Mallinckrodt ECP for CTCL MSAC Protocol FINAL

Executive SummaryMSAC Application 1420–Integrated, validated ECP System for CTCL

Application number 1420 to the

Medical Services Advisory Committee

For the listing of integrated, closed-system, extracorporeal photopheresis (ECP) systems

For the treatment oferythrodermic (stage T4, M0) cutaneous T-cell lymphoma patients, who are refractory to one or more systemic treatments

FINAL PROTOCOL

November 2016

COMMERCIAL IN CONFIDENCE

Mallinckrodt

166 Epping Rd, Lane Cove West, NSW, 2066

Table of ContentsMSAC Application 1420 –Integrated ECP systems for treatment of cutaneous T-cell lymphoma

Table of contents

For the listing of integrated, closed-system ECP systems

Abbreviations and terms

1Title of application

2Purpose of application

3Population and medical condition

3.1Description of medical condition

3.2Proposed patient population

3.3Evidence for proposed patient population

3.4Expected utilisation

4Intervention

4.1Description of proposed medical service

4.1.1Integrated, closed-system ECP overview

4.1.2Components of integrated, closed-system ECP

4.1.3How integrated, closed-system ECP works

4.2Technical specification

4.3Registered trademark with distinguishing characteristics

4.4Proposed setting for delivery

4.5Service delivery in clinical setting

5Co-dependent information

6Comparator and clinical claim

7Expected health outcomes

7.1Expected patient relevant health outcomes

7.1.1Outcomes overview

7.1.2Existing clinical evidence

7.1.3Clinician’s perspective

7.1.4Important health outcomes within CTCL treatment

7.1.5Safety endpoints

7.2Potential risks to patients

7.3Type of economic evaluation

8Fee

8.1Proposed funding type

8.2Direct costs

8.3Details of proposed fee

9Clinical management algorithm

9.1Current clinical management algorithm

9.2Proposed clinical management algorithm

10Regulatory information

11Decision analytic

12Healthcare resources

13Questions for public funding

Refrences

List of tables

Table 1: ISCL/EORTC revision to the classification of mycosis fungoides and Sézary syndrome[9]

Table 2: ISCL/EORTC Revision to the staging of mycosis fungoides and Sézary syndrome [8, 9]

Table 3: Treatment options for mycosis fungoides/Sézary syndrome by disease stage [11].

Table 4: Summary of recommended population to be treated using ECP in CTCL.

Table 5: Guideline recommendations for treatment schedule for ECP use in CTCL patients

Table 6: Proposed PBS restriction for methoxsalen in CTCL treatment (initial treatment)

Table 7: Proposed PBS restriction for methoxsalen in CTCL treatment (continuing treatment)

Table 8: Outcomes used within ECP monotherapy studies [36]

Table 9: The proposed MBS restriction for integrated, closed-system ECP use within CTCL

Table 10: Summary of PICO to define the research question

Table 11: List of resources to be considered in the economic analysis

List of figures

Figure 1: Actuarial disease-specific survival of 525 patients with mycosis fungoides or Sézary syndrome according to their clinical stage at diagnosis (stages IA-IV) [8].

Figure 2: Current treatment algorithm for CTCL

Figure 3: Current clinical management algorithm in T4 and M0 cutaneous T-cell lymphoma patients that are refractory to initial therapy

Figure 4: Proposed economic model format for treatment with integrated, closed-system ECP vs usual care (basket of comparators)

Mallinckrodt Australia Pty Ltd — Commercial-In-Confidence1

AbbreviationsMSAC Application 1420 –Integrated ECP systems for treatment of cutaneous T-cell lymphoma

Abbreviations and terms

Mallinckrodt Australia Pty Ltd — Commercial-In-Confidence1

MSAC Application 1420 –Integrated ECP systems for treatment of cutaneous T-cell lymphoma

1Title of application

The use of integrated, closed-system ExtracorporealPhotopheresis(ECP) with ultraviolet-A (UVA) irradiation in conjunction with a photoactive drugmethoxsalen, to treat cutaneous T-cell lymphoma patients.

2Purpose of application

Please indicate the rationale for the application and provide one abstract or systematic review that will provide background

Cutaneous T-cell lymphoma (CTCL) is a rare disease with a high burden of illness and an annual incidence of 0.23-0.75 per 100,000 in Australia[1]. CTCLinvolves malignant T-cell clones that accumulate in the skin, leading to plaques, patches, lesions, pruritus, tumoursand lung and spleen damage[2, 3]. Even with treatment the disease results in eventual terminal visceral involvement or sepsis secondary to skin breakdown. There is no cure for the disease, and very few currently reimbursed treatments within Australia. Currently integrated, closed-systemECPis used within Australia to treat CTCL patients using ad hoc funding which limits treatment to a select few. It is proven within a local setting to provide effective relief for patients and has a preferable adverse event profile in comparison to other treatments (See Appendix 2). Reimbursement fortreatment would lead to improvements in outcomes for patients while reducingadverse events associated with other treatment methods, somewhich are also used off label and with ad hoc funding (See Appendix 2).

This Protocol relates to the request for Medical Services Advisory Committee (MSAC) approval for subsidization of both integrated Extracorporeal Photopheresis devices and the active ingredientmethoxsalen for use in the treatment of Cutaneous T-cell lymphoma (CTCL) patients. It is acknowledged that mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common variants of CTCL, accounting for 65% of all CTCL patients (Section 3.1).. The proposed medical service is a hybrid system of both a device and a drug, and is associated with improved patient outcomes shown through extensive single arm studies. Studies ranging from 1987-2011 showed an overall mean response rate of 63% (range: 33%-100%), measured by improvement in skin scores [3], with higher response rates observed inpatients with erythrodermic CTCL. Mean complete response rate for the studies that reported them was20% (range: 0%-62%) [3]. The treatment is also known to have a better adverse event profile than observed with other treatments within the same indication (See Appendix 2).

Please refer to the JEADV guidelines by Knobler et al (2014) [3] attached withinAppendix 1 for further information on ECP use within CTCL.Four other key guidelines are also attached as Appendix 1 for further reference [3-7].

3Population and medical condition

3.1Description of medical condition

CTCL is a rare heterogeneous group of diseases involving malignant T-cell clones that accumulate to the skin [2, 3]. The two most common CTCL variants are Sézary Syndrome (SS) and mycosis fungoides (MF). SS accounts for around 5% [3] of all CTCL patients and is a leukemic form of CTCL, where
T-cell’s circulate in the peripheral blood and affect internal organs such as the spleen and lungs [2, 3]. MF accounts for around 60% [3]of all CTCL patients and is characterized by clonal T-cells in the cutaneous environment that present early on as plaques and patches (which can resemble eczema or psoriasis) and eventually result in lesions, pruritus and tumours [2, 3]. Diagnosing CTCL requires clinical and pathologic symptom correlation, and consultation with an experienced pathologist is strongly recommended[8]. CTCL is most commonly found in adult males (twice as common as women) of all races, between the ages of 40-60 years [4].

When patients present with symptoms of CTCL, they are classified into stages of disease severity. A widely used set of staging criteria are the ISCL/EORTC revisions to the staging of MF and SS, as outlined in Olsen et al (2007). The tests completed that are used within the staging process usually include a complete physical exam, a skin biopsy, a blood test, a radiologic test and a lymph node biopsy [8]. The staging criteria use the test results and allow doctors to give patients a stage rating that helps determine treatment options [8]. Table 1and Table 2 below outline the complete ISCL/EORTC revision to the staging process for both MF and SS.

Table 1: ISCL/EORTC revision to the classification of mycosis fungoides and Sézary syndrome[9]

*For skin, patch indicates any size skin lesion without significant elevation or induration. Presence/absence of hypo- or hyperpigmentation, scale, crusting, and/or poikiloderma should be noted.

†For skin, plaque indicates any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features such as folliculotropism or large-cell transformation (25% large cells), CD30_ or CD30_, and clinical features such as ulceration are important to document.

‡For skin, tumour indicates at least one 1-cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest size lesion, and region of body involved. Also note if histologic evidence of large-cell transformation has occurred. Phenotyping for CD30 is encouraged.

§For node, abnormal peripheral lymph node(s) indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed or 1.5 cm or larger in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically.

¶For viscera, spleen and liver may be diagnosed by imaging criteria.

For blood, Sézary cells are defined as lymphocytes with hyper convolutedcerebriform nuclei. If Sézary cells are not able to be used to determine tumour burden for B2, then one of the following modified ISCL criteria along with a positive clonal rearrangement of the TCR may be used instead: (1) expanded CD4_ or CD3_ cells with CD4/CD8 ratio of 10 or more, (2) expanded CD4_ cells with abnormal immuno-phenotype including loss of CD7 or CD26.

#A T-cell clone is defined by PCR or Southern blot analysis of the T-cell receptor gene.

Table 1shows the ISCL/EORTC revision to the classification of mycosis fungoides and Sézary syndrome. TheISCL/EORTC revisionstaging process for both MF and SS encompassesthe various ailments CTCL presents in patients. In practice this allows practitioners to better determine treatment options suitable for patients. Table 2below shows how the revised TNMB system is used to calculate ISCL/EORTC revised staging of disease.

Table 2: ISCL/EORTC Revision to the staging of mycosis fungoides and Sézary syndrome [8, 9]

Table 2 shows how the ISCL/EORTC revised staging system classifies the test results of patients into disease stages and defines early-stage disease andadvanced-stage CTCL. While many existing therapies for CTCL focus on palliation[8], treatment options are dependent on the both the stage of disease a patient is in as well as of the number of previous treatments that patients have received. The difference between early-stage disease and advanced-stage disease is important for informing treatment decisions as patients with early stage disease often only have skin related disease, while advanced disease may have disseminated disease into lymph nodes and other organs [10]. Advanced stages can involve multiple immune derangements and require systemic therapy; however, no regimen has been proven to prolong overall survival in the advanced stages of treatment[10]. Survival by treatment stage is outlined within Figure 1 below.

Figure 1: Actuarial disease-specific survival of 525 patients with mycosis fungoides or Sézary syndrome according to their clinical stage at diagnosis (stages IA-IV)[8].

For stage IA versusIB disease, P = .007; for stage IB versus IIA disease, P = .006; for stage IIA versusIIB disease, P = .001; for stage IIA versus III disease, P = .03; for stage IIB versus IIIdisease, P = .09; and for stage IA-III versus IV disease, P = .001.

Immuno-modulatory regimens are often used before others to reduce the need for cytotoxic therapies. The different treatment optionsand their effectiveness within each disease stage are outlined within Table 3below.

Table 3: Treatment options for mycosis fungoides/Sézary syndrome by disease stage[11].

Treatment in advanced stages is whereintegrated, closed-system ECP has traditionally been used, although several studies have shown its effectiveness when usedin ‘early-stage’ CTCL patients[12, 13]. The National Comprehensive Cancer Network (NCCN) Guidelines also recommend ECP in those patients with stage IA, IB and IIA refractory disease [3, 14]. They are, however, one of the only guidelines to do so, as shown in Table4.

Table4 also outlines the Australian Cancer Councils 2005 Clinical Practice Guidelines for the Diagnosis and Management of Lymphoma, which recommended ECP for first, second or third-line treatment in patients with stage IIB to IV MF, while also recommending ECP as a more effective treatment in SS patients. The number and type of previous treatmentsa patient is refractory to dictates future treatment options, since past treatmentsare not usually reused.There are a number of prognostic factors that have been shown to increase the chance of response rate to ECP[3]:

• short duration of disease, preferably <2 years;
• absence of bulky lymphadenopathy or major internal organ involvement;
• white blood cell count <20 000 mm3;
• presence of a discrete number of Sézary cells (10–20% of mononuclear cells);,
• natural killer cell activity close to normal;
• cytotoxic T lymphocytes close to normal (CD8+ > 15%);
• absence of prior intensive chemotherapy; and
• plaque stage disease not covering more than 10–15% of total skin surface[3].

Patients movefrom one treatment to the next based on two factors; the first is a recurrence in itch or pain, with the second being a lack of response to the given treatment. Figure 2shows the available treatments within each successivetherapy used in normal clinical practice in Australia which has been verified byProfessor Miles Prince, Director for the Centre for Blood Cell Therapies at the Peter MacCallum Cancer Centre in Victoria.While Table 3 does not show that patients with SS are recommended for treatment, Professor Prince states that this indication is fitting with the clinical norm within Australia for ECP use. ECP has also been recommended for use within both MF and SS patients in the EORTC consensus for treatment of MF and SS (2006)[7], The UK Photopheresis expert group’s guidelines (2008)[6], the BritishPhotodermatology group and UK skin lymphoma group recommendations (2006)[5], the North Derbyshire, South Yorkshire and Bassetlaw Commissioning Consortium review of ECP (2008)[4] and within the guidelines for use on ECP by the journal of the European Academy of Dermatology and Venereology (2014)[3].The applicability of ECP erythrodermic MF (stage T4) patients is also specifically recommended by 4 out of 5 of those guidelines (EORTC 2008 does not use the word both erythrodermicwithin its recommendation for ECP use, however it does not exclude it). Professor Miles Prince is an internationally renowned specialist haematologist who is an expert in blood-related conditions including bleeding and blood clotting disorders, anaemia, and cancers of the blood. He is on the Board of the International Society of Cutaneous Lymphoma and has co-authored numerous guidelines on the staging and treatment of CTCL. He has contemporary experience in using ExtracorporealPhotopheresis to treat CTCL and has published clinical experience within the Australian patient population [8, 15]. A consultation conducted with him on the 22nd of March 2016 (for more details see Appendix 2) was carried out to ensure the wider literature and the existing international guidelines matched current clinical practice being used within Australia.

3.2Proposed patient population

The proposed patient population is:

Erythrodermic (stage T4, M0)cutaneous T-cell lymphoma patients, who are refractory to one or more systemic treatments.

This proposed patient population is based on the combination of recommendations made within guidelines on ECP use for CTCLtreatment and evidence from the literature [3-7], with confirmation that this restriction fits with howintegrated, closed-system ECP is currently being used in Australia though expert clinical advice from consultation with Professor Miles Prince (See Appendix 2).The proposed indication includes T4 and M0 patients, which correspond to patients in stages III, IIIA, IIIB, IVA1 and IVA2.Given that the proposed population typically comprise of adults between 40-60 years of age[4], and that CTCL is very rare in children and adolescents and so there are unlikely to be many studies in paediatric patients, , it is proposed that the population be limited to patients aged 18 and above.While there are certain prognostic factors that increase the effectiveness of ECP usage, as this treatment is aimed as a therapy for patients with a high clinical need, and with a crippling debilitating disease, it was considered preferable to allow the clinician to determine a patients eligibility based on prognostic factors rather than limit the population to those that display those factors. This allows patients that have no other treatment options to attempt ECP to potentially gain some relief.