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
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.
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-trt biopsy) must be positive for CAIX via IHC before
screening assessments listed below should 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 sperms) 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.
- Acute hepatitis B infection or chronic hepatitis B not currently on suppressive
therapy.
- 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.
