopenia (55%), diarrhoea (10%) and febrile neutropenia (45%), nausea (3%). anaemia (33%), neutropenia (33%), and pneumonia (21%). The most common grade 5 events were sepsis (10%) and pneumonia (6%). Expected Previously reported as Nov - - reporting 2015. date

ESTIMATED COST and IMPACT

COST

The cost of sapacitabine is not yet known. The cost of other selected treatments for acute myeloid leukaemia include22:

Drug Dose Unit cost Cytarabine 2mg/kg IV each day. 5mL vial (20mg/mL) costs £20.98

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  Reduced drug treatment costs

 Other increase in costs  Other reduction in costs

 Other: uncertain unit cost compared to  None identified existing treatments.

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Other Issues

 Clinical uncertainty or other research question  None identified identified: expert opinion notes that the phase III clinical trial (NCT01303796) is a randomised comparison between decitabine therapy and decitabine alternating with sapacitabine. However, decitabine is not routinely used for AML management in the UK, it is not NICE approved and not available via the Cancer Drugs Fund, therefore the relevance of this study to UK practice as it stands is limiteda.

REFERENCES

1 ClinicalTrials.gov. A study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid (SEAMLESS). www.clinicaltrials.gov/ct2/show/record/NCT01303796 Accessed 14 June 2016. 2 Montalban-Bravo G and Garcia-Manero G. Novel drugs for older patients with acute myeloid leukaemia. Leukemia 2015;29:760-769. 3 O’Donnell M, Abboud C, Altman J et al. Acute myeloid leukaemia: clinical practice guidelines in oncology. National Compehensive Cancer Network 2012;10(8):984-1021. 4 Patient Info. Acute myeloid leukaemia. www.patient.info/doctor/acute-myeloid-leukaemia-pro#ref- 1 Accesed 14 June 2016. 5 NIHR Horizon Scanning Research and Intelligence Centre. CPX-351 (VYXEOS) for elderly patients with newly diagnosed acute myeloid leukaemia – first line. University of Birmingham, February 2016. www.hsric.nihr.ac.uk 6 Fey M and Buske C. Acute myeloblastic leukaemias in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2013;24(6):138-143. 7 Ferrara F and Schiffer C. Acute myeloid leukaemia in adults. The Lancet 2013;381:484-495. 8 Hassan S and Smith M. Acute myeloid leukaemia. Hematology 2014; doi:10.1179/1024533214Z.000000000312. 9 National Cancer Institute. Adult acute myeloid leukaemia treatment. hwww.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq Accessed 14 June 2016. 10 Pollyea D, Kohrt H and Medeiros B. Acute myeloid leukaemia in the elderly: a review. British Journal of Haematology 2011;152(5):524-542. 11 Cancer Research UK. Acute myeloid leukaemia (AML) incidence statistics. www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer- type/leukaemia-aml/incidence#ref-0 Accessed 14 June 2016. 12 Office for National Statistics. Cancer Statistics Registrations, England (Series MB1), No.44, 2013. www.ons.gov.uk 13 Dombret H, Raffoux E and Gardin C. Acute myeloid leukaemia in the elderly. Seminars in Oncology 2008;35(4):430-438. 14 Office for National Statistics. Mortality statistics: Deaths registered in England and Wales (Series DR), 2014. www.ons.gov.uk 15 Health & Social Care Information Centre. Hospital Episode Statistics for England. Inpatient statistics, 2014-15. www.hscic.gov.uk 16 National Comprehensive Cancer Network. Clinical practice guidelines in oncology: acute myeloid leukaemia. www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gl s/pdf/aml.pdf Accessed 14 June 2016. 17 Döhner H, Estey E, Amadori S et al. Diagnosis and management of in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115(3):453-474.

a Expert personal communication.

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18 National Institute for Health and Clinical Excellence. Azacitidine for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukaemia and acute myeloid leukaemia. Technology appraisal TA218. London: NICE; March 2011. 19 Burnett A, Russell N, Hills R et al. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia. Leukemia 2015;29:1312-1319. 20 Kantarjian H, Faderl S, Garcia-Manero G et al. Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study. The Lancet Oncology 2012;13(11):1096-1104. 21 ClinicalTrials.gov. Efficacy study of oral sapacitabine to treat acute myeloid leukemia in elderly patients. www.clinicaltrials.gov/ct2/show/NCT00590187 Accessed 14 June 2016. 22 Joint Formulary Committee. British National Formulary. BNF June 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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