Horizon Scanning Centre September 2013

Paclitaxel polyglutamate (Opaxio) in combination with temozolamide and radiotherapy for glioblastoma – first line

SUMMARY NIHR HSC ID: 7653

Paclitaxel polyglutamate (Opaxio) in combination with temozolamide and radiation is intended to be used as first line therapy for the treatment of newly This briefing is diagnosed glioblastoma. If licensed, paclitaxel polyglutamate will offer an additional treatment option for this patient group. Paclitaxel polyglutamate based on links paclitaxel to a biodegradable polyglutamate polymer. Once inside the information tumour cell, enzymes metabolize the protein polymer, releasing active available at the time paclitaxel, a microtubule inhibitor and radiosensitiser. of research and a limited literature There are about 4,500 new cases of primary brain cancer in the UK each search. It is not year. Approximately 1,860 new cases of malignant glioma are diagnosed in intended to be a England and Wales each year, equating to a mean incidence of 3.6 cases definitive statement per 100,000 per year. Glioblastoma, the most aggressive form, accounts for on the safety, around 40-50% of all gliomas with an annual incidence of 1.2-2 per 100,000 efficacy or population. Malignant gliomas are generally regarded as incurable. effectiveness of the Approximately 30% of adults with high-grade gliomas survive for at least one health technology year and 13% survive for five years. Glioblastoma has a median overall covered and should survival of 12-14 months. Glioblastoma is one of the commonest causes of not be used for cancer death in men and women aged under 40 years. commercial purposes or The standard of care for glioblastoma is surgery with adjuvant temozolomide commissioning and radiotherapy. Paclitaxel polyglutamate in combination with temozolomide without additional and radiation is currently in two phase II clinical trials comparing its effect on information. progression-free survival in a single arm trial, and toxicity in a controlled trial against temozolomide and radiation. The single arm trial is completed and the controlled trial is expected to complete in December 2013.

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

• Glioblastoma: newly diagnosed – first line; in combination with temozolomide and radiotherapy.

TECHNOLOGY

DESCRIPTION

Paclitaxel polyglutamate (Opaxio; Xyotax; paclitaxel poliglumex; PG-paclitaxel; poly(L- glutamic acid)-paclitaxel conjugate; polyglutamate-Taxol; PPX; PG-TXL; CHC-12103; CT- 2103) links paclitaxel to a biodegradable polyglutamate polymer. Once inside the tumour cell, enzymes metabolize the protein polymer, releasing active paclitaxel. Paclitaxel is a microtubule inhibitor and radiosensitiser. When bound to the polymer, paclitaxel has the potential to: 1) enhance the radiosensitivity of tumour cells and reduce radiation toxicity to normal tissue (paclitaxel polyglutamate has a radiosensitisation index of 4-8 compared with paclitaxel which has an index of 1.5-2); 2) spare normal tissue from exposure to high levels of toxicity (paclitaxel is inactive when bound to the polymer); and 3) increase the therapeutic index of paclitaxel (leaky blood vessels in tumour tissue are porous to macromolecules such as paclitaxel polyglutamate allowing preferential distribution to tumours)1. Paclitaxel polyglutamate in combination with temozolamide and radiation is intended for the treatment of newly diagnosed glioblastoma.

Paclitaxel polyglutamate is administered by intravenous (IV) infusion at 50mg/m2 on days 1, 8, 15, 22, 29 and 36 of a 6 week cycle in combination with radiotherapy 60Gy (2Gy/fraction for 30 fractions) with or without temozolomide maintenance therapy administered orally at 75mg/m2/day2,3.

Paclitaxel polyglutamate is in phase III clinical trials for the treatment of ovarian, non-small cell lung, peritoneal and breast cancers. It is in phase II clinical trials for colorectal, prostate, fallopian tube and head and neck cancers.

INNOVATION and/or ADVANTAGES

If licensed, paclitaxel polyglutamate will offer an additional treatment option for glioblastoma.

DEVELOPER

Cell Therapeutics, Inc.

AVAILABILITY, LAUNCH OR MARKETING

Paclitaxel poliglumex is a designated orphan drug in the USA for glioblastoma.

In phase II clinical trials.

2 NIHR Horizon Scanning Centre

PATIENT GROUP

BACKGROUND

Glioma is the most common primary brain tumour, accounting for 32% of all central nervous system tumours and 80% of malignant CNS tumours4. It originates from the glial cells that support nerve cells in the brain and spinal cord5. Grade I and II gliomas are considered low- grade, and are well-differentiated and usually associated with a better outcome6. Grade III and IV gliomas are considered high-grade, and are undifferentiated or anaplastic with a worse prognosis6. Grade III gliomas include anaplastic astrocytoma, anaplastic ependymoma, anaplastic oligodendroglioma and anaplastic oligoastrocytoma. Grade IV gliomas include glioblastoma (glioblastoma multiforme [GBM]), giant cell glioblastoma (rare) and gliosarcoma (rare)5,7. Grade III gliomas often occur in young adults and despite treatment with surgery, radiotherapy and chemotherapy, typically recur or progress to glioblastoma within several years of diagnosis8. The average age of onset of glioblastoma is 53 years, and approximately 60% of glioblastomas appear to evolve de novo5.

Prognostic factors for high-grade glioma include age, performance status, extent of surgical resection, mini mental score examination and O6-methylguanine-DNA methyltransferase (MGMT) status9. MGMT is an enzyme that repairs DNA damage at a site commonly targeted by cytotoxic drugs, thereby inhibiting the effect of chemotherapy5. In gliomas, the MGMT promoter region can exhibit hypermethylation. In these cases, MGMT activity will be decreased or absent5, which is associated with a better response to combined temozolamide-radiation treatment10.

NHS or GOVERNMENT PRIORITY AREA

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

CLINICAL NEED and BURDEN OF DISEASE

Brain tumours account for less than 2% of all primary cancers11. There are about 4,500 new cases of primary brain cancer in the UK each year12. High-grade tumours are the most common; glioblastoma accounts for 20.3%, anaplastic astrocytoma 3.2%, and anaplastic oligodendroglioma 1.2% of all primary brain tumours8,13. Approximately 1,860 new cases of malignant glioma are diagnosed in England and Wales each year11, equating to a mean incidence of 3.6 cases per 100,000 per year5. Glioblastoma, the most aggressive form, accounts for around 40-50% of all gliomas with an annual incidence of 1.2-2 per 100,000 population14. This equates to between 679 to 1,131 new cases in England and Wales in 2012. Aberrant MGMT promoter methylation and/or reduced MGMT expression is detectable in a little under half of glioblastomas, with reported incidence from 38% to 68%5 (therefore 42% to 62% with unmethylated MGMT). High grade gliomas are more common in men than women11, less common in those from Black and Asian ethnic groups13, and the incidence increases with age11.The average age of diagnosis is 55 years6.

Symptoms of high-grade glioma depend on the size, location and degree of infiltration of the tumour. They include headache, nausea, vomiting, seizures, visual disturbance, speech and language problems, and changes in cognitive and/or functional ability11. Patients with high- grade gliomas have a better prognosis if they are younger, have a good performance status, have a grade III tumour or if complete resection is achieved11. Large tumours and those crossing the cerebral midline are associated with worse outcome9. Malignant gliomas are generally regarded as incurable; more than 80% recur within 2-3cm of the margin of the

3 NIHR Horizon Scanning Centre

original tumour5. Approximately 30% of adults with high-grade gliomas survive for at least one year and 13% survive for five years11. Grade III gliomas have a median progression free survival (PFS) of approximately two years, and a median overall survival (OS) of around three years9. Glioblastoma has a worse prognosis, the median OS is 12-14 months, however there are an increasing number of longer term survivors, beyond 2-3 years9. Glioblastoma is one of the commonest causes of cancer death in men and women aged under 40 yearsa.

In 2011-12, there were 16,576 admissions in England and Wales for malignant neoplasms of the brain (ICD-10 C71), resulting in 105,163 bed days and 20,516 finished consultant episodes15. In 2011, there were 3,443 deaths from malignant neoplasms of the brain registered in the UK16.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Glioma (newly diagnosed and high grade) – carmustine implants and temozolomide (TA121) 11. June 2007. • NICE technology appraisal. Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer) (TA23). April 200117. • NICE cancer service guidance. Brain tumours: service guidance for improving outcomes for people with brain and other central nervous system tumours (CSGBraincns). June 200618. • NICE interventional procedure guidance. Photodynamic therapy for brain tumours. 200919.

Other Guidance

• Merseyside and Cheshire Neuro-oncology Cancer Network Group. High grade glioma guidelines. 20119. • ESMO Guidelines Working Group. High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 201020.

EXISTING COMPARATORS and TREATMENTS

The standard of care for glioblastoma is surgery followed by concomitant chemoradiotherapy9. Anaplastic astrocytoma are usually treated with radiotherapy, unless the tumour is large9. Anaplastic oligodendroglial and large anaplastic astrocytomas are typically treated with chemotherapy to avoid radiotherapy-induced neurotoxicity9.

Treatment options for high-grade glioma are as follows21: • Surgical: tumour debulking (or maximum resection, if feasible) with adjuvant treatment at the time of surgery • Non-surgical (following biopsy)b: o radical radiotherapy only (for patients aged ≥70 years or with WHO performance status >19)

a Expert personal communication. b Expert personal communication.

4 NIHR Horizon Scanning Centre

o hypofractionated radiation only (patients with a poor prognosis) (not standard practice in the UK)c o first-line chemotherapy . Temozolomide − adjuvant and concomitant to surgery and radiotherapy (for patients aged <70 years or with WHO performance status 0 or 19) . Temozolomide monotherapy (elderly patients)20 (not standard practice in the UK)b . Carmustine implants (wafers) – adjuvant therapy to surgery and radiotherapy (for patients in whom 90% or more of the tumour has been resected)11 o second-line chemotherapy (for relapsed patients) . eg procarbazine in combination with lomustine, and vincristine (PCV), temozolomide, or single-agent lomustine17.

Corticosteroids reduce peritumoural oedema and may thereby ameliorate clinical symptoms but should be administered only for a short time at a low dose22.

EFFICACY and SAFETY

Trial NCT00763750, BrUOG-Brain-223; NCT01402063, BrUOG 244; paclitaxel polyglutamate (PPX) in paclitaxel polyglutamate vs combination with temozolomide and temozolomide, both in combination with radiation; phase II. radiation and temozolomide maintenance treatment; phase II. Sponsor Howard Safran, Brown University. Howard Safran, Brown University. Status Complete but unpublished. Ongoing. Source of Abstract23, poster24, trial registry3, Trial registry2, manufacturer. information manufacturer. Location USA. USA. Design Non-randomised, single arm. Randomised, active-controlled. Participants n=25; aged ≥18 years; glioblastoma or n=60 (planned); aged ≥18 years; anaplastic glioma (anaplastic glioblastoma or gliosarcoma; astrocytoma, anaplastic unmethylated MGMT; treatment naïve; oligodendroglioma, and anaplastic Karnofsky performance score >60d. oligoastrocytoma); newly diagnosed; treatment naïve; Zubrod performance status 0-2. Schedule Paclitaxel polyglutamate 50mg/m2 IV on Randomised to paclitaxel polyglutamate days 1, 8, 15, 22, 29 and 36 of a 6-week 50mg/m2 IV on days 1, 8, 15, 22, 29 and cycle in combination with radiation at 36; or temozolomide, 75mg/m2 orally, 2Gy/fraction for 30 fractions and every day from the first to the last day of temozolomide 75mg/m2 orally from day 1 radiotherapy; both in combination with of radiation until completion of study. radiation at 2Gy/fraction for 30 fractions and temozolomide maintenance 75mg/m2 orally, days 1-5 of a 28-day cycle for ≤12 cycles (beginning 4 weeks after completion of chemoradiation). Follow-up Active treatment for 6 weeks. Active treatment for ≤58 weeks, follow-up until death or 3 years. c Expert personal communication. d Karnofsky performance score (KPS). The KPS runs from 0-100, where 100 is "perfect" health and 0 is death. A KPS of ≥60 equates to a Zubrod score of 0-2.

5 NIHR Horizon Scanning Centre

Primary Response by MRI 30 days after Toxicity at years 1 and 2. outcome treatment. Secondary Safety and tolerability. - outcome Key results All tumours, n=25: - 6-month PFS, 76%; 12-month PFS, 52%; median PFS, 16.3 months; complete response, 28%; partial response, 12%; stable disease, 40%.

Glioblastomas, n=15: 6-month PFS, 66.7%; median PFS, 13.5 months.

13/16 patients with post-paclitaxel polyglutamate enhancement exhibited pseudoprogressione. 2/13 pseudoprogression patients exhibited progressive disease at a mean time to progression of 105 days

Adverse Grade 4 AEs: thrombocytopenia, 24%; - effects (AEs) neutropenia, 12%. Grade 3 AEs: neutropenia, 4%; dehydration, 4%; anorexia, 4%; weakness, 4%; headache, 4%. Expected - Study completion date reported as Dec reporting 2013. date

ESTIMATED COST and IMPACT

COST

The cost of paclitaxel polyglutamate is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

e Pseudoprogression is defined as when post-treatment imaging suggests disease progression that subsequently resolves.

6 NIHR Horizon Scanning Centre

Impact on Services

 Increased use of existing services: expert  Decreased use of existing services commented that current chemotherapy for glioblastoma is oral, well tolerated and can be taken at home. Since paclitaxel polyglutamate is given IV, clinical oncologists may require some degree of training and there would be an impact on patient attendance at oncology units and service planning.

 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: additional costs for IV  Other reduction in costs: administration in clinic.

 Other:  None identified

Other Issues

 Clinical uncertainty or other research question  None identified identified: expert commented that PFS reported from the phase II clinical trial result is better than current gold standard in glioblastoma, however there is no overall survival data presented.

REFERENCES

1 Cell therapeutics, Inc. Paclitaxel poliglumex (Opaxio™). http://www.celltherapeutics.com/opaxio Accessed 9 August 2013. 2 ClinicalTrials.gov. PPX and concurrent radiation for newly diagnosed glioblastoma without MGMT methylation: a randomised phase II study http://clinicaltrials.gov/show/NCT01402063 Accessed 8 August 2013. 3 Clinical Trials.gov. BrUOG-Brain-223: A Phase II Study of PPX (CT-2103), Temozolomide, and concurrent radiation for newly diagnosed brain tumours (CTI # CT2103) http://www.clinicaltrials.gov/ct2/show/NCT00763750?term=NCT00763750 Accessed 8 August 2013. 4 Agnihotri S, Burrell KE, Wolf A et al. Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies. Archivum Immunologiae et Therapiae Experimentalis 2013;61(1):25-41. 5 National Institute for Health and Clinical Excellence. Assessment report: Glioma (newly diagnosed and high grade) - carmustine implants and gemozolomide. December 2005. http://www.nice.org.uk/nicemedia/live/11619/34040/34040.pdf 6 Patient.co.uk. Gliomas and Glioblastoma Multiforme. April 2012. http://www.patient.co.uk/doctor/Gliomas-and-Glioblastoma-Multiforme.htm 7 Dutch Society for Neuro-Oncology. Gliomas. Amsterdam, The Netherlands: Association of Comprehensive Cancer Centres (ACCC); 2008: 28. http://www.guideline.gov/content.aspx?f=rss&id=13555 8 DeAngelis LM. Anaplastic glioma: how to prognosticate outcome and choose a treatment strategy. Journal of Clinical Oncology 2009;27(35):5861-5862. 9 Jenkinson M. High grade glioma guidelines. Merseyside and Cheshire Neuro-oncology CNG, December 2011 http://www.mccn.nhs.uk/userfiles/documents/High%20grade%20glioma%20 guidelines%20December%202011.pdf

7 NIHR Horizon Scanning Centre

10 Thomas RP, Recht L and Nagpal S. Advances in the management of glioblastoma: the role of temozolomide and MGMT testing. Clinical Pharmacology: Advances and Applications 2013;5:1-9. 11 National Institute for Health and Clinical Excellence, Technology Appraisal. Glioma (newly diagnosed and high grade) – carmustine implants and temozolomide. TA121. NICE; London; June 2007. 12 NHS choices. Benign brain tumour (non-cancerous). July 2011. http://www.nhs.uk/Conditions/Brain-tumour/Pages/Introduction.aspx 13 Garside R, Pitt M, Anderson R et al. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. Health Technology Assessment 2007;11(45). http://www.journalslibrary.nihr.ac.uk/__data/assets/pdf_file/0004/65173/FullReport-hta11450.pdf 14 Dinnes J, Cave C, Huang S et al. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma. Draft report to NICE, Wessex Institute for Health Research and Development, 2000. 15 NHS Hospital episode statistics. NHS England 2011-12 HES data. 2013. www.hesonline.nhs.uk 16 Office for National Statistics. Mortality statistics: Deaths registered in 2011. http://www.ons.gov.uk Accessed 8 August 2013. 17 National Institute for Health and Clinical Excellence. Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer). Technology appraisal TA23. London: NICE; April 2001. 18 National Institute for Health and Clinical Excellence. Brain tumours: service guidance for improving outcomes for people with brain and other central nervous system tumours. Cancer service guidance CSGBraincns. London: NICE; June 2006. 19 National Institute for Health and Clinical Excellence. Photodynamic therapy for brain tumours: guidance. Interventional procedure guidance IPG290. London: NICE; March 2009. 20 Stupp R, Tonn JC, Brada M et al. High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 21 (Supplement 5): v190– v193, 2010 21 Map of Medicine. Primary brain tumour – management. September 2011. http://app.mapofmedicine.com/mom/1/page.html?department-id=3&specialty-id=1007&pathway- id=11388&page-id=11391&pathway-prov-cert=/attachments/15651_provcert.pdf 22 Dutch Society for Neuro-Oncology. Gliomas. Amsterdam, The Netherlands: Association of Comprehensive Cancer Centres (ACCC); 2008: 28. http://www.guideline.gov/content.aspx?f=rss&id=13555 23 Jeyapalan S A, Goldmann M, Donahue J et al. A phase II study of paclitaxel poliglumex (PPX), temozolamide (TMZ), and radiation (RT) for newly diagnosed high-grade gliomas. Journal of Clinical Oncology 29: 2011 (suppl; abstr 2036). 2011 ASCO Annual Meeting. Abstract 2036. Poster. http://meetinglibrary.asco.org/content/82937-102 24 Jeyapalan S, Goldman M, Boxerman J et al. Paclitaxel Poliglumex (PPX), Temozolamide (TMZ) and Radiation (RT) for newly diagnosed high-grade gliomas: A Brown University Oncology Group (BrUOG) Phase II Study. 2011 ASCO Annual Meeting. Poster. http://www.celltherapeutics.com/pdf/ASCO2011OPAXIO.pdf.pdf

8