Clinical Trials /

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

NCT03450018

Description:

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

Related Conditions:
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of SLC-0111 and Gemcitabine for Metastatic Pancreatic Ductal Cancer in Subjects Positive for CAIX
  • Official Title: 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 (mPDAC) Subjects Positive for Carbonic Anhydrase IX (CAIX)

Clinical Trial IDs

  • ORG STUDY ID: H17-02841
  • NCT ID: NCT03450018

Conditions

  • Metastatic Pancreatic Ductal Adenocarcinoma

Interventions

DrugSynonymsArms
SLC-0111WBI-5111SLC-0111 + Gemcitabine
Gemcitabine InjectionGemcitabineSLC-0111 + Gemcitabine

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
SLC-0111 + GemcitabineExperimentalDose 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)
  • SLC-0111
  • Gemcitabine Injection

Eligibility Criteria

        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 109/L

               -  Platelets ≥ 100 x 109/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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
Safety Issue:
Description:Adverse events (AEs) as assessed by CTCAE v4.03 will be determined by changes in safety assessments, including laboratory parameters, vital signs, ECG and physical examinations.

Secondary Outcome Measures

Measure:The maximum tolerated dose [MTD] of SLC-0111 in combination with gemcitabine
Time Frame:Up to Safety Follow-Up Visit (30 days +/- 7 days after permanently stopping study treatment)
Safety Issue:
Description:Dose limiting toxicities (adverse events) will be determined by changes in safety assessments, including vital signs, clinical laboratory evaluations and ECG.
Measure:Maximum Plasma Concentration [Cmax]
Time Frame:Up to 4 years
Safety Issue:
Description:Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the maximum (peak) plasma concentration (Cmax).
Measure:Time to Reach Maximum Plasma Concentraiton [Tmax]
Time Frame:Up to 4 years
Safety Issue:
Description: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).
Measure:Elimination Rate Constant from the Central Compartment [Kel]
Time Frame:Up to 4 years
Safety Issue:
Description:Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the elimination rate constant from the central compartment (Kel).
Measure:Volume of Distribution During Terminal Phase after Intravenous Administration [Vz]
Time Frame:Up to 4 years
Safety Issue:
Description: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).
Measure:Area Under the Concentration-Time Curve from Zero up to a Definite Time T [AUC(0-T)]
Time Frame:Up to 4 years
Safety Issue:
Description: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)).
Measure:Area Under the Concentration-Time Curve from Zero up to Infinity [AUC(0-inf)]
Time Frame:Up to 4 years
Safety Issue:
Description: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)).
Measure:Elimination Half-Life
Time Frame:Up to 4 years
Safety Issue:
Description:Analyze the pharmacokinetic profile of SLC-0111 and gemcitabine when used in combination by measuring the elimination half-life (T1/2).
Measure:Determine the Recommended Phase II Dose of SLC-0111 in combination with gemcitabine
Time Frame:Up to 2 years
Safety Issue:
Description:Recommended Phase II Dose (RP2D) Safety and PK
Measure:Objective Response Rate [ORR] as Assessed by RECIST 1.1
Time Frame:Up to 1 year
Safety Issue:
Description: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.
Measure:Progression-Free Survival [PFS] as Assessed by RECIST 1.1
Time Frame:Up to 1 year
Safety Issue:
Description: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.
Measure:Duration of Response as Assessed by RECIST 1.1
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Overall Survival [OS]
Time Frame:Up to the end of the study
Safety Issue:
Description:Overall survival (OS) is defined as the time from initiation of investigational product(s) to death due to any cause.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:British Columbia Cancer Agency

Trial Keywords

  • Gemcitabine
  • SLC-0111
  • PDAC

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