A Dose Escalation and Expansion Study of [177Lu]Lu-SN201 in Participants With Advanced Cancer

Ph I/IIa Escalation/Expansion FIH, Open, Multi Center, Single Arm Study Evaluating Safety, Dosimetry and Early Efficacy of 177Lu-SN201 in Progressive/Treatment-refractory, Locally Advanced, Unresectable Metastatic or Recurrent Solid Tumors

The purpose of this first-in-human (FIH) study is to determine the maximum tolerated dose (MTD) and to characterize the safety, tolerability, PK, and dosimetry profile of [177Lu]Lu-SN201 in adult participants with advanced solid tumors who have no standard of care treatment options.

[177Lu]Lu-SN201 is a radiolabeled, nanomedical investigational medicinal product (IMP) whose mechanism of delivery is based on the Enhanced Permeability and Retention (EPR) effect.

Eligible participants will receive [177Lu]Lu-SN201 via slow intravenous infusion on Cycle 1 Day 1. Participants will initially receive one cycle of treatment and will progress to a 2nd and 3rd cycle of treatment, provided retreatment criteria are met before the start of each cycle. The dosing schedule visit frequency will be every 6 weeks (with an allowable window to delay each cycle by +3 weeks per retreatment criteria), each participant may receive up to 3 cycles, with the treatment duration up to 22 weeks. A total of 3 treatment cycles will be given unless the participant meets early discontinuation criteria. For Cycle 1, an overnight hospitalization for standard-of-care observation following Day 1 clinic assessments to Day 2 is mandatory for all participants receiving Cycle 1.

Whole-body planar imaging, and single photon emission computed tomography (SPECT)/computed tomography (CT) will be performed post-administration of [177Lu]Lu-SN201 to assess biodistribution and dosimetry. CT or magnetic resonance imaging (MRI) will be used to assess the response of the disease to treatment using Response Evaluation Criteria (RECIST v1.1).

The general procedures for participants in Phase I and Phase IIa are summarized below:

• Baseline values are defined as the last collected value prior to the start of infusion.
• Continual assessment of adverse events (AEs) and concomitant medication usage will be conducted.
• Whole-body planar on Day 1, Day 2, Day 4, and Day 8 and SPECT/CT on Day 2, Day 4 and Day 8 will be used for biodistribution and dosimetry evaluation of all participants. If dosimetry has been met by previous participants at each dose level, the DMC may partly or fully exclude the requirement for dosimetry procedures in remaining participants at this dose level.
• For participants that will continue to treatment Cycle 2 or 3, eligibility assessment and IMP procurement will take place within the coming 17 days.

Inclusion criteria:

1. Male or female participants ≥ 18 years of age on the day of signing informed consent.

2. Histologically or cytologically documented, recurrent, locally advanced, or metastatic solid malignancy that has failed at least one prior systemic standard therapy, or for which standard therapy is not appropriate, or for which no standard therapy exists.

3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

4. Life expectancy ≥ 3 months.

5. Adequate bone marrow, liver, and renal function, as assessed by the following laboratory requirements, to be conducted within 28 days before the start of the study IMP administration:

   1. Hemoglobin ≥ 9.0 g/dL (transfusions are allowed).
   2. Absolute neutrophil count (ANC) ≥ 1500/mm3.
   3. Platelet count ≥ 100,000 mm3.
   4. Total bilirubin ≤ 2.5 x upper limit of normal (ULN) (in participants with liver metastases ≤ 5 ULN).
   5. Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 5 x ULN.

6. On a stable dose of anti-coagulation therapy will be allowed to participate if they have no sign of bleeding or clotting and prothrombin/international normalized ratio and partial thromboplastin time (PT/INR and PTT, respectively) test results are compatible with the acceptable benefit-risk ratio at the Investigator's discretion.

7. Serum creatinine ≤ 1.5 x ULN and estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 (per local values).

8. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

   1. Male participants must agree to use a highly effective method of birth control as defined in ICH M3(R2) starting with the first dose of study medication through 120 days after the last dose of study medication.

   2. Female participants of childbearing potential* must have a negative pregnancy test documented at Screening and Baseline and be willing to use a highly effective method of contraception** or practice abstinence starting from ICF signature through to 120 days after the last dose of study medication.

      • A female of childbearing potential is a sexually mature female who 1) has not undergone a hysterectomy or bilateral oophorectomy, or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., had had menses at any time in the preceding 24 consecutive months).

        • Effective contraception is defined as contraceptive methods with a failure rate of < 1% to prevent pregnancy (combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], progestogen-only hormonal contraception associated with inhibition of ovulation [oral, injectable, implantable], intrauterine device [IUD] or intrauterine hormone-releasing system).

9. Written informed consent to study participation.

10. Be able to understand and comply with the requirements of the study, as judged by the Investigator.

11. Phase I: At least one lesion as per RECIST v1.1.

12. Phase IIa: At least one measurable lesion as per RECIST v1.1.

Exclusion criteria:

1. Unstable systemic disease (including but not limited to active infection, hepatic, renal, or metabolic disease).

2. Clinically significant cardiac disease including any of the following:

   1. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2).
   2. LVEF of < 50%, as determined by MUGA or ECHO.
   3. Uncontrolled hypertension, defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
   4. History or presence of clinically significant ventricular arrhythmias or atrial fibrillation.
   5. Clinically significant resting bradycardia.
   6. Unstable angina pectoris ≤ 3 months before the start of study treatment.
   7. Acute myocardial infarction ≤ 3 months before the start of study treatment.
   8. Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value > 480 msec (as specified in Section 10.5).

3. Known hypersensitivity to pegylated drugs or vaccines (e.g., covid-19 vaccines).

4. Concurrent or active solid or hematologic malignancy within the last 2 years with a distinct primary site or histology from the cancer being evaluated in this study except for the following cancer types: cervical cancer in situ, treated basal cell carcinoma, superficial bladder tumors (Ta and Tis).

5. Infections not responding to therapy or active clinically serious infections.

6. Known human immunodeficiency virus (HIV) infection, active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection requiring treatment. Participants with chronic HBV or HCV infection are eligible at the Investigator's discretion provided that the disease is stable and sufficiently controlled under treatment.

   NB: Participants with CNS metastases may be included after discussion with Sponsor, except for the sentinel participants.

7. Chemotherapy, experimental cancer therapy, biologic therapy, or immunotherapy within 2 weeks (or 5 half-lives, whatever is shortest) before the start of the study IMP administration.

8. Palliative radiotherapy completed less than 2 weeks before the start of the study IMP administration will be allowed as long as no more than 10% of the participant's bone marrow was irradiated.

9. Not recovered to Grade 1 from any prior anti-cancer therapy, excluding alopecia.

10. Previous high-dose chemotherapy needing hemopoietin-stem-cell-rescue.

11. Major surgery, open biopsy, or significant trauma within 4 weeks before the start of study treatment.

12. A psychiatric or functional disorder that prevents participants from providing informed consent or following protocol instructions.

13. A participant that has a condition or is in a situation, in the Investigator's opinion may put the individual at significant risk, may confound the study results, or may interfere significantly with their participation in the study.

14. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 2 weeks or 5 half-lives of the agent, whichever is the shortest.