A Study of SLC-0111 and Gemcitabine for Metastatic Pancreatic Ductal Cancer in Subjects Positive for CAIX

Study Overview
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Brief Summary
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This is a multi-center, open-label Phase 1b study of SLC-0111 (oral) in combination with IV gemcitabine in CA IX positive subjects with mPDAC and comprises of 2 parts: Part 1: Dose Escalation Part 2: Dose Expansion

Detailed Description
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This is a multi-center, open-label Phase 1b study of SLC-0111 (oral) in combination with IV gemcitabine in CA IX positive subjects with mPDAC and comprises of 2 parts: Part 1: Dose Escalation Part 2: Dose Expansion Biopsy or archival tissue will be collected and tested for the presence of CAIX via Immunohistochemistry (IHC) and only subjects positive for CAIX will be enrolled in the dose-escalation and dose-expansion parts. Part 2 can only begin after a dosing regimen has been characterized in Part 1. Subjects who participated in Part 1 of study will not be eligible to participate in Part 2. The dose escalation will aim to identify the safety, tolerability and MTD of the oral formulation of SLC-0111 in combination with IV gemcitabine. Additional subjects may be enrolled at the MTD in dose expansion cohort. Data collected will allow evaluation of safety, tolerability, PK, Pharmacodynamics (PD) and tumour response of SLC-0111 in combination with gemcitabine. A traditional 3 + 3 dose escalation design will be utilized for this study. Cohorts (same dose level) of 3 to 6 evaluable subjects will participate in a dose escalation scheme in which the dose of SLC-0111 will be increased in each consecutive cohort. Dose escalation to a new cohort of subjects will occur after review of available Cycle 1 data. The dose of SLC-0111 will be escalated based on Table 1 and Table 2 in the protocol. Based on emerging data alternative dosing schedules, or dose reductions may be considered. Gemcitabine will be administered at the standard dose (1000 mg/m^2) and schedule (day 1, 8, and 15 of each cycle) but dose reductions may be considered if necessary. Each cohort will initially consist of up to 3 subjects. If none of the first 3 subjects in a cohort demonstrates dose limiting toxicities (DLTs), then the cohort will be declared safe and the next cohort will be opened for enrollment If 1 of the first 3 subjects in a cohort demonstrates DLTs, then 3 additional subjects will be accrued to that cohort for a total of 6 subjects If 1 out of 6 subjects in a cohort demonstrates DLTs, then the cohort will be declared safe and the next cohort (n=3)will be opened for enrollment If 2 or more subjects in a cohort demonstrates DLTs, that cohort will be declared to exceed the MTD Following the identification of a Cohort that exceeds the MTD, the next lowest dose, or an intermediate dose level may be further explored. The MTD will be defined as the highest dose level at which no more than 1 of 6 subjects demonstrates DLTs. Intra-subject dose escalation will not be allowed in this study.

Official Title
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An Open-label, Multi-center, Phase 1b Study to Investigate the Safety and Tolerability of SLC-0111 (WBI-5111) in Combination With Gemcitabine in Metastatic Pancreatic Ductal Adenocarcinoma Subjects Positive for Carbonic Anhydrase IX

Conditions
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Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: SLC-0111
* Drug: Gemcitabine Injection


Participation Criteria
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Eligibility Criteria
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Pre-Screening Inclusion Criteria: Males or females aged ≥ 18 years old. Able and willing to provide written pre-screening informed consent and to comply with the study protocol and procedures. A biopsiable tumour and a willingness to provide biopsies if no archival tumour tissue exists. Histologically or cytologically-confirmed metastatic pancreatic ductal adenocarcinoma (this can include distant lymph nodes). Subjects with locally advanced disease or regional lymph node involvement are to be excluded. Regional lymph nodes are considered: Lymph nodes superior and inferior to head and body of pancreas, anterior and posterior pancreaticoduodenal, pyloric, proximal mesenteric nodes, and common bile duct lymph nodes, splenic hilar, pancreatic tail, peripancreatic, hepatic artery, infrapyloric (head only), subpyloric (head only), celiac (head only), superior mesenteric, pancreaticolienal (body and tail only), splenic (body and tail only), retroperitoneal, lateral aortic. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Life expectancy greater than 3 months in the investigator's opinion. Subject (archival tissue or pre-treatment biopsy) must be positive for CAIX via IHC before screening assessments listed below begin (i.e. Study Inclusion and Exclusion Criteria) Main Study Inclusion Criteria: Males or females aged ≥ 18 years old. Able and willing to provide written informed consent and to comply with the study protocol and procedures. Histologically or cytologically-confirmed metastatic pancreatic ductal adenocarcinoma (this can include distant lymph nodes). Subjects with locally advanced disease or regional lymph node involvement are to be excluded. Regional lymph nodes are considered: Lymph nodes superior and inferior to head and body of pancreas, anterior and posterior pancreaticoduodenal, pyloric, proximal mesenteric nodes, and common bile duct lymph nodes, splenic hilar, pancreatic tail, peripancreatic, hepatic artery, infrapyloric (head only), subpyloric (head only), celiac (head only), superior mesenteric, pancreaticolienal (body and tail only), splenic (body and tail only), retroperitoneal, lateral aortic. ≥1 prior line of systemic therapy with a 14-day washout period or if investigational combination is being considered for first line of therapy, subject was not eligible for FOLFIRINOX or gemcitabine + nab-paclitaxel. Recovery to ≤ Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies. ECOG performance status 0 or 1. Life expectancy greater than 3 months in the Investigator's opinion. The following time must have elapsed between previous therapy for cancer or medical history event and first administration of SLC-0111 and gemcitabine: At least 2 weeks since previous cancer-directed therapy (cytotoxic agents, targeted therapy including monoclonal antibody therapy, immunotherapy, hormonal therapy, and prior radiotherapy). At least 2 weeks or five times the elimination half-life (whichever is shortest) of any investigational drug/biologic or combination product prior to first dose of study treatment. At least 4 weeks since any major surgery At least 12 weeks since any incidence of severe gastrointestinal bleeding. Adequate renal function: Creatinine ≤ 1.5 times upper limit of normal (ULN) or calculated creatinine clearance (CrCl) using the Cockcroft Gault formula ≥ 60 mL/min, or measured CrCl ≥ 60 mL/min. Adequate hepatic function: Serum total bilirubin ≤ 1.5 times upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN (≤ 5 x ULN if liver lesions present [i.e. liver metastasis or primary tumour of the liver for HCC]). Adequate hematologic function (without G-CSF support): Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L Hemoglobin ≥ 85 g/L Adequate coagulation tests: INR ≤ 1.5 PTT ≤ 1.5 times ULN Corrected QT interval (QTc) < 470 ms Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption. Negative pregnancy test in female subjects of child-bearing potential (defined as women who have not undergone hysterectomy/oophorectomy or who have not been naturally post-menopausal for ≥ 12 months). Subjects must agree not to donate gametes (oocyte or sperm) during study and for 4 months following last dose of study treatment. Sexually active subjects (male and female) must agree to use acceptable methods of contraception to avoid pregnancy prior to start of dosing, during the course of the study and for 4 months after the last dose of study treatment. Collect post-treatment biopsy if the tumour is biopsiable and a willingness to provide biopsies exists (optional) Additional Inclusion Criteria for Dose Expansion (Part 2): Measurable disease as per RECIST 1.1. Exclusion Criteria: Subjects negative for CAIX via IHC (biopsy or archival tissue) Previous treatment with any known CAIX Inhibitor Females who are pregnant, planning to become pregnant or breastfeeding. Severe cardiac disease which has required hospitalization within the past 3 months or which functionally limits a patient. Severe respiratory illness requiring supplemental oxygen or that significantly impacts functional status in daily life. Untreated CNS metastasis or CNS metastasis that has not been clinically stable for 28 days. History of myocardial infarction, unstable angina, congestive heart failure (New York Heart Association class ≥ III/IV), cerebrovascular accident, transient ischaemic attack, limb claudication at rest in the 6 months prior to enrolment, or ongoing symptomatic dysrhythmias, or uncontrolled atrial or ventricular arrhythmias, or uncontrolled hypertension. Any condition or illness that, in the opinion of the Investigator would compromise subject safety or interfere with the evaluation of the safety of the investigational products. Subjects with documented cases of human immunodeficiency virus (HIV) and viral load detectable. Hypersensitivity to investigational products or their excipients or severe allergy to sulfonamides. Refractory nausea and vomiting, chronic gastrointestinal diseases, gastrointestinal bleeding, ulceration, or perforation within 12 weeks prior to the first administration of investigational products or significant bowel resection that would preclude adequate absorption. Known acute hepatitis B infection or chronic hepatitis B not currently on suppressive therapy. Known hepatitis C antibody positive and RNA positive. Subjects with hepatitis C antibody positivity but RNA negativity may enroll after consultation with hepatology. Active uncontrolled bacterial, viral, or fungal infections. Malignancy within the preceding 5 years (Subjects may be included in the trial if malignancy was a non-melanoma skin cancer, ductal carcinoma in-situ, early cervical malignancy, or at the discretion of the primary investigator if the malignancy has had curative intent treatment and has a < 10% chance of recurring within 5 years as per a well-recognized risk stratification tool specific for that malignancy.) Additional Dose Expansion Exclusion Criteria: Subjects cannot be enrolled in the dose expansion if they were enrolled during the dose escalation of the current study.

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: This is a traditional Phase I 3+3 study designed to identify the MTD by assessment of DLT of SLC-0111. Sample size estimates are not statistically based, but are based on acquisition of appropriate numbers of subjects to adequately describe the safety, tolerability, PK, and PD of SLC-0111 in combination with gemcitabine. Up to 18 subjects are anticipated to be enrolled in the dose escalation part; however, the actual number recruited will be dependent upon the number of dose escalations. Dose expansion (Part 2) may enroll up to 12 subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SLC-0111 + Gemcitabine<br>Dose Level 1 - SLC-0111 (500 mg/day PO daily for 28 days) and Gemcitabine (1000 mg/m^2 IV on day 1, 8, and 15) Dose Level 2 - SLC-0111 (750 mg/day PO daily for 28 days) and Gemcitabine (1000 mg/m^2 IV on day 1, 8, and 15) Dose Level 3 - SLC-0111 (1000 mg/day PO daily for 28 days) and Gemcitabine (1000 mg/m^2 IV on day 1, 8, and 15) | Drug: SLC-0111<br>* Oral SLC-0111<br>* Other names: WBI-5111;Drug: Gemcitabine Injection<br>* 1000 mg/m^2 IV<br>* Other names: Gemcitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Adverse events (AEs) as assessed by CTCAE v5.0 will be determined by changes in safety assessments, including laboratory parameters, vital signs, ECG and physical examinations. | Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The maximum tolerated dose [MTD] of SLC-0111 in combination with gemcitabine | Dose limiting toxicities (adverse events) will be determined by changes in safety assessments, including vital signs, clinical laboratory evaluations and ECG. | Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment) | 
| Maximum Plasma Concentration [Cmax] | Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the maximum (peak) plasma concentration (Cmax). | Up to 4 years | 
| Time to Reach Maximum Plasma Concentraiton [Tmax] | Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by the time to reach maximum (peak) plasma concentration following drug administration (Tmax). | Up to 4 years | 
| Elimination Rate Constant from the Central Compartment [Kel] | Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the elimination rate constant from the central compartment (Kel). | Up to 4 years | 
| Volume of Distribution During Terminal Phase after Intravenous Administration [Vz] | Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the volume of distribution during terminal phase after intravenous administration (Vz). | Up to 4 years | 
| Area Under the Concentration-Time Curve from Zero up to a Definite Time T [AUC(0-T)] | Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the area under the concentration-time curve from zero up to a definite time T (AUC(0-T)). | Up to 4 years | 
| Area Under the Concentration-Time Curve from Zero up to Infinity [AUC(0-inf)] | Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the area under the concentration-time curve from zero up to infinity with extrapolation of the terminal phase (AUC(0-inf)). | Up to 4 years | 
| Elimination Half-Life | Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the elimination half-life (T1/2). | Up to 4 years | 
| Determine the Recommended Phase II Dose of SLC-0111 in combination with gemcitabine | Recommended Phase II Dose (RP2D) Safety and PK | Up to 2 years | 
| Objective Response Rate [ORR] as Assessed by RECIST 1.1 | Objective response rate (ORR) as assessed by RECIST 1.1 or clinical examination, where appropriate. ORR is the change in tumour volume from baseline to best overall response. | Up to 1 year | 
| Progression-Free Survival [PFS] as Assessed by RECIST 1.1 | Progression-free survival (PFS) as assessed by RECIST 1.1 or clinical examination, where appropriate. PFS is defined as the duration of time from start of treatment to progression or death, whichever occurs first. Subjects alive at the time of last follow up without disease progression will be censored at that time point. | Up to 1 year | 
| Duration of Response as Assessed by RECIST 1.1 | Duration of response as assessed by RECIST 1.1 or clinical examination, where appropriate. Duration of response is defined as the time from start of response [Complete Response (CR) or Partial Response (PR)] until progression or death due to any cause. | Up to 2 years | 
| Overall Survival [OS] | Overall survival (OS) is defined as the time from initiation of investigational product(s) to death due to any cause. | Up to the end of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gemcitabine, SLC-0111, PDAC