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A Trial to Assess the Safety and Effectiveness of Lutetium-177 Octreotate Therapy in Neuroendocrine Tumours

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ClinicalTrials.gov Identifier: NCT01876771
Recruitment Status : Recruiting
First Posted : June 13, 2013
Last Update Posted : November 20, 2017
Sponsor:
Information provided by (Responsible Party):
AHS Cancer Control Alberta

Brief Summary:

Neuroendocrine tumours (NETs) are rare, slow growing, and diagnosis is often delayed with advanced metastases at presentation. In select patient populations, radioisotope therapy with Lutetium-177 (Lu-DOTA-TATE) has been shown to be a safe and effective palliative therapy, and has been widely used by research groups in Europe. Lu-DOTA-TATE has been used at the Cross Cancer Institute to treat more than 200 patients with NETs since August, 2010. This study is being done because the Lu-DOTA-TATE treatment was initially given under Health Canada's Special Access Programme (SAP), with each individual treatment requiring separate approval. Health Canada requested that the investigators conduct a clinical trial with Lu-DOTA-TATE, with the goal of receiving approval to use Lu-DOTA-TATE as a marketed treatment agent.

The purpose of this study is to: 1) assess the efficacy of Lu-DOTA-TATE treatment in patients with somatostatin receptor positive tumours; 2) and assess the safety of Lu-DOTA-TATE.


Condition or disease Intervention/treatment Phase
Carcinoma, Neuroendocrine Drug: [177]Lu-DOTA-TATE Phase 2

Detailed Description:

The proposed clinical trial will be a Phase II, open label, single site study in subjects with somatostatin receptor positive tumours. Radioactive Lu-DOTA-TATE doses are fixed within a range of 1.85 - 5.55 GBq ± 10%, with individual doses based on specified risk factors. There will be two groups of subjects enrolled in this study. Group A subjects (primary therapy) will have somatostatin receptor positive tumours and have never received Lu-DOTA-TATE. Group B subjects (maintenance therapy) will be those subjects who have previously received Lu-DOTA-TATE under the Special Access Programme (SAP) and will maintain their treatment schedule when they are entered into the study.

All subjects in Group A will be treated in an induction stage using 10-14 week dosing for up to 4 treatments. If an individual patient shows stable or improving disease status with no significant toxicities after the 4 induction treatments, they will be assessed 12-20 weeks after the last therapeutic treatment for entry into the maintenance stage. Patients will be re-assessed for stable or improving disease status with no significant toxicities 12-20 weeks after the last treatment of each cycle (1 cycle = 2 treatments at 22-40 week intervals) of the maintenance stage for consideration of further maintenance cycles (re-evaluations), up to a maximum of 4 cycles per patient if there have been no significant toxicities or progression. At each treatment, an amino acid solution is infused prior to and during the Lu-DOTA-TATE infusion to protect the kidneys. Subjects will be followed for 6 months and 1 year (± 4 weeks) following their last treatment dose to determine progression-free survival. All subjects meeting evaluation criteria will be analysed for safety, and all Group A subjects who have received at least two treatments of Lu-DOTA-TATE will be evaluated for efficacy (progression free survival and effect on Quality of Life). Those Group B subjects with adequate baseline data for comparison collected retrospectively from a chart review study (REV-LUT-001) may also be evaluated for safety and efficacy. Additional optional characterization of tumour samples from subjects who have had surgery before or during the study may be performed to characterize NET tumour biology changes following Lu-DOTA-TATE treatment.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Phase II Study of Lutetium-177 [DOTA0, Tyr3] Octreotate (Lu-DOTA-TATE) Treatment in Patients With Somatostatin Receptor Positive Tumours
Actual Study Start Date : April 29, 2014
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: [177]Lu-DOTA-TATE Therapy

Nominal, induction stage dose of 150 mCi (5.55 GBq) [177]Lu-DOTA-TATE every 10 - 14 weeks for 4 treatments.

Nominal maintenance stage dose of 75 mCi (2.78 GBq) [177]Lu-DOTA-TATE every 22 - 40 weeks, up to a maximum of 8 treatments.

Drug: [177]Lu-DOTA-TATE
Peptide receptor radionuclide therapy (PPRT)
Other Name: Lu-DOTA-TATE




Primary Outcome Measures :
  1. Change in Tumour response (modified RECIST criteria, CT/MRI or Lu-177 scan) of the target lesion through end of treatment [ Time Frame: At screening, 12-20 weeks after each treatment cycle, and 6 months and 1 year after the last maintenance stage treatment ]
    Tumor response of the target lesions(s) identified by CT/MRI or Lu-177 scan is assessed at each re-evaluation, and at 6 months and 1 year after the last maintenance stage treatment. If a target lesion outside of the liver cannot be identified using the Lu-177 scan, CT/MRI will be used to identify a target lesion in the liver to evaluate tumour response and disease status.

  2. Progression-free survival [ Time Frame: Up to 1 year after last treatment ]
    Time from date of enrolment to the first documented target lesion progression as measured by modified RECIST (CT/MRI or Lu-177 scan) or death due to any cause, which ever occurs first.

  3. Lu-177 scan disease evaluation [ Time Frame: Up to 3 days after each Lu-DOTA-TATE treatment ]
    A post-therapy Lu-177 scan will be conducted up to 3 days after each Lu-DOTA-TATE treatment to determine the intensity of tumour uptake of Lu-DOTA-TATE and the extent of tumour burden. Changes in Lu-177 scan data will also be used to evaluate tumour response prior to obtaining the CT/MRI scans.

  4. Change in tumour marker levels [ Time Frame: At screening, prior to treatments 1 and 3, 12-20 weeks after each treatment cycle, and 6 months and 1 year after last maintenance stage treatment ]
    TSH and Serum Chromogranin-A will be evaluated at screening, prior to treatments 1 and 3, at each re-evaluation, and at 6 months and 1 year after the last maintenance stage treatment. Where indicated, urinary 5-HIAA and metanephrines will be evaluated at screening, prior to treatments 1 and 3, at each re-evaluation, and at 6 months and 1 year after the last maintenance treatment. Tumour marker parameters will be recorded and all changes will be summarized.


Secondary Outcome Measures :
  1. Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Up to 1 year after last treatment ]
    All participants will be evaluated for AE occurence from treatment 1 up to 1 year after the last treatment.

  2. Change in pulse (bpm) [ Time Frame: within 30 min prior to start of amino acid through to within 30 min of amino acid end for each treatment ]
    Pulse is measured at each treatment visit: 1) 30 min prior to start of amino acid infusion; 2) 15 min prior to the start of the Lu-DOTA-TATE infusion; 3) 10-20 min after the start of the Lu-DOTA-TATE infusion; 4) 15 min after the Lu-DOTA-TATE infusion ends; 5) and within 30 min after the amino acid infusion ends. Changes will be analyzed using descriptive statistics, and any identified adverse events will be tabulated and categorized according to CTCAE v.4.

  3. Change in blood pressure (mm Hg) [ Time Frame: within 30 min prior to start of amino acid through to within 30 min of amino acid end for each treatment ]
    Blood pressure is measured at each treatment visit: 1) 30 min prior to start of amino acid infusion; 2) 15 min prior to the start of the Lu-DOTA-TATE infusion; 3) 10-20 min after the start of the Lu-DOTA-TATE infusion; 4) 15 min after the Lu-DOTA-TATE infusion ends; 5) and within 30 min after the amino acid infusion ends. Changes will be analyzed using descriptive statistics, and any identified adverse events will be tabulated and categorized according to CTCAE v.4.

  4. Change in oxygen saturation (%) [ Time Frame: within 30 min prior to start of amino acid through to within 30 min of amino acid end for each treatment ]
    Oxygen saturation is measured at each treatment visit: 1) 30 min prior to start of amino acid infusion; 2) 15 min prior to the start of the Lu-DOTA-TATE infusion; 3) 10-20 min after the start of the Lu-DOTA-TATE infusion; 4) 15 min after the Lu-DOTA-TATE infusion ends; 5) and within 30 min after the amino acid infusion ends. Changes will be analyzed using descriptive statistics, and any identified adverse events will be tabulated and categorized according to CTCAE v.4.

  5. Change in haematology (CBC & Differential) / biochemistry (SMA-12 panel) [ Time Frame: Within 2 weeks prior to each treatment to 1 year after last treatment. ]
    Blood samples are collected: within 2 weeks prior to each treatment, 6 weeks after each treatment, at each re-evaluation (12-20 weeks after treatments 4, 6, 8, and 10) and at 6 months and 1 year after the last treatment. Changes will be analyzed using descriptive statistics, and any identified adverse events will be tabulated and categorized according to CTCAE v.4.

  6. Change in renal function [ Time Frame: Within 2 weeks prior to each treatment to 1 year after last treatment. ]
    GFR will be monitored from blood samples collected: within 2 weeks prior to each treatment, 6 weeks after each treatment, at each re-evaluation (12-20 weeks after treatments 4, 6, 8, and 10) and at 6 months and 1 year after the last treatment. Changes will be summarized.

  7. Change in Quality of Life [ Time Frame: Prior to each treatment and up to 1 year after last treatment ]
    The EORTC QLQ-C30 v.3 in conjunction with the supplementary module QLQ-GI.NET21 Quality of Life questionnaires will be administered prior to each treatment on the visit date, and at 6 months and 1 year after the last treatment. The core questionnaire and supplementary module will be scored according to the scoring manual, and changes analyzed to assess the effect of Lu-DOTA-TATE treatment on Quality of Life.

  8. Change in Quality of Life [ Time Frame: Prior to each treatment and up to 1 year after last treatment ]
    The Edmonton Symptom Assessment System Revised (ESAS-r) will be administered prior to each treatment on visit date, and at 6 months and 1 year after the last treatment. The questionnaire will be scored according to the scoring manual, and changes analyzed to assess the effect of Lu-DOTA-TATE treatment on Quality of Life.

  9. Change in tumour biology (optional) [ Time Frame: Up to 1 year after last treatment ]
    Subjects who have had surgery prior to or after Lu-DOTA-TATE therapy may have existing tumour tissue sample tested to characterize NET tumour biology and the effects of Lu-DOTA-TATE therapy on tumour cell function.



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Ages Eligible for Study:   14 Years to 90 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Group A (Primary Therapy) Inclusion Criteria:

  1. Male or female ≥ 14 - 90 years of age.
  2. Presence of somatostatin receptor positive tumour(s) [either histologically or radionuclide imaging proven (Octreoscan or Ga-68 Dotatate / NETSPOT)], with at least 1 tumour site reliably evaluable by CT or MRI of at least 1.5 cm (smallest dimension) with respect to RECIST criteria (the target lesion) within 26 weeks of enrolment.
  3. Life expectancy greater than 12 weeks from enrollment.
  4. Serum creatinine ≤ 150 µmol/L, and a calculated (Cockcroft-Gault) or estimated GFR of ≥ 50 mL/min measured within 2 weeks of enrollment.
  5. Haemoglobin concentration ≥ 90 g/L; white blood cell (WBC) count ≥ 2 x 10^9/L; platelets ≥ 100 x 10^9/L measured within 2 weeks of enrolment.
  6. Liver function tests (total bilirubin, alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase) ≤ 5X the limit of normal measured within 2 weeks of enrolment. Serum albumin ≥ 23 g/L within 2 weeks of enrolment.
  7. Eastern Cooperative Oncology Group (ECOG) Performance Scale Score ≤ 2 measured within 2 weeks of enrolment.
  8. Provide written informed consent prior to enrolment.

Group B (Maintenance Therapy) Inclusion Criteria:

  1. Male or female ≥ 14 - 90 years of age.
  2. Have previously received Lu-DOTA-TATE treatment under the SAP.
  3. Life expectancy greater than 12 weeks from enrolment.
  4. Serum creatinine ≤ 150 μmol/L, and a calculated (Cockcroft-Gault) or estimated glomerular filtration rate (GFR) of ≥ 50 mL/min measured within 2 weeks of enrolment.
  5. Haemoglobin concentration ≥ 90 g/L; white blood cell (WBC) count ≥ 2 x 10^9/L; platelets ≥ 100 x 10^9/L measured within 2 weeks of enrolment.
  6. Liver function tests (total bilirubin, alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase) ≤ 5X the limit of normal measured within 2 weeks of enrolment. Serum albumin ≥ 23 g/L within 2 weeks of enrolment.
  7. Eastern Cooperative Oncology Group (ECOG) Performance Scale Score ≤ 2 measured within 2 weeks of enrolment.
  8. Provide written informed consent prior to enrolment.

Group A (Primary Therapy) Exclusion Criteria:

  1. Have previously received Lu-DOTA-TATE therapy.
  2. Potential for surgery with curative intent. Local surgery for symptomatic relief permitted as long as target lesion unaffected.
  3. Surgery within 12 weeks of enrolment. Surgery for removal of superficial skin lesions, laser eye surgery, or cataract surgery is permitted.
  4. Liver embolization [transcatheter arterial embolization (TAE), TACE, or TARE] within 4 weeks of enrolment.
  5. Radioisotope therapy within 12 weeks of enrolment.
  6. Systemic therapy: mTOR inhibitors and tyrosine kinase inhibitors within 6 weeks of enrolment; chemotherapy and interferon within 8 weeks of enrolment.
  7. Change in long acting somatostatin analogues, dosage, or dosage frequency within 12 weeks of enrolment.
  8. Localized external beam irradiation with target lesion(s) in the radiation field. Other localized external beam therapy is permitted.
  9. Known brain metastases unless these metastases have been treated and stabilized (confirmed by CT) for ≥ 4 months prior to enrolment
  10. Uncontrolled diabetes mellitus defined as random glucose ≥ 2X the upper limit of normal (or HbA1c > 10%, if results available) within 12 weeks of enrolment.
  11. Another significant medical, psychiatric or surgical condition uncontrolled by treatment, which may interfere with completion or conduct of the study (such as urinary incontinence, co-existing malignancies).
  12. Pregnancy.
  13. Breast feeding.
  14. Prior radiation therapy to more than 25% of the bone marrow.

Group B (Maintenance Therapy) Exclusion Criteria:

  1. Another significant medical, psychiatric or surgical condition uncontrolled by treatment, which may interfere with completion or conduct of the study (such as urinary incontinence or co-existing malignancies).
  2. Pregnancy.
  3. Breast feeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01876771


Contacts
Contact: Cindy Duncan 780-577-8080 ACB.NeuroEndocrine@ahs.ca

Locations
Canada, Alberta
Cross Cancer Institute Recruiting
Edmonton, Alberta, Canada, T6G 1Z2
Contact: Cindy Duncan    780-577-8080    ACB.NeuroEndocrine@ahs.ca   
Principal Investigator: Alexander McEwan, MB         
Sub-Investigator: Todd McMullen, MD, PhD, FRCSC, FACS         
Sub-Investigator: Donald Morrish, MD, PhD, FRCPC         
Sub-Investigator: Michael Sawyer, MD, FRCPC         
Sub-Investigator: Marguerite Wieler, BScPT, PhD         
Sponsors and Collaborators
AHS Cancer Control Alberta
Investigators
Principal Investigator: Alexander McEwan, MB Department of Oncology, Cross Cancer Institute

Responsible Party: AHS Cancer Control Alberta
ClinicalTrials.gov Identifier: NCT01876771     History of Changes
Other Study ID Numbers: TX-LUT-001
Ethics # 26064 ( Other Identifier: ACREC )
First Posted: June 13, 2013    Key Record Dates
Last Update Posted: November 20, 2017
Last Verified: November 2017

Keywords provided by AHS Cancer Control Alberta:
177lutetium-DOTA(O)Tyr3)octreotate

Additional relevant MeSH terms:
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue