Patient case: 58-year-old male with gastrointestinal stromal tumor; genetic feature: KIT (exon 9 502_503 duplication)

Clinical trial: Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1.

Summary: This study is being done because new treatment for patients with metastatic or locally advanced cancers expressing Neurotensin receptor 1 (NTSR1) is being studied. This study will be the first administration of a radioactive drug called 177Lu-3BP-227 to patients under controlled conditions of a clinical study. The purpose of this study is to evaluate how safe this investigational drug is as well to verify how well it is tolerated by patients after several intravenous administrations. In addition, we will evaluate the effect of the study drug on tumoral lesions and how it distributes throughout the body and at which rate it is removed from the body. Since 177Lu-3BP-227 is a radio-labelled drug, it will also be measured how the emitted radiation is distributed throughout the body (dosimetry).
  The study consists of a phase I with a dose escalation part (and potential expansion cohorts) and a phase II either in selected or over multiple indications in a basket approach. For the dose escalation part, it is anticipated that approximately 30 subjects will be included, in up to six escalation steps. In case of the implementation of phase I expansion cohorts, up to 45 additional subjects will be enrolled. For the phase II, approximately 125 subjects (55 Pancreatic ductal adenocarcinoma and 70 Colorectal cancer subjects) are planned to be enrolled for Basket trial or Optimal Simon's Two Stage design. If additional cohorts of subjects with Gastric cancer (GC) or Squamous-cell carcinoma of head and neck (SCCHN) in the phase II are to be studied, approximately 100 additional subjects will be enrolled.


Eligibility: Inclusion Criteria :
  -  Signed informed consent form prior to all study procedures
  -  Aged 18 years or older.
  -  Histologically or cytologically confirmed metastatic or locally advanced disease and no compelling treatment option as per standard-of-care and documented decision by a multidisciplinary oncology board including a specialist of the concerned pathology.
  -  Subjects have: (a) pancreatic ductal adenocarcinoma (PDAC), or (b) colorectal cancer (CRC), or (c) gastric adenocarcinoma (GC), or (d) gastrointestinal stromal tumours (GIST), or (e) squamous-cell carcinoma of head and neck (SCCHN), or (f) Ewing Sarcoma (ES)
  -  Tumour tissue expressing NTSR1 as determined by uptake of 177Lu-3BP-227 (screening formulation) in tumour lesions judged by the investigator to more avid than in the non-tumoral surrounding tissue based on whole body scan (planar scintigraphy); single photon emission computed tomography (SPECT)/ computed tomography (CT) can be performed as per investigator's judgement.
  -  Measurable disease (based on RECIST version1.1).
  -  Tumour biopsy obtained during screening period or in the 21 days prior to Informed consent signature and after the end of previous treatment.
  -  Documentation of progressive disease in the 6 months prior to study start (treatment).
  -  Eastern Cooperative Oncology Group performance status of 0 or 1 (unless if disability is related to surgery in ES and Agreed with the Sponsor).
  -  Adequate organ function as evidenced by: (a) Leukocytes ≥3000/μL (b) Absolute neutrophil count ≥1500/µL (c) Platelets ≥75,000/µL (d) Hb >9 g/dL or >10 g/dL (if history of cardiac disease) (e) Total serum bilirubin ≤2 times upper normal institutional limits (ULN) (f) Aspartate aminotransferase/alanine aminotransferase (ALT) ≤2.5×ULN (or ≤5×ULN, if subject has liver metastases) (g) Estimated glomerular filtration rate (eGFR) ≥55 mL/min.
  -  Estimated life expectancy >3 months.
  -  Female subjects of childbearing potential must agree to use an adequate double-barrier method of contraception during the study and for 6 months after discharge. Adequate methods of contraception for subjects or their partners include vasectomised partner (at least 6 months prior to dosing); intrauterine device; condom with spermicidal gel, foam, cream, film, or suppository; diaphragm with spermicidal gel, foam, cream, film, or suppository; or cervical cap with spermicidal gel, foam, cream, film, or suppository Female subjects of childbearing potential are defined as those who have not undergone surgical sterilisation, or those who are not considered postmenopausal. Postmenopause is defined as absence of menstruation for at least 2 years. If necessary, follicle stimulating hormone results >50 IU/L at screening are confirmatory in the absence of a clear postmenopausal history.
  -  For male subjects, agreement that, if a partner is of childbearing potential, a medically accepted and effective method of contraception (i.e. condom) will be used for the duration of the study. Subjects must agree not to donate sperm up to 90 days after the last study visit.
  -  Must be willing and able to comply with study restrictions and to remain at the clinic for the required time during the study period and willing to return to the clinic for the follow-up evaluation, as specified in the protocol.
  Exclusion Criteria :
  -  Prior treatment received (a) Any antitumour treatment since last documentation of disease progression (b) Any chemotherapy within 3 weeks or nitrosourea within 6 weeks prior to first treatment investigational medicinal product (IMP) administration (c) Any curative radiotherapy within 4 weeks, or palliative radiotherapy within 7 days prior to first treatment IMP administration (d) Any monoclonal antibodies within 4 weeks or tyrosine kinases inhibitors within 2 weeks prior to the first treatment IMP administration, if the previous compound is a mechanism-based molecularly targeted agent whose half-life (t1/2) is not well-characterised.
  -  Brain metastases.
  -  Nephrectomy, renal transplant or concomitant nephrotoxic therapy putting the subject at high risk of renal toxicity during the study.
  -  Only non measurable metastatic bone lesions
  -  Existing or planned colostomy during study participation.
  -  Any history of inflammatory bowel disease.
  -  Any uncontrolled significant medical, psychiatric or surgical condition or laboratory finding, that would pose a risk to subject safety or interfere with study participation or interpretation of individual subject results.
  -  Clinically significant abnormalities on electrocardiogram (ECG) at screening including corrected QT interval (Fridericia's formula) >450 msec for males or 470 msec for females at screening.
  -  Previously received external beam irradiation to a field that includes more than 30% of the bone marrow or kidney.
  -  Body weight <50 kg. Unless agreed upon with sponsor fro ES subjects.
  -  Any unresolved NCI-CTCAE Grade 2 or higher toxicity (except alopecia) from previous antitumour treatment and/or medical/surgical procedures/interventions.
  -  Known allergy to IMP or its excipients administered in this study, including imaging contrast media.
  -  Positive pregnancy test (female subjects).
  -  Likely to be uncompliant or uncooperative during the study, in the judgment of the investigator.
  -  Unable to understand the nature, scope and possible consequences of the study, in the judgment of the investigator.
  -  Sponsor employees or investigator site personnel directly affiliated with this study, and their immediate families. Immediate family is defined as a spouse, parent, child or sibling, whether biological or legally adopted.

Relevance to patient case: not relevant