177Lu-DOTATOC for the Treatment of Patients With Somatostatin Receptor Positive NETs

Study Overview
=================
Brief Summary
-----------------
This study is to assess if personalized peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATOC results in fewer adverse events than standard PRRT. Subjects will be randomized to either receive personalized or standard PRRT. Personalized PRRT will be determined based on dosimetry calculations after the first cycle. In addition comparisons, will be made with progression-free survival, serial CT imaging, ctDNA, and quality of life questionnaires. Subjects will be followed for 5 years or until they have progression and are switched to another systemic treatment (not including treatment with somatostatin analogues).

Detailed Description
-----------------
Overall, 200 subjects will be randomized (1:1 randomization ratio) to receive standard injected activities of 177Lu-DOTATOC PRRT or personalized injection of 177Lu-DOTATOC PRRT. Randomization will be stratified for grade and primary location. Screening Phase: Subjects will be screened against the inclusion and exclusion criteria. Screening by SSR imaging will be completed to determine expression of SSR and feasibility of treatment by PRRT. Once eligibility has been confirmed they will be randomized. Subjects will undergo a physical exam, complete a medical history questionnaire, quality of life questionnaires, blood work, and a diagnostic CT. Treatment Phase: During the treatment phase, subjects will undergo 4 cycles of treatment. Each treatment cycle will be followed by 2 dosimetry SPECT/CT scans on day 1 (18 - 32 hours after treatment administration) and day 2 (64 - 80h after treatment administration) After cycle 3 quality of life questionnaires will be completed again. Follow up Phase: At the end of treatment or after discontinuation of any cause, subjects will be followed for 5 years to continue data collection for the other objectives. Objective tumour response will be assessed every 6 months by diagnostic CT according to the RECIST 1.1 criteria.

Official Title
-----------------
A Prospective Randomized Study of the Efficacy and Safety of 177Lu-DOTATOC With Either Standard or Personalized Dosing for the Treatment of Patients With Somatostatin Receptor Positive NETs

Conditions
-----------------
Neuroendocrine Tumors, Carcinoid Tumor, Pulmonary Carcinoid Tumor, Gastroenteropancreatic Neuroendocrine Tumor, Vipoma, Insulinoma, Gastrinoma

Intervention / Treatment
-----------------
* Drug: 177Lu-DOTATOC


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Able to provide written informed consent Age greater than or equal to 19 years Biopsy-proven, well-differentiated grade 1 - 3 NET Gastroenteropancreatic tumors (e.g. carcinoids, gastrinoma, insulinoma, glucagonoma, VIPoma, etc.), functioning and non-functioning Sympathoadrenal system tumors (phaeochromocytoma, paraganglioma) Pulmonary NET, functioning and non-functioning Easter Cooperative Oncology Group (ECOG) ≤ 2 Ki67 ≤ 55% Progressive disease demonstrated by RECIST 1.1 criteria within the 6 months preceding the study. Patients with other evidence of progressive disease that is not demonstrated on CT (like rising biomarkers) may be included, at the discretion of the Tumour Review Board. If response to other treatments is considered adequate according to other criteria, the Tumour Review Board may consider excluding the patient from participation in the study. Tumour Review Board confirmation of suitability to proceed to PRRT treatment and enrollment in this trial. Positive PET SSR imaging (Krenning score 2 or higher) in previous 6 months (68Ga-DOTATOC, 68Ga-DOTATATE, 18F-AmBF3-TATE). If PET SSR imaging is not available 111In-penetreotide scintigraphy (Octreotide scan) is acceptable. Adequate laboratory parameters within two weeks of enrollment Kidneys Serum creatinine ≤ 150 µmol/L GFR ≥ 40 ml/min (using plasma clearance values) Marrow Hemoglobin ≥ 80 g/L WBC ≥ 2 x 109/L Platelets ≥ 75 x 109/L Liver Total bilirubin ≤ 3 x upper limit of normal (ULN) ALT ≤ 3 x ULN or ≤ 5 x ULN if liver metastasis Alkaline phosphatase ≤ 3 x ULN or ≤ 5 x ULN if liver metastasis Subject's ability to comply with scheduled visits, treatment plans, laboratory tests, imaging tests, and other procedures required as detailed in the protocol. Exclusion Criteria: Women and men of childbearing potential Procreation Women: pregnancy test done before enrollment before each treatment cycle. And subject must use adequate contraception for the duration of therapy, be surgically sterile, or post-menopausal. Men: must be surgically sterile or use adequate contraception for the duration of the therapy. Patient with another non-cutaneous (excluding melanoma) active cancer requiring therapeutic intervention. Curative medical or surgical treatment, local liver embolization, or debulking are appropriate options. Life expectancy is less than 12 weeks. Radiotherapy to target lesions ≤ 12 weeks ago or to more than 25% of bone marrow. PRRT at any time prior to randomization in this study. Systemic therapy (chemotherapy) within 4 weeks of PRRT and other locoregional therapies (radioisotope, embolization) within 12 weeks prior to enrollment. Ongoing use of somatostatin analogs for control of symptoms is allowed. Known brain metastases (unless treated and stable for more than 3 months). Co-morbidities that could, in the opinion of the PI, interfere with safe delivery of PRRT (like urinary incontinence, psychiatric illness), uncontrolled congestive heart failure (NYHA II, III, IV) Breastfeeding (if patients elect to discontinue breast feeding, they can participate in the trial).

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a prospective randomized phase II study two-arm study of efficacy and safety of 177Lu-DOTATOC for treatment of patients with NETs who are referred to BC Cancer - Vancouver for treatment of progressive tumours.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard PRRT<br>For standard PRRT 177Lu-DOTATOC therapy, the administered activity will be 7.4 GBq ± 10% as an intravenous infusion over a time of 10 to 30 minutes. | Drug: 177Lu-DOTATOC<br>* Subjects will receive 177Lu-DOTATOC PRRT treatment over 4 cycles, each cycle occurs every 8 weeks.<br>|
| Experimental: Personalized PRRT<br>For 177Lu-DOTATOC therapy, for the first cycle the administered activity will be 7.4 GBq ± 10% as an intravenous infusion over a time of 10 to 30 minutes.Subsequent cycles will be adjusted based on dosimetry calculations. | Drug: 177Lu-DOTATOC<br>* Subjects will receive 177Lu-DOTATOC PRRT treatment over 4 cycles, each cycle occurs every 8 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine whether personalized 177Lu-DOTATOC PRRT reduces adverse events (AE). | Frequency of AEs, will be compared between the two treatment arms. | 8 months | 
| Compare the 12-month progression-free survival (PFS) of subjects receiving personalized or standard injected activity PRRT with RECIST criteria. | PFS will be determined by RECIST1.1 criteria on serial CT, and analysed independently. The 12-month PFS will be evaluated by univariate analysis but different criteria for determination of PFS will be compared. | 12 months | 
| Compare the 12-month progression-free survival (PFS) of subjects receiving personalized or standard injected activity PRRT with ITMO criteria. | PFS will be determined by biochemical criteria (ITMO) on serial CT, and analysed independently. The 12-month PFS will be evaluated by univariate analysis but different criteria for determination of PFS will be compared. | 12 months | 
| Compare the 12-month progression-free survival (PFS) of subjects receiving personalized or standard injected activity PRRT with Choi criteria. | PFS will be determined by Choi criteria on serial CT, and analysed independently. The 12-month PFS will be evaluated by univariate analysis but different criteria for determination of PFS will be compared. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine response rate of both treatment arms with RECIST1.1 criteria | Response rate as determined by structural criteria RECIST1.1 | 4 months | 
| Determine response rate of both treatment arms with Choi criteria | Response rate as determined by structural criteria Choi. | 4 months | 
| Determine response rate of both treatment arms with ITMO criteria | Response rate as determined by structural criteria biochemical markers (ITMO criteria) (chromogranin A, 24h urinary HIAA). | 4 months | 
| Quality of life (QoL) questionnaire scores (EORTC QLQ30) will be compared between the two treatment arms | For QoL questionnaire scores (EORTC QLQ30) before, during, and after treatment | 8 months | 
| Quality of life (QoL) questionnaire scores (EORTC GINET21) will be compared between the two treatment arms | For QoL questionnaire scores (EORTC GINET21) before, during, and after treatment | 8 months | 
| Quality of life (QoL) questionnaire scores (EQ-5D) will be compared between the two treatment arms | For QoL questionnaire scores (EQ-5D) before, during, and after treatment | 8 months | 
| Correlation of QoL scores (EORTC QLQ30) to ctDNA | To assess correlation of QoL scores (EORTC QLQ30) to ctDNA allele frequency change from pre-treatment to on-treatment, using spearman correlation | 8 months | 
| Correlation of QoL scores (EORTC GINET21) to ctDNA | To assess correlation of QoL scores (EORTC GINET21) to ctDNA allele frequency change from pre-treatment to on-treatment, using spearman correlation | 8 months | 
| Correlation of QoL scores (EQ-5D) to ctDNA | To assess correlation of QoL scores (EQ-5D) to ctDNA allele frequency change from pre-treatment to on-treatment, using spearman correlation | 8 months |