A Study Testing SOT109 for the First Time in Patients, to Assess How Safe SOT109 is, How Well it Works, and How the Body Handles it in Patients With Advanced Colorectal Cancer That Can Not be Removed by Surgery or is Metastatic

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 SOT109 in participants with advanced unresectable or metastatic colorectal cancer 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 SOT109 in participants with advanced unresectable or metastatic colorectal cancer who have no further standard treatment options.

Inclusion criteria

• ≥18 years of age on the day of signing the ICF
• Able to understand, sign, and provide written informed consent to participate in the trial
• 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
• Estimated life expectancy ≥3 months as assessed by the investigator
• An appropriate candidate for experimental therapy as assessed by the investigator
• Agrees not to participate in other interventional clinical trial while enrolled in the present trial (with the exception of survival follow-up period)
• Absolute neutrophil count ≥1.5×109/L, platelets ≥100×109/L, hemoglobin ≥9 g/dL
• Creatinine clearance ≥60 mL/min calculated by Cockcroft-Gault formula
• 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), and
• There is no evidence of active liver disease, clinically significant hepatic impairment, hemolysis, or biliary obstruction, as determined by the investigator
• Prothrombin time/international normalized ratio ≤1.5×ULN
• Albumin ≥3.0 mg/dL
• Serum concentrations of potassium, magnesium, and calcium with abnormalities of maximum grade 1 that should be treated according to standard practice
• Left ventricular ejection fraction (LVEF) ≥50% as determined by echocardiography or nuclear medicine methodology (MUGA)
• QTcF interval ≤470 msec on screening ECG
• Histological or cytological evidence of advanced unresectable or metastatic colorectal cancer
• Participants that received and progressed on standard systemic therapies (fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and, only when locally indicated and available, a BRAF/RAS/HER2 inhibitor) and who have no further standard treatment options. Participants with a known microsatellite instability-high (MSI-H) status must have received treatment with an immune checkpoint inhibitor (if locally indicated and available) unless contraindicated
• Measurable or non-measurable disease according to RECIST 1.1
• Previous cancer therapies:

18.1. Europe: previous cancer therapies and any agents that have not received regulatory approval for any indication must have been discontinued either ≥21 days prior to day 1 of cycle 1 or ≥5x half-life, 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) 18.2. US: eligibility should be determined based on patient recovery from clinically significant adverse events from their most recent therapy or intervention prior to study enrollment

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and one of the following conditions applies: 19.1. Not a woman of childbearing potential (WOCBP). A WOCBP is defined as fertile, following menarche, and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single follicle stimulating hormone measurement is insufficient.

19.2. 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 SOT109

• WOCBP can only be included after a negative serum pregnancy test at screening
• Highly effective contraception includes:

• 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
• Intrauterine hormone-releasing system
• Bilateral tubal occlusion
• Vasectomized partner provided the partner is the sole sexual partner of the WOCBP participant and that the vasectomized partner has received medical assessment of the surgical success
• Sexual abstinence defined as refraining from heterosexual intercourse during the entire treatment period and for at least 6 months after the last dose of SOT109. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant.
• Male participants must agree to use a condom during the treatment period and for at least 6 months after the last dose of SOT109. 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 SOT109 discontinuation.

Exclusion criteria

• Received radiation therapy ≤14 days before day 1 of cycle 1 or not recovered to grade ≤1 from treatment-related side effects
• Any prior systemic therapy for metastatic cancer other than colorectal cancer; 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 (PI) and the intervention must receive prior approval from the sponsor
• 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
• Time since last transfusion of red blood cells ≤14 days before day 1 of cycle 1
• Severe preexisting medical conditions as per judgment of the investigator
• History of interstitial pneumonitis or pulmonary fibrosis
• 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
• Peripheral sensory neuropathy grade ≥2
• Active infection requiring systemic therapy that is not clinically controlled before the signature of the ICF
• 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 ICF signature or incomplete wound healing after surgical intervention 20. Hypersensitivity or intolerance to any component of trial intervention 21. Medical history of inflammatory bowel disease or active inflammatory bowel disease (IBD)
• Participants with signs or symptoms suggestive of IBD who have not undergone colonoscopy to rule out IBD will be excluded