64Cu-LNTH-1363S in Patients with Sarcoma or Gastrointestinal Tract Cancer

This is a multicenter, open-label, prospective Phase 1/2a study to assess safety and tolerability, establish dosimetry and to identify an optimal imaging dose (radioactivity and mass dose) and imaging time window of 64Cu-LNTH-1363S (64Cu Radiolabeled FAPi PET/CT Imaging Agent) and to compare its imaging biodistribution with FAP expression by immunohistochemistry (IHC) in patients with sarcomas or GIT cancers. The study will be conducted in 2 parts (Part 1 and Part 2).

Part 1 will determine the biodistribution, dosimetry, optimal dose (radioactivity and mass dose) and imaging time window of 64Cu-LNTH-1363S in 12 evaluable patients with supposed FAP-expressing solid tumors (metastatic sarcomas). Two 64Cu-LNTH-1363S mass doses of \~50 μg and \~90 μg will be studied. Six patients will receive 8 ± 1 millicurie (mCi) (\~50 μg mass dose), followed by another 6 patients will receive 8 ± 1 mCi (\~90 μg mass dose). Two additional radioactivity (6 and 4 mCi) doses will be simulated by reprocessing raw data from each patient's PET scans.

This study does not involve randomization for dose groups. It will commence with the lower dose group (\~50 μg mass dose). After enrolling 6 evaluable patients in this dose group, recruitment for the next dose group (\~90 μg mass dose) will begin and conclude upon enrolling 6 evaluable patients. Subsequently, the images will undergo analysis by blinded central readers.

Part 1 of the study will last approximately 3 weeks for each patient and includes a Screening Period (up to 14 days), a 1-day Intervention Period, and a Safety Follow-up Period (7 days post dose).

Part 2 will evaluate 64Cu-LNTH-1363S imaging correlation with FAP expression measured by IHC (SUVmax and SUVmean vs IHC score) in 20 evaluable patients with non-metastatic, operable, supposed FAP-expressing solid tumors (sarcomas, esophageal, gastric, pancreatic, colorectal) planned for surgery within 60 days (from study imaging). If the optimal radioactivity determined from Part 1 is less than 8 ± 1 mCi, the first 6 patients in Part 2 will be used to validate this optimal radioactivity. This mean the image quality scores of the first 6 patients will need to be calculated. If the sum of the average image quality scores of the 6 patients is higher or equal to 10.5, then the lower optimal radioactivity determined in Part 1 will be used for the remaining 14 patients, otherwise the remaining 14 patients in Part 2 will be injected with 8 ± 1 mCi of 64Cu-LNTH-1363S. Part 2 of the study will last approximately 10 to 11 weeks for each patient and includes: a Screening Period (up to 14 days), a 1-day Intervention Period, a 1-day Safety Follow-up Period (Day 2), and a Scheduled Surgery: IHC Sample Collection Period (from Day 2 to Day 60).

Both Part 1 and Part 2 of the study will also monitor cardiac safety by detecting changes in HR, T wave, ST segment and other ECG parameters and look for signals suggesting a concentration-response relationship of 64Cu-LNTH-1363S for QT and corrected QT interval (QTc) prolongation.

Eligibility Criteria:
Inclusion Criteria: Part 1

Patients are eligible to be included in the study only if all of the following criteria apply:

1. Patient must be ≥ 18 years of age and must have provided written informed consent.
2. Patients with suspected FAP-expressing metastatic sarcoma.
3. Patients must have histological, pathological, and/or cytological confirmation of a metastatic sarcoma (e.g., undifferentiated pleomorphic sarcoma, liposarcoma, Leiomyosarcoma, myxofibrosarcoma, solitary fibrous tumor, Ewing's sarcoma, synovial sarcoma, sarcoma not otherwise specified, osteosarcoma).
4. Patients must be willing to consent to provide sufficient and adequate archived tumor tissue samples (formalin fixed, paraffin embedded sample), preferably from a biopsy of a tumor lesion obtained either at the time of or after the diagnosis of disease; if archival tissue sample is unavailable, a new biopsy should be performed on the most accessible lesion(s) to obtain the tumor tissue sample.
5. Adequate renal function as determined by a calculated creatinine clearance ≥ 60 mL/min (Cockcroft Gault equation).
6. Women of childbearing potential (WOCBP) must have a negative beta-human chorionic gonadotropin (β-hCG) test and must not be breastfeeding. WOCBP must agree to use a highly effective method of contraception during the study and for 28 days after the last injection of the study drug.
7. Male subjects who are able to father a child must agree to avoid impregnating a partner, to adhere to a highly effective method of contraception and to not donate sperm during the study and for 28 days after the last injection of the study drug.

Inclusion Criteria: Part 2

1. Patients must be ≥ 18 years of age and must have provided written informed consent.
2. Patients must have histological, pathological, and/or cytological confirmation of a sarcoma or GIT cancers e.g., esophageal, gastric, pancreatic, colorectal cancer.
3. Patients must have suspected FAP expressing sarcoma or GIT cancers and planned for surgery within 60 days (from study imaging).
4. Patients must be willing to consent to provide sufficient and adequate tumor tissue samples (formalin fixed, paraffin embedded sample), from their planned surgery after participating in study imaging.
5. Adequate renal function as determined by a calculated creatinine clearance ≥ 60 mL/min (Cockcroft Gault equation).
6. Women of childbearing potential (WOCBP) must have a negative beta-human chorionic gonadotropin (β-hCG) test and must not be breastfeeding. WOCBP must agree to use a highly effective method of contraception during the study and for 28 days after the last injection of the study drug.
7. Male subjects who are able to father a child must agree to avoid impregnating a partner, to adhere to a highly effective method of contraception and to not donate sperm during the study and for 28 days after the last injection of the study drug.

Exclusion Criteria: Part 1

Patients are excluded from the study if any of the following criteria apply:

1. Unlikely to comply with protocol procedures, restrictions and requirements and judged by the investigator to be unsuitable for participation.
2. Known pregnancy or breastfeeding.
3. Any PET scan done within 10 physical half-lives of the PET agent prior to receiving study intervention.
4. They are participating as patients in another clinical study with an Investigational Product or another systemic therapy administered in the last 3 weeks.
5. Has undergone or plans to undergo PET or single-photon emission computerized tomography (SPECT) imaging with any other FAPi imaging agent within 6 months prior to or after participating in this trial.
6. History of QT/QTc interval prolongation, a marked baseline QT/QTc interval prolongation (e.g., repeated demonstration of a QTc interval, calculated with Fridericia's correction, \> 450 milliseconds) or taking medications known to cause QT/QTc prolongation.
7. A history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome).
8. Have history of QT prolongation or is taking a medication known to cause QT prolongation.

Exclusion Criteria: Part 2

1. Patients who have received or are scheduled to receive neoadjuvant anti-cancer therapy.
2. Evidence of metastatic or advanced, inoperable disease.
3. Unlikely to comply with protocol procedures, restrictions and requirements and judged by the investigator to be unsuitable for participation.
4. Known pregnancy or breastfeeding.
5. Any PET scan done within 10 physical half-lives of the PET agent prior to receiving study intervention.
6. They are participating as patients in another clinical study with an Investigational Product or another systemic therapy administered in the last 3 weeks.
7. Has undergone or plans to undergo PET or SPECT imaging with any other FAPi imaging agent within 6 months prior to or after participating in this trial.
8. History of QT/QTc interval prolongation, a marked baseline QT/QTc interval prolongation (e.g., repeated demonstration of a QTc interval, calculated with Fridericia's correction, \> 450 milliseconds) or taking medications known to cause QT/QTc prolongation.
9. A history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome)
10. Have history of QT prolongation or is taking a medication known to cause QT prolongation.