PET-imaging of Two Vartumabs in Patients with Solid Tumors

VARTUTRACE is a first-in-human PET/CT molecular imaging study in patients with solid tumors. This study will investigate the biodistribution and pharmacology of two antibody fragments binding oncofetal Chondroitin Sulfate (CS).

Oncofetal CS are tumor-specific carbohydrate motifs present in proteoglycans and identified by VAR2 Pharmaceuticals as expressed during fetal development. Oncofetal CS reappears in the vast majority of cancers while remaining largely absent from normal tissues.

VAR2 Pharmaceuticals recently developed antibodies specific for oncofetal CS. VARTUTRACE uses two of these as radiolabeled antibody fragments to study biodistribution, tumor accumulation, pharmacodynamics and clearance pathways in a diverse patient population.

VARTUTRACE aims to investigate the biodistribution and pharmacology in patients with solid tumors of two antibody fragments specific for oncofetal CS.

VAR2 Pharmaceuticals has identified and characterized oncofetal CS as a group of tumor-specific carbohydrate motifs that appear in placental tissue during fetal development and in most cancers while remaining largely absent from healthy tissue. VAR2 Pharmaceuticals recently developed a panel of antibodies specific for oncofetal CS and characterized their tumor specificity, therapeutic, and safety in pre-clinical models under various formats.

VARTUTRACE is a Phase 0 microdosing study of a single administration of \<30 nmol of one of the two most promising antibody fragments identified by VAR2 Pharmaceuticals - C9 and F8. Both antibody fragments will be used as short chain variable fragments (scFvs) labelled with the radioisotope Zirconium-89 (89Zr) and are therefore respectively named 89Zr-C9scFv or 89Zr-F8scFv. As it remains unclear from the pre-clinical in vitro and in vivo data which of the two will have the most optimal tumor targeting properties in patients with solid tumors, both scFvs will be evaluated.

The biodistribution, pharmacokinetics, pharmacodynamics, and clearance of two of these antibody fragments is planned to be studied in up to 32 patients with various cancers (i.e. a basket-trial).

Eligibility Criteria:
General Inclusion Criteria:

1. Willing to adhere to the prohibitions and restrictions specified in this protocol.
2. Capable of giving signed informed consent (voluntarily), indicating that the patient understands the purpose and procedures required for the study and is willing to comply with the requirements and restrictions listed in the informed consent form and in this protocol.
3. Patients aged ≥ 18 years at moment of signing informed consent form.
4. Life expectancy of \> 12 weeks.
5. ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.
6. BMI ≥ 18.0 and ≤ 35.0 kg/m2 and weight at least 50 kg and no more than 120 kg at screening.
7. Overtly healthy based on medical history, physical findings, vital signs, ECG at the time of screening, as judged by the Investigator. Note: one retest of vital functions and ECG is allowed within the screening window.
8. Adequate liver- and kidney function, defined by the following laboratory results obtained during screening visit:

   * AST, ALT, and alkaline phosphatase ≤ 2.5x the upper limit of normal (ULN) as determined by the UMCG laboratory reference values.
   * Serum bilirubin ≤ 2.0x ULN as determined by the UMCG laboratory reference values. Patients with known Gilbert disease who have serum bilirubin level ≤ 3x ULN may be enrolled.
   * INR or APTT ≤ 1.5x ULN as determined by the UMCG laboratory reference values. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
   * eGFR (based on plasma-creatinine) = \>30 mL/min.
   * Serum albumin \>35 g/L.
9. No other clinically significant laboratory abnormalities as determined by the investigator. Note: one retest of lab tests is allowed within the screening window.
10. Female patients should be at least 1 year post-menopausal (amenorrhea \>12 months and/or follicle-stimulating hormone \>30 mIU/mL) at screening or surgically sterile (bilateral oophorectomy, hysterectomy, or tubal ligation).
11. Male subjects who are sexually active with a female partner of childbearing potential must agree to the use of an effective method of birth control, and must not donate sperm, until 3 months after administration of 89Zr-DFO-N-Suc-scFv (F8 or C9).

Medical inclusion Criteria:

Colon Carcinoma:

1. Patients diagnosed with colon carcinoma T1-2-3N0-1M0 (stage I-II-III), according to the 8th edition of the TNM-classification.
2. Histologically confirmed diagnosis of colon carcinoma.
3. Neo-adjuvant treatment according to the standard of care.
4. Patients who are scheduled for surgical resection of the tumor.

Rectal Carcinoma:

1. Patients diagnosed with rectal carcinoma T1-2-3N0M0 (stage I-II), according to the 8th edition of the TNM-classification.
2. Histologically confirmed diagnosis of rectal carcinoma.
3. Neo-adjuvant treatment according to the standard of care.
4. Patients who are planned for surgical resection of the tumor.

Osteosarcoma:

1. Patients diagnosed with osteosarcoma stage I-IV, according to AJCC staging for Bone Sarcoma.
2. Histologically confirmed diagnosis of osteosarcoma.
3. Patients who are planned for surgical resection of the tumor.
4. Neo-adjuvant treatment according to the standard of care.

Chondrosarcoma:

1. Patients diagnosed with chondrosarcoma stage I-IV, according to AJCC staging for Bone Sarcoma.
2. Histologically confirmed diagnosis of chondrosarcoma.
3. Neo-adjuvant treatment according to the standard of care.
4. Patients who are planned for surgical resection of the tumor.

Lung Carcinoma:

1. Anticipated diagnosis of Non-Small Cell Lung Carcinoma (NSCLC) T1-4N0M0 (stage I-II-III), according to the 8th edition of the TNM-classification, based on imaging modalities such as (PET)/CT or based on cytology
2. Neo-adjuvant treatment according to the standard of care.
3. Patients who are planned for surgical resection of the tumor.

Head and Neck Squamous Cell carcinoma (HNSCC):

1. Patients diagnosed with HNSCC of the oral cavity, oropharynx, nasal cavity, nasopharynx, hypopharynx and larynx.
2. Histologically confirmed diagnosis of HNSCC.
3. Neo-adjuvant treatment according to the standard of care.
4. Patients who are planned for surgical resection of the tumor.

Oesophageal and gastric carcinoma:

1. Patients diagnosed with oesophagus carcinoma T1-3N0-3M0 according to the 7th edition of the TNM-classification.
2. Patients diagnosed with gastric carcinoma T1-4N0-3M0 according to the 7th edition of the TNM-classification.
3. Histologically confirmed diagnosis of oesophageal- or gastric carcinoma.
4. Patients who are planned for surgical resection of the tumor.
5. Neo-adjuvant treatment according to the standard of care.

Pancreas carcinoma:

1. Patients diagnosed with pancreas carcinoma T1-3N0-2M0 (stage I, II and III) according to the 8th edition of the TNM-classification.
2. Histologically or cytologically confirmed diagnosis of pancreas carcinoma.
3. Patients who are planned for surgical resection of the tumor.
4. Neo-adjuvant treatment according to the standard of care.

Bladder carcinoma:

1. Patients diagnosed with invasive bladder carcinoma T2-4aN0M0 according to the 7th edition of the TNM-classification.
2. Histologically confirmed diagnosis of bladder carcinoma.
3. Patients who are planned for surgical resection of the tumor.
4. Neo-adjuvant treatment according to the standard of care.

Glioblastoma:

1. Anticipated diagnosis of a high-grade glioma (glioblastoma, grade 4 according to the WHO-classification) based on imaging modalities such as MRI and/or CT or a biopsy.
2. Karnofsky performance status of at least 70%.
3. Neo-adjuvant treatment according to the standard of care.
4. Patients who are planned for surgical resection of the tumor.

General Exclusion Criteria:

1. Behavioral or cognitive impairment or psychiatric disease that, in the investigator's opinion, affects the patient\&#39;s ability to understand and cooperate with the study protocol.
2. Insufficient venous access for the study procedures.
3. Close affiliation with the investigator, e.g. a close relative of the investigator, dependent person (e.g. employee or student), employee of the department of surgery or nuclear department of the UMCG,TRACER or affiliates.
4. Any finding in the medical examinations or medical history giving, in the opinion of the investigator, reasonable suspicion of a disease or condition that makes treatment with the investigational drug unadvisable, or that might affect interpretation of the results of the study or render the patient at high risk for treatment complications.
5. Participation in an interventional clinical study within 30 days prior to tracer administration that involved treatment with any drug (excluding vitamins and minerals) or medical device.

Medical Exclusion Criteria:

1. The existence of a second concomitant active malignancy or treatment for a second malignancy within 1 year prior to IMP-administration, except for localized basal or squamous cell cancer that has been cured at least 90 days before screening.
2. Cardiac impairment with an estimated LVEF \<35 % Prolonged QTcF (\>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the investigator.
3. Any abnormalities in the vital signs of the patient, as judged by the investigator, as a result of which the patient cannot participate. Note: One retest of vital functions is allowed within the screening window.
4. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
5. Major surgical procedure other than for the included diagnosis within four weeks before IMPadministration. Disease-related procedures, e.g. the placement of a port-a-cath, placement of a drain,ERCP, are allowed.
6. Current evidence or history of bacterial, viral or fungal infections within 7 days before 89Zr-DFON-Suc-scFv (F8 or C9) administration as judged by the Investigator.

   * T \> 38.0°C or lab confirmed viral/bacterial/fungal infection (PCR) or symptoms suggestive of an infection)
   * Received oral or IV antibiotics within \<7 days before administration.
7. Any planned major surgery within the duration of the study (until follow-up visit) that is not related to the tumor, with the exception of any emergency surgeries.
8. Prior allogeneic bone marrow transplantation or solid organ transplant.
9. A history of anaphylaxis, history of allergic reaction(s), known allergy to one of the drugs or excipients administered as part of this study. Mild allergies without angio-edema or treatment need can be acceptable if deemed not of clinical significance (including allergy to animals or mild seasonal hay fever).
10. Any other diseases, metabolic dysfunction, physical examination finding, or clinically significant laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.