Safety, tolerability and clinical implementation of 'ready-to-use' 68gallium-DOTA0-Tyr3-octreotide (68Ga-DOTATOC) (SomaKIT TOC) for injection in patients diagnosed with gastroenteropancreatic neuroendocrine tumours (GEP-NETs).

BACKGROUND: 68Ga-DOTA0-Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography-CT (PET-CT) has superior diagnostic performance compared to the licensed tracer OctreoScan single photon emission CT-CT in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). A new preparation of 68Ga-DOTATOC using a new 'ready-to-use' 68Ga-DOTATOC formulation for injection has been developed (68Ga-DOTATOC (SomaKIT TOC)). OBJECTIVES: This study aimed to assess the safety and tolerability of 68Ga-DOTATOC (SomaKIT TOC) and evaluate the feasibility and robustness of implementing it in a NET clinical imaging service. METHODS: A first-in-human phase I/II multicentre, open-label study of a single dose of 68Ga-DOTATOC (SomaKIT TOC) 2 MBq/kg±10% (range 100-200 MBq) in patients with biopsy-proven grade 1-2 GEP-NETs. PET-CT was performed post injection. Patients were followed up for 28 days. We next implemented this new synthesis methodology in a clinical service assessed over 11 months. RESULTS: Twenty consenting patients were recruited; 14 males, 6 females; mean (SD) age 58 years (12); NET grade 1 (70%), grade 2 (30%); and 75% with stage IV disease. Twelve patients experienced at least one adverse event (AE) during the study with no grade 3-4 toxicities. Only four AEs were classified as possibly (headache (n=1; 4%), nausea (1; 4%)) or probably (dysgeusia (1; 4%), paraesthesia (1; 4%)) related to the study preparation. One hundred thirteen vials of 68Ga-DOTATOC (SomaKIT TOC) were synthesised with the 'kit' over a period of 11 months for clinical utility. Only 2/113 vials (1.77%) were rejected. CONCLUSIONS: The new ready-to-use preparation of 68Ga-DOTATOC (SomaKIT TOC) for injection was safe and well tolerated. This has led to the world's first (EMA) licensed 68Ga-DOTATOC (SomaKIT TOC) radiopharmaceutical for the utility of PET imaging in patients with NETs. This preparation can be robustly implemented into routine clinical practice.

Use of 18F FDG PET and the short temporal response of Hodgkin's disease to RIT.

Radioimmunotherapy (RIT) has been available for some time to treat patients with non-Hodgkin's lymphoma, but its use in Hodgkin's lymphoma has been less available, partly because of the need to find an appropriate antibody. A new radioiodinated chimeric antibody directed against the CD25 epitope (131I basiliximab) seems promising, but assessment of response has been difficult. 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) has become a standard method by which the response of Hodgkin's disease to chemotherapy is both predicted and assessed with well-understood criteria of response. The aim of this study is to determine 18F-FDG-PET can be used to assess response to RIT. Pre- and post-treatment 18F-FDG-PET imaging was performed in a series of 13 patients with advanced Hodgkin's disease who had failed conventional therapy and had been enrolled on a compassionate use program for treatment with 131I basiliximab. The 131I basiliximab was given at an activity of 1200MBq/m2 with one patient receiving 2 cycles and the rest a single cycle. The 18F-FDG-PET studies were compared using the "Deauville" criteria and by comparing the maximum standardized uptake value (SUVmax) of target tumors before and 4 and 8 weeks after treatment. All patients survived long enough for their initial 18F-FDG-PET-computed tomography scan at 4 weeks after their 131I basiliximab therapy. One out of ten patients with "Deauville" Grade 4 or 5 response died during the 6-month follow-up period. Two out of three patients with a "Deauville" Grade 2 or 3 response died in the follow-up period. The mean SUVmax pretreatment was 11.9 (±4.7); at 4-week posttreatment, the mean SUVmax was significantly lower at 6.5 (±5.8) (P = 0.02). At 8 weeks, the mean SUVmax was 8.8 (±7.0), which was not significantly different from the pretreatment level. 18F-FDG-PET imaging is able to predict the short-term response to treatment of Hodgkin's disease by RIT, and an initial poor response appears to predict poor outcome. Early changes in 18F-FDG-PET uptake did not predict sustained response and by 8 weeks all but one patient had recurrent disease.

A Phase I Clinical Trial of CHT-25 a 131I-Labeled Chimeric Anti-CD25 Antibody Showing Efficacy in Patients with Refractory Lymphoma.

PURPOSE: There is a need for new treatments for Hodgkin and T-cell lymphoma due to the development of drug resistance in a proportion of patients. This phase I study of radioimmunotherapy used CHT-25, a chimeric antibody to the alpha-chain of the interleukin-2 receptor, CD25, conjugated to iodine-131 ((131)I) in patients with refractory CD25-positive lymphomas. EXPERIMENTAL DESIGN: Fifteen patients were treated (Hodgkin lymphoma, 12; angioimmunoblastic T-cell lymphoma, 1; adult T-cell leukemia/lymphoma, 2). Tumor was monitored by computed tomography and in all but two patients by (18)F-fluorodeoxyglucose positron emission tomography. RESULTS: There were no grade 3 or 4 infusion reactions. At the maximum tolerated dose of 1,200 MBq/m(2), the major side effect was delayed myelotoxicity with the nadir for platelets at 38 days and for neutrophils at 53 days. One patient treated with 2,960 MBq/m(2) developed prolonged grade 4 neutropenia and thrombocytopenia and died of Pneumocystis jiroveci pneumonia. Nonhematologic toxicity was mild. Single photon emission computer tomography imaging showed tumor-specific uptake and retention of (131)I and no excessive retention in normal organs. Of nine patients receiving >/=1,200 MBq/m(2), six responded (three complete response and three partial response); one of six patients with administered radioactivity of

A phase I trial of radioimmunotherapy with 131I-A5B7 anti-CEA antibody in combination with combretastatin-A4-phosphate in advanced gastrointestinal carcinomas.

PURPOSE: In preclinical models, radioimmunotherapy with (131)I-A5B7 anti-carcinoembryonic antigen (CEA) antibody ((131)I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. EXPERIMENTAL DESIGN: Patients had CEA of 10 to 1,000 microg/L, QTc < or =450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m(2) of (131)I-A5B7 on day 1 and 45 mg/m(2) CA4P given 48 and 72 hours post-(131)I-A5B7, then weekly for up to seven weeks. RESULTS: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m(2), and CA4P escalated to 54 mg/m(2). Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (K(trans)/IAUGC(60)) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. CONCLUSIONS: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.