Personalized CAPTEM Radiopeptide Therapy of Advanced, Non-resectable Neuroendocrine Cancer

This is a non-randomized, phase II, open label study. The purpose of this study is to estimate Progression Free Survival (PFS) after treatment with Peptide Receptor Radionuclide Therapy (PRRT) 177Lu-DOTATOC standard dose (up to 4x7,4GBq 177Lu DOTATOC) in combination with capecitabine (CAP) and temozolomide (TEM) - CAPTEM.

Patients with advanced, non-resectable and/or progressive gastro-entero-pancreatic neuroendocrine tumors, GEP-NET, (G1, G2), in selected cases with high proliferation index (Ki-67\> 20%, usually below 55%), NETG3, with overexpression of somatostatin receptor (SSTR positive) will be enrolled in the study.

This is a non-randomized, phase II, open label study.

The purpose of this study is to:

• estimate Progression Free Survival (PFS) after treatment with Peptide Receptor Radionuclide Therapy (PRRT) 177Lu-DOTATOC standard dose (up to 4x7,4GBq 177Lu DOTATOC) in combination with capecitabine (CAP) and temozolomide (TEM) - CAPTEM.

Patients with advanced, non-resectable and/or progressive gastro-entero-pancreatic neuroendocrine tumors, GEP-NET according to WHO 2017 classification, (histological grade G1, G2), in selected cases patients with high proliferation index (Ki-67\> 20%, usually below 55%), NETG3 - pancreatic, midgut neuroendocrine tumors and carcinoma of unknown primary (CUP). All with overexpression of somatostatin receptor (SSTR positive) based on somatostin receptor scintigraphy (SRS), will be enrolled in this study.

* evaluate the safety and tolerability of combination therapy using 177Lu-DOTATOC and CAPTEM.
* evaluate the health related quality of life (QoL) as measured by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-G.I.NET21 questionnaire.
* evaluate internal dosimetry, in a subset up to 20 patients, but at least 10 patients.
* explore the correlation of clinical efficacy outcomes with Somatostatin Receptor Scintigraphy (SRS) using 99mTc HYNICTOC (Tektordyt®) tumour uptake score.
* explore the correlation of clinical efficacy outcomes with the levels of some specific and non-specific biomarkers and gene transcripts analysis.
* compare the Time to Tumour Progression (TTP).

The schedule of treatment will include 4 courses; capecitabine (CAP), which will be administrated for 14 days with 8-week breaks, combined at 10th day with 177Lu-DOTATOC (PRRT - Peptide Receptor Radionuclide Therapy) in doses from 5,55GBq up to 7,4 GBq administered i.v. up to four times in every patient during whole therapy.

In selected patients, in those with only liver involvement or dominant liver bulky disease third and fourth administration of PRRT will be used intra-arterial administration (i.a.) via hepatic artery. The administered dose will be from 2.85 GBq up to 3.7GBq, up to two times per whole therapy, followed in each case of i.v. or i.a. PRRT by Temozolomide (TEM) p.o. administration, which will be given during 10-14th days in each therapy sessions.

Doses of PRRT could be modified due to clinical stage and laboratory parameters. Treatment will be discontinued in the case of a cumulative dose 29,6 GBq, corresponding to the radiation dose on the bone marrow below 2 Gy and cumulative dose on kidney below 23 Gy. In case of radiation dose on kidney above 23 Gy treatment will be interrupted.

Eligibility Criteria:
Inclusion Criteria:

* Adults ≥18 years old, male or female;
* All patients with histologically proven, well/moderate-differentiated G1/2 GEP-NET (according to WHO 2017 classification), with Ki-67 ≤20%, in selected cases patients with NETG3 will be included if there will be reported well/moderate morphological appearance but Ki-67\>20% but less then Ki\<30% (pancreatic, midgut NET and cancer with unknown primary (CUP)); and there will be high expression of somatostatin receptor seen in functional imaging utilized functional imaging 99mTc HYNICTOC or 68Ga DOTATATE or 68Ga DOTATOC;
* The presence of high expression of somatostatin receptors demonstrated on Somatostatin Receptor Imaging using 99mTc HYNICTOC (SPECT) or 68Ga DOTATATE or 68Ga DOTATOC (PET) scans, et least as uptake in not involved liver, Krenning \>2;
* Non-resectable, advanced determined by an appropriately specialized surgeon or deemed not suitable for liver directed therapies where liver is the only site of disease;
* Performance status (PS) based on ECOG 0-2;
* Unresectable, advanced/metastatic progressive disease evaluated as clinical, biochemical, bad control symptoms of tumour hypersecretion or disease progression seen in imaging structural or functional;
* Parameteres of laboratory test:

  1. Morphology: Hb\>10g/dl, PLT\>75x103/ml, WBC\> 2x103 /ml with ACN\> 1.5x103/ml
  2. Adequate renal function (GFR\>30 ml/min)\*, creatinine \<1.5 mg/dl
  3. Adequate liver function (Bilirubin \<1.8 mg/dl, ALAT and ASPAT, AP \<5 ULN (ULN - upper limit of normal) \* The patient may be qualificated to supportive treatment if the patient's condition is stable.
* Life expectancy of at least 6 months;
* The tumor parameters that can be measured objectively as the size to be assessed in radiological studies on the basis of the RECIST 1.0 and RECIST 1.1;
* In the absence of the ability to measure tumor size based on RECIST criteria, they have tumor parameters that can be measured objectively as tumor markers determined in the blood or urine CgA, 5HIAA;
* Study treatment both planned and able to start within 28 days of inclusion;
* Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
* Signed, written informed consent.

Exclusion Criteria:

* Patients \<18 years old;
* Coexistence of another cancer during recent 5 years, except cancers treated with curative intention and confirmed cured in follow-up with no or low risk of relapse;
* Allergy on somatostatin receptor analogues or capecitabine and temozolomide;
* Previous cytotoxic chemotherapy e.g. CAPTEM, and/or radiopeptide therapy PRRT;
* Pre-existing locoregional treatment such as radiomebolization (SIRspheres) or HDR brachytherapy under CT control, performed in the last 6 months;
* Uncontrolled metastases to the central nervous system, in the case of surgical and/or radiotherapeutic treatment, patients should remain on a stable dose of steroids for at least 2 weeks before enrollment, without deterioration of the general state associated with the presence of metastatic disease in the CNS;
* Poorly controlled concurrent medical illness. E.g. unstable diabetes with glycosylated hemoglobin (HbA1c\> 9.0), the optimal glycaemic control should be achieved before starting trial therapy);
* Major surgery/surgical therapy for any cause within three months before starting trial therapy;
* Symptomatic heart failure NYHA class III or IV, congestive cardiac failure, myocardial infarction in the last 6 months, serious uncontrolled cardiac arrhythmia, unstable angina, or other serious cardiac problems;
* Patients with malabsorption or other gastrointestinal disorders that may interfere with the oral absorption of capecitabine and temozolomide (e.g. colitis ulcerosa, persistent nausea, vomiting, persistent diarrhea) not suitable for conservative treatment and no reaction to SST receptor analogs (Sandostatin LAR or Somatulina Autogel), malabsorption syndrome, short bowel syndrome after resection
* Active uncontrolled infection, including Hepatitis and Hepatitis, HIV, in the case of HCV and HBV infection, the patient can be included in the study confirming the suppression of viral replication and the patient remains on the correct therapeutic dose of antiviral drugs;
* Pregnant patients (a negative pregnancy test is required);
* Women of childbearing age must present a negative pregnancy test at the beginning of the study and must use double barrier to contraception. Women of childbearing age are defined as menopausal if they remain not menstrual for at least 1 year, or surgical sterilization or removal of the uterus before the start of the study;
* Breast-feeding female patients;
* Patients in a mental state who can't understand the nature, extent and possible consequences of participating in the study associated with radioisotope treatment, or there is evidence of a lack of cooperation by the patient;
* Exclusive clinical and laboratory findings that may compromise the patient's safety or reduce the chances of obtaining satisfactory data to achieve the goal (s) of the study;
* Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
* The patient may be included in the maintenance treatment if the patient's clinical condition is stable.