Bladder Carcinoma, Breast Cancer, Chondrosarcoma, Colon Carcinoma, Esophageal Carcinoma, Gastric Carcinoma, Glioblastoma, Head and Neck Squamous Cell Carcinoma, Lung Carcinoma, Osteosarcoma, Pancreas Carcinoma, Rectal Carcinoma, Soft Tissue Sarcoma (STS), Solid Tumor
Conditions
Keywords
Basket-trial, Oncology, Solid tumors
Brief summary
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.
Detailed description
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).
Interventions
BIOLOGICAL89Zr-DFO-N-Suc-F8scFv
89-Zirconium labeled short-chain variable fragment F8 targeting oncofetal CS.
BIOLOGICAL89Zr-DFO-N-Suc-C9scFv
89-Zirconium labeled short-chain variable fragment C9 targeting oncofetal CS.
RADIATIONPET/CT scan
IMP administration will be followed by PET/CT scans on day 1, 2 and 4.
Sponsors
TRACER Europe BV
Var2 Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Intervention model description
Initially, three patients per compound (89Zr-C9scFv and 89Zr-F8scFv) will be included according to alternating inclusion or patient availability (n=6). Subsequently, an interim analysis will be conducted to determine the optimal radiation dose and optimal scanning day for each radiolabeled antibody fragment. After the interim analysis, cohorts will be expanded with additional solid tumor indications and will include 13 more subjects per compound (n=26), resulting in 32 subjects overall. This basket trial aims to include at least one patient per indication. For expansion cohort subjects, IMP-administration will occur on day 1, with one PET/CT scan performed on the most optimal day (this was determined to be day 4). Optionally, patients can receive an additional day 6 scan to gain more insight into tumor retention.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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 stage I-IV, 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. Rectal Carcinoma: 1. Patients diagnosed with rectal carcinoma stage I-IV, 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. Bone- and soft-tissue sarcoma 1. Patients diagnosed with a bone- or soft-tissue sarcoma stage I-IV, according to AJCC staging for Sarcoma. 2. Histologically confirmed diagnosis of sarcoma. 3. Neo-adjuvant treatment according to the standard of care. Breast carcinoma 1. Patients diagnosed with breast carcinoma stage I-IV, according to the 8th edition of the TNM-classification. 2. Histologically confirmed diagnosis of breast carcinoma. 3. Neo-adjuvant treatment according to the standard of care. Lung Carcinoma: 1. Anticipated diagnosis of Non-Small Cell Lung Carcinoma (NSCLC) stage I-IV, 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. 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. Oesophageal and gastric carcinoma: 1. Patients diagnosed with oesophagus carcinoma stage I-IV according to the 7th edition of the TNM-classification. 2. Patients diagnosed with gastric carcinoma stage I-IV according to the 7th edition of the TNM-classification. 3. Histologically confirmed diagnosis of oesophageal- or gastric carcinoma. 4. Neo-adjuvant treatment according to the standard of care. Pancreas carcinoma: 1. Anticipated diagnosis of pancreas carcinoma stage I-IV according to the 8th edition of the TNM-classification, based on imaging modalities such as (PET)/CT or based on cytology. 2. Histologically or cytologically confirmed diagnosis of pancreas carcinoma. 3. Neo-adjuvant treatment according to the standard of care. Bladder carcinoma: 1. Patients diagnosed with invasive bladder carcinoma stage I-IV according to the 7th edition of the TNM-classification. 2. Histologically confirmed diagnosis of bladder carcinoma. 3. 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. General
Exclusion criteria
1. Behavioral or cognitive impairment or psychiatric disease that, in the investigator's opinion, affects the patient'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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biodistribution and pharmacokinetics of the radiolabeled IMP | Day 1, 2, and 4 after dosing | Biodistribution and pharmacokinetics of the IMP are defined by the amount of IMP that is taken up per target organ or tissue over time. The radioactive dose absorbed per target organ or tissue over time is determined using whole-body PET/CT imaging at various time points post-injection. In addition, blood samples will be taken at various time points post-injection to determine IMP plasma level concentrations. The ICRP 89 values will be used to calculate the effective dose in each organ. Descriptive statistics of absorbed doses to target organs and tissues specified will be tabulated. The blood concentrations will be presented using descriptive summary statistics. |
| Tumor-specific uptake of the IMP | Day 1 - 7 after dosing | Tumor-specific uptake of the IMP is defined as the amount of IMP that tumors uptake compared to normal tissue. Tumor-specific uptake of the IMP is captured using PET/CT imaging and quantified by calculating the tumor-to-background ratio (TBR), which is determined by the ratio of radioactivity taken up by the tumor and radioactivity taken up by healthy reference tissue. A qualified PET investigator will obtain the raw data. PET/CT-derived TBR will be quantified for each patient and compared to standard of care imaging techniques. Variables will be presented as qualitative data. Data interpretation is considered descriptive. |
| Incidence of treatment emergent adverse events (AE) (safety and tolerability) | Study duration (up to 56 days) | Safety and tolerability will be assessed by the number of participants with treatment-emergent AEs, with abnormal laboratory tests results (including the occurrence of anti-drug antibodies), abnormal vital signs, abnormal ECG readings, and abnormal physical examination findings from the time of i.v. administration of the IMP until the end of the follow-up period. For this objective, variables will be presented as qualitative data. Interpretations of this data will be descriptive |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor-specific uptake of the IMP per cancer type | Day 1 -7 after dosing | Tumor-specific uptake of the IMP will be quantified, as described in outcome measure 2, for each cancer type and compared across cancer types included in this study. Variables will be presented as qualitative data. Data interpretation is considered descriptive. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Presence of IMP and target in patient-derived tumor tissue | Day 1 - 7 after dosing | The presence of the IMP and the oncofetal CS target in tumor tissue will be determined ex vivo and compared to the tracer signal measured in the tumor tissue in vivo. Presence of the IMP and the oncofetal CS target in patient-derived tissue slices will be determined using immunohistochemical stainings. Tumor-specific uptake of the IMP in vivo will be quantified using PET/CT imaging as described in outcome measure 2. For this objective, variables will be presented as qualitative data. Interpretations of this data will be descriptive. |
Countries
Netherlands
Contacts
Primary ContactAnne-Fleur Verhaar, MD
Backup ContactNoortje van Dijk, Msc
Outcome results
None listed