Randomized Phase II Trial in sstr2 Positive Tumors to Optimize the Interval Between Cycles of PRRT With 177lu-dotatate

The main objective of this randomized phase II comparative study is to evaluate the Progression Free survival (PFS) and the safety as co-primary objective of two different schedule of administrations of 177lu-dotatate: intensive (every 5 weeks) vs no intensive (every 8-10 weeks) The secondary objectives are DCR, the late toxicity, OS and dosimetry. Patients with any tumor histotype documented as sst2-positive in pre-study period will be enrolled in the study.

The study will include a total of 618 planned patients. They will be randomly assigned to receive 5 cycles of PRRT at intervals of 5 or 8-10 weeks between cycles.

Inclusion Criteria:

1. Age >18 years.
2. Patients must have histologically or cytologically confirmation of neuroendocrine tumors or any other tumor histotype documented as sst2-positive), that may benefit from receptor radionuclide therapy and for which there aren't any other effective treatments. For cerebral sst2-positive tumors, if biopsy is no feasible for technical reason or risk benefit balance, patients may be enrolled if CT or MRI strongly suggest oncological lesion confirming the 68Ga PET-CT dota-peptide SSTr2 positivity..
3. Measurable disease according to RECIST 1.1.criteria also patients without measurable but with evaluable disease disease can be enrolled.
4. Any disease stage is allowed. Patients with documented disease will be admitted to therapeutic phase only if the diagnostic OctreoScan (the tumour uptake will be evaluated with a 3-grade scale, where 1 = liver uptake, 2 > liver uptake and < kidney uptake and 3 > kidney uptake: only tumour uptakes grade 2 and 3 will be considered for therapy) and/or Positron Emission Tomography (PET)/CT 68Ga-peptide images demonstrate a significant uptake in the tumour.
5. Patients with progressive disease in pre-study period (PD within the last 12 months), refractory to conventional standard treatments; clinical progression is allowed
6. Patients with or without concurrent therapy with somatostatin analogs
7. Life expectancy of greater than 6 months.
8. Eastern Cooperative Oncology Group (ECOG) performance status =<2
9. Adequate haematological, liver and renal function: haemoglobin >= 9 g/dL, absolute neutrophil count (ANC) >= 1.5 x 109 /L, platelets >= 100 x 109 /L, bilirubin ≤1.5 X upper normal limit (UNL) , alanine aminotransferase ( ALT) and Aspartate aminotransferase (AST) <2.5 X UNL (< 5 X UNL in presence of liver metastases, creatinine < 2 mg/dL.
10. If female of childbearing potential highly effective birth control methods, according to guideline "Recommendation related to contraception and pregnancy testing in clinical trials", (2014_09_15 section 4.1) are mandatory. Highly effective birth control methods are required beginning at the screening visit and continuing until 6 months following last treatment with study drug. Negative serum pregnancy test for females of childbearing potential within 14 days of starting treatment. Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 6 months after final study drug administration. Two acceptable methods of birth control thus include Condom (barrier method of contraception) and one of the following is required (established use of oral, or injected or implanted hormonal method of contraception by the female partner; placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner; additional barrier method like occlusive cap with spermicidal foam/gel/film/cream/suppository in the female partner; tubal ligation in the female partner; vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy), for more than 6 months.
11. Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

1. Patients treated with chemotherapy and therapeutic radiotherapy within 4 weeks and treated within 2 weeks with palliative radiotherapy, hormonal or biological therapy.
2. Patients treated with previous radiometabolic therapy with an adsorbed dose to the kidney more than 23 Gy and more than 1.8 Gy for the bone marrow or as surrogate of dosimetry (13).
3. Patients which are included in the indication of LUTATHERA®
4. All acute toxic effects of any prior therapy (including surgery radiation therapy, chemotherapy) must have resolved to a grade ≤ 1 according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE)
5. ECOG performance status >2
6. Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
8. Assessed bone marrow invasion > 50% (with Bone Marrow biopsy or instrumental exams i.e. bone scan or CT or MRI)
9. Pregnant or breastfeeding women are excluded from the present study.