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Pixantrone dimaleate for relapsed or refractory non-Hodgkin’s lymphoma, third or fourth line.

Source agency:

NHSC

Date of Submission:

07/01/2010

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Pixantrone

Technology - description:

Pixantrone dimaleate (BBR 2278; BBR 2778; BBR2278; BBR2778) is an aza-anthracenedione analogue and inhibitor of topoisomerase II. It has structural similarities to doxorubicin (anthracycline compound) and mitoxantrone (an anthracenedione), but lacks the 5,8-dihydroxy substitution pattern of mitoxantrone, and has a tricyclic rather than the tetracyclic structure pattern of doxorubicin. Pixantrone does not contain hydroxyl groups and may therefore retain efficacy with a reduced risk of anthracycline-associated cardiotoxicity. It is administered at 85mg/m2 intravenously (IV) into a peripheral vein on days 1, 8 and 15 of a 28 day cycle for up to 6 cycles, as monotherapy. Label expansion studies are planned in combination with current anti-cancer agents.

Company or developer:

Cell Therapeutics, Inc.

Reason for database entry:

Pixantrone may be able to offer efficacy with reduced cardiotoxicity and a more convenient administration route compared to current anthracyclines. Pixantrone may also offer the ability to exceed lifetime recommended limits of other anthracyclines and thus to re-treat patients with lymphoma when they have reached these limits.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Investigational - phase III

Licensing, reimbursement and other approval:

In phase III clinical trials.

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

Non-Hodgkin’s lymphoma (NHL) - relapsed or refractory aggressive, third or fourth line, monotherapy.

Disease description and associated mortality and morbidity:

Diffuse large B-cell lymphoma (DLBCL) is a group of intermediate to high-grade lymphomas which have an aggressive course. Disease remissions characteristically become shorter with each successive treatment.

Number of Patients:

In England and Wales there were 7,145 new cases of NHL diagnosed in 2006(7), and 4,013 deaths occurred in 2007(8). Thirty to forty percent of new cases of NHL are DLBCL (2,143-2,858)(4).

Technology - specialities(s):

Oncology & radiotherapy, Haematology & blood products

Technology - setting(s):

General hospital and ambulatory care, Specialist hospital

Setting - further information:

-

Impact

Alternative and/or complementary technology:

Additive and substitution

Current Technology:

Treatment options for relapsed or refractory aggressive NHL include:

Single agent chemotherapy with vinorelbine, oxaliplatin, ifosfomide, etopside, mitoxantrone, gemicitabine or rituximab.

Granulocyte colony-stimulating factor (G-CSF) can be used adjunctively with chemotherapy.

Health Impact:

-

Diffusion:

-

Cost, infrastructure and economic consequences:

-

Ethical, social, legal, political and cultural impact:

-

Evidence & Policy

Clinical evidence and safety:

Trial: PIX301 EXTEND, NCT00088530; pixantrone vs other chemotherapeutic agents; phase III.

Sponsor: Cell Therapeutics.

Status: Ongoing.

Source of information: Abstract 9,10.

Location: EU (inc UK), USA and other countries.

Design: Randomised, open-label, active control.

Participants and schedule: n=140; adults; NHL; relapsed aggressive; 2 prior therapies. Randomised to pixantrone 85mg/m2 on days 1, 8 and 15 per 28 day cycle for up to 6 cycles or investigator’s choice of single-agent comparator (vinorelbine, oxaliplatin, ifosfomide, etopside, mitoxantrone, gemicitabine or rituximab) at standard doses and regimens.

Follow-up: Treatment period of 24 weeks with 18 months follow-up.

Primary outcomes: Complete remission (CR) or unconfirmed remission (CRu) rates.

Secondary outcomes: Overall response rate (ORR): CR, CRu or partial remission (PR); response lasting ≥4 months; progression-free survival (PFS); overall survival (OS); safety.

Key results: For pixantrone and comparator respectively: CR or CRu rate: 20% vs 5.7% (p=0.021); ORR: 37.1% vs 14.3% (p=0.03)10; response lasting ≥ 4 months: 25.7% vs 8.6% (p=0.012)9; median PFS ≥ 9 month follow-up (months): 5.6 vs 2.6 (p=0.002; 95% CI=0.39-0.81)10; median OS (months): 10.2 vs 6.9 (p=0.35)10.

Adverse effects (AEs): Most common (>5%) AEs pixantrone vs comparator respectively: neutropenia 41.2% vs 19.4%; leukopenia 23.5% vs 4.5%; anaemia 5.9% vs 13.4%; pyrexia 4.4% vs 9%; febrile neutropenia 7.4% vs 3%; abdominal pain 7.4% vs 4.5%; pneumonia 5.9% vs 4.5%; dyspnea 5.9% vs 4.5%10.

Economic evaluation:

-

Ongoing research:

-

Ongoing or planned HTA:

-

Web link:

http://www.nhsc-healthhorizons.org.uk/outputs/specialties/

References and sources:

1. National Institute for Health and Clinical Excellence. Temsirolimus for the treatment of relapsed or refractory mantle cell lymphoma. Technology appraisal in development. London: NICE; expected completion September 2010. 19th wave.

2. National Institute for Health and Clinical Excellence. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma (review of technology appraisal guidance 37). Technology appraisal TA137. NICE; London: February 2008.

3. National Institute for Health and Clinical Excellence. Rituximab for the treatment of follicular lymphoma.

Technology appraisal TA110. London: NICE; September 2006.

4. National Institute for Health Clinical and Excellence. Rituximab for aggressive non-Hodgkin’s lymphoma. Technology appraisal TA65. London: NICE; September 2003.

5. National Institute for Clinical and Excellence. Improving outcomes in haemato- oncology cancer. Cancer Service Guideline. London: NICE; October 2003.

6. European Society for Medical Oncology. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow up. Clinical recommendations. Annals of Oncology 19. 2008.

7. Cancer Research UK http://info.cancerresearchuk.org/cancerstats/types/nhl/incidence/index.htm Accessed 7th December 2009.

8. Office for National Statistics. Mortality statistics: deaths registered in 2007.

http://www.statistics.gov.uk/downloads/theme_health/DR2007/DR_07_2007.pdf Accessed 8th October 2009.

9. Pettengell R, Narayanan G, Hurtado de Mendoza F et al. Randomized phase 3 trial of pixantrone versus other chemotherapeutic agents for third-line single-agent treatment of relapsed aggressive non-Hodgkin’s lymphoma. American Society of Clinical Oncology, 45th Annual Meeting, May 2009. Abstract No. 8523. Poster. Also published in: Journal of Clinical Oncology 27:15s, 2009 (suppl; abstr 8523)

10. Pettengell R, Coiffier B, Narayanan G et al. Phase III trial of pixantrone dimaleate compared with other agents as third-line, single-agent treatment of relapsed aggressive non-Hodgkin’s lymphoma (EXTEND): Results from the treatment and follow-up periods. American Society of Hematology. 51st Annual Meeting, December 2009. Abstract No. 1677. Poster.

Notes: