Carcinoid Heart Disease and Peptide Receptor Radiotargetted Therapy

Phase II Randomised Trial to Assess Progression of Carcinoid Heart Disease in Patients Treated With Lutathera Therapy Compared to Best Supportive Care.

Randomised trial to assess progression of carcinoid heart disease in patients treated with Lutathera therapy compared to best supportive care.

This is an open-label, phase II, multicentre, randomised (1:1) clinical trial of an interventional medicinal product. This study will open at 3 centres across the UK. King's College Hospital NHS Foundation Trust will act as the coordinating centre for the study.

In this study, treatment with Lutathera will be compared to treatment with current best supportive care (somatostatin analogues) in patients with inoperable, somatostatin receptor positive, histologically confirmed small bowel NENs and these patients should have stable disease according to RECIST criteria for a period of 6 months prior to study entry.

Patients on the treatment arm will receive four administrations of 7.4 GBq (200 mCi) of Lutathera (and concomitant amino acids will be given with each administration for kidney protection). Patients are scheduled to continue to receive study treatment until any of the following occurs:

1. Unacceptable toxicity;
2. Progressive disease as determined by RECIST Criteria;
3. Inability or unwillingness of the patient to comply with study procedures;
4. Patient withdraws consent to participate Patients on the best supportive care arm will receive somatostatin analogue treatment every 4 weeks according to local standard of care practices.

Tumour response in both arms will be assessed after cycles 2 and 4 of 177Lu-Dotatate therapy, or every 16 weeks for patients enrolled under the best supportive care arm, according to RECIST criteria.

The study population is comprised of patients with stable carcinoid heart disease (CHD) and carcinoid syndrome. King's College Hospital performed surgery on 30 patients with carcinoid heart disease over the last 5 years. On review of patient records at King's, a further 30 patients with carcinoid heart disease were identified during the same time period who did not require surgery.

Other centres participating in this study have similar populations of patients with CHD, with specific multi-disciplinary team meetings and outpatient clinics for identification and recruitment of suitable patients into the study.

Inclusion Criteria:

1. Echocardiographic evidence of mild/ moderate carcinoid heart disease.
2. Carcinoid syndrome with Echocardiographic evidence of carcinoid heart disease- to be defined further
3. Elevated urinary 5-HIAA or NYHA class I or II on therapy [not necessarily exceeding label dose of SSA LAR; eg, could be 30mg SMS LAR plus sc SMS for breakthrough]
4. Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, Grade 1 or Grade 2 gastroenteropancreatic neuroendocrine (GEP-NET) or Lung-NET tumor
5. Age >18
6. Ki67 index ≤ 20%
7. Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities
8. Confirmed presence of somatostatin receptors on all target lesions documented by CT/MRI scans, within 8 weeks prior to randomization (centrally confirmed), as assessed by the following somatostatin receptor imaging (SRI) modalities: [68Ga]-DOTA-TOC (Somakit-TOC™) PET/CT imaging or [68Ga]-DOTA-TATE PET/CT imaging (NETSPOTTM) or Somatostatin Receptor scintigraphy (SRS) with 111In-pentetreotide (Octreoscan®).

10. Irresectable disease 11. Karnofsky Performance Score (KPS) ≥60.

Exclusion Criteria:

1. Patients with progressive disease by RECIST progressed within 6 months
2. Unable to consent
3. Pregnant
4. Chemotherapy within 3 months
5. PRRT within 3 years
6. Grade 3 tumours (WHO 2010)
7. Severe or Uncontrolled carcinoid heart disease
8. Renal impairment with eGRF <40 ml/min
9. NYHA class III,IV