On October 2, 2016, CNETS Canada held a Toronto Patient Education Day entitled PRRT Clinical Trial Update – PMH Site, with presentations by Dr. Rebecca Wong and Dr. Shereen Ezzat.  There were 30 attendees, an audience comprised of NET patients, family members and caregivers. These are companion notes to the presentations (notes prepared by CNETS Canada) and highlight key takeaway messages only.  Please ensure you refer to the presentations when reviewing these notes.

Dr. Shereen Ezzat an Endocrine Oncologist at UHN, set the stage for the afternoon by speaking about the – Role of PRRT in NET Management.

Dr. Ezzat’s presentation was on the following key areas:

Advances in classification of NETs

  • NETs are on the rise with lung and rectal NETs seeing the largest increase in incidence.
  • There has been a huge increase in rectal NETs, specifically in China
  • Pancreatic NETs are relatively unchanged in incidence

Clinical Features & Biomarkers

  • Key point to remember for the PMH trial is you must have a Ki67 of less than 30%
  • Over the years an individual’s Ki67 can change. Therefore if it has been many years since your Ki67 assessment you may need to have the pathology and grading re-done prior to being considered for the PRRT trial.
  • Surgical and core biopsies are the only acceptable biopsy methods for Ki67 assessment. Fine needle biopsy does not provide sufficient tissue to carry out Ki67 analysis.

Genetics

  • It has been determined that NETs do have a susceptibility genes.
  • Italy has been able to use genetics to plan treatment options for NET patients.

Reference Article:

  • DAXX/ATRX gene mutations have been identified in pNET and brain tumours. Temozolomide has been an effective treatment for reducing brain tumours.

Reference Articles:

  • There have been specific abnormalities exposed in certain families and Dr. Ezzat is working with an international NET consortium. They know that the causes of pancreatic, small bowel and colorectal NETs are all very different and doctors need to listen to this information and going forward tailor treatments on this basis.

Molecular Imaging

  • A negative Octreoscan does not mean that there are not somatostatin receptors in the tumours. The Octreoscan only binds to receptor 2.
  • Gallium 68 is already being surpassed and the best agents are the antagonists

Reference Article:

Prior to thinking of PRRT always look at all of the options:

  • Surgery
  • Debulking
  • Medical Therapy
  • Irradiation

Today’s Therapeutic Landscape

  • We define the grade of tumours as how active the cells are and stage as how far the disease has progressed. Both are very important factors that contribute to outcomes.
  • If extent of liver involvement is >30% liver directed therapy should be considered
  • The overriding goal of treatment is to ensure that patients who have good quality of life are not negatively impacted by treatment. Radiant 3 Study – Everolimus slowed down the disease but had no impact on survival
  • Sunitinib Study – Overall survival effect was minimal
  • Radiant 2 Study – Minimal impact on survival
  • CAPTEM (Capecitabine/Temozolomide) has typically not been used as 1st line treatment for NETs. Need to consider if CAPTEM should be used earlier.
    • Trials have highlighted some issues – 1. It is expensive and 2. It can be difficult to tolerate. Efficacy: complete response in only 4% of patients and partial response in 21% of patients.  Must keep in mind though that these were patients who failed on other therapies.
  • Pasireotide Study: the drug hits all somatostatin receptors but caused bad side effects including diarrhea and caused diabetes

Dr. Rebecca Wong the Principal Investigator Ontario PRRT Trial and a Radiation Oncologist at Princess Margaret Cancer Center, then spoke about the PMH Trial – Study Design and Logistics.  

Efforts to get this PRRT trial with 177Lu-DOTATATE & 68Ga-DOTATATE, first started in 2010.  In 2012 the Consortium for the Ontario PRRT protocol was approved with 4 sites including: Sunnybrook, Hamilton, London and Princess Margaret Hospital.  In 2014, Cancer Care Ontario approved the funding for the trial.  An initial meeting was held with Health Canada in 2015 and Health Canada approved the trial in May 2016.  The trial sponsor is the University Health Network (UHN). The trial enrolled the first patient in July 2016.

The study is titled: “A Prospective Single-Arm, Multi-Centre, Study of the Efficacy and Safety of 177Lu-DOTATATE Treatment, with individualized dosimetry, in Patients with 68Ga-DOTATATE PET identified Somatostatin Receptor Positive Neuroendocrine Tumours”

The study design is a phase II single arm study (everyone gets the treatment), including best practices as guided by the literature for the use of 177Lu including 68Ga, individualized dosimetry, incorporation of patient reported outcomes, and incorporation of early 68Ga (after cycle 1) to examine its ability to predict long term response.

A total of 150 – 68Ga positive patients will be enrolled in the study and undergo the treatment phase with 177Lu. Patients will be treated at one of the four sites according to their location.

All  68Ga scans will be done at PMH only (no scans at Sunnybrook, Juravinski or London Health Sciences Centre).

UHN is the “sponsor site” and all centres are contributing to the trial financially.

London and Sunnybrook should be up and running by end of October.  For London this is a transition from their existing trial protocol to the consortium trial protocol.  Juravinski is expected to open in January.

British Columbia is also working on a trial and they are probably a year away from commencement.

Study objectives:

Primary

  • Evaluate progression-free survival (PFS) at 12 months.

Secondary

  • Determine overall response rate (using RECIST)
  • Determine biochemical response rate in subgroup with elevated tumour markers
  • Determine acute and late adverse effects of 177Lu-DOTATATE
  • Determine overall survival and impact to quality of life

Inclusion Criteria:

  • Progressive neuroendocrine tumours with a Ki67 <30.

Study Protocol:

If a patient meets the inclusion criteria, they will then be evaluated by the Tumour Board.  The Tumour Board discusses the case to determine suitability for participation in the clinical trial.

Once a patient is approved for the study, they enter the diagnostic phase and undergo a 68Ga PET scan.

If the 68Ga scan is negative, the patient does not go to the treatment phase and gets follow-up only.

If the 68Ga is positive, the patient enters the treatment phase.

Treatment phase with 177Lu:

  • Blood work (Renal, bone marrow)
  • Switch from long to short acting during treatment
  • 4 cycles of 177Lu (Total duration approximately 24-48 weeks)
  • Max dose (200+ 300×3 = 1100mCi)
  • Dose adjustment based on individualized dosimetry, CBC, renal function FU based on CT imaging
  • 50 patients will get a second 68Ga scan after the first cycle of 177Lu
  • Patients will be followed for five years in total

Patient Experience: 2 IV’s are set up treatment takes about 5 hours

IV 1

  • N Saline (hydration) 500cc over 4 hours
  • 30 – 60 min – 177Lu

IV 2

  • Amino Acid (renal protection) 1000cc over 4 hours

Post infusion at 24 and 72 hours

  • Nuclear Medicine SPECT & PLANAR scans

 General Notes:

  • Other countries are experimenting with PRRT in combination with other therapies:
    • Lu177 and Y90 in Europe with positive results
    • Lu177 & CAPTEM in Australia
  • Lu177 and Ga68 are currently being tested in other cancer groups such as prostate and ovarian cancer
  • NETTER 1 study revealed the 2 most significant side effects of PRRT treatment are nausea and vomiting but this was likely due to the type of amino acids used for this particular trial.
  • Bone marrow and kidney toxicity are the two most serious side effects of the PRRT treatment.

Toronto October 2