Clinical Trial of SOT102 Antibody Drug Conjugate in Patients With Advanced Gastric and Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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This trial will assess the MTD and RP2D of SOT102 administered as monotherapy (Part A) and in combination with first-line SoC treatment (mFOLFOX6 with nivolumab and nab-paclitaxel/ gemcitabine; Part B) and efficacy of SOT102 administered as monotherapy (Part C) and in combination with first-line SoC treatment (Part D) in patients with advanced inoperable or metastatic gastric/GEJ adenocarcinoma or inoperable or metastatic pancreatic adenocarcinoma.

Detailed Description
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The trial will have the following parts: Part A: Dose escalation, first-in-human, single-agent phase 1 trial of SOT102 in advanced/metastatic gastric/GEJ or pancreatic cancer patients with unmet medical need (CLDN18.2 agnostic) Part B gastric cohort: Phase 1b dose escalation combination trial of SOT102 in combination with mFOLFOX6 and nivolumab as SoC regimen for first-line treatment of patients with advanced/metastatic gastric/GEJ cancer (CLDN18.2 agnostic) Part B pancreatic cohort: Phase 1b dose escalation combination trial of SOT102 in combination with nab-paclitaxel/gemcitabine as SoC regimen for first-line treatment of patients with advanced/metastatic pancreatic cancer (CLDN18.2 agnostic) Once an RP2D in the respective phase 1 evaluation (Part A and Part B) has been identified expansion cohorts for gastric/GEJ and pancreatic cancer (Part C and Part D) are planned: Part C gastric cohort: Single-agent SOT102 expansion at RP2D identified in Part A in gastric/GEJ cancer after two or more prior systemic therapies (third+ line) for locally advanced or metastatic disease (CLDN18.2 positive) Part C pancreatic cohort: Single-agent SOT102 expansion at RP2D identified in Part A in pancreatic cancer after one or more prior systemic therapies (second+ line) for locally advanced or metastatic disease (CLDN18.2 positive) Part D gastric cohort: SOT102 in combination with mFOLFOX6 and nivolumab expansion at RP2D identified in Part B for first-line treatment in gastric/GEJ cancer (CLDN18.2 positive) Part D pancreatic cohort: SOT102 in combination with nab- paclitaxel/gemcitabine for first-line treatment expansion at RP2D identified in Part B in pancreatic cancer (CLDN18.2 positive)

Official Title
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A Multicentric Phase 1/2 Trial to Evaluate the Safety and Efficacy of SOT102 as Monotherapy and in Combination With Standard of Care Treatment in Patients With Gastric and Pancreatic Adenocarcinoma

Conditions
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Gastric Cancer, Pancreatic Cancer, Gastro-Esophageal Junction Cancer

Intervention / Treatment
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* Drug: SOT102


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Parts (key criteria) Hematologic: Absolute neutrophil count ≥1.5×109/L, platelets ≥100×109/L, hemoglobin ≥9 g/dL (time since last transfusion ≥14 days) Hepatic: Bilirubin ≤1.5× upper limits of normal (ULN), ALT and AST ≤2.5×ULN; in case of liver involvement: AST and ALT ≤5×ULN Renal: Creatinine clearance ≥60 mL/min calculated by Cockcroft-Gault formula Prothrombin time/international normalized ratio (INR) ≤1.5×ULN Albumin ≥3.0 mg/dL Proteinuria <1 g/24 hours Eastern Cooperative Oncology Group (ECOG) performance status ≤1 Estimated life expectancy ≥3 months as per investigator's assessment A female patient is eligible to participate if she is not pregnant, not breastfeeding, not of childbearing potential/ agreed with contraception Part A Patient has advanced inoperable or metastatic disease Patient has no better treatment option available Measurable or non-measurable disease according to RECIST 1.1 Histological or cytological evidence of adenocarcinoma of the stomach or GEJ or pancreas that is advanced or metastatic Part B (in addition to relevant A criteria) Histological or cytological evidence of adenocarcinoma of the stomach or GEJ that is advanced or metastatic Must have HER2-negative tumors (gastric) Histological or cytological evidence of adenocarcinoma of the pancreas that is advanced or metastatic (pancreas) Part C (in addition to relevant A criteria) Must have received at least two prior systemic therapies for advanced or metastatic disease. If HER2 overexpression: must have received anti-HER2 therapy (gastric) Must have received at least one prior systemic therapy for advanced or metastatic disease (pancreas) Part D (in addition to relevant B criteria) Histological or cytological evidence of adenocarcinoma of the stomach or GEJ that is advanced inoperable or metastatic Must have HER2-negative tumors (gastric) Histological or cytological evidence of adenocarcinoma of the pancreas that is advanced inoperable or metastatic (pancreas) Exclusion Criteria: All Parts (key criteria) Prior therapy with any agent directed at CLDN18.2 Patient has received radiation therapy ≤14 days before day 1 of cycle 1 or has not recovered to grade ≤1 from treatment-related side effects Severe preexisting medical conditions as per judgement of the investigator (e.g., active gastric or GEJ ulcer with or without bleeding, complete or incomplete gastric outlet syndrome with persistent or repetitive bleeding) History of interstitial pneumonitis or pulmonary fibrosis Symptomatic central nervous system malignancy. Patients 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. Patient has peripheral sensory neuropathy grade ≥2 Active infection requiring systemic therapy within ≤7 days prior to day 1 of cycle 1 Known history of HIV infection or known active hepatitis B or hepatitis C History or family history of congenital long QT syndrome Major surgical intervention ≤28 days prior to ICF signature or incomplete wound healing after surgical intervention Part B/D (key) Patients with contraindications to any component of the first-line SoC treatment Dihydropyrimidine dehydrogenase (DPD) deficiency (gastric)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: SN201 is a multi-modular clinical trial in patients with gastric adenocarcinoma or adenocarcinoma of the gastroesophageal junction (GEJ) and pancreatic adenocarcinoma.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOT102<br>SOT102 is administered as intravenous infusion over 45 minutes as monotherapy or in combination with established standard of care therapy, every 14 days until the disease progression or intolerance to SOT102. SoC therapy is administered as per approved local standards. Starting dose of SOT102 is 0.032 mg/kg. Dose levels are to be escalated according modified Fibonacci scheme. | Drug: SOT102<br>* SOT102 is an antibody-drug conjugate (ADC) targeting CLDN18.2 with the anthracycline PNU as cytotoxic moiety.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and B: The definition of the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of SOT102 given as monotherapy and in combination with first-line SoC treatment | MTD is defined as the highest dose level tested below the dose level associated with ≥33% of dose-limiting toxicity (DLT)-evaluable patients experiencing a DLT. The RP2D will be selected based on evaluation of the totality of all data. | Through Cycles 1-2 (28 days) | 
| Parts C and D: The assessment of the efficacy of SOT102 in monotherapy and in combination with first-line SoC treatment | Efficacy is determined by objective response rate (ORR) determined according to RECIST 1.1 criteria | From Day 1 of Cycle 1 until disease progression or start of new anticancer therapy, whichever is first, assessed up to approximately 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and B (monotherapy and combination with SoC): Number of participants with DLTs | Adverse events (AEs) graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 considered DLTs: All grade 5 events not clearly related to disease progression or any other causes Any grade 3 or higher non-hematologic toxicity regardless of duration Hy's law cases Any grade 2 pneumonitis that does not resolve to grade 1 within 3 days of the initiation of maximal supportive care Recurrent grade 2 pneumonitis Grade 4 neutropenia lasting more than 7 days Febrile neutropenia Grade 3 thrombocytopenia with bleeding Grade 4 thrombocytopenia AEs NOT considered DLTs: Grade 3 nausea, vomiting, or diarrhea that can be controlled within 72 hours Grade 3 fatigue less than 5 days Grade 3 or higher correctable electrolyte abnormalities that last less than 72 hours and not associated with clinical complications Grade 3 or higher amylase or lipase not associated with clinical manifestations of pancreatitis | Through Cycles 1-2 (28 days) | 
| Parts A and B (monotherapy and combination with SoC): Number of participants with treatment-emergent AEs (TEAEs) | A TEAE is defined as an AE that: emerges during SOT102 treatment, having been absent at the time of pre-treatment (screening), or re-emerges during SOT102 treatment, having been present at the time of pre-treatment (screening), or worsens in severity during SOT102 treatment relative to the pre-treatment state if the AE is continuous. | From Day 1 of Cycle 1 until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts A and B (monotherapy and combination with SoC): Number of participants with SOT102-related AEs | Causal relationship (relatedness) of all AEs will be assessed by investigators and classified as follows: Not suspected: It is not plausible that the AE is caused by medication/procedure and a likely alternative explanation exists. No reasonable possibility of a causal or temporal relationship. Suspected: It is plausible that the AE is caused by medication/procedure. Reasonable possibility of a causal relationship. | From Day 1 of Cycle 1 until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts A and B (monotherapy and combination with SoC): Number of participants with serious AEs (SAEs) | An SAE is any untoward medical occurrence that at any dose fulfills one or more of the following criteria: Results in death Is immediately life-threatening Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Requires inpatient hospitalization or prolongation of existing hospitalization Is another medically significant event defined as an event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent any of the above listed outcomes | From the date of the patient's signing the Informed Consent Form (ICF) until 30 (+5) days after the last dose of SOT102, assessed up to approx. 4 years; SAEs with a suspected causal relationship to SOT102 per the investigator's judgment: at any time | 
| Parts A and B (monotherapy and combination with SoC): Number of participants with AEs leading to premature discontinuation of SOT102 | AEs (intercurrent illness or trial treatment-related toxicity) that would, in the judgment of the investigator, affect assessments of clinical status to a significant degree or require discontinuation of trial treatment | From Day 1 of Cycle 1 until the end of SOT102 treatment, assessed up to approximately 4 years | 
| Parts A and B (monotherapy and combination with SoC): Number of participants who died | Date of death and immediate and underlying causes of death will be collected. | From the date of the patient's signing the ICF until disease progression or start of new anticancer therapy, whichever is first, assessed up to approximately 4 years | 
| Parts A and B (monotherapy and combination with SoC): Number of participants with clinical laboratory test abnormalities (coagulation, hematology, clinical chemistry and urinalysis) of grade 3 or higher graded according to NCI CTCAE version 5.0 | The following laboratory parameters will be assessed: Coagulation: prothrombin time, INR Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential Clinical chemistry: ALT, albumin, ALP, amylase, AST, bilirubin, blood urea nitrogen or blood urea, calcium, creatinine, glucose (fasting), LDH, lipase, magnesium, potassium, sodium, TSH (gastric adenocarcinoma only) Urinalysis: blood, glucose, ketones, pH, protein, specific gravity, urine leukocyte esterase | From the date of the patient's signing the ICF until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts A and B (monotherapy and combination with SoC): Characterization of pharmacokinetics (PK) of total SOT102 and its derivates | Assessment of concentration of SOT102 and its derivates at various timepoints | From Day 1 of Cycle 1 until Day 1 of Cycle 5 | 
| Parts A and B (monotherapy and combination with SoC): Evidence of SOT102 activity in monotherapy in individual patients | Detection of anecdotal tumor response in individual patient, as per RECIST 1.1 criteria | From Day 1 of Cycle 1 until disease progression or start of new anticancer therapy, whichever is first, assessed up to approximately 4 years | 
| Parts A and B (monotherapy and combination with SoC): Number of participants with antibodies against SOT102 | Identification of patients who develop detectable antibodies against any part of SOT102 | From Day 1 of Cycle 1 until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Duration of response (DoR) according to RECIST 1.1 | The DoR is defined as the time from the first achieved response (complete or partial, confirmed) until the first date of radiological progression or death. | From Day 1 of Cycle 1 until disease progression or start of new anticancer therapy, whichever is first, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Progression-free survival (PFS) according to RECIST 1.1 | PFS is defined as the time from trial enrolment until the first date of radiological progression or death. | From Day 1 of Cycle 1 until disease progression or start of new anticancer therapy, whichever is first, assessed up to approximately 4 years | 
| Part C (monotherapy): Clinical benefit rate (CBR) according to RECIST 1.1 | The CBR is defined as the number of complete responses, partial responses, and stable diseases from all evaluable best overall responses. | From Day 1 of Cycle 1 until disease progression or start of new anticancer therapy, whichever is first, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Overall survival (OS) | OS is defined as the time from eligibility verification until the date of death. | From Day 1 of Cycle 1 until the end of the trial, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Number of participants with TEAEs | A TEAE is defined as an AE that: emerges during SOT102 treatment, having been absent at the time of pre-treatment (screening), or re-emerges during SOT102 treatment, having been present at the time of pre-treatment (screening), or worsens in severity during SOT102 treatment relative to the pre-treatment state if the AE is continuous. | From Day 1 of Cycle 1 until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Number of participants with SOT102-related AEs | Causal relationship (relatedness) of all AEs will be assessed by investigators and classified as follows: Not suspected: It is not plausible that the AE is caused by medication/procedure and a likely alternative explanation exists. No reasonable possibility of a causal or temporal relationship. Suspected: It is plausible that the AE is caused by medication/procedure. Reasonable possibility of a causal relationship. | From Day 1 of Cycle 1 until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Number of participants with SAEs | An SAE is any untoward medical occurrence that at any dose fulfills one or more of the following criteria: Results in death Is immediately life-threatening Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Requires inpatient hospitalization or prolongation of existing hospitalization Is another medically significant event defined as an event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent any of the above listed outcomes | From the date of the patient's signing the ICF until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years; SAEs with a suspected causal relationship to SOT102 per the investigator's judgment: at any time | 
| Parts C and D (monotherapy and combination with SoC): Number of participants with AEs leading to premature discontinuation of SOT102 | AEs (intercurrent illness or trial treatment-related toxicity) that would, in the judgment of the investigator, affect assessments of clinical status to a significant degree or require discontinuation of trial treatment | From Day 1 of Cycle 1 until the end of SOT102 treatment, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Number of participants who died | Date of death and immediate and underlying causes of death will be collected. | From the date of the patient's signing the ICF until the end of the trial, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Number of participants with clinical laboratory test abnormalities (coagulation, hematology, clinical chemistry and urinalysis) of grade 3 or higher graded according to NCI CTCAE version 5.0 | The following laboratory parameters will be assessed: Coagulation: prothrombin time, INR Hematology: leukocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential Clinical chemistry: ALT, albumin, ALP, amylase, AST, bilirubin, blood urea nitrogen or blood urea, calcium, creatinine, glucose (fasting), LDH, lipase, magnesium, potassium, sodium, TSH (gastric adenocarcinoma only) Urinalysis: blood, glucose, ketones, pH, protein, specific gravity, urine leukocyte esterase | From the date of the patient's signing the ICF until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC, patients with gastric cancer): Patient-reported quality of life questionnaire EORTC QLQ-C30 scores | To determine the effect of trial intervention on the quality of life. | From the date of the patient's signing the ICF until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC, patients with gastric cancer): Patient-reported quality of life questionnaire EORTC QLQ-STO22 scores | To determine the effect of trial intervention on the quality of life. | From the date of the patient's signing the ICF until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC, patients with pancreatic cancer): Patient-reported quality of life questionnaire EORTC QLQ-C30 scores | To determine the effect of trial intervention on the quality of life. | From the date of the patient's signing the ICF until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC, patients with pancreatic cancer): Patient-reported quality of life questionnaire EORTC QLQ-PAN26 scores | To determine the effect of trial intervention on the quality of life. | From the date of the patient's signing the ICF until 30 (+5) days after the last dose of SOT102, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Patient-reported quality of life questionnaire EQ-5D-3L scores | To determine the effect of trial intervention on the quality of life. | From the date of the patient's signing the ICF until the end of the trial, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Characterization of PK of total SOT102 and its derivates | Assessment of concentration of SOT102 and its derivates at various timepoints | From Day 1 of Cycle 1 until the end of SOT102 treatment, assessed up to approximately 4 years | 
| Parts C and D (monotherapy and combination with SoC): Number of participants with antibodies against SOT102 | Identification of patients who develop detectable antibodies against any part of SOT102 | From Day 1 of Cycle 1 until the end of SOT102 treatment, assessed up to approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric Cancer, Pancreatic Cancer, Gastro-Esophageal Junction Cancer, Advanced Cancer, Metastatic Cancer