CommNETS Year 3 Project Overview + Working Groups Micheal Michael - - PowerPoint PPT Presentation

CommNETS Year 3

Project Overview + Working Groups Micheal Michael and Rachel Goodwin Ben Lawrence, Sharon Patterson,

AGENDA PRESENTOR SURGICAL GROUP Indigenous peoples and tissue banking Methodological issues in NET surgical trials Systemic review of NET surgical trials Jonathan Koea Jonathan Koea Jonathan Koea PRRT Group Pituitary dysfunction after PRRT PRRT and QOL Marianne Elston Gabby Cehic Shared care models Radhika Yelamanchili Financial toxicity in NETs David Wyld MEN database Richard Carroll Making pNETS immunogenic Ben Lawrence Pediatric and Adolescence/Young Adults NETs Kate Parker

CABERNET Study Cabozantinib versus Everolimus in NETs

PIs: David Ransom Project team: Cabernet drinkers only

Background and aims

• In a small phase 2 study, cabozantinib 60mg

has shown activity in NETs.

• 41 pts with small bowel and 20 patients with

pancreatic NET were entered into the study.

• The progression free survival (PFS) for small

bowel NETs was 31 months and 21 months for pancreatic NETs.

Background and aims

• Radiant 3 pancreas NETS everolimus versus

placebo PFS in treatment arm 11 months

• Radiant 4 lung or GI NETs PFS again 11

months in treatment arm

• US trial cabozantinib versus placebo
• The hypothesis is that cabozantinib increases

the PFS from 11 months to more than 17 months.

Methods and anticipated

• utcomes
• Phase two randomised trial with 2 :1

randomisation (95 patients study)

• Functional and non functional Grade 1 or 2 NET
• f GI tract, pancreas or lung.
• One or two lines prior systemic therapy. This

could be chemotherapy, somatostatin analogue, peptide receptor radiotherapy.

• No prior everolimus ?? sunitinb

Anticipated Outcomes

• Cabozantinib blows everolimus out of the

water

• The US study becomes irrelevant
• This positive study forms the rationale for a

large international phase 3 study

• The investigators drink large quantities of

cabernet courtesy of Ipsen

Questions

• The US study will be positive therefore this

will end up as a sequencing question. Is it important?

• Budget What do you get for $750K, $500k,

$250K

Project Update: Paediatric and AYA NETs

Sharon Pattison, Ruellyn Cockcroft, Kate Parker

Background

• Information on NETS in the paediatric, adolescent and young adult (PAYA)

patient group is sparse globally

• Guidelines for the treatment of NETs do not specifically address PAYA

population and whether the adult guidelines are appropriate for the AYA population is not known.

• The NETWork! Registry provides a unique opportunity to examine NETs in

this population over a discrete time period, and to explore what would be a valuable minimal dataset for a larger global NET registry in a wider population.

Project aims

• To describe the incidence and characteristics of NETs in the AYA

population in New Zealand, patterns of care with comparison to current adult guidelines will also be explored

• To explore the datapoints included in the NET registry, the limitations of

their collection and propose a minimum dataset as the starting point for an

• ngoing international NET registry
• To collaborate with the Queensland NET registry to compare incidence,

anatomical site of origin and outcome between data sets

Methods

• Identify cases via NETwork! Registry
• Diagnosed ≤30 years and ≤15 years
• Review patient demographics:
• Family / individual history of cancer
• Tumour characteristics (site, grade, stage, etc.)
• Treatment and outcome

263 patients identified in total

(44 ≤15 years)

5 10 15 20 25 30 7 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

NETs by age at diagnosis

Primary site

20 40 60 80 100 120 140 160 180

Mode of presentation

20 40 60 80 100 120 140 160 180 Acute admission Incidental finding Referral from health professional Unknown

Distant disease?

20 40 60 80 100 120 140 160 No Unknown Yes

247/ 263 patients treated with surgery

Follow up status

238 20 50 100 150 200 250 Alive Dead

Expected outputs

• Abstract / publication on description of population in NZ
• Ideally alongside comparison with Queensland data
• Data will inform service provision
• Recommendation on minimum data points for any future registry

Other key questions

(requiring additional input)

• Right hemicolectomy?
• Key clinical question, can review with follow up data (will require going back to notes)
• Can we identify genetic predispositions to early presentation of NETs?

Surgical Group

• Principal Investigator: Jonathan Koea
• Co-PI (optional): Arend Merrie
• Aim: To review and determine the optimal outcome measure(s) in

trials of surgical management of NET

• Overall Timeline: 12 months
• Outputs:
• 1. Optimal outcome measures in surgical trials in NET
• 2. Template for a feasible surgical trial in NET
• 3. List of surgical questions for which equipoise exists
• Report back:

CommNETS 2017

Potential Numbers

• NZ Data: Annual NET incidence 8/100,000

– Jejunal/ileal 12%, Pancreas 7%

• New Zealand

– 47 jejunal/ileal NET – 25 PNET

• Australia

– 230 jejunal/ileal NET – 134 PNET

• Canada

– 345 jejunal/ileal NET – 201 PNET

Studies included in quantitative synthesis (meta- analysis) (n = 5 ) Records after duplicates removed (n =788 ) Additional records identified through other sources (n =0 )

Identification

Eligibility

Included Screening

Studies included in qualitative synthesis (n = 5 ) Records identified through database searching (n =1222 ) Full-text articles excluded, with reasons (n = 29 ) Full-text articles assessed for eligibility (n = 34 ) Records excluded (n = 754 ) Records screened (n =788 )

Randomized Surgical Trials in NET

• Huang J; et al. Endoscopic mucosal resection with circumferential

incision for treatment of rectal carcinoid tumours. World J Surg Oncol 2014;12.

• Wu G; et al. Effect of early adrenal vein ligation on blood pressure

and catecholamine fluctuation during laparoscopic adrenalectomy for pheochromocytoma. Urology 2013;82:606.

• Ju DT; et al. Hypofractionated Cyberknife stereotactic radiosurgery

for acoustic neuromas with and without association to neurofibromatosis Type 2. Acta Neurochir Suppl 2008;101:169-173.

• Tibero G; et al. Prospective randomized comparison of laparoscopic

versus open adrenalectomy for sporadic pheochromocytoma. Surg Endosc 2008;22:1435.

• Sakata H; et al. A pilot randomized control study to evaluate

endoscopic resection using a ligation device for rectal carcinoid

• tumours. World J Gastro 2006;12:4026.

Systematic Reviews of Surgery in NET

• Bacchetti S; et al. Surgical treatment and survival in patients with liver

metastases from neuroendocrine tumours. Int J Hepatol 2013

• Capurso G; et al. Role of resection of the primary pancreatic

neuroendocrine tumour only in patients with unresectable metastatic liver

• disease. Neuroendo 2011;93:223.
• Fendrich V; et al. Surgical treatment of gastrointestinal neuroendocrine
• tumours. Lang Arch Surg 2011;396:299.
• Finkelstein et al. Pancreatic neuroendocrine tumours: Analysis of overall

survival of non-surgical versus surgical resection. JoGS 2017; DOI 10.1007/s11605-017-3365-6

• Guo J; et al. Systematic review of resecting primary tumor in MNETS

patients with unresectable liver metastases. Oncotarget 2017;8:17396.

• Gurusamy KS; et al. Liver resection versus other treatments for

neuroendocrine tumours in patients with resectable liver metastases. Cochrane Review 2009. DOI: 10.1002/14651858.CD007060.pub 2

Systematic Reviews of Surgery and NET

• Gurusamy KS; et al. Palliative cytoreductive surgery versus other palliative

treatments in patients with unresectable liver metastases from gastro- entero-pancreatic neuroendocrine tumours. Cochrane Review 2009. DOI:10.1002/14651858.CD007118.pub2.

• Ravaioli M; et al. Liver transplantation for hepatic tumors: A systematic
• review. World J Gastro 2014;20:5345.
• Rossi R; et al. Endoscopic techniques to detect small bowel endocrine

tumours: A literature review. UEG Journal 2017;5:5.

• Rossi R; et al. Liver transplantation for unresectable neuroendocrine

tumor metastases. Ann Surg Oncol 2014;21:2398.

• Tohti M; et al. Is perioperative steroid replacement therapy necessary for

pituitary adenomas treated with surgery. Plos One 10(3): e0119621

• Yuan C; et al. Meta-analysis of liver resection versus nonsurgical

treatments for pancreatic neuroendocrine tumors with liver metastases. Ann Surg Oncol 2016;23:244.

Capurso G; et al. Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease. Neuroendo 2011;93:223. Guo J; et al. Systematic review of resecting primary tumor in PNETS patients with unresectable liver metastases. Oncotarget 2017;8:17396.

• Question:

Resection of the primary in pancreatic NET with unresectable liver or other site metastases.

• Format:

Prospective, randomized non-blinded trial

• Outcome measures:
• Primary: Overall survival
• Secondary: Progression free survival, treatment related

morbidity and mortality, relief of symptoms, QoL, genome analysis.

• Power calculation: 30% survival difference in non-randomised cohorts
• α error 0.1, β error 0.05
• 50 patients per arm for 30% survival difference
• 118 patients per arm for 25% survival

difference

Fendrich V; et al. Surgical treatment of gastrointestinal neuroendocrine

• tumours. Lang Arch Surg 2011;396:299.

Guo J; et al. Systematic review of resecting primary tumor in SBNETs patients with unresectable liver metastases. Oncotarget 2017;10:17396.

• Question:

Resection of the primary in small bowel NET with unresectable liver or other site metastases.

• Format:

Prospective, randomized non-blinded trial

• Outcome measures:
• Primary: Overall survival
• Secondary: Progression free survival, treatment related morbidity and

mortality, relief of symptoms, QoL, genomic analysis.

• Power calculation: 57-81% survival difference in non-randomised cohorts
• α error 0.1, β error 0.05
• 136 patients per arm for 40% survival difference
• 240 patients each arm for 30% survival difference

Finkelstein et al. Pancreatic neuroendocrine tumours: Analysis of

• verall survival of observation versus surgical resection. JoGS

2017;DOI 10.1007/s11605-017-3365-6

• Question:

Resection or observation of small primary (≤3 cm) in PNETS.

• Format:

Prospective, randomized non-blinded trial

• Outcome measures:
• Primary: Overall survival
• Secondary: Progression free survival, treatment related morbidity

and mortality, relief of symptoms, QoL, technique (resection versus enucleation), genomic analysis.

• Power calculation:

19% survival difference at 3 years in non- randomized cohorts

• α error 0.1, β error 0.05
• 541 patients per arm for 20% survival difference

Gurusamy KS; et al. Liver resection/ablation versus other treatments for neuroendocrine tumours in patients with resectable GEPNET liver

• metastases. Cochrane Review 2009. DOI:

10.1002/14651858.CD007118.pub2.

• Question:

Resection/ablation of liver metastases versus systemic therapy in patients with resectable liver metastases.

• Format:

Prospective, randomized non-blinded trial

• Outcome measures:
• Primary: Overall survival
• Secondary: Progression free survival, treatment related morbidity

and mortality, relief of symptoms, genome analysis.

• Power calculation: 10% survival difference in non-randomised cohorts
• α error 0.2, β error 0.05
• 389 patients per arm

Gurusamy KS; et al. Palliative cytoreductive surgery versus other palliative treatments in patients with unresectable liver metastases from gastro- entero-pancreatic neuroendocrine tumours. Cochrane Review 2009. DOI: 10.1002/14651858.CD007118.pub2.

• Question:

Cytoreductive resection/ablation in patients with unresectable GEPNET liver metastases.

• Format:

Prospective, randomized non-blinded trial

• Outcome measures:
• Primary: Overall survival
• Secondary: Progression free survival, treatment related morbidity

and mortality, relief of symptoms, genome analysis.

• Power calculation: 10% survival difference in non-randomised cohorts
• α error 0.1, β error 0.05
• 776 patients per arm

Summary of Outputs

• No randomised clinical trials in surgery for GEP NET

– Surgical perspective written for ANZ J Surgery on why there are so few surgical trials in NET

• Utilize genomic classification, QoL, progression free survival

– Systematic review of attitudes of indigenous peoples to tissue banking and genomics

• Recommend develop one trial protocol for presentation in December 2018,

and commencement in 2019. » Resection versus observation in small bowel primary » Primary resection versus observation in PNET with unresectable liver metastases » Resection versus observation for primary pnet ≤ 3cm » Resection versus enucleation in PNET

• Anything we do will be progress………

Search Strategy

• (((("Neuroendocrine Tumors"[Mesh] OR

"Carcinoma, Neuroendocrine"[Mesh]) OR "Carcinoid Tumor"[Mesh]) AND ("General Surgery"[Mesh] OR "Surgical Procedures, Operative"[Mesh] OR "surgery"[Subheading])) AND ("Randomized Controlled Trial"[Publication Type] OR "Controlled Clinical Trial"[Publication Type])) NOT "Melanoma"[Mesh]

• Cochrane, Pubmed, Medline, Embase, Cinahl,

Web of Science, Google Scholar, Google.

Search Strategy

• (((("Neuroendocrine Tumors"[Mesh] OR

"Carcinoma, Neuroendocrine"[Mesh]) OR "Carcinoid Tumor"[Mesh]) AND ("General Surgery"[Mesh] OR "Surgical Procedures, Operative"[Mesh] OR "surgery"[Subheading])) AND ("Randomized Controlled Trial"[Publication Type] OR "Controlled Clinical Trial"[Publication Type])) NOT "Melanoma"[Mesh]

• Cochrane, Pubmed, Medline, Embase, Cinahl,

Web of Science, Google Scholar, Google.

COMNETS The Slow Burning/Stalled & Cold Project List Slow Burning/Stalled: Slow or No progress Feedback from group- still level of interest Cold: No feedback

The Slow Burning/Stalled Project List

Recommendations for optimal clinical trial design in advanced NET:

Previous PIs unable to continue to take project forward: Danny Rayson: Change to Administrative and Research Lead Role Aimmee Hayes: Not able to devote time Katrin Sjoquist? Seeking alternate PI to move forward

The Slow Burning/Stalled Project List

NET classification by cell type

PIs – Chris Hemmings, Sylvia Asa Currently on hold (funding and workload) May be restarted 2018 Neither PIs attending. Chris has indicated by email that she hopes to get back into this project next year Additional Collaborators to feedback to Chris?

Cold Projects

NET registry

PIs? ?Issues with Canadian database contribution

• Simron to update

PLANET Database: Australia, NZ, Currently progressing in the mean time Supported by major NET centres IT by University of Melbourne

How to deal with Slow Burning/Stalled and Cold Projects: FOR DISCUSSION

Where PIs have still ongoing interest:

• Provide them with ongoing support for a fixed period of time before

closing?

Projects requiring new PIs or no feedback

• If no response within say 3 months- then close

• F-NET Project: Financial Outcomes in people with

Neuro-Endocrine Tumours

• David Wyld, John Leyden
• Kate Wakelin, Louisa Gordon, Jan Mumford
• Nick Pavlakis, Michael Michael
• Simone Leyden

Post CommNETS 2016, initial discussion re Project between Australian and Canadian Collaborators - Simron Singh, Lesley Moody Health Economic Advice from Canada – Christopher Longo Australia – Louisa Gordon Final decision was that there were sufficient differences between Health Systems in the Canada and Aust that Country Specific Survey tools would be required Presenting the Australian project

Objectives

• The aim of our study is to assess the financial burden experienced by patients

with NETs. Specifically, the aims are:

• 1. To quantify the medical cost outlays to patients over a defined period
• f time;
• 2. To identify the sources of patients facing high economic burden;
• 3. To understand the impact of financial burden on everyday living and

quality of life

• 4. To describe impacts that NETs has had on employment and insurance

experiences

• In addition, an exploratory analysis will be undertaken on medicare data, in

the patient cohort who consent to this separate project.

Methods

• Study design: Cross-sectional online survey of all NET patients referred by the

Investigating sites in this project or via the Unicorn Foundation.

• Population and setting: All people with NETs who are willing to complete the online
• survey. The survey will be specifically advertised via
• 1. The Unicorn Foundation via their current information sharing to NET

patients

• 2. Australian NET Clinical Services including Royal Brisbane and Women’s

Hospital, Peter MacCallum Cancer Centre, and Royal North Shore Hospital

• Sample size: We will target 250 NET patients which provides a sample size sufficient

for exploratory analyses and enables subgroups of interest e.g. with/without financial stress

• Data collection: An online survey will be constructed in ‘LabPortal’ which is

Queensland Institute of Medical Research (QIMRB’s) internal survey web design.

Progress to Date

• Australian survey tool developed in conjunction with Louisa Gordon.
• Protocol written and finalized
• Project initially submitted for approval to QIMRB ethics committee
• Development of online survey / database
• RBWH Ethics approval
• Peter MacCallum and Royal North Shore Hospital ethics applications

underway

• Some funding obtained from Ipsen to cover above costs including

payments to access individual Medicare data

Current Status

• Decision made to commence project / survey to go live 3

weeks ago

– Other sites ethics approvals likely to be at least 1-2 months away – Allow a period of at least a month to advertise the survey pre Christmas

• Recruitment via

– Direct email to individuals on Unicorn Foundation closed group – Direct discussion with patients seen in clinic at RBWH

Current Status

• Completion figures to 6th Dec:
• 32 entries (2 did not proceed but did consent, ?re-entered)
• 30 have undertaken the survey
• 23 completed in full – of these 4 did not consent to Medicare
• 7 partially completed (all in first week of commencement – nil

last 2 weeks)

• 14 from RBWH, 16 via Unicorn
• 1 paper survey posted

Current / Future Issues

• Survey tool/ logistics

– ? Taking longer to complete that first estimated – Already a couple of RBWH patients indicating cannot complete

• nline – have set up a process to provide paper copy of survey
• Recruitment

– Somewhat slower than expected (Unicorn Foundation) – Reminders via Unicorn Foundation, actively approach RBWH patients

• utside of clinic visits

– Aiming to open at other sites (Ethics Approval)

• Additional funding for data analysis by Health Economic team,

especially additional data obtained from Medicare

– Plan to review this with Unicorn Foundation in the new year

CommNETS Project 2017

De Desi sign and C nd Crea eation o

• f a

an Op n Optimal Sha hared ed C Care e Model f for N r NET patients i in the Co Community

Principal Investigator: Radhika Yelamanchili Co-PIs: Dorothy Lo, Alia Thawer, David Wyld, David Chan, Simron Singh Research Assistant: Harsh Naik

• The management of a NET patient often involves a multidisciplinary approach,

among the referring oncologists, surgeons, endocrinologists and a NET specialty centers.

• Given the increasing prevalence of NET patients, it is our hope to develop an
• ptimal shared care model that brings quality care closer to a patient.
• Very little has been published to date looking at models of shared care between

community oncologists (or equivalent) and experts in oncology, and no data was found ,defining such a model in NETs specifically.

• The first part of our project was to understand, the current landscape of

practice involving medical oncologists and NET specialty centers, using a survey.

Background

Methods

Survey Development

• Survey premise and domains were initially generated, at CommNETS 2016

roundtable discussion

• Questions generated during 3 conference calls and finalized over numerous

email communications (with input from all 6 members). Survey Dissemination

• Survey Monkey was used as the online platform.
• Survey link emailed to oncologists in Ontario (ONTMOA list)
• Queensland: respondents recruited through list serve used for local educational

meetings

• Survey sent out 2nd week of November 2017.

Methods

Survey Components

• Key domains: demographics, comfort with NETs treatment decisions and

management, interest in shared-care model and NETs education, barriers to collaboration, ideas for collaboration

• 30 questions (7-14 used modified Likert scale, 26-30 free text)

Responses To-Date

• 59 medical oncologists (MO) responded as of December 1.
• Data reviewed and analyzed for recurrent themes.

Demographics

• Only 11% of the MO were

practicing at a NET specialty center

• Majority of the MO had <= 5

NET patients in their individual practice.

28 13 13 5

5 10 15 20 25 30 0-5 6-10 10-50 > 50

6 . W hat is the approxim ate total num ber

• f NET patients in your individual

practice?

Highlights extent of involvement of MO, with limited experience Therefore need for education and collaboration

Approximate distance from the nearest NET specialty center

• Majority of the MO were

<100Km away,from the NET specialty center.

• However, atleast 1/3 of

them Australia and 1/6 of them in Canada were > 100 Km away with about 5-10 % of them > 250 Km away .

1 6 3 3 2 4 14 12 4 2

2 4 6 8 10 12 14 16 I am at a NET specialty centre < 50km 50-100km 100-250km > 250km

Australia Canada

6.67 11.11 40 38.89 20 33.33 20 11.11 13.33 5.56

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Australia Canada

> 250km 100-250km 50-100km

Travel times and financial toxicity to patients.

8.I f you have > 5 NET patients in your practice, w hat are your levels of com fort in m anaging NET patients ?

• About a quarter of the MO are

not comfortable with managing NET patients , despite being involved in the care of NET patients.

7 11 13

2 4 6 8 10 12 14 Not comfortable/ Somewhat uncomfortable/ Neutral Somewhat comfortable Very comfortable

7 23% 11 35% 13 42% Not comfortable/ Somewhat uncomfortable/ Neutral Somewhat comfortable Very comfortable

Need for education/increased collaboration

Levels of comfort with treatment decisions

2 16 13

2 4 6 8 10 12 14 16 18

Not comfortable/ Somewhat uncomfortable/ Neutral Somewhat comfortable Very comfortable

• 9. What are your levels of comfort with treatment

decisions for new ly diagnosed NET patient?

9 15 7

2 4 6 8 10 12 14 16 18

Not comfortable/ Somewhat uncomfortable/ Neutral Somewhat comfortable Very comfortable

• 10. What are your levels of comfort with treatment

decisions at progression?

At progression- transition point in the shared care model

1 6 24

5 10 15 20 25

1 2 . What are your levels of comfort with prescribing and managing som atostatin analogues?

4 8 19

5 10 15 20 25

1 3 . What are your levels of comfort with

• ral chemotherapy

( capecitabine/ tem ozolam ide) administration and monitoring?

20 7 4

5 10 15 20 25

1 4 . What are your levels of comfort in referral and m onitoring w hile

• n PRRT ( Peptide receptor

radionuclide therapy) ?

4 10 17

2 4 6 8 10 12 14 16 18

1 1 . What are your levels of comfort with prescribing and managing targeted agents?

LEVELS OF COMFORT WITH PRESCRIBING AND MANAGING VARIOUS TREATMENTS

Levels of comfort with referring

and monitoring while on PRRT

by country

• Majority of the Canadian(Ontarian)

MO not comfortable with PRRT, unlike their Australian(QL) colleagues.

2 4 1 17 3

2 4 6 8 10 12 14 16 18 Not comfortable/ Somewhat uncomfortable/ Neutral Somewhat comfortable Very comfortable

Australia Canada

28.6 85.00 57.1 15.00 14.3

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Australia Canada

Not comfortable/ Somewhat uncomfortable/ Neutral Somewhat comfortable Very comfortable

Interest ??

• About 55% not interested in

incorporating NET patients in their practice BUT WHY??

15 55% 8 30% 4 15%

7 . If you ha

u have < <5 N NETs pa patie ients i in n your indiv ndivid idual pr l practice, , then how interested are you in incorporating these patients in n your i indiv ndividual pr practice?

Not interested/ Somewhat not interested/ Neutral Somewhat interested Very interested

16 4 22 8 22 27 5 9 6 7 16 7

5 10 15 20 25 30

Disease site specific practice Lack of perceived need Lack of clinical experience with NET patients Labs restrictions Lack of access to site specific tumor board Limited or lack of access to nuclear imaging (Octreoscan/ Gallium 68 PET) Human resources/ allied health restrictions or challenges I ndividual time constraints Lack of support from speciality center Lack of interest Patient prefers to be referred to NET speciality center (for transfer of care) Not applicable (I am at a NET speciality center)

1 5 . Potential barriers to your involvem ent in the m anagem ent of NET patients: ( Please select all that apply)

Referral patterns

• Majority of MO refer 50-75% of their NET patients to a NET

specialty center.

• About 20 % of them refer ALL OF THEIR NET pts .
• Majority of the referrals are for specific procedures

/treatments and to some extent for treatment decisions,but less so for transfer of care

8 12 20 11 7

5 10 15 20 25 < 25% 25-50% 50-75% 100% I am a NET speciality center (I do not refer)

2 0 . W hat percentage of your NET patients do you refer to a NET specialty center?

Increased education and collaboration/ACCESS to specific procedures /treatments, could possibly help these stats and therefore wait time issues.

9 13 27

10 20 30 Transfer of care For treatment decisions PRRT / clinical trials / specific procedures / interventions

2 2 . W hen you refer patients to the NET specialty center, w ould you refer m ajority of them for: ( select one)

38 69% 10 18% 7 13%

2 3 . For patients referred to a NET specialty center, do the m ajority of them return to you?

Yes

Collaboration

• 50 % of the MO discussed

patients in the non NET specific MDT

9 25% 18 50% 9 25%

2 1 . I f you refer < 1 0 0 % of your NET patients, do you discuss the m anagem ent of these patients at:

NET specific multidisciplinary tumor board (MDT) Other MDT (Lung/ GI) Directly with a NET expert (via phone/ email)

Highlights gap in the care of the NET patients

Coordination of Care

• Majority of the coordination of

care is via email/phone .

• Telehealth and NET specific

tumor boards used to a lesser degree

13 13 40

5 10 15 20 25 30 35 40 45

Telehealth Provincial / Regional tumor boards Email / phone communication 2 5 . Are you using the follow ing services for coordination

• f care / shared care currently? ( select all that apply)

Highlights the time spent by providers- room for improvement…

Qs 26 to 30: Qualitative Themes

Asked about current challenges faced by providers (NET and non NET specialty centers)

ACCESS challenges Medical Oncologists outside a NET specialty center

• lack of timely access to expert services /opinion/tumor boards
• Access to treatment plan once established with expert (lack of

common EMR)

• Lack of resources to help stay current if you don’t see many NET

patients

• Patients retained in the NET centers and therefore not developing

experience

• Limited experience during training

Oncologists at NET specialty center

• Once they see an expert, patient rejects return to local health care

provider and therefore patient volumes in the clinics.

Qs 26 to 30: Qualitative Themes

COORDINATION challenges

• Too much time spent in coordination /collaborating with NET

specialty centers and the onus falls on the local provider

• Discussion at provincial tumour boards gives you more

questions than answers Suggestions

• Streamlined process required that tells you: when to seek

advice, who to seek it from, what avenue to use (email, telehealth, accessible tumor boards)

• Maintaining and distributing list of providers interested/experts

in NET

• Educating providers outside NET centers

Qs 26 to 30: Qualitative Themes

Asked about current challenges faced by patients and suggestions for improvement Challenges

faced by

patients

• Wait times to see a NET expert
• Wait times for nuclear imaging and treatment
• Redundant imaging /investigations
• Frustration due to lack of communication between centers
• Travel distances and financial toxicity involved in seeing a NET expert

PRRT

• Lack of access to Gallium scan
• Limited access to PRRT
• Lack of clarity/comfort with PRRT as a treatment option

Summary

• Medical oncologists outside NET specialty centers are involved in the care of

NET patients, but not necessarily comfortable/experienced .

• Key barriers to the management of NET patients include, limited access to

nuclear imaging, lack of access to NET specific tumor boards, lack of experience with NET patient management .

• PRRT is an area where more education is required, as to how it fits into the

NET treatment algorithm (particularly in ON, Canada).

• Lack of a streamlined process for coordination amongst providers, limited

access to experts /imaging , wait times and travel times for the patients are current foreseen barriers to the successful implementation of a shared care model.

Next Steps

• Review the current data more closely.
• Expanding the survey to surgeons/endocrinologists involved
• Work on educating the HCP outside the NET centers.
• Work on improving the tumor board access/ communication between the

NET and non NET specialty centers.

• Using the recurring themes and to come up with a ? pilot project (shared

care model) to streamline the transition of care between the NET specialty centre and the referring provider in the community

Pituitary Dysfunction after PRRT

Marianne Elston Richard Carroll Amanda Love David Wyld David Pattison Dale Bailey David Ransom

Hypotheses

• That the pituitary receives a clinically significant

dose of radiation during PRRT

• That patients who receive PRRT for unresectable

NET have higher rate hypopituitarism at 5+ years after therapy than those who have not received PRRT

• That the pattern of hypopituitarism differs from

external beam RT with higher rate 2° hypothyroidism

Background

• Normal tissues may express SSTRs

– Pituitary expresses SSTR1, 2a, 5 & poss. 3 – Pituitary SSTR subtype varies by pituitary cell type

• Highest SSTR2 – thyrotrophs, somatotrophs

Panetta Life Sci 1995; Miller JCEM 1995, O’Carroll 1995; Day 1995

• Limited data on PRRT & pituitary effects

– Two studies – up to 24/12, N=79

• Decr FSH/LH levels 21 postmenopausal females c.f. baseline
• Transient reduction spermatogenesis 35 males

Teunissen 2009; Kwekkeboom 2005

Background 2

• Hypopituitarism 2° external beam RT well known
• Hypopituitarism

– Associated with impaired QoL & premature mortality

Darzy 2013; Tomlinson 2001

– Onset may be insidious, not recognised or diagnosed late – Risk increases with time – Extent & time of onset is dose-dependent

• <30Gy isolated GH deficiency
• >60Gy 30-60% gonadotrophin, ACTH & TSH def. after 10 years

– Treatment is readily available

Aim

• To assess the prevalence of hypopituitarism in

patients >5 years after PRRT therapy compared to patients with unresectable NET who have not received PRRT

Methods

• Measurement basal pituitary hormone profile
• Hypopituitarism = loss >1 axes
• Effect size unknown – convenience sample 50

each group

Progress to Date

• NZ

– Multicentre ethics obtained (17/STH/23) – Locality assessment obtained – Waikato/Wellington

• Patient recruitment started
• Australia

– QLD

• Ethics obtained Royal Brisbane & Women’s Hospital

– WA

• Ethics submitted

Issues

• Not using a central lab

– Cost, logistically more difficult

• No baseline sample available

– Would take minimum 5 years to complete

• Effects of disease process itself on pituitary & treatment effects

– E.g. sick euthyroid syndrome; LAR effects

• Trying to mitigate by including controls
• Ability to recruit adequate numbers 5 years after PRRT
• Time interval may still be too short

NET Indicators Workshop

Facilitator: Ben Lawrence CommNETs 3 Honolulu Dec 9, 2017

Primary Objective

Develop a starting list of ~40 potential quality performance indicators for NET diagnosis and treatment services (in New Zealand, Australia and Canada) that can enter further assessment in a modified Delphi consensus

Setting the scene – measuring quality

Network! registry (NZ) – Primary data New Zealand Cancer Registry using ICD-03 codes. – Secondary data public and private pathology records in every district health board (n=20) – Inspection of individual medical record – Pulmonary small cell carcinoma excluded

• 3334 patients, including presentation, pathology, investigation,

treatment type and survival.

• We will show only 2008 to 2012 today

New Zealand is divided into…

Data analysis

Anonymised / ordered highest to lowest / 2008 and 2012 Comment on availability of (ease of access to) data Readily available in patient record Available but often difficult to find Often not recorded

Presented acutely

10 20 30 40 50 60 70 80 90 100 A B C D E F G H I J K L M N O P Q R S % patients presenting acutely % patients not presenting acutely

Family history of cancer recorded

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% A B C D E F G H I J K L M N O P Q R S % Recorded % Not Recorded

Distant metastases at diagnosis

10 20 30 40 50 60 70 80 90 100 A B C D E F G H I J K L M N O P Q R S % patients without metastases at diagnosis % patients metastic at diagnosis

Unknown primary site

0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 A B C D E F G H I J K L M N O P Q R S % patients with known primary site % patients with unknown primary site

Chromogranin A measured

10 20 30 40 50 60 70 80 90 100 A B C D E F G H I J K L M N O P Q R S % patients not having CgA measurement % patients having CgA measurement

MDM review documented

10 20 30 40 50 60 70 80 90 100 A B C D E F G H I J K L M N O P Q R S % patients reviewed at MDT % patients not reviewed at MDT

GEP NET with Ki-67% recorded

0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 A B C D E F G H I J K L M N O P Q R S % patients with ki67 recorded % patients with ki67 not recorded

Lung NET with mitotic count recorded

0.00 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 A B C D E F G H I J K L M N O P Q R S % patients with mitotic count not recorded % patients with mitotic count recorded

Patient received cross sectional imaging (CT, MRI)

10 20 30 40 50 60 70 80 90 100 A B C D E F G H I J K L M N O P Q R S % patients not receiving cross sectional imaging % patients receiving cross sectional imaging

Patient received functional imaging (Octreoscan, FDG PET or Ga-tate PET)

0.00 20.00 40.00 60.00 80.00 100.00 120.00 A B C D E F G H I J K L M N O P Q R S % patients not receiving functional imaging % patients receiving functional imaging

Patient received surgery

10 20 30 40 50 60 70 80 90 100 A B C D E F G H I J K L M N O P Q R S % patients having surgery % patients not having surgery

Patient received somatostatin analogue

10 20 30 40 50 60 70 80 90 100 A B C D E F G H I J K L M N O P Q R S % patients not receiving somatostatin % patients receiving somatostatin

Pts by Cancer Region

100 200 300 400 500 600 700 800 Central Midland Northern Southern

Number of patients

Number of patients

Overall survival by region

A B C D

A B C B 7.6e-05 C 0.322 0.018 D 0.018 0.136 0.270

Lessons

Quality is difficult to measure!

– Important but not measurable – Important but reflect historic practice – Variability might indicate an area of need (or a bad indicator) – Some measures reflect multiple practices – Some measures are only relevant to subtypes of NETs – The definition of subtypes can be stable or unstable – Determining subtypes means more data to collect

Primary Objective

Develop a starting list of ~40 potential quality performance indicators for NET diagnosis and treatment services (in New Zealand, Australia and Canada) that can enter further assessment in a modified Delphi consensus

Secondary Objectives

Strengthen links and share perspectives between patients, pharmacists, nurses, specialties and countries by working together Contribute to research with a high chance of leading to real world change that improves patient outcomes

Method - Modified RAND/UCLA Delphi

Literature review and synthesis Delphi Round 1 Online survey (Feb 2018) Delphi Round 2 Panel Meeting (ENETs 2018)

Method - Modified RAND/UCLA Delphi

Delphi Round 0 Nominal Group Technique Delphi Round 1 Online survey (Feb 2018) Delphi Round 2 Panel Meeting (ENETs 2018)

Method - Modified RAND/UCLA Delphi

Delphi Round 0 Nominal Group Technique Delphi Round 1 Online survey (Feb 2018) Delphi Round 2 Panel Meeting (ENETs 2018)

Workflow in principle

Delphi Round 0 Nominal Group Technique Delphi Round 1 Online survey (Feb 2018) Delphi Round 2 Panel Meeting (ENETs 2018) International Comparison Negotiation with Health Services (rational, data required, targets, fit with existing) Presentation and publication

Method - Modified RAND/UCLA Delphi

Delphi Round 0 Nominal Group Technique 945 – 1015 Introduction 1015 – 1100 Question 1 1130 – 1215 Question 2 1215 – 1300 Question 3 1500 – 1545 Question 4

Method - Modified RAND/UCLA Delphi

Delphi Round 0 Nominal Group Technique 945 – 1015 Introduction

• NET Registry data – measuring quality is hard
• What is an indicator?
• Nominal Group Technique – a how-to-guide
• Toolkit for inspiration- stay in the headspace

What is a NET quality performance indicator?

• An objective measure of NET diagnosis and treatment service quality that

allows comparison by:

– Country – Region – Institution

• drive quality improvement in NET diagnosis and treatment services
• closely related to standards of service provision

NZ Ministry of Health CommNETs

Principles of good indicators

• Measurable
• Related to best practice
• Uniformly applicable is easier, but might not be better
• Likely to identify equity gaps

– e.g., impact of ethnicity, age

• Data-driven – but if no data then broad expertise
• Don’t be (too) limited by what is currently available

– Identify areas where data quality improvement is required (e.g., grade)

Why is CommNETs interested in indicators?

• NET care is variable.
• Measuring indicators

– changes health practitioner behaviour – identifies inequity – will improve patient outcomes

• BUT ONLY IF HEALTH SYSTEMS CHOOSE THE RIGHT INDICATORS

Workshop Questions Best indicators of….

• 1. Outcome
• 2. Treatment and Follow-up
• 3. Pathology and Staging
• 4. Initial presentation and clinical assessment

Question 1: Name indicators of outcome quality for people with NETs

Table 1 Simone Richard Prasanta Jonathan B Matthew Val Marguerite Table 2 Enrico Marianne Alia Gabby Tehmina Dorothy David R Simron Table 3 Jan Dev Kate Win Nadia Tim Eva Table 4 Alana Amanda Chris Calvin David L Jamil Michael M Andrew Table 5 Celia Lucy Jonathan K Daryl Bill Cindy Daenik Michael V Table 6 Radhika Sten Bin Paul Rachel Sharon Aimee

Nominal Group Technique

a structured method for group brainstorming that encourages contributions from everyone.

– When some group members are much more vocal than others. – When some group members think better in silence. – When there is concern about some members not participating. – When all or some group members are new to the team. – When the issue is controversial.

NGT Method

1. State the subject. Clarify the statement as needed. 2. Choose your facilitator 3. Each team member silently thinks of and writes down as many ideas as possible in a set period

• f time (5 minutes).

4. Each member in turn states aloud one idea. Facilitator records it (numbered) on the flipchart (verbatim).

• No discussion is allowed, not even questions for clarification.
• Ideas given do not need to be from the team member’s written list. Indeed, as time goes on, many ideas will not be.
• A member may “pass” his or her turn, and may then add an idea on a subsequent turn.

Continue around the group until all members pass (or 10 minutes). 4. Discuss each idea in turn (20 mins)

• Wording may be changed only when the idea’s originator agrees.
• Ideas may be stricken from the list only by unanimous agreement.
• Discussion may clarify meaning, explain logic or analysis, raise and answer questions, or state agreement or

disagreement.

5. Vote on the ideas privately then using dot voting and add up to choose top 5 indicators (5 min). 6. Facilitator shares top five to other groups (5 min).

Facilitator role – really important!

• During first reading of ideas in turn, do not allow any discussion – at all!
• During first reading – write statements verbatim.
• Discussion should be equally balanced among all ideas.
• Do not allow discussion to turn into argument! The primary purpose of the

discussion is clarification. It is not to resolve differences of opinion.

• Keep all ideas visible. When ideas overflow to additional flipchart pages, lay

pages across table so all ideas are still visible to everyone.

Remember all primary sites and secretory syndromes

Rectum Colon Appendix Ileum / Jejenum Duodenum Pancreas Stomach Oesophagus Adrenal Paraganglioma Lung Thymus Thyroid

Tools – some food for thought

1. Recent draft CRC indicators in NZ 2. ENETs guideline consensus statements

• 1. Name indicators of outcome quality for people with NETs

1. State the subject. Clarify the statement as needed. 2. Choose your facilitator 3. Each team member silently thinks of and writes down as many ideas as possible in a set period

• f time (5 minutes).

4. Each member in turn states aloud one idea. Facilitator records it (numbered) on the flipchart (verbatim).

• No discussion is allowed, not even questions for clarification.
• Ideas given do not need to be from the team member’s written list. Indeed, as time goes on, many ideas will not be.
• A member may “pass” his or her turn, and may then add an idea on a subsequent turn.

Continue around the group until all members pass (or 10 minutes). 4. Discuss each idea in turn (20 mins)

• Wording may be changed only when the idea’s originator agrees.
• Ideas may be stricken from the list only by unanimous agreement.
• Discussion may clarify meaning, explain logic or analysis, raise and answer questions, or state agreement or

disagreement.

5. Vote on the ideas privately then using dot voting and add up to choose top 5 indicators (5 min). 6. Facilitator shares top five to other groups (5 min).

Question 2: Name indicators of treatment and follow-up quality for people with NETs

Table 1 Simone Sten Kate Calvin Nadia Val David R Table 2 Enrico Richard Chris Daryl David L Dorothy Eva Table 3 Jan Marianne Jonathan K Paul Bill Tim Michael M Simron Table 4 Alana Dev Bin Jonathan B Rachel Jamil Daenik Andrew Table 5 Celia Amanda Prasanta Gabby Matthew Cindy Aimee Michael V Table 6 Radhika Lucy Alia Win Tehmina Sharon Marguerite

2: Name indicators of treatment and follow-up quality for people with NETs

1. State the subject. Clarify the statement as needed. 2. Choose your facilitator 3. Each team member silently thinks of and writes down as many ideas as possible in a set period

• f time (5 minutes).

4. Each member in turn states aloud one idea. Facilitator records it (numbered) on the flipchart (verbatim).

• No discussion is allowed, not even questions for clarification.
• Ideas given do not need to be from the team member’s written list. Indeed, as time goes on, many ideas will not be.
• A member may “pass” his or her turn, and may then add an idea on a subsequent turn.

Continue around the group until all members pass (or 10 minutes). 4. Discuss each idea in turn (20 mins)

• Wording may be changed only when the idea’s originator agrees.
• Ideas may be stricken from the list only by unanimous agreement.
• Discussion may clarify meaning, explain logic or analysis, raise and answer questions, or state agreement or

disagreement.

5. Vote on the ideas privately then using dot voting and add up to choose top 5 indicators (5 min). 6. Facilitator shares top five to other groups (5 min).

Question 3: Name indicators of pathology and staging quality

Table 1 Simone Lucy Jonathan K Jonathan B Bill Dorothy David R Simron Table 2 Enrico Sten Bin Gabby Rachel Tim Eva Michael V Table 3 Jan Richard Prasanta Win Matthew Jamil Michael M Table 4 Alana Marianne Alia Calvin Tehmina Cindy Daenik Andrew Table 5 Celia Dev Kate Daryl Nadia Sharon Aimee Table 6 Radhika Amanda Chris Paul David L Val Marguerite

• 3. Name indicators of pathology and staging quality

1. State the subject. Clarify the statement as needed. 2. Choose your facilitator 3. Each team member silently thinks of and writes down as many ideas as possible in a set period

• f time (5 minutes).

4. Each member in turn states aloud one idea. Facilitator records it (numbered) on the flipchart (verbatim).

• No discussion is allowed, not even questions for clarification.
• Ideas given do not need to be from the team member’s written list. Indeed, as time goes on, many ideas will not be.
• A member may “pass” his or her turn, and may then add an idea on a subsequent turn.

Continue around the group until all members pass (or 10 minutes). 4. Discuss each idea in turn (20 mins)

• Wording may be changed only when the idea’s originator agrees.
• Ideas may be stricken from the list only by unanimous agreement.
• Discussion may clarify meaning, explain logic or analysis, raise and answer questions, or state agreement or

disagreement.

5. Vote on the ideas privately then using dot voting and add up to choose top 5 indicators (5 min). 6. Facilitator shares top five to other groups (5 min).

Question 4: Name indicators of quality regarding the initial presentation and clinical assessment (including biochemistry)

Table 1 Simone Amanda Kate Calvin Matthew Tehmina Aimee Simron Table 2 Enrico Lucy Chris Daryl Rachel Sharon Marguerite Andrew Table 3 Jan Sten Jonathan K Paul Matthew Cindy David R Table 4 Alana Richard Bin Jonathan B David L Sharon Eva Michael V Table 5 Celia Marianne Prasanta Gabby Bill Val Michael M Table 6 Radhika Dev Alia Win Rachel Dorothy Daenik

• 4. Name indicators of quality regarding the initial presentation

and clinical assessment (including biochemistry)

1. State the subject. Clarify the statement as needed. 2. Choose your facilitator 3. Each team member silently thinks of and writes down as many ideas as possible in a set period

• f time (5 minutes).

4. Each member in turn states aloud one idea. Facilitator records it (numbered) on the flipchart (verbatim).

• No discussion is allowed, not even questions for clarification.
• Ideas given do not need to be from the team member’s written list. Indeed, as time goes on, many ideas will not be.
• A member may “pass” his or her turn, and may then add an idea on a subsequent turn.

Continue around the group until all members pass (or 10 minutes). 4. Discuss each idea in turn (20 mins)

• Wording may be changed only when the idea’s originator agrees.
• Ideas may be stricken from the list only by unanimous agreement.
• Discussion may clarify meaning, explain logic or analysis, raise and answer questions, or state agreement or

disagreement.

5. Vote on the ideas privately then using dot voting and add up to choose top 5 indicators (5 min). 6. Facilitator shares top five to other groups (5 min).

Workflow in principle

Delphi Round 0 Nominal Group Technique Delphi Round 1 Online survey (Feb 2018) Delphi Round 2 Panel Meeting (ENETs 2018) International Comparison Negotiation with Health Services (rational, data required, targets, fit with existing) Presentation and publication

Workflow in principle

Delphi Round 0 Nominal Group Technique Delphi Round 1 Online survey (Feb 2018) Delphi Round 2 Panel Meeting (ENETs 2018) International Comparison Negotiation with Health Services (rational, data required, targets, fit with existing) Presentation and publication

Working Group – next step

• 1. Collate statements
• 2. Review statements
• 1. Rewrite as appropriateness statements
• 2. Rewrite as quality indicators (if performance measures)
• 3. Prepare Delphi 1 survey
• a. Ensure even coverage of patient journey
• b. Ensure coverage of speciality areas and non-medical
• c. Develop criteria for assessment

a. Measurable, clinically meaningful, presence of supporting data

Workflow in principle

Delphi Round 0 Nominal Group Technique Delphi Round 1 Online survey (Feb 2018) Delphi Round 2 Panel Meeting (ENETs 2018) International Comparison Negotiation with Health Services (rational, data required, targets, fit with existing) Presentation and publication

Thank you CommNETs!!

NET Lit search

• Pubmed: ("performance indicator" OR "quality indicator" OR "quality of care"

OR "quality assurance" OR "quality-related process") AND (neuroendocrine OR carcinoid) = 22 =>0

• Medline (ovid): ((Carcinoma, Neuroendocrine/ or Neuroendocrine Tumors/)

OR (carcinoid.mp. or Carcinoid Tumor/)) AND (Quality Assurance, Health Care/ or Quality Indicators, Health Care/ or quality indicator.mp. or "Quality

• f Health Care"/) = 10 +> 0
• Embase: (health care quality/ or quality indicator.mp. OR quality control/)

AND (neuroendocrine tumor/ or gastroenteropancreatic neuroendocrine tumor/ OR neuroendocrine tumor.mp. OR carcinoid/ or stomach carcinoid/

• r bronchus carcinoid/ or gastrointestinal carcinoid/ ) = 206 => 0
• Scopus: ( TITLE-ABS-KEY ( "neuroendocrine tumor" ) OR TITLE-ABS-

KEY ( carcinoid ) OR TITLE-ABS- KEY ( neuroendocrine AND tumour ) OR TITLE-ABS- KEY ( neuroendocine AND carcinoma ) AND TITLE-ABS- KEY ( quality AND indicator ) OR TITLE-ABS- KEY ( quality AND improvement ) OR TITLE-ABS- KEY ( quality AND care ) OR TITLE-ABS- KEY ( quality AND indicator ) =470 => 0

Making pNETs immunogenic

Investigators: Ben Lawrence, Eva Segelov, Simron Singh, Lorriane Chantrill, Nick Pavlakis, Chris O’Callahan, Kate Parker, Rachel Goodwin, Ralph Wong, David Ransom, David Wyld, Micheal Michael, Danny Rayson, Bridget Robinson, Sharon Pattison, Katrin Sjoquist.

Revised Agenda today

• 9-945 New ideas
• 945-11 – Developing Quality Indicators for

NETs

• 11-1130- Morning Tea
• 1130-1300 – Developing Quality Indicators
• 1300-1500 – BREAK!!!!!!
• 1500-1545 – Developing Quality Indicators
• 1545-1630 – COMMNETs future planning

New ideas 3 minute presentations

• Nutrition Tookit for NETs – Sharon Pattison
• Nutrition in NETs – Michael Michael
• NET SANGIUS – Michael Michael
• The CABERNET Study – David Ransom
• NET Registry - Simron Singh

Nutrition Toolkit for NETs in New Zealand

PIs: Sharon Pattison (Senior Lecturer and Med Onc, Dept of Med, University of Otago) Tracy Perry (Senior Lecturer, Dept Human Nutrition, University of Otago) Project team: Olivia Cochrane (Mdiet student), Kelsey Paterson (Mdiet student), Siobhan Conroy (CEO Unicorn Foundation NZ), Avril Hull (NET nurse specialist), Adeline Wong (Dietitian Practitioner)

Background and aims

• Information on nutrition for NET patients identified as

an area of need by Unicorn Foundation NZ members at 2017 patient education day

• Collaboration between Departments of Medicine and

Human Nutrition, University of Otago and Unicorn Foundation NZ

• Aim: to develop a nutrition tookit for NET patients in

New Zealand

– Forms two Master of Dietetics research projects

Methods and anticipated

• utcomes
• 1. Literature review – description of the current

evidence

• 2. Identify the information gaps and nutrition

priorities of NET patients in New Zealand

• 3. Development and focus group testing of a

nutrition toolkit for NETs

Funding, opportunities for collaboration and contacts

• Nutrition in NETs is an area of need not just

identified by NET patients in Aotearoa

• Opportunity for CommNETs to create a

Nutrition working group

PAYA NETs

• Queensland registry – David Wyld
• Australian Paediatric Oncology contacts – Eva

Segelov

• Additional questions to answer from NETWork!

registry when MoH data available

– Survival when minimum 5 year survival data mature (22 years maximum follow up)

• What we need – Canadian contacts!

– Additional Australian contacts

1st outputs

• Description of PAYA NETs

– NETWork! registry with international comparison – Survival data (where possible) – Appendiceal NETs

• Rate of right hemi-colectomy and outcomes with and

without

– Others

• Associations with familial cancer syndromes

Future directions

• No guidelines exist for this NET patient group

– Follow up – what, where, for how long and with whom – Does follow up need to be tailored for the PAYA NET group – or are adult guidelines adequate

• Comparison to adult NET group – are outcomes different?
• Use dataset to inform

– Guidelines for follow up for this group – Areas where evidence is lacking

• Appendiceal NET diagnosed ≤30 – patient survey of
• utcome with and without R hemicolectomy

Minimum recommended registry data points – starting suggestions

Minimum

• Patient demographics

– Age, gender, ethnicity, regional code

• Personal history of malignancy
• Family history of malignancy
• Tumour description

– Primary, grade, stage – Ki67, mitotic count, differentiation

• Treatment description

– Surgery – Systemic

• Outcome

– Death (last alive date)

Minimum recommended registry data points – starting suggestions

Minimum

• Patient demographics

– Age, gender, ethnicity, regional code

• Personal history of malignancy
• Family history of malignancy
• Tumour description

– Primary, grade, stage – Ki67, mitotic count, differentiation

• Treatment description

– Surgery – Systemic

• Outcome

– Death (last alive date)

Additional data-points

• Imaging

– Anatomical – Functional

• Type of surgery
• MDM discussion

– Hard to collect, not always NET MDM

• Outcome

– Relapse

Familial Endocrine Disorder Registry

Richard Carroll Marianne Elston Alana Gould Wellington, NZ Hamilton, NZ Wellington, NZ Amanda Love Win Meyer-Rochow Simon Harper Brisbane, Aus Hamilton, NZ Wellington, NZ

Aim

To establish a regional/national/international registry for patients and families with confirmed or suspected germline mutations predisposing to endocrine neoplastic disorders

Progress to date

• Discussion with other national registries
• Investigator review
• Ethics application submitted November 2017
• Regional Maori application submitted November 2017
• Recruitment to commence January 2018

Next step

• Commence recruitment in Greater Wellington/Central region and

Hamilton/Midlands region early 2018 (population 2 million)

• Review of progress and presentation of data
• Commence recruitment in South Island (0.9 million), Auckland region (1.6

million), and rest of NZ later in 2018

• Establish registry in other CommNETS countries/regions or align with

similar registries 2019 onwards

Effective Date: 25 April 2013 Page 1 of 6

All fields are required, an incomplete form will be returned to the submitter. If a field is not completed, please note the reason.

Proposed Study Title

Study Title: TEMPTATION: Temozolomide and PD-L1 To Activate The Immunogenicity Of NETs Request Date: 11 March 2017

Principal Investigator Contact Information

Name: Dr Benjamin Lawrence Title: Consultant Medical Oncologist and Senior Research Fellow Address 1 University of Auckland Address 2 85 Park Road, Grafton City, ST, Zip Auckland, New Zealand Phone/Fax: +64 21 494 337 E-mail: b.lawrence@auckland.ac.nz

Institution Contact Information

Name: Kate Parker Address 1 University of Auckland Address 2 85 Park Road, Grafton City, ST, Zip Auckland Phone/Fax: +64 21 678 907 website www.network.ac.nz

Contracting Information (if applicable)

Name: Phone/Fax: E-mail:

Study Information

Indication Advanced well differentiated pancreatic neuroendocrine tumours Phase: II Number of Subjects: 105

Effective Date: 25 April 2013 Page 2 of 6

Background and Rationale

• Provide background on unanswered question(s) the study is attempting to answer (do not exceed one page)

The incidence and prevalence of pancreatic neuroendocrine tumours is increasing (1). Unresectable pancreatic NETs are inevitably fatal. Current pharmacological therapies have a modest impact with 40 - 60% of patients progression free at 12 months (2, 3, 4, 5). Temozolomide (with capecitabine) is an accepted systemic option for advanced pancreatic NETs (4, 5). Temozolomide is an alkylator that creates multiple ‘nicks’ in tumour DNA by causing excess methylation of guanine nucleosides leading to DNA strand breaks (6). These ‘nicks’ require repair by the DNA repair enzyme MGMT, or in the absence of MGMT, by standard DNA mismatch repair enzymes MLH1, PMS2, MSH2, and MSH6. Prior to repair, these DNA ‘nicks’ are likely to be immunogenic. Temozolomide can be rendered ineffective in mouse models by removal of CD8+ T-cells (7, 8), supporting the hypothesis that the action of temozolomide is dependent on the immune infiltrate reacting to DNA ‘nicks’. Our data (9) show that pancreatic NETs have a low mutation rate, and are therefore not obvious candidates for single agent PDL-1 inhibitor therapy. Our group and others (10, 11, 11) have shown that approximately half of metastatic pancreatic NETs have reduced MGMT expression, and we have shown that this sub-group can be predicted by a stereotyped aneuploidy where the NET loses one copy of the same 10 distinct chromosomes (9). This sub-group, more than other pancreatic NETs, may be vulnerable to temozolomide, and more likely to develop the DNA ‘nicks’ that occur when repair is not possible. We propose that temozolomide creates an artefactual hypermutable phenotype, that tempts the immune system, and this immune response can be enhanced using concurrent immune checkpoint inhibitor therapy. We therefore hope to exploit a vulnerability in the pancreatic NET genome by coupling an existing standard therapy (temozolomide and capecitabine) with durvalumab, or durvalumab and tremilimumab, to increase the efficacy of these immune agents. This trial concept has been developed collaboratively by the NETwork! group in New Zealand, the Australasian Gastrointestinal trials group, and the Canadian Cancer Trials Group.

Objectives

• List the objectives to correspond directly with the listed hypotheses:

Assess the anti-cancer activity of durvalumab and tremelimumab in pancreatic NETs given concurrently with temozolomide-based cytotoxic chemotherapy Prospectively assess a genomic biomarker that might predict sensitivity to combined alkylator and PD-L1 +/- CTLA4 inhibitor therapy (measured by simple FISH) Assess the immune and genomic milieu of pancreatic NETs before and during durvalumab +/- tremelimumab and temozolomide-based therapy.

Hypothesis

• List the clinical Hypotheses in order of priority:
• 1. Concurrent durvalumab +/- tremelimumab and temozolomide-based cytotoxic chemotherapy improves

response rate in people with advanced pancreatic NETs.

• 2. Pancreatic NETs with stereotyped aneuploidy will be more vulnerable to concurrent durvalumab +/-

tremelimumab and temozolomide-based cytotoxic chemotherapy than pancreatic NETs with alternative genomes.

Effective Date: 25 April 2013 Page 3 of 6

• 3. Temozolomide-based cytotoxic chemotherapy will sensitize pancreatic NETs to PD-

L1 inhibitor therapy by increasing the immunogenicity of pancreatic NETs.

Study Design/Clinical Plan

• Provide a concise overview stating the type of experimental design

Participants: Advanced pancreatic neuroendocrine tumours (metastatic or locally advanced and not suitable for surgical management). Well-differentiated histology. Ki-67 < 55%. 0-2 lines of prior therapy (not including somatostatin analogue) but no previous temozolomide, streptozotocin, dacarbazine, PD-L1 or CTLA4 inhibitor. Evidence of progression within previous 6 months. Requires a pre-treatment core biopsy (FFPE, if not already available). Intervention: A prospective phase II trial (n=105) with 1) Safety run in of Tem / Cap / Durv / Trem Arm (n = 5). 2) Then 1:2:2 randomization to 3 cohorts a) Tem Cap alone (n = 20) b)Tem Cap Durv (n = 40) c) Tem Cap Durv Trem (n = 4). Temozolomide and capecitabine given as per existing protocols, concurrently with durvalumab +/- tremelimumab given using existing 4 weekly protocols. Assessment: 12 weekly CT scans until progression. Translational endpoints at 12 weeks including biopsy (optional), blood for ctDNA. Prespecified variables for planned analysis: Grade, line of therapy, presence of stereotyped aneuploidy (FISH), PD-LI expression, MGMT expression. Endpoints:

• Primary endpoint – RR measured by RECIST
• Secondary endpoints - 12 month PFS, iRR, median PFS, Safety (rates of adverse events).
• Translational endpoints – aneuploidy, MGMT expression. Change in circulating tumour DNA, change in

immune infiltrate and genome on rebiopsy.

Treatment

• List the clinical dosage/dosage form, route, and dose regimen:

4 week cycle (28 days): Oral capecitabine 825mg/m2 Day 1 to 14. Treat to progression. Oral temozolomide 200mg/m2 nocte Day 10 to 14. Treat to progression. IV Durvalumab 1500mg Day 14. Treat to progression. IV Tremelimumab 75mg Day 14. Stop after 4 cycles.

Collateral Research

• Include biomarkers, PK, etc.
• Genomic analysis of pre-therapy biopsy for aneuploidy, DNA repair enzyme expression (including but not

limited to MGMT), whole genome methylation, tumour suppressor gene mutation mapping. Comparison to subsequent response. (separate funding source)

• Analysis of immune infiltrate in baseline (e.g., CD8+ TIL density, MHC class, PDL1 and PD1 expression,

effector and memory T cell frequency, TH 1:2 ratio, MDSC’s, M2 macrophages, TReg frequency). Comparison to 12-week biopsy when available.

• Change in circulating tumour DNA (focus on aneuploidy) in responders and non-responders
• Change in baseline and 3 month Ga-tate PET as an earlier predictor of long term response (exploratory)

Commented [BL1]: We initially had Ga-tate PET here – can the Canadians do this? Would be good if no RECIST response. Commented [BL2]: Check

Effective Date: 25 April 2013 Page 4 of 6

Statistical Plans

• Include justification for clinical sample size and primary hypothesis testing:

Prior studies suggest a RR with temozolomide / capecitabine chemotherapy ranging from 50% to 70% (4, 5) however these are seen in retrospective studies and the true RR is likely to be lower in a prospective study, more in keeping with the 30- 40% seen in other trials of alkylator therapy (12). INSERT STATS COMMENT HERE REGARDING 3 NON-COMPARTIVE COHORTS AND A PICK THE WINNER DESIGN AFTER DISCUSSION WITH STATISTICIAN

Budget Summary

• Please be sure to complete budget template (excel document)

Total Amount Requested: (Include overhead) Cost estimate (to be refined): Per patient Local site costs 105 @ 15,000 (note: longer than usual natural history) $1,050,000 (plus $100K for additional biopsy costs as non-standard of care) Individual site opening costs and coordinator employment: 16 @ $10,000 = AU $160K Central coordination via AGITG and NMHRC Clinical Trial Centre AND CCTG $400K Total cost estimate: $1,710,000K Additional sources of funding required? (Yes/No) If Yes, please be specific. 105 plus 30 (n=30 estimated voluntary rebiopsy) = 135 samples @ $400 per tumour sample including costs of pulling blocks = AU $54,000 for basic MGMT, FISH, T cell subtyping etc as above). All cases with blood collect at baseline and 12 weeks for germline DNA and pre and post treatment measurement of ctDNA) = 210 samples at $50 per sample including transport costs = AU$10,500K Total cost estimate: AU$64,500

Timelines and Study Plans

Number of Sites: 16 sites Site Names: Auckland Hospital, Auckland, New Zealand. PI B Lawrence Monash Health, Melbourne Australia. PI E Segelov Odette Cancer Centre, Sunnybrook Hospital, Toronto, Canada. PI S Singh Royal North Shore Hospital, Sydney Australia. PI N Pavlakis. Kinghorn Cancer Centre, Sydney, Australia. PI L Chantrill. Royal Brisbane Hospital, Brisbane, Australia. PI Wyld St John of God Hospital, Perth, Australia. PI D Ransom Peter MacCallum Cancer Institute, Melbourne, Australia. PI M Michael Ottawa Hospital Cancer Centre, Ottawa, Canada. PI R Goodwin Cancer Care Manitoba, Winnipeg, Canada. PI R Wong. Atlantic Clinical Cancer Research Unit, Halifax, Canada. PI D Rayson. Christchurch Hospital, Christchurch, New Zealand. PI B Robinson Dunedin Hospital, Dunedin, New Zealand. PI S Pattison University of Calgary; Tom Baker Cancer Centre. Canada. PI C Card Saskatoon Cancer Centre, Saskatchewan Cancer agency. Canada. PI T Asif University of Sydney, Sydney, Australia. PI K Soquist Study Start Date: Sept 2018 Study End Date: Recruitment close September 2020

Commented [BL3]: Chris to liaise with statistician

Effective Date: 25 April 2013 Page 5 of 6

Number of Subjects: 110 First Patient In Date: September 2018 Last Patient Out Date: Treat to progression Enrollment Period in Months: 24

Publication Plan

Where are you planning to submit for publication? (journals, etc): High Impact Journal if findings are appropriate Are you planning to present your data at a scientific meeting? ASCO 2021 or ESMO 2021

• Primary endpoint analysis
• Early Secondary Endpoints (Interim Safety)
• Early translational endpoints (Change in immune infiltrate, FISH and IHC

predictors of response, Ga-tate PET response) ASCO 2022 or ESMO 2022

• Intermediate Secondary Endpoint analysis (1 year PFS)
• Translational endpoints

ASCO 2023 or ESMO 2023

• Final secondary endpoints (OS, Final Safety)

Drug Supply Information

Drug Supplies Required (Yes/No)? Yes List Drug Supplies and Amount Required: Drug Name: Durvalumab Amount: 1500mg q 4 weekly until first of either: progression or intolerance List Drug Supplies and Amount Required: Drug Name: Tremelimumab Amount: 75mg q 4 weekly until first of either: progression or intolerance List Drug Supplies and Amount Required: Drug Name: temozolomide 200mg/m2 on Day 10 to 14 of a 28 day cycle. Repeating until progression, with dose reductions for toxicity. Expected median 13 cycles (with dose reductions). List Drug Supplies and Amount Required: Drug Name: capecitabine 825mg/m2 bd for 14 days of every 28 days. Repeating until progression, with dose reductions for toxicity. Expected median 13 cycles (with dose reductions). Placebo Required (Yes/No)? No Additional Sources of Drug Supply (Yes/No). If Yes, please specify

• Yes. Temozolomide and capecitabine provided via public funding as part of

standard of care in some participating countries (e.g., New Zealand, some Canadian states)

Commented [BL4]: Check Commented [BL5]: Check Commented [BL6]: Which Canadian states. What about Australia?

Effective Date: 25 April 2013 Page 6 of 6

References (1) Lawrence et al. Endo and Metabol Clin Nth Am. 40(1): 111-35. 2011 (2) Raymond et al. NEJM. 364(6): 501-13. 2011 (3) Yao et al. NEJM. 364(6): 514-23. 2011 (4) Fine et al. Cancer Chemother Pharmacol 71:663-70. 2013 (5) Strosberg et al. Cancer. 117(2): 268-75. 2011 (6) Wick et al. Nature Reviews Neurology. 10: 372-85. 2014. (7) Fritzell et al. Cancer Immunol Immunother. 62:1463-74. 2013 (8) Chitadze et al. Oncoimmunology. 5(4): e1093276. 2016. (9) Lawrence et al. Oral presentation ESMO Congress. Copenhagen. 2016 (10) Cives et al. Endocr Relat Cancer. 23: 759-67. 2016 (11) Cros et al. Endocr Relat Cancer. 23: 625-33. 2016 (12) Kouvaraki et al. JCO. 22(23) 4762-71. 2004.