Alvocidib (Flavopiridol) for refractory/relapsed chronic lymphocytic leukaemia

December 2009

This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes.

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December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

Alvocidib (Flavopiridol) for refractory/relapsed chronic lymphocytic leukaemia

Target group • Chronic lymphocytic leukaemia (CLL): refractory/relapsed.

Technology description Alvocidib (Flavopiridol, HMR1275) is a cyclin-dependent kinase 1 inhibitor which can induce cancer cell death by causing arrest. Alvocidib is intended as a substitute for current treatments and is administered by intravenous (IV) infusion at 30mg/m2 for 30 minutes followed by a 4 hour infusion at 30 or 50mg/m2 weekly for 4 weeks in a 6 week cycle. In clinical trials patients have been treated for up to 6 cycles.

Innovation and/or advantages If licensed, alvocidib would be the first cyclin-dependent kinase inhibitor licensed and may offer an additional option for patients who generally have a poor prognosis.

Developer Sanofi-aventis.

Availability, launch or marketing dates, and licensing plans Alvocidib is a designated orphan drug in the EU.

NHS or Government priority area This topic relates to the NHS Cancer Plan (2000) and Cancer Reform Strategy (2007).

Relevant guidance • NICE technology appraisal in development. Chronic lymphocytic leukaemia – ofatumumab. Expected date of issue to be confirmed1. • NICE technology appraisal in development. Rituximab for relapsed chronic lymphocytic leukaemia. Expected April 20102. • NICE technology appraisal. Rituximab for first-line chronic lymphocytic leukaemia. July 20093. • NICE technology appraisal. monotherapy for the first-line treatment of chronic lymphocytic leukaemia. 20074. • NICE cancer service guidance. Improving outcomes in haemato-oncology cancer. 20035. • British committee for Standards in Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. 20046.

Clinical need and burden of disease CLL is a chronic, life-threatening and incurable disease, and is the most common form of leukaemia in the Western World. It mainly affects older people, with 75% of diagnoses being made in people over the age of 60. CLL has a heterogeneous range of symptoms including increasing tiredness, swollen lymph glands, night sweats, weight loss, bleeding, anaemia, and susceptibility to infection. About 2,600 cases of CLL are diagnosed in the UK each year7, with a male:female ratio of approximately 2:16. In 2007 CLL caused 1,019 deaths (611 men and 408 women) in England and Wales (ICD10 C91.1)8.

There are two distinct genetic sub-types of CLL, one having a median survival of about 25 years and the other of about 8 years for patients who present with early stage disease9. 2 December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

Seventy-five per cent of patients present by chance (having had a blood test for another reason) and with early stage disease. Many will not require active treatment. Indications for treatment are bulky lymph node or splenic enlargement, systemic features of disease or bone marrow failurea.

Existing comparators and treatments A number of factors can affect the choice of second-line therapy including: first-line therapy used, patient response, disease state (refractory disease is less responsive to treatment than progressive disease)6, and which genetic variant the patient has10. Current second-line therapies include: • Single alkylating agent. • Monotherapy with fludarabine where an alkylating agent alone has proved inadequate. • Fludarabine plus (FC). • Alemtuzumab (with or without methylprednisolone) - licensed for patients who have failed to respond to an alkylating agent or fludarabine. • Rituximab with FC. • Methylprednisolone.

Efficacy and safety

Trial HMR1275A/2001; CLL. CALGB-19805, NCT00098371; CLL or NCT00003620; CLL; prolymphocytic leukaemia phase II. (PLL); phase II. Sponsor Sanofi-aventis. National Cancer Institute CLL Research Consortium, (NCI). NCI. Status Published. Published. Published. Source of Publication11. Publication12. Publication13,14. information Location USA. USA. USA. Design Open label. Open label. Open label. Participants n=26; adults; CLL; >1 but n=51; adults; symptomatic n=64; adults; CLL or PLL; and <5 prior chemotherapy CLL; ≥1 but <3 prior prior chemotherapy. schedule agents; fludarabine chemotherapy agents. Dose 1: alvocidib 30mg/m2 refractory. Cohort 1: alvocidib by IVB then alvocidib Treatment every two weeks 50mg/m2 by continuous 30mg/m2 by CIVI for 4 hrs. for up to 12 doses. intravenous infusion (CIVI) Dose 2 and onwards: Cohort 1: alvocidib once every 2 weeks for up 30mg/m2 IVB plus 80mg/m2. to 12 doses. 50mg/m2 CIVI. Treatment Cohort 2: alvocidib Cohort 2: alvocidib weekly for 4 doses every 6 80mg/m2 then dose 50mg/m2 daily by weeks for up to 6 cycles. increases to 100, 120 and intravenous bolus (IVB) for Treatment plan amended to 140mg/m2. 3 days every 3 weeks for 3 doses in a 4 week cycle up to 8 doses. (days 1, 8 and 15). Follow-up 24 weeks active treatment 24 weeks active treatment. Maximum 36 weeks period. 5 yrs follow up. treatment (amended plan maximum 24 weeks). Primary Overall response rate Complete and partial Toxicity; ORR. outcomes (ORR). response rate. Secondary Progression free survival Toxicity; PFS; T-cell Response in patients with outcomes (PFS), safety, subsets; immunoglobulin del(17p13.1) and pharmacokinetics (PK), levels. del(11q22.3), PFS and aExpert opinion. 3 December 2009 National Horizon Scanning Centre News on emerging technologies in healthcare

PK/pharmacodynamic (PD) cytokine release syndrome relationship, quality of life (CRS). (QOL) Key results Two patients completed 12 Cohort 1: No complete or 34 patients (53%) courses. 17 patients partial responses. 4 (27%) responded. Median PFS 8.6 discontinued due to stable and 11 (63%) mths. Estimated median progression, 3 from lack of progressive disease. PFS for responders 12 mths improvement and 4 with Median 3.5 doses. No (95% CI, 8.5-13.1 mths). toxicity. No complete or evidence of acute tumour PFS did not differ partial responses. No lysis. Median survival 27 significantly according evidence of acute tumour mths (95% CI 20-42 mths). to genomic risk. Excluding lysis. Only 1 patient had a Cohort 2: No complete 7 responders who ≥50% decline in responses; 4 (11%) partial underwent allogenic stem lymphocyte count. 18 of 24 response, cell transplantation, patients with enlarged 19 (53%) stable and 13 estimated median PFS 10 lymph nodes and 2 of (36%) progressive disease; mths (95% CI, 8.5-3.1 15 with splenomegaly had responders had fludarabine mths). Patients with CRS a ≥50% decrease in refractory CLL. Median 3 demonstrated increased IL- measurable disease. courses. Median PFS 3 6 expression sooner than mths. Median survival 24 those who did not. mths (95% CI, 18-31 mths). Adverse - One or more grade 3 and 4 Common toxicities were: effects toxicities respectively: neutropenia (97%), (AEs) CIVI 20% and 27%; IVB anaemia (59%), 39% and 33%. Common thrombocytopenia (66%), grade 3 and 4 toxicities infection (67%), fatigue included: granulocytopenia, (94%), diarrhoea (94%), anaemia, infection, nausea/vomiting (75%), diarrhoea and fatigue. tumour lysis syndrome (44%), CRS (42%).

Trial NCT00058240; CLL; phase I. EFC6663, NCT00464633; CLL or PLL; phase II. Sponsor NCI. Sanofi-aventis. Status Published. Ongoing. Source of Publication15,16. Trial registry17. information Location USA. EU (inc UK), USA, Puerto Rico and Australia. Design Open label. Open label. Participants n=58; adults; CLL; prior chemotherapy. n=165; adults; CLL or PLL; symptomatic and Cohort 1 (n = 20): alvocidib 30mg/m2 IVB and progressive disease; prior alkylating schedule then alvocidib 30mg/m2 CIVI. agent(s); fludarabine refractory. Cohort 2 (n = 3): alvocidib 40mg/m2 IVB Alvocidib 30mg/m2 IVB then alvocidib then alvocidib 40mg/m2 CIVI. 30mg/m2 CIVI. Dose 2 and onwards: Cohort 3 (n = 19): alvocidib 30mg/m2 IVB 30mg/m2 IVB plus 50mg/m2 CIVI. then alvocidib 30mg/m2 CIVI for doses 1 Treatment weekly for 4 doses every 6 to 4 of a 6 week cycle, then 30mg/m2 IVB weeks for up to 6 cycles. and 50mg/m2 CIVI in non-responders who were tolerant. Cohort 4 (n = 16): alvocidib 30mg/m2 IVB then 30mg/m2 CIVI for dose 1 of a 6-week cycle; then 30mg/m2 IVB and 50mg/m2 CIVI at doses 2 to 4 of cycle 1 in non-

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responders who were tolerant. Treatment weekly for 4 doses every 6 weeks for up to 6 cycles. Follow-up Maximum 36 weeks treatment. Maximum 36 weeks treatment. Primary Maximum tolerated dose (MTD), toxicity. ORR. outcomes Secondary Complete response (CR) and ORR. PFS, overall survival, clinical benefit. outcomes Key results 21 patients (40%) responders - all partial responses (PRs). Median PFS for responders 12 mths. Responses in 7 of 18 (39%) patients with del(17p13.1), 14 of 19 patients (74%) with del(11q22.3), and 17 of 38 (45%) with bulky lymphadenopathy. The results of Cohort 4 indicate safe dose escalation can occur from second treatment of cycle in those without severe tumour lysis syndrome (TLS) with the first dose. Expected Reported grade 3 and 4 toxicities for Interim safety and efficacy assessment reporting cohorts 1-3 include: absolute neutrophils expected Jan 2010. date count (77%), biochemical tumour lysis (55%), diarrhoea (41%), platelets (39%), aspartate aminotransferase (AST) or alanine aminotransferase (ALT) [33%]. Reported grade 3 and 4 toxicities for cohort 4 include: absolute neutrophils count (100%), diarrhoea (75%), white blood cells (69%), platelets (44%), biochemical tumour lysis (44%).

Estimated cost and cost impact The cost of alvocidib is not yet known.

Claimed or potential impact – speculative Patients ; Reduced mortality or increased ; Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use ; Other: facilities required for None identified administration and monitoring.

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed ; New costs: if in addition to Savings: ; Other: Unknown relative cost. current treatment or used sequentially.

References

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1National Institute for Health and Clinical Excellence. Chronic lymphocytic leukaemia – ofatumumab. Technology appraisal in development. Expected date of issue to be confirmed. 2National Institute for Health and Clinical Excellence. Rituximab for relapsed chronic lymphocytic leukaemia. Technology appraisal in development. Expected August 2010. 3National Institute for Health and Clinical Excellence. Rituximab for first line chronic lymphocytic leukaemia. Technology appraisal TA174. London; NICE; July 2009. 4National Institute for Health and Clinical Excellence. Fludarabine monotherapy for the first-line treatment of chronic lymphocytic leukaemia. Technology appraisal TA119. London: NICE; February 2007. 5National Institute for Health and Clinical Excellence. Improving outcomes in haemato-oncology cancer. Cancer service guidance. London: NICE; October 2003. 6Oscier D, Fegan C and Hillmen P. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. British Journal of Haematology 2004;125:294-317. 7Cancer Research UK. Chronic lymphocytic leukaemia (CLL) risks and causes http://www.cancerhelp.org.uk/type/cll/about/chronic-lymphocytic-leukaemia-risks-and-causes#common. Accessed 9th December 2009. 8Office of National Statistics, Mortality statistics: Deaths registered in 2007. http://www.statistics.gov.uk/StatBase/Product.asp?vlnk=15096 9Montillo M, Hamblin T, Hallek M. et al. Chronic lymphocytic leukemia: novel prognostic factors and their relevance for risk adapted therapeutic strategies. Haematologica 2005; 90: 391-399. 10Auer RL, Gribben J and Cotter FE. Emerging therapy for chronic lymphocytic leukaemia. British Journal of Haematology. 2007;139:635-644. 11Flinn I, Byrd J, Bartlett N et al. Flavopiridol administered as a 24-hour continuous infusion in chronic lymphocytic leukemia lacks clinical activity. Leukemia Research 2005;29:1253-1257. 12Byrd J, Peterson B and Gabrilove J. Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from cancer and leukemia group b study 19805. Clinical Cancer Research 2005;11:4176-4181. 13Lin T, Ruppert A, Johnson A et al. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. Journal of Clinical Oncology. Prepublished online October 13, 2009 as 10.1200/JCO.2009.22.6944. 14Lin T, Andritsos L, Jones J et al. Activity of the cyclin-dependent kinase (CDK) inhibitor flavopiridol in relapsed, genetically high risk chronic lymphocytic leukemia (CLL). Journal of Clinical Oncology 2008;26:373s. 15Byrd J, Lin T, Dalton J et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical activity in refractory, relapsed, genetically high-risk chronic lymphocytic leukaemia. Blood 2007;109:399-404. 16Phelps M, Lin T, Johnson A et al. Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood 2009;113:2637-2645. Prepublished online November 3, 2008 doi 10, 1182/blood -2008-07-168583. 17ClinicalTrials.gov. Alvocidib in patients with previously treated chronic lymphocytic leukemia or prolymphocytic leukemia arising from chronic lymphocytic leukemia (CLL). http://clinicaltrials.gov/ct2/show/NCT00464633?term=NCT00464633&rank=1. Accessed 3 November 2009.

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

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