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

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

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).

Study Overview

• Status: Withdrawn
• Conditions: Neuroendocrine Tumors; Carcinoid Tumor; Gastrinoma; Insulinoma; Vipoma; Gastroenteropancreatic Neuroendocrine Tumor; Pulmonary Carcinoid Tumor
• Intervention / Treatment: Drug: 177Lu-DOTATOC

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.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Administrative Research Manager; Phone Number: 2818 604-877-6000; Email: hayley.allan@bccancer.bc.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BC Cancer
      • Contact: Administrative Research Manager; Phone Number: 2818 604-877-6000; Email: hayley.allan@bccancer.bc.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard PRRT; 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; Subjects will receive 177Lu-DOTATOC PRRT treatment over 4 cycles, each cycle occurs every 8 weeks.
Experimental: Personalized PRRT; 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; Subjects will receive 177Lu-DOTATOC PRRT treatment over 4 cycles, each cycle occurs every 8 weeks.

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS and QoL scores to ctDNA levels	To assess correlation of PFS and QoL scores (EORTC QLQ30) to ctDNA levels (ctDNA allele frequency change from pre-treatment to on-treatment), the following tests will be used, Spearman correlation for quality of life and Kaplan- Meier curves stratified at a median for PFS.	8 months

Collaborators and Investigators

• Sponsor: British Columbia Cancer Agency

Study record dates

Study Major Dates

• Study Start (Anticipated): January 15, 2023
• Primary Completion (Anticipated): December 31, 2027
• Study Completion (Anticipated): December 31, 2031

Study Registration Dates

• First Submitted: April 28, 2021
• First Submitted That Met QC Criteria: May 31, 2021
• First Posted (Actual): June 7, 2021

Study Record Updates

• Last Update Posted (Estimate): February 20, 2023
• Last Update Submitted That Met QC Criteria: February 17, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Adenoma; Pancreatic Neoplasms; Adenoma, Islet Cell; Carcinoma, Islet Cell; Neuroendocrine Tumors; Carcinoid Tumor; Insulinoma; Gastrinoma; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Edotreotide lutetium LU-177
• Other Study ID Numbers: H20-03401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No