FAPi Radioligand OpeN-Label, Phase 1 Study to Evaluate Safety, Tolerability and DosImetry of [Lu-177]-PNT6555; A Dose Escalation Study for TReatment of Patients With Select Solid Tumors (FRONTIER)

FAPi Radioligand OpeN-Label, Phase 1 Study to Evaluate Safety, Tolerability and DosImetry of [Lu-177]-PNT6555; A Dose Escalation Study for TReatment of Patients With Select Solid Tumors (FRONTIER)

This Phase 1 study will evaluate the safety and tolerability of [Ga-68]-PNT6555 and [Lu-177]-PNT6555 in subjects with select solid tumors that have FAP over-expression, in order to determine a recommended Phase 2 dose.

Inclusion Criteria:

1. Adult (>18 years) male and female patients

2. Females of childbearing potential and males and their female partner(s) of childbearing potential must use two acceptable forms of contraception, one being a barrier method, during the study and also for 31 weeks (females) or 18 weeks (males) after last study drug administration.

3. Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations

4. The patient has read, understood, and signed the written informed consent form(s)

5. Advanced or metastatic solid tumor that is refractory to standard treatment, for which no standard treatment is available, or it is contraindicated, or the patient refuses standard therapy:

   • Adenocarcinoma of the Pancreas
   • High grade Soft Tissue Sarcoma (excluding Chordoma)
   • Esophageal Cancer (Squamous Cell Carcinoma or Adenocarcinoma, excluding Gastroesophageal Junction Cancer at US sites only)
   • Colorectal Cancer
   • Melanoma Skin Cancer
   • Head and Neck Squamous Cell Carcinoma (oral cavity, oropharynx, hypopharynx, nasopharynx, and larynx) (only at Canadian sites)
   • Cholangiocarcinoma (only at Canadian sites)

6. Laboratory values at initial screening and also within three days prior to dosing of [Lu-177]-PNT6555:

   1. Platelets greater than 120,000/ mm^3 at dosing. Transfusions allowed, but not for first dose

   2. Neutrophils greater than 1500cells/mm^3

   3. Hemoglobin:

      • Greater than 8.0 g/dL (only in Canada)
      • Greater than 8.5 g/dL (only in US)

   4. Liver Chemistries:

      • ALT and AST < 2.5 x ULN or < 5 x ULN for patients with liver metastases
      • Bilirubin < 2 mg/dL (<34.2 µmol/L); patients with Gilbert's syndrome are permitted if bilirubin is < 3 mg/dL (< 51.3 µmol/L) (only in Canada).
      • Total Bilirubin ≤ 1.5 x upper limit of normal (ULN); Total bilirubin ≤ 3 ULN is acceptable if a patient has Gilbert's provided that direct bilirubin ≤ 1.5 ULN (only in US)

   5. Normal PT(secs) and aPTT(sec); normal INR (ratio). Patients taking anticoagulants must be in therapeutic range

7. Glomerular filtration rate defined as creatinine clearance >60 ml/min/1.73 m2 based on Cockcroft-Gault formula

8. Life expectancy of at least 6 months per investigator judgement

9. Eastern Cooperative Oncology Group (ECOG) 0 to 1

10. Patients must have previously received treatment for their underlying disease and have no potentially curative options available

11. Positive [Ga-68]-PNT6555 PET/CT scan, defined as at least 50% of lesions with an SUVmax of 1.5 times or greater the SUVmean of the liver

Exclusion criteria

1. Patient has metastatic brain disease

2. Women who are pregnant, lactating, or planning to attempt to become pregnant during the study or within 31 weeks after last administration of study drug

3. Males with female partners who are pregnant, lactating or planning to attempt to become pregnant during this study or within 18 weeks after last administration of study drug

4. Subject has received prior hemi- or total- body radiation

5. Subject has received whole brain radiation

6. History of any grade 4 myelosuppression, or grade 3 myelosuppression requiring more than 6 weeks recovery

7. History of any kidney dysfunction (e.g., acute kidney failure, acute tubular necrosis (ATN)) for any reason (only in US)

8. Secondary malignancy that may interfere with the safety assessments of this study

9. Patient has any concurrent severe and/or uncontrolled medical conditions that could increase the patient's risk for toxicity while on the study or that could confound discrimination between disease- and study treatment-related toxicities

   a. Or the patient has persistent NCI-CTCAE version 5.0 Grade ≥ 2 toxicity due to prior cancer therapy. Permitted exceptions include Grade 2 neuropathy, alopecia, endocrinopathy with replacement therapy, and anemia (only in US)

10. Patient has received any other investigational agents within 4 weeks of starting the study treatment

11. Patient has received systemic anti-cancer therapy:

    1. Within 4 weeks or 5 half-lives, whichever is shorter of starting the study treatment; hormone maintenance therapy may be permitted with approval by the medical monitor if the patient is on a stable dose (preferred duration of a stable dose will be 4 weeks) (only in Canada)
    2. Patient has received systemic anti-cancer therapy within 4 weeks of starting the study treatment; hormone maintenance therapy may be permitted with approval by the medical monitor if the patient is on a stable dose (preferred duration of a stable dose will be 4 weeks) (only in US)

12. Patient has undergone surgery within 4 weeks of starting the study treatment; exceptions are permitted with approval by Medical Monitor

13. Previous radioligand therapy

14. Previous Adoptive T-Cell Therapy (e.g. CAR-T therapy, TCR therapy, etc.)

15. Prolonged QT, defined as QTc > 470 ms regardless of sex (only in US)

16. In patients who have received prior EBRT, each case should be reviewed by the site Investigators to determine appropriateness of eligibility given potential increased risk for radiation toxicities. In patients who have received a prior course of radiation therapy adjacent to either kidney, the mean kidney dose from EBRT must be available to inform potential risk, otherwise the patient will be ineligible. Patients who have previously exceeded dose limits for critical organs from prior EBRT are ineligible (only in US)