A Study of SOT101 in Combination With Cetuximab to Evaluate the Efficacy and Safety in Patients With Colorectal Cancer

Sponsor

SOTIO Biotech AG (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05619172

Collaborator

(none)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The primary objective of the study is to estimate the antitumor efficacy of SOT101 in combination with cetuximab in RAS wild-type colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: SOT101 Drug: Cetuximab	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

64 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Two safety cohorts will be implemented in a 3+3 dose escalation design. The main cohort will start only after data from safety cohorts are assessed by an internal safety committee.Two safety cohorts will be implemented in a 3+3 dose escalation design. The main cohort will start only after data from safety cohorts are assessed by an internal safety committee.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2, Open-label, Single-arm, Multicenter Study to Evaluate the Efficacy and Safety of SOT101 in Combination With Cetuximab in Patients With RAS Wild-type Colorectal Cancer

Anticipated Study Start Date :

Dec 1, 2022

Anticipated Primary Completion Date :

Nov 1, 2025

Anticipated Study Completion Date :

Nov 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SOT101 and Cetuximab Participants will be first treated with 9 µg/kg of SOT101 and then proceed to be treated with either 12 µg/kg or 6 µg/kg of SOT101 in combination with cetuximab (depending on the safety evaluation of the first safety cohort). SOT101 treatment will be administered on day 1 (from cycle 2 onwards, ±1 day), day 2 (±1 day), day 8 (±1 day), and day 9 (±1 day) of each 21-day cycle, Cetuximab treatment will be administered on day 1 (from cycle 2 onwards, ±1 day), day 8 (±1 day), and day 15 (±1 day) of each 21-day cycle; on day 1 and day 8, cetuximab infusion will start within 30 minutes after SOT101 administration.	Drug: SOT101 Subcutaneous (SC) injection Drug: Cetuximab Intravenous (IV) infusion via peripheral or central venous line

Arm

Intervention/Treatment

Experimental: SOT101 and Cetuximab

Participants will be first treated with 9 µg/kg of SOT101 and then proceed to be treated with either 12 µg/kg or 6 µg/kg of SOT101 in combination with cetuximab (depending on the safety evaluation of the first safety cohort). SOT101 treatment will be administered on day 1 (from cycle 2 onwards, ±1 day), day 2 (±1 day), day 8 (±1 day), and day 9 (±1 day) of each 21-day cycle, Cetuximab treatment will be administered on day 1 (from cycle 2 onwards, ±1 day), day 8 (±1 day), and day 15 (±1 day) of each 21-day cycle; on day 1 and day 8, cetuximab infusion will start within 30 minutes after SOT101 administration.

Drug: SOT101

Subcutaneous (SC) injection

Drug: Cetuximab

Intravenous (IV) infusion via peripheral or central venous line

Outcome Measures

Primary Outcome Measures

Objective response rate (ORR) according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) [Day 1 up to approximately 3 years]

Secondary Outcome Measures

ORR according to RECIST for immune-based therapeutics (iRECIST) (iORR) [Day 1 up to approximately 3 years]
Best overall response according to RECIST 1.1 (BOR) and iRECIST (iBOR) [Day 1 up to approximately 3 years]
Duration of response according to RECIST 1.1 (DoR) and iRECIST (iDoR) [Day 1 up to approximately 3 years]
Clinical benefit rate according to RECIST 1.1 (CBR) and iRECIST (iCBR) [Day 1 up to approximately 3 years]
Progression-free survival (PFS) according to RECIST 1.1 and iRECIST (iPFS) [Day 1 up to approximately 3 years]
Time to response according to RECIST 1.1 (TtR) and iRECIST (iTtR) [Day 1 up to approximately 3 years]
Time to progression according to RECIST 1.1 (TtP) and iRECIST (iTtP) [Day 1 up to approximately 3 years]
Number of participants with treatment-emergent AEs (TEAEs) [Day 1 up to approximately 3 years]
A TEAE is defined as an AE that started or worsened at or after the start of study treatment.
Number of participants with clinical laboratory test abnormalities (coagulation, hematology, clinical chemistry and urinalysis) [Day 1 up to approximately 3 years]
The following laboratory parameters will be assessed: Coagulation: prothrombin time, activated partial thromboplastin time, international normalized ratio, D-dimer, and fibrinogen Hematology: hemoglobin, glycated hemoglobin at screening, hematocrit, red blood cell count, reticulocytes, white blood cell count (with full differentiation), absolute lymphocyte count, and platelet count Clinical chemistry: Na, K, Cl, phosphate, Mg, Ca, albumin, total protein, ALT, AST, bilirubin (direct, total), alkaline phosphatase, lactate dehydrogenase, creatinine clearance calculated by the Cockcroft-Gault formula, creatinine, glucose (preferably fasting), urea or blood urea nitrogen, cholesterol, triglyceride, C-reactive protein, uric acid, amylase, and lipase Urinalysis: pH, glucose, protein, bilirubin, urobilinogen. Microscopic examination (mandated only if clinically indicated): red blood cell count, white blood cell count, epithelial cells, bacteria
Number of participants with vital signs abnormalities [Day 1 up to approximately 3 years]
The following vital signs parameters will be assessed: Blood pressure (systolic and diastolic, after ≥5 minutes of rest), body temperature, and heart rate
Number of participants with electrocardiography abnormalities [Day 1 up to approximately 3 years]
Number of participants with DLTs [Through Cycle 1 (21 days)]
AEs as per NCI CTCAE v5.0 considered DLTs: All G5 events not clearly related to disease progression or any other causes will be considered DLTs Any G3 or higher non-hematologic toxicity regardless of duration will be considered a DLT, with the following exceptions that are not considered DLTs: G3 nausea, vomiting, or diarrhea that can be controlled within 72 hours G3 fatigue that lasts less than 5 days G3 or higher correctable electrolyte abnormalities that last less than 72 hours and are not associated with clinical complications G3 or higher serum amylase or lipase not associated with clinical manifestations of pancreatitis G3 AST or ALT increase or G3 blood bilirubin increase that lasts 5 days or less Hy's law cases will be considered DLTs. Hematologic DLTs will include the following: G4 decreased neutrophil count or decreased platelet count lasting more than 7 days Febrile neutropenia G3 or higher decreased platelet count with bleeding
Characterization of area under the curve (AUC) of SOT101 and cetuximab [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Characterization of maximum concentration (Cmax) of SOT101 and cetuximab [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Characterization of time to maximum concentration (Tmax) of SOT101 and cetuximab [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Characterization of pre-dose concentration (Ctrough) of SOT101 and cetuximab [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Characterization of terminal elimination half-life (T1/2) of SOT101 and cetuximab [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Characterization of systemic clearance (CL) of SOT101 and cetuximab in single dose and steady state [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Characterization of volume of distribution of SOT101 and cetuximab at steady state and during terminal phase (Vss, Vz) [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Characterization of accumulation ratio (RAUC, RCmax) of SOT101 and cetuximab [Day 1 of Cycle 1 until Day 1 of Cycle 3]
Assessment of concentration of SOT101 and cetuximab at various timepoints
Incidence of anti-drug antibodies (ADAs) against SOT101 [Day 1 until 30 (±2) days after the last dose of SOT101]
Measured by occurrence in time
Titer of ADAs against SOT101 [Day 1 until 30 (±2) days after the last dose of SOT101]
Measured as lowest reactive dilution
Time course of ADAs against SOT101 [Day 1 until 30 (±2) days after the last dose of SOT101]
Development in time
Incidence of ADAs against cetuximab [Day 1 until 30 (±2) days after the last dose of cetuximab]
Measured by occurrence in time
Titer of ADAs against cetuximab [Day 1 until 30 (±2) days after the last dose of cetuximab]
Measured as lowest reactive dilution
Time course of ADAs against cetuximab [Day 1 until 30 (±2) days after the last dose of cetuximab]
Development in time

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Type of patients

≥18 years of age on the day of signing informed consent
Ability to understand and sign written informed consent to participate in the study
Provides written informed consent for the study
Life expectancy >6 months Disease characteristics
Histologically or cytologically confirmed advanced and/or metastatic RAS wild-type colorectal cancer as confirmed by the investigational site within 3 months prior to the first administration of study treatment. For the assessment of the RAS mutational status, a US Food and Drug Administration (FDA)-approved test or an experienced local laboratory using validated test methods for the detection of K-RAS and N-RAS (exons 2, 3, and 4) mutations must be used.
EGFR mutation status should be available from a tumor biopsy taken within 3 months prior to the first administration of study treatment
Patients who are relapsed/refractory or intolerant to prior treatment with irinotecan- and oxaliplatin-containing chemotherapy
Have at least one measurable lesion according to RECIST 1.1
Eastern Cooperative Oncology Group (ECOG) performance score 0-2
Must have recovered from all AEs due to previous therapies to grade ≤1 toxicity (excluding alopecia) Organ function Have adequate organ function as defined below. Specimens must be collected within 7 days prior to the start of study treatment.
Hematology:

11.1. Absolute neutrophil count ≥1,500/µL 11.2. Platelets ≥100,000/µL 11.3. Hemoglobin ≥9.0 g/dL (criteria must be met without packed red blood cell transfusion within the prior 2 weeks; patients can be on stable dose of erythropoietin [≥3 months])

Renal function: Creatinine clearance rate ≥50 mL/min as calculated using Cockcroft-Gault equation
Hepatic function: ALT/AST ≤2.5× upper limit of normal (ULN) and total bilirubin ≤2×ULN in patients without liver metastasis (benign hereditary hyperbilirubinemias, e.g., Gilbert's syndrome, are permitted if total bilirubin <3 mg/dL). In patients with liver metastasis, ALT/AST ≤5×ULN is allowed but total bilirubin must be ≤2×ULN.
Prothrombin time and activated partial thromboplastin time ≤1.5×ULN Hepatitis
A locally performed hepatitis B (HBV) test is required during screening. Patients who are HBV surface antigen positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks and have undetectable HBV viral load before study entry (ICF signature). Patients should remain on anti-viral therapy throughout study treatment and follow local guidelines for HBV anti-viral therapy post completion of study treatments.
A locally performed hepatitis C (HCV) test is required during screening. Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening. Patients must have completed anti-viral therapy at least 4 weeks before study entry (ICF signature).

Special requirements for contraception

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

17.1. Not a woman of childbearing potential (WOCBP). A WOCBP is defined as fertile, following menarche and until becoming post-menopausal 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 post-menopausal 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.

17.2. A WOCBP who agrees to use a highly effective contraceptive method during the treatment period and for at least 60 days after the last dose of cetuximab or at least 30 days after last dose of SOT101, whichever is later.

• WOCBP can only be included after a negative serum pregnancy test at screening within 7 days before day 1 of cycle 1.

Male patients must agree to use a condom during the treatment period and for at least 60 days after the last dose of cetuximab or at least 30 days after last dose of SOT101, whichever is later.

Exclusion Criteria:

Prior/concomitant therapy

Prior exposure to drugs that are agonists of IL-2 or IL-15
Therapy with cetuximab within 3 months prior to ICF signature or patients who had progressive disease as best response to prior cetuximab-containing regimen
Prior systemic anti-cancer therapies, including investigational agents before study entry (ICF signature):

3.1. Less than 3 weeks or 5 half lives (whichever shorter) for anti-cancer treatments 3.2. Less than 4 weeks from major surgeries and not recovered adequately from the procedure and/or any complications from the surgery

Has received prior radiotherapy within 2 weeks of the start of study treatments. A 1-week radiation-free period is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system disease. Patients must have recovered from all radiation-related toxicities and not require corticosteroids.
Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatments Prior/concurrent clinical study experience
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 3 weeks or 5 half lives (whichever longer) before study entry (ICF signature). Patients who have entered the follow-up phase of an investigational study may participate as long as it has been 3 weeks or 5 half lives (whichever longer) after the last dose of the previous investigational agent.

Medical conditions

Patients with known BRAF mutations
Clinically significant cardiac abnormalities including prior history of any of the following:

8.1. Cardiomyopathy, with left ventricular ejection fraction lower than the lower limit of the institutional normal range at screening 8.2. Congestive heart failure of New York Heart Association grade ≥2 8.3. History of clinically significant (i.e., active) atherosclerotic cardiovascular disease, specifically myocardial infarction, unstable angina, cerebrovascular accident within 6 months prior to the first dose of study treatments, and any history of coronary heart disease and clinically significant peripheral and/or carotid artery disease 8.4. Prolongation of QTcF >450 msec; history or family history of congenital long QT syndrome 8.5. Uncontrolled cardiac arrhythmia requiring medication

Uncontrolled hypertension defined as systolic blood pressure >160 mmHg, diastolic blood pressure >110 mmHg. Patients with uncontrolled hypertension should be medically managed on a stable regimen to control hypertension prior to study entry (ICF signature).
Has a clinical diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatments. Systemic steroid pretreatment prior to cetuximab infusion according to local guidelines is permitted.
History of or serology positive for HIV. A locally performed HIV test is required during screening.
Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Patients with basal cell carcinoma of the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are eligible.
Has known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks confirmed during screening.
Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
Has an active infection requiring systemic therapy
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
Has a known psychiatric or substance abuse disorder that would interfere with the patient's ability to cooperate with the requirements of the study
History of hypersensitivity to any component of cetuximab or to compounds of similar biological or chemical composition of SOT101 and/or the excipients contained in the study drug formulations