Trial of Lu-177 DOTATATE (Lutathera®) in Unlicensed Indications

Inclusion Criteria:

1. Patients ≥18 years of age.
2. Participants capable of giving informed consent
3. Presence of unresectable or metastatic, well differentiated, somatostatin receptor positive non gastroenteropancreatic neuroendocrine tumours. Or for those having 2 cycles repeat therapy, GEP NET \> 18 months from start of previous PRRT.
4. Patients must have progressive disease based on RECIST Criteria, Version 1.1. In order to make the assessment, two CT (or MRI) scans are required. The oldest scan must not be older than 3 years from the date of enrolment. The most recent scan must not be older than 6 weeks from the date of enrolment.
5. Confirmed presence of somatostatin receptors on all target lesions (for target/non-target/measurable lesions definition see RECIST Criteria, Version 1.1) documented by CT/MRI scans, based on positive OctreoScan or Ga68 Dotatate PET imaging within 24 weeks prior to enrolment in the trial.
6. The tumour uptake observed in each target lesion (for target/non-target/measurable lesions definition see RECIST Criteria, Version 1.1) using OctreoScan/Tc-99m-SRS should be ≥ normal liver uptake observed on planar imaging.
7. The tumour uptake observed in each target lesion (for target/non-target/ measurable lesions definition see RECIST Criteria, Version 1.1) using Ga68 Dotatate PET should be ≥ normal liver uptake observed on PET imaging.
8. KPS ≥60.
9. Presence of at least 1 measurable site of disease on cross-sectional imaging.
10. Females of childbearing potential (defined as \<2 years after last menstruation and not surgically sterile) and males, who are not surgically sterile or with female partners of childbearing potential must be willing to use a highly effective method of contraception during treatment and for a minimum of 6 months after the end of treatment (hormonal or barrier method of birth control; abstinence). Contraceptive methods that can achieve a failure rate of less than 1% per year when used consistently and correctly are considered as highly effective birth control methods. Such methods include:

    • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
    * oral
    * intravaginal
    * transdermal

      * progestogen-only hormonal contraception associated with inhibition of ovulation
    * oral
    * injectable
    * implantable

      • intrauterine device (IUD)

      • intrauterine hormone-releasing system (IUS)

      • bilateral tubal occlusion

      • vasectomised partner

      • sexual abstinence
      * Women of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days prior to treatment initiation). NOTE: Participants are considered not of childbearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or they are postmenopausal. Inclusion Criteria for Subsequent Treatments

1\. Both serum creatinine ≤150 μmol/L (≤1.7 mg/dL) and calculated creatinine clearance ≥40 mL/min, eventually confirmed by measured creatinine clearance (or measured GFR) using isotopic GFR measurement ≥40 mL/min (the measured creatinine clearance/GFR is required only as confirmatory exam).

2\. Haemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); WBC ≥2 x109/L (≥2000/mm3); platelets ≥75 x109/L (≥75 x103/mm3).

3\. Total bilirubin ≤3x ULN. 4. Serum albumin \>3.0 g/dL, or serum albumin ≤3.0 g/dL, but normal prothrombin time.

5\. KPS ≥60.

Exclusion Criteria:

* Participants will not be eligible for trial participation if they meet any of the exclusion criteria, or will be discontinued at the discretion of the Investigator if they develop any of the exclusion criteria during the trial.

Exclusion Criteria at Baseline

1. Either serum creatinine \>150 μmol/L (\>1.7 mg/dL), or calculated creatinine clearance \<40 mL/min, eventually confirmed by measured creatinine clearance (or measured GFR using isotopic GFR measurement) \<40 mL/min (the measured creatinine clearance/GFR is required only as confirmatory exam).
2. Haemoglobin concentration \<5.0 mmol/L (\<8.0 g/dL); WBC \<2 x109/L (2000/mm3); platelets \<75 x109/L (75 x103/mm3).
3. Total bilirubin \>3x upper limit of normal (ULN).
4. Serum albumin \<3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy, planning a pregnancy or lactation.
6. Any surgery, radioembolization, chemoembolization, chemotherapy, and radiofrequency ablation within 12 weeks prior to enrolment in the trial.
7. Interferon, Everolimus (mTOR-inhibitors), or other systemic therapies within 4 weeks prior to enrolment in the trial.
8. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to enrolment in the trial.
9. Uncontrolled congestive heart failure (NYHA II, III, IV).
10. Uncontrolled diabetes mellitus as defined by a fasting blood glucose \>2x ULN.
11. Any participant receiving treatment with short-acting Octreotide, which cannot be interrupted for 12 hours before and 24 hours after the administration of Lutathera, or any participant receiving treatment with Octreotide LAR or Lanreotide Autogel, which cannot be interrupted for at least 28 days before the administration of Lutathera, unless the tumour uptake observed on target and non-target but measurable lesions by OctreoScan or Ga68 Dotatate PET imaging during continued Octreotide LAR or Lanreotide Autogel treatment is at least as high as normal liver uptake observed by planar imaging (Kwekkeboom, Krenning et al. 2009).
12. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the trial.
13. Prior external beam radiation therapy to more than 25% of the bone marrow.
14. Current spontaneous urinary incontinence.
15. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
16. Patients who have not provided a signed ICF to participate in the trial, obtained prior to the start of any protocol related activities.
17. Patient with known incompatibility to CT Scans with IV contrast due to allergic reaction or renal insufficiency. If such participants can be imaged without the use of CT contrast material (ie, can tolerate MRI scans), such participants would not be excluded.
18. Patients who have participated in any therapeutic clinical trial/received any investigational agent within the last 30 days are excluded from participation in this trial.
19. Patients with hypersensitivity to Lutathera (active substance or any of the excipients).
20. Involved in the planning or conduct of this trial.
21. Unwilling or unlikely to comply with the requirements of the trial. Exclusion Criteria for Subsequent Treatments

1\. Exclusion criteria for Baseline # 1, 2, 3, 4, and 10 apply to all subsequent treatments, when a relationship cannot be excluded with either trial drugs or the corresponding toxicity has not resolved.

2\. In relation to renal function, participants are also excluded from further therapy in case of \>40% increase of serum creatinine over the baseline and with a concomitant decrease of \>40% in creatinine clearance as calculated according to the Cockroft-Gault method, eventually confirmed by measured creatinine clearance (or GFR), if a relationship may not be excluded and the corresponding toxicity has not resolved.

3\. When such exclusion criteria events occur, the participant will postpone any subsequent trial treatment until resolution of the event (normalisation or return to baseline values). The participant remains in the trial and continues observation with the scheduled tumour and clinical assessments.

4\. All other exclusion criteria for enrolment eligibility apply to all subsequent treatments.