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

An Open-label Phase II Study of Lutetium-177 [DOTA0, Tyr3] Octreotate (Lu-DOTA-TATE) Treatment in Patients With Somatostatin Receptor Positive Tumours

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. A brand of Lu-DOTA-TATE (Lutathera(R)) is approved for the treatment of gastroenteropancreatic NETs in Europe, the U.S., and more recently in Canada. While Lutathera(R) is approved in Canada, it is not publicly funded in Alberta. Lu-DOTA-TATE has been used at the Cross Cancer Institute to treat more than 300 patients with NETs since August, 2010. Our Lu-DOTA-TATE treatment was initially given under Health Canada's Special Access Programme (SAP), with each individual treatment requiring separate approval. In 2014, Health Canada requested we conduct a clinical trial with Lu-DOTA-TATE instead.

The purpose of this study is to: 1) assess the efficacy of Lu-DOTA-TATE treatment in patients with somatostatin receptor positive tumours; 2) assess the safety of Lu-DOTA-TATE; 3) assess the effect of Lu-DOTA-TATE on Quality of Life and survival.

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 progressive 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 every other treatment of the maintenance stage for consideration of further maintenance treatments (re-evaluations), up to a maximum of 8 treatments 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, and annually (± 4 weeks) for up to 5 years following their last treatment dose to determine overall 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. 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.

Group A (Primary Therapy) Inclusion Criteria:

1. Male or female ≥ 14 - 90 years of age.
2. At least 1 tumour site reliably evaluable by CT or magnetic resonance imaging (MRI) of at least 1.0 cm (smallest dimension) or ≥ 1.5 cm lymph node disease (smallest dimension) (the target lesion) within 26 weeks of enrolment, with documented presence of somatostatin receptors on radionuclide imaging, with uptake greater than liver background as assessed by planar Octreoscan® images or Ga-68 labelled somatostatin analogue (68Ga-DOTATATE or 68Ga-HA-DOTATATE) PET imaging (or other available somatostatin receptor targeting PET agents) obtained within 1 year of enrolment. Patients with bone-only disease can be enrolled provided there is presence of somatostatin receptor positive tumour(s) on radionuclide imaging corresponding to osteolytic or osteoblastic bone lesions on CT or MRI, with uptake greater than liver background as assessed by planar Ocgtreoscan(R) images or somatostatin receptor PET imaging regardless of size.
3. Histologically confirmed diagnosis of neuroendocrine tumor.
4. Progressive disease documented by anatomic imaging and/or presence of new lesions on somatostatin receptor imaging assessed by comparable studies. In the opinion of the investigator, patients with no progression on imaging may still be considered eligible in presence of carcinoid symptoms refractory to treatment with somatostatin receptor analogues or functional Pheochromocytoma/Paraganglioma symptoms that are not well controlled with current medical treatment.
5. 18F-FDG PET/CT whole-body imaging within 26 weeks of enrolment.
6. Life expectancy greater than 12 weeks from enrollment.
7. Serum creatinine ≤ 150 µmol/L, and a calculated (Cockcroft-Gault) or estimated GFR of ≥ 50 mL/min measured within 2 weeks of enrollment.
8. 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.
9. Liver function tests (total bilirubin, alanine transaminase (ALT), aspartate transaminase (AST)) ≤ 3X the limit of normal measured within 2 weeks of enrolment. Serum albumin ≥ 23 g/L within 2 weeks of enrolment.
10. Eastern Cooperative Oncology Group (ECOG) Performance Scale Score ≤ 2 measured within 2 weeks of enrolment.
11. 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)) ≤ 3X 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. Major surgery within 12 weeks of enrolment. Minor surgeries such as removal of superficial skin lesions, laser eye surgery, cataract surgery, laparoscopic procedures and other procedures that are minimally invasive are permitted at the Investigator's discretion.
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 unless changes are required to manage uncontrolled symptoms.
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.
15. If, in the opinion of the investigator, other treatments are considered more appropriate than the investigational therapy, based on patient and disease characteristics.
16. Known allergy to somatostatin analogues or any components of the study medication.

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.
4. Known allergy to somatostatin analogues or any components of the study medication.