A Study to Assess Safety and Efficacy of SOT106 in Patients With LRRC15-positive Advanced Unresectable or Metastatic Osteosarcoma or Soft Tissue Sarcoma

A First-in-human Phase 1/2 Trial to Evaluate the Safety, Pharmacokinetics, and Preliminary Efficacy of SOT106 in Patients With LRRC15-positive Advanced Unresectable or Metastatic Osteosarcoma and Soft Tissue Sarcoma

SOT106 is a special cancer medicine designed to find and kill certain cancer cells that carry a marker called LRRC15, while causing less harm to healthy cells. The study consists of two parts, Part A and Part B. The goal of Part A is to collect information about SOT106, understand its effects, and see whether it is safe and well tolerated at different dose levels. Part B of the study collects information on which of the two selected safe dose levels chosen in Part A gives the best balance between benefit and risk.

The trial will consist of the following parts:

• Part A: a multinational, multicenter, open-label, TITE-BOIN-guided trial to determine the MTD and RP2Ds, to evaluate the safety, PK, and preliminary efficacy of escalating doses of SOT106 in participants with LRRC15-positive advanced or metastatic osteosarcoma or soft tissue sarcoma (STS) who have received and/or have been determined to be intolerant of all standard of care therapy known to confer clinical benefit.
• Part B: This is a randomized, multinational, multicenter, open-label dose optimization trial evaluating the two recommended doses for optimization (RDOs) identified in Part A. After the determination of the MTD in Part A and identification of RDOs, a randomized dose optimization part will be initiated to evaluate the two selected RDOs and to identify the optimal biological dose that offers the best balance between benefit and risk and to evaluate safety and efficacy of SOT106 in participants with advanced unresectable or metastatic osteosarcoma or STS who have no further standard treatment options.

Inclusion Criteria:

1. ≥18 years of age and body weight of ≥30 kg on the day of signing the prescreening ICF

   • In the US after dose levels 1 and 2 have been declared safe (following DEC review of the safety and PK data from the first two adult dose levels), participants aged ≥12 years on the day of signing the prescreening ICF may be enrolled from dose level 3 onwards
   • In the EU participants aged ≥12 years on the day of signing the prescreening ICF may be enrolled in backfilling cohorts once dose level 3 has been cleared in adults, following DEC review of safety, PK and efficacy data. In addition, preliminary signs of efficacy should have been observed in adults, based on the investigator's judgment.

2. Participants ≥ 18 years of age are able to understand, sign, and provide written informed consent to participate in the trial. For participants under 18 years of age, their legal representative must provide a written informed consent. Participants aged 12 to 17 must be willing and able to provide a written assent.

3. Performance status: Eastern Cooperative Oncology Group (ECOG) performance score 0-1. Patients with ECOG performance score 2 will be discussed with the sponsor's Medical Monitor to be agreed for inclusion.

4. Estimated life expectancy ≥3 months as assessed by the investigator

5. An appropriate candidate for experimental therapy as assessed by the investigator

6. Availability of adequate tumor tissue from an archival biopsy (FFPE block or unstained slides) or willingness to undergo a fresh tumor biopsy. A minimum of ≥1% (1+) of cells must exhibit LRRC15 expression with an intensity of at least 1+ by IHC.

   Note: Tumor samples will be sent to a central laboratory for LRRC15 expression analysis.

7. Agrees not to participate in other interventional clinical trials while enrolled in the present trial (with the exception of survival follow-up period). For participants under 18 years of age, their legal representative must agree that they will not participate in other interventional clinical trials while enrolled in the present trial (with the exception of survival follow-up period).

8. Absolute neutrophil count ≥1.5×109/L, platelets ≥100×109/L, hemoglobin ≥9 g/dL

9. Renal function:

   • For participants ≥ 18 years of age: creatinine clearance ≥ 60 mL/min calculated by Cockcroft-Gault formula
   • For adolescent participants (aged 12-17 years): estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m², calculated using the Bedside Schwartz formula

10. Bilirubin ≤1.5× upper limits of normal (ULN), ALT and AST ≤2.5×ULN; in case of liver involvement: AST and ALT ≤5×ULN.

    • Participants with a documented history of Gilbert syndrome may be eligible if:
    • Total bilirubin is ≤2.0 × ULN
    • Direct (conjugated) bilirubin is within normal limits (≤ULN)
    • There is no evidence of active liver disease, clinically significant hepatic impairment, hemolysis, or biliary obstruction, as determined by the investigator

11. Prothrombin time/international normalized ratio ≤1.5×ULN

12. Albumin ≥3.0 g/dL

13. Serum concentrations of potassium, magnesium, and calcium with abnormalities of maximum grade 1 that should be treated according to standard practice

14. Left ventricular ejection fraction (LVEF) ≥50% as determined by echocardiography or nuclear medicine methodology (MUGA)

15. QTcF interval <470 msec on screening ECG

16. Ophthalmologic examination (slit lamp examination and Snellen Eye Chart) performed

17. Histologically confirmed diagnosis of advanced unresectable or metastatic osteosarcoma or STS

18. Measurable or non-measurable progression of disease according to RECIST 1.1 after previous treatment within 6 months prior to screening

19. Received and/or determined to be refractory to, or intolerant of, standard therapies appropriate for their specific malignancy (osteosarcoma or soft tissue sarcoma)

20. Previous cancer therapies:

    • EU and Moldova: Previous cancer therapies and any agents that have not received regulatory approval for any indication must have been discontinued either ≥21 days or ≥ 5x half-life prior to day 1 of cycle 1, whichever is longer; toxicities of earlier anticancer therapy must be grade ≤1 at the time of screening and prior to cycle 1 day 1 (exception: alopecia); mitomycin-C and nitrosoureas must have been discontinued for ≥42 days.
    • US: eligibility should be determined based on patient recovery from clinically significant AEs from their most recent therapy or intervention prior to study enrollment

21. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and one of the following conditions applies:

    • Not a woman of childbearing potential (WOCBP). For the definition of a WOCBP
    • A WOCBP who agrees to use a highly effective contraceptive method during the treatment period and for at least 6 months after the last dose of SOT106

22. Male participants must agree to use a condom during the treatment period and for at least 6 months after the last dose of SOT106. Male participants wishing to become a father during or after the trial should consider sperm preservation. WOCBP partners of male participants should use highly effective contraception methods for 6 months after SOT106 discontinuation

Exclusion Criteria:

1. Received radiation therapy ≤14 days before day 1 of cycle 1 or not recovered to grade ≤1 from treatment-related side effects

2. Any prior systemic therapy for metastatic cancer other than osteosarcoma and STS; exception: stable disease under hormonal treatment for prostate cancer, stable disease under hormonal treatment for breast cancer; radiochemotherapy is allowed if such treatment is completed at least 4 weeks prior to day 1 of cycle 1; participants must have recovered to grade ≤1 from all side effects (exception: alopecia). Participants must not receive any concurrent antitumor therapy while participating in the trial. In exceptional circumstances where urgent palliative radiotherapy to symptomatic non-target lesions is clinically indicated, the case must be reviewed with the Principal Investigator and the intervention must receive prior approval from the sponsor.

3. Vaccination with a live or live-attenuated vaccine within 30 days prior to the first dose of trial interventions; the full series (e.g., both doses of a two-dose vaccination series) should be completed prior to dosing if feasible.

4. Time since last transfusion of red blood cells ≤14 days before day 1 of cycle 1

5. Concomitant use of strong CYP3A4 inhibitors or P-gp inhibitors without an adequate washout period of 7 days or 5 half-lives, whichever is longer, prior to the first SOT106 administration

6. Severe preexisting medical conditions as per judgment of the investigator

7. History of interstitial pneumonitis or pulmonary fibrosis

8. Symptomatic central nervous system malignancy. Participants with asymptomatic or treated central nervous system metastases may be eligible if they are not treated with corticosteroids or anticonvulsants and the disease is stable for at least 60 days.

9. Peripheral sensory neuropathy grade ≥2

10. Active infection requiring systemic therapy that is not clinically controlled before the signature of the prescreening ICF

11. Known symptomatic HIV positive, symptomatic active HBV, or symptomatic active HCV

    Note:

    • Participants with HIV will be eligible if:

      • CD4+ T-cell counts ≥350 cells/μL
      • they have no history of AIDS-defining opportunistic infections
      • they are not currently on HIV therapy

    • Participants with HBV will be eligible if there is serologic evidence of a resolved prior HBV infection (HBsAg-negative and HBcAb-positive)

    • Participants with HCV will be eligible if they have completed curative antiviral treatment and have HCV viral load below the limit of quantification

12. Alcohol or drug abuse as determined by the investigator

13. Psychiatric condition or social situation that, in the opinion of the investigator, preclude that the participant is able to comply with trial requirements

14. New York Heart Association class ≥2 heart failure, unstable angina, coronary angioplasty, coronary stenting, coronary artery bypass graft, myocardial infarction, cerebrovascular accident or hypertensive crisis within 6 months prior to day 1 of cycle 1

15. History of major ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsades de Pointes)

16. History or family history of congenital long QT syndrome

17. Bradycardia (<50 beats per minute)

18. Family history of sudden cardiac death before age 50

19. Major surgical intervention ≤28 days prior to prescreening ICF signature or incomplete wound healing after surgical intervention

20. Hypersensitivity or intolerance to any component of trial intervention