AvidinOX + [177Lu]DOTA-biotin (or 177Lu-ST2210) Complex in Patients With Liver Metastases From Colorectal Cancer

The purpose of the study is to assess a new treatment for patients with liver tumor metastases from colorectal cancer. The treatment has never been used in humans before. The treatment foresees the use of two compounds: AvdinOX and \[177Lu\]DOTA-biotin.

AvidinOX is a new compound, essentially a natural protein obtained from hen eggs, while \[177Lu\]DOTA-biotin is a new chemical compound resulting from the combination of the DOTA-biotin (also deriving from a natural vitamin which is biotin) with the 177Lutetium, an atom which emits radiation.

AvidinOX will be injected directly into the metastases in the liver and \[177Lu\]DOTA-biotin will be injected into the arm vein.

One specific property of AvidinOX is that it chemically links to the tumor tissues when it is injected while maintaining the capacity to take up \[177Lu\]DOTA-biotin. Once locally bound in tumor tissue, AvidinOX becomes an "artificial receptor" for intravenously injected \[177Lu\]DOTA-biotin, which allows an internal radiation therapy of the tumor tissue.

The treatment of liver metastases with local injection of AvidinOX and the following intra-venous injection of \[177Lu\]DOTA-biotin could be simpler and more tolerable than the current available treatments.

Primary objectives

1. To identify the Maximum Tolerated Dose (MTD) of 177Lu-ST2210 after prior intra-lesional injection of AvidinOX in the liver.
2. To assess safety and tolerability of intra-lesionally injected AvidinOX + IV injected 177Lu-ST2210
3. To evaluate intra-lesional distribution and retention of AvidinOX + 177Lu-ST2210 complex in liver metastases
4. To evaluate systemic biodistribution and pharmacokinetics of 177Lu-ST2210 and {AvidinOX + 177Lu-ST2210}- complex

Secondary objectives

1. To evaluate proportional 177Lu-ST2210 tumor binding, as a function of total tumor load, and AvidinOX dose injected
2. To demonstrate AvidinOX post-deposition reactivity with 177Lu-ST2210 over time
3. To evaluate whole body dosimetry of IV 177Lu-ST2210 after prior AvidinOX injection (radiation safety dosimetry)
4. To record individual tumor dosimetry
5. To evaluate preliminary efficacy of {AvidinOX + 177Lu-ST2210}-complex in reducing tumor size
6. To evaluate whole body safety dosimetry and dose linearity of IV administered 177Lu-ST2210 after prior intra-lesional injection of AvidinOX
7. To evaluate pharmacokinetics of ST2210 in plasma and urine

Eligibility Criteria:
Inclusion Criteria:

1. Male or female ≥ 18 years of age
2. Liver metastases from histologically confirmed colorectal cancer and at least one liver metastasis ≥ 1 cm (measurable disease), which is chemo-resistant, not eligible for curative surgery and suitable for intra-lesional injection as assessed by the investigator.
3. Total liver tumor burden requiring ≤ 75 ml AvidinOX
4. Maximum of 9 liver metastases
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
6. Life expectancy of at least 3 months.
7. Clotting parameters as follows, with local normal ranges to be taken as reference:

   * Prothrombin Time (Quick).Patients showing an increase of the Upper Limit of the Normal (ULN) range of about 20% can also be considered for inclusion.
   * International Normalised Ratio (INR). Patients showing an increase of the ULN of about 20% can also be considered for inclusion
   * Activated Partial Thromboplastin Time (aPTT). Patients showing an increase of the ULN of about 20% can also be considered for inclusion
   * Fibrinogen. Patients showing a decrease of the Lower Limit of the Normal range (LLN) of about 20% can also be considered for inclusion.
8. Haematological, liver and renal function test results ≤ grade 2 toxicity (according to US National Cancer Institute's "Common Terminology Criteria for Adverse Events v4.03 \[CTCAE\]"), i.e.:

   * Haematology:

     * Haemoglobin ≥ 8 g/dl
     * White blood cell count ≥ 2 x 109/L
     * Platelets ≥ 80x 109/L
   * Liver:

     * Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP) ≤ 5 times upper limit of normal
     * Bilirubin ≤ 3 times upper limit of normal
   * Renal:

     * Urine protein dipstick: 0
     * estimated Glomerular Filtration Rate (eGFR)\> 30 ml/min/1.73 m2 (with CKD-EPI formula)
9. Written informed consent

Exclusion Criteria:

1. Known hypersensitivity to Avidin or AvidinOX (e.g. hen egg)
2. Known hypersensitivity to ST2210(DOTA biotin) or any excipient.
3. Life limiting metastases outside the liver. Metastases outside the liver are allowed only in case the residual metastases (after liver treatment) are amenable to further treatments (e.g. surgical removal)
4. Presence of unreachable (e.g. located in a region in the liver that cannot be reached by needle, or too close to major blood vessels or adjacent to main organs) or untreatable hepatic lesions so that the benefit from the treatment of the treatable lesions does not justify patient's inclusion
5. Active infection at screening or history of severe infection within the previous 3 months, if clinically relevant at screening as considered by the investigator
6. Known human immunodeficiency virus (HIV) positive serology or chronically active hepatitis B or C.
7. Administration of another investigational medicinal product within 30 days before the screening period.
8. Previous treatment with Selective Internal Radiation Therapy (SIRT) spheres or any radiopharmaceutical within a period corresponding to 8 half-lives of the radionuclide used for labeling the respective radiopharmaceutical prior to the administration of study drug.
9. Women of child-bearing potential. A permanent postmenopausal status must be proven as follows: history of hysterectomy or hormone analysis in serum: estradiol \< 20 pg/ml and follicle stimulating hormone (FSH) \> 40 IU/L, or amenorrhea starting at least 1 year prior to the study start andnegativeβHCG .
10. Men unwilling to use appropriate contraceptive methods during the study and up to six months after the end of the study
11. Inability or unwillingness to be catheterized
12. History of somatic or psychiatric disease/condition that may interfere with the objectives of the study
13. Clinically significant illness or clinically relevant trauma within 15 days before the screening period
14. Patient who underwent chemotherapy, radiation therapy within 15 days before the screening period