Duo Nen - Tandem therapy LutaPol/ItraPol (177Lu / 90Y-DOTATATE) as an effective method in the treatment of neuroendocrine neoplasmas

Although neuroendocrine neoplasms (NENs) are considered rare, recent years have seen a significant increase in NENs incidence and detection in many epidemiological studies and research. Long-acting somatostatin analogues remain at the forefront of treating these conditions. For patients with disease progression identified during this treatment (at a stage in which they are not eligible for surgery), second-line therapy becomes radioisotope therapy (Peptide Receptor Radionuclide Therapy, PRRT) using somatostatin analogues labeled with 177Lu or 90Y radioisotopes (tandem-PRRT).

NEN neoplasms are heterogeneous, moreover, many patients simultaneously have large neoplastic lesions and small metastases, hence the hypothesis that in their destruction combining the radiation effect of two radionuclides with different radiation energy and different range in tissue, such as 177Lu (max. 2 mm) and 90Y (range 10-12 mm) will be more effective. For the first time in the world, such research was started in Poland, in the first decade of the 21st century and their effects were published in 2011. As a consequence, similar attempts were made by other centers, mainly in Germany and Australia. There are no randomized studies in the literaturę assessing the effect of tandem-PRRT on the overall survival of patients with NEN, or comparing this type of treatment with the use of therapy using only 177Lu (177Lu-DOTATATE). However, published studies, including non-randomized studies and own experience of clinical centers, suggest an advantage of a mixture of two radioisotopes over mono-radioisotope therapy.

At the National Center for Nuclear Research, Radioisotope Centre POLATOM in Świerk, two radiopharmaceutical precursors, ItraPol (90Y chloride, registration certificate No. 22069 issued on 08/09/2014) and LutaPol (177Lu chloride, registration certificate No. 22081 issued 09/08/2014) were developed and are on the market In addition, as a result of the MultiSom project (POIR/01.02.00-00-00-0041/15), a new MultiSom kit (active substance: DOTATATE) was developed, when labeled with 177Lu or 90Y and a mixture of 177Lu and 90Y, it could be used to carry out such randomized trial.

The National Center for Nuclear Research as a scientific unit is interested in further research aimed at more effective use of the produced radiopharmaceutical precursors, therefore it acts as a sponsor of the proposed non-commercial, randomized clinical trial DuoNen. In turn, interest in conducting such a study is expressed by clinicians from clinical centers conducting PRRT therapy and having experience in the treatment of patients with NENs. These centers expressed their will in the form of letters of intent to cooperate in the study.

The aim of the study is to develop an algorithm for the treatment of NEN patients using ItraPol and LutaPol isotope mixtures (177Lu-DOTATATE and 90Y-DOTATATE). The specific goal is to assess the effectiveness of personalized treatment of NEN patients using 177Lu-DOTATATE and 90Y-Lu-DOTATATE mixtures compared to standard treatment of NEN patients using 177Lu-DOTATATE. Approximately 120 adult patients with advanced, unresectable, confirmed in histopathological test, well and moderately differentiated (G1 and G2) neuroendocrine neoplasms, in which high expression of somatostatin receptors have been confirmed, will be qualified for the study.

Patients will be randomized into four groups:
    • Group A – treatment with 177Lu-DOTATATE with constant radioactivity doses of 200 mCi;
    • Group B – treatment with 177Lu-DOTATATE from 90Y/177Lu-DOTATATE – initially at a ratio of 100: 50 mCi / mCi. Based on imaging and pharmacokinetic studies, and calculated doses in the tumor and kidneys in subsequent cycles, the ratio of 90Y to 177Lu constant radioactivity will be individually selected;
    • Group C – treatment with 177Lu-DOTATATE from 90Y/177Lu-DOTATATE – initially at a ratio of 100: 50 mCi / mCi. Based on imaging and pharmacokinetic studies as well as calculated doses absorbed in the tumor and kidneys in subsequent cycles, the ratio of 177Lu to 90Y radioactivity will be individually selected;
    • Group D – treatment with 177Lu-DOTATATE initially with a dose of 200 mCi and then with an individualized dose based on imaging and pharmacokinetic studies as well as calculated doses absorbed in the tumor and kidneys.
Assessment of treatment effects will include imaging tests as well as biochemical and hormonal tests. Based on the results obtained in each group there will be assessed:
    • progression-free survival (PFS), overall survival (OS), percentage of patients with regression, stabilization or disease progression,
    • security of individual PRRT methods.
The expected effect of the study will be the development of individualized treatment algorithms for patients with NEN using PRRT or tandem-PRRT, allowing for increased treatment effectiveness compared to standard therapy.

Duration of the project:

2020 – 2026
68%

Source of financing:

Projekt finansowany przez Agencję Badań Medycznych, Polska, numer projektu 2019/ABM/01/00077.

Grant amount:

16 225 166.35 PLN

OR POLATOM (NCBJ) role in the project:

Leader

Project manager:

prof. dr hab. inż. Renata Mikołajczak

Project website:

https://www.abm.gov.pl/