Clinical Trials /

A Phase 1B Study of Canakinumab, Spartalizumab, Nab-paclitaxel, and Gemcitabine in Metastatic PC Patients

NCT04581343

Description:

This study combines canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1), with the chemotherapy combination of gemcitabine and nab-paclitaxel. This study will confirm for this 4-drug combination the tolerable doses, the acceptable safety profile, and the dose to be used for a Phase II combination treatment regimen.

Related Conditions:
  • Pancreatic Adenosquamous Carcinoma
  • Pancreatic Ductal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1B Study of Canakinumab, Spartalizumab, Nab-paclitaxel, and Gemcitabine in Metastatic PC Patients
  • Official Title: A Phase 1B Study to Determine the Safety and Tolerability and Confirm the Dose of Canakinumab and Spartalizumab in Combination With Nab-paclitaxel and Gemcitabine for Patients With Metastatic Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: PanCAN-SR1
  • NCT ID: NCT04581343

Conditions

  • Metastatic Pancreatic Ductal Adenocarcinoma

Interventions

DrugSynonymsArms
Canakinumab injection; spartalizumab, nab-paclitaxel, gemcitabineIlaris, AbraxaneCanakinumab, spartalizumab, nab-paclitaxel and gemcitabine

Purpose

This study combines canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) monoclonal antibody (mAb), and spartalizumab (PDR001), a mAb directed against human Programmed Death-1 (PD-1), with the chemotherapy combination of gemcitabine and nab-paclitaxel. This study will confirm for this 4-drug combination the tolerable doses, the acceptable safety profile, and the dose to be used for a Phase II combination treatment regimen.

Detailed Description

      This is an open-label multi-center phase Ib study to confirm the recommended phase II/III
      dose of canakinumab and spartalizumab in combination with nab-paclitaxel and gemcitabine.

      The study will recruit patients with metastatic pancreatic adenocarcinoma treated in the
      first line setting. The starting dose level of canakinumab explored will be 250 mg Q4W
      ("starting dose level"). In case of unacceptable toxicity of the starting dose devel of
      canakinumab, the dose of canakinumab will be de-escalated to the "-1 dose level" administered
      as 250 mg Q8W, while other components of the combination stay at the same dose as the
      starting dose level.

      Patients will be observed for DLTs for a minimum duration of 56 days (8 weeks). To achieve
      study objectives and to ensure the adequate number of DLT evaluable patients, the study will
      recruit approximately ten patients to have at least 6 evaluable patients per dose level of
      canakinumab. Additional approximately ten patients (to have at least 6 additional evaluable
      patients) may be enrolled at lower dose level in case a dose de-escalation is necessary.

      Dose confirmation will be guided by an adaptive Bayesian logistic regression model (BLRM)
      based on any DLTs observed for two cycles of treatment (i.e. 56 days, or 8 weeks). The
      adaptive BLRM will be guided by the Escalation with Overdose Control (EWOC) principle to
      control the probability of DLT in future patients on the study. BLRM is a well-established
      and widely used method to estimate the recommended dose for expansion (RDE) or maximal
      tolerable dose (MTD) in clinical trials in patients with cancer with small sample size. The
      use of Bayesian response adaptive models for small datasets has been endorsed by academic
      publications (Babb et al. 1998, Neuenschwander et al. 2008, Neuenschwander et al. 2010,
      Natanegara et al. 2014), by the European Medicines Agency (Guideline on Clinical Trials in
      Small Populations, 2007) and it constitutes an important aspect of the FDA's Critical Path
      Initiative (Clinical Path White Paper, FDA, 2004). The Bayesian analysis incorporates prior
      toxicity data of single agent and drugs combinations together with the currently available
      data to predict the probability of DLT and excessive toxicity of a dose level of interest.

      The Bayesian method is be based on a Meta-Analytical-Combined (MAC) approach (Spiegelhalter
      2004, Neuenschwander 2016) to combine all historical and concurrent data. Prior toxicity
      information included in the BLRM model was obtained from three studies with canakinumab as a
      single agent and combination of canakinumab and spartalizumab (PDR001X2101, ACZ885I2202,
      PRD001X2103) and from a phase I/II study of nab-paclitaxel + gemcitabine (Von Hoff D, et.al.,
      2011). Simulation was used to illustrate the recommendation from BLRM under a set of
      hypothetical scenarios with assumed number of evaulable patients and DLTs.

      The decisions on a recommended dose will be made by the Investigators and the Sponsor in a
      Safety Review meeting when at least 6 DLT evaluable patients per dose level will be observed
      for DLTs for a minimum duration of 56 days (8 weeks). Safety review will be based upon the
      review of all relevant data available including treatment tolerability and safety information
      together with the BLRM summaries of DLT probability, PK, PD, and preliminary activity
      information (if available) at the time of the meeting.

      Patients will be treated until disease progression per RECIST 1.1, unacceptable toxicity, or
      until the patient or treating physician decides to stop treatment.

      Pharmacokinetic (PK) and immunogenicity (IG) samples will be collected at specific time
      points throughout treatment. Each treatment cycle is 4 weeks. All patients must be followed
      for safety up to 150 days after the last dose of spartalizumab or canakinumab, or 30 days
      after the last dose of the combination chemotherapy, whichever the later. After the end of
      safety follow-up, patients will be followed for disease progression if discontinuation of
      treatment is due to reason other than progression, and for survival (via telephone call or
      onsite visit if a patient happens to be visiting the site) until the end of study The study
      completion is defined as when the last patient has completed the study treatment, safety
      follow up, and completed survival follow up period up to 1 year from first treatment,
      whichever is later or in the event of an early study termination decision, the date of that
      decision.
    

Trial Arms

NameTypeDescriptionInterventions
Canakinumab, spartalizumab, nab-paclitaxel and gemcitabineExperimentalSpartalizumab (PDR001),IV infusion, 400 mg, D1 of each 28-day cycle; Canakinumab (ACZ885), s.c. injection, 250 mg, Day 1 of each 28- day cycle; Gemcitabine, IV Infusion, 1000 mg/m2, Days 1, 8, 15 of each 28-day cycle; Nab-paclitaxel, IV Infusion, 125 mg/m2, Days 1, 8, 15 of each 28-day cycle.
  • Canakinumab injection; spartalizumab, nab-paclitaxel, gemcitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Age > 18 years at the time of informed consent

          -  Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC)
             (determined by a local laboratory) with metastatic spread of disease (adenosquamous is
             also allowed).

          -  Patients must have not received previous anti-cancer therapy for the treatment of
             metastatic pancreatic ductal adenocarcinoma.

          -  Patients who received previous neo-/adjuvant systemic therapy for non-metastatic PDAC
             ≥12 months from the last treatment to study enrollment date are allowed unless this
             therapy included immunotherapy and/or IL-1 inhibitors.

          -  Radiographically measurable disease of at least one site by computed tomography (CT)
             scan (or magnetic resonance imaging, if allergic to CT contrast media) as defined by
             Response Evaluation Criteria In Solid Tumors (RECIST 1.1). Primary lesion is allowed
             as long as it is measurable (per RECIST 1.1) and has not been previously irradiated.
             Imaging results must be obtained within the 28-day screening window.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          -  Adequate organ function (laboratory results must be obtained within the 28-day
             screening window)

               -  Absolute neutrophil count > 1500/mm3

               -  Hemoglobin > 9 g/dL

               -  Platelets > 100,000/mm3

               -  Serum creatinine < 1.5 x upper limit normal (ULN), or calculated creatinine
                  clearance > 60 mL/min (Cockcroft Gault)

               -  Albumin > 3.0 g/dL

               -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)
                  and/or alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT)
                  < 3.0 x ULN (< 5 x ULN in presence of liver metastasis).

        In patients with elevated ALT or AST, the values must be stable for at least 2 weeks and
        with no evidence of biliary obstruction on imaging

          -  Total bilirubin ≤ 1.5 X ULN

          -  INR ≤ 1.5 x ULN

               -  Consent to provide protocol-mandated tissue and blood samples for diagnostic, PK,
                  and research purposes

               -  Able to adhere to study visit schedule and other protocol requirements

        Exclusion Criteria:

          -  Diagnosis of pancreatic neuroendocrine carcinoma or pancreatic acinar cell carcinoma

          -  Previous immunotherapy (e.g. anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody,
             or any other antibody or drug specifically targeting T-cell co-stimulation or immune
             checkpoint pathways).

          -  Known microsatellite instability-high (MSI-H) or mismatch repair-deficient pancreatic
             cancer

          -  Prior treatment with canakinumab or drugs of a similar mechanism of action (IL-1
             inhibitor).

          -  History of known hypersensitivity to any of the drugs used in this study or any of
             their excipients, or patient has contraindication to any of the study drugs as
             outlined in the local prescribing information (e.g. United States Prescribing
             Information [USPI])

          -  Active autoimmune disease that has required systemic treatment in the past 2 years
             prior to enrollment i.e. with use of disease modifying agents, corticosteroids or
             immunosuppressive drugs. Control of the disorder with replacement therapy (e.g.,
             thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
             pituitary insufficiency, etc.) is permitted.

          -  Patient with suspected or proven immunocompromised state or infections, including:

               -  Evidence of active or latent tuberculosis (TB) as determined by locally approved
                  screening methods. If the results of the screening per local treatment guidelines
                  or clinical practice require treatment, then the patient is not eligible.

               -  Chronic or active hepatitis B or C

               -  Known history of testing positive for Human Immunodeficiency Virus (HIV)
                  infections.

               -  Any other medical condition (such as active infection, treated or untreated),
                  which in the opinion of the investigator places the patient at an unacceptable
                  risk for participation in immunomodulatory therapy.

        Note: Patients with localized condition unlikely to lead to a systemic infection e.g.
        chronic nail fungal infection are eligible.

          -  Allogeneic bone marrow or solid organ transplant

          -  Treatment with any immune modulating agent in doses with systemic effects e.g.:

               -  Systemic treatment with prednisone > 10 mg (or equivalent) for >14 days within 4
                  weeks prior to the first dose of study treatment.

               -  Equivalent dose of methotrexate > 15 mg weekly

               -  Patient receiving any biologic drugs targeting the immune system (for example,
                  TNF blockers, anakinra, rituximab, abatacept, or tocilizumab).

               -  Note: Daily glucocorticoid-replacement for conditions such as adrenal or
                  pituitary insufficiency is allowed.

               -  Note: Topical, inhaled, or local steroid use in doses that are not considered to
                  cause systemic effects are permitted (based on investigator's discretion and
                  consultation with the Medical Monitor if needed).

          -  Patient has concurrent malignancy other than the disease under investigation, with
             exception of malignancy that was treated curatively and has not recurred within 2
             years prior to the date of screening. Fully resected basal or squamous cell skin
             cancers, and any carcinoma in situ are eligible.

          -  Uncontrolled or severe cardiac disease (history of unstable angina, myocardial
             infarction, coronary stenting, or bypass surgery within the prior 6 months),
             symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia
             [including atrial flutter/fibrillation], requirement for inotropic support or use of
             devices for cardiac conditions [pacemakers/defibrillators]), uncontrolled hypertension
             defined by a systolic blood pressure =>160 mg and/or diastolic blood pressure =>100 mg
             Hg

          -  Pre-existing peripheral neuropathy > Grade 1 (CTCAE V 5.0)

          -  Receipt of live vaccines within 3 months prior to the first dose of study treatment or
             while on active treatment within the trial (examples of live vaccines include, but are
             not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever,
             rabies, BCG, and typhoid (oral vaccine). Seasonal influenza vaccines for injection are
             generally killed virus vaccines and are permitted. However, intranasal influenza
             vaccines (e.g. Flu-mist) are live attenuated vaccines and are not permitted.

          -  Patient has had major surgery within 14 days prior to enrollment

          -  Patient has symptomatic brain metastases, or brain metastases that require directed
             therapy (such as focal radiotherapy or surgery). Patients with treated brain
             metastases have to be neurologically stable and not using systemic steroids for at
             least 4 weeks prior to the study drug administration.

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are willing to use highly effective methods of
             contraception during treatment with study drugs (canakinumab, spartalizumab,
             gemcitabine and nab-paclitaxel).

          -  Highly effective contraception methods are required while on treatment and for 150
             days after stopping spartalizumab. No contraception is required after treatment with
             canakinumab is stopped. Contraception use after chemotherapy is stopped should be
             followed per the local drug label requirements.

        Highly effective contraception methods include:

          -  Total abstinence (when this is in line with the preferred and usual lifestyle of the
             patient. Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation
             methods) and withdrawal are not acceptable methods of contraception

          -  Female sterilization (have had bilateral surgical oophorectomy (with or without
             hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks
             before taking study treatment. In case of oophorectomy alone, only when the
             reproductive status of the woman has been confirmed by follow up hormone level
             assessment.

          -  Male sterilization (at least 6 months prior to screening). The vasectomized male
             partner should be the sole partner for that patient.

          -  Use of oral, injected or implanted hormonal methods of contraception or placement of
             an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal
             contraception that have comparable efficacy (failure rate <1%), for example hormone
             vaginal ring or transdermal hormone contraception In case of use of oral contraception
             women should have been stable on the same pill for a minimum of 3 months before taking
             study treatment.

        Note: Women of non-childbearing potential is defined as women who are physiologically
        and/or anatomically incapable of becoming pregnant, as now further described:

          -  They are post-menopausal as evidenced by 12 months of natural (spontaneous) amenorrhea
             with an appropriate clinical profile (i.e., age appropriate history of vasomotor
             symptoms).

          -  They have had bilateral surgical oophorectomy (with or without hysterectomy), total
             hysterectomy or bilateral tubal ligation at least six weeks prior. In the case of
             oophorectomy alone, only when the reproductive status of the woman has been confirmed
             by follow up hormone level assessment is she considered not of childbearing potential.

        Note: Sexually active male patients and their partners who are women of childbearing
        potential should follow the contraception recommendations and any other precautionary
        measures as required by the local prescribing information for the SOC anti-cancer.

          -  Any significant medical condition, laboratory abnormality or psychiatric condition
             that would constitute unacceptable safety risks to the patients, contraindicate
             patient participation in the clinical study, limit the patient's ability to comply
             with study requirements, or compromise patient's compliance with the protocol and all
             requirements of the study as stated in the Informed Consent Form. Significant medical
             conditions include but are not limited to known history or current interstitial lung
             disease or non-infectious pneumonitis, medical history or current diagnosis of
             myocarditis, chronic active hepatitis, liver cirrhosis or any other significant liver
             disease with moderate to severe hepatic impairment (Child-Pugh B or C), serious
             non-healing wound/ulcer/bone fracture, uncompensated/symptomatic hypothyroidism, or
             requirement for hemodialysis or peritoneal dialysis.

          -  Unwillingness or unable to comply with all requirement of the study as stated in the
             Informed Consent Form
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Confirm the recommended Phase 2/3 dose of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:Assess the incidence of dose limiting toxicities (DLT) in the first 56 days (8 weeks) of dosing
Safety Issue:
Description:Confirm the recommended Phase 2/3 dose of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer

Secondary Outcome Measures

Measure:Determine the Safety [Frequency and severity of (S)AEs, Lab abnormalities and ECGs] of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:From Day 1 of study treatment through Safety Follow-up period (150-days after the last study treatment)
Safety Issue:
Description:Determine the Safety [Frequency and severity of (S)AEs, Lab abnormalities and ECGs] of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine
Measure:Determine the Tolerability [Frequency of dose interruptions and dose reductions] of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:From Day 1 of study treatment through End of Treatment visit, an average of 6 months
Safety Issue:
Description:Determine the Tolerability [Frequency of dose interruptions and dose reductions] of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine
Measure:Determine the response-related efficacy assessments Objective Response Rate (ORR) and Duration of Response (DOR) of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:Tumor response data from CT/MRI scans will be taken at screening visit and every 8 weeks throughout study treatment, an average of 6 months;
Safety Issue:
Description:Objective Response Rate (ORR) and Duration of Response (DOR) are calculated based on tumor response data [complete Response (CR) and Partial Response (PR)] assessed at the local site using RECIST 1.1 Criteria of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine
Measure:Determine the Disease Control Rate (DCR) of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:Tumor response data from CT/MRI scans will be taken at screening visit and every 8 weeks throughout study treatment, an average of 6 months;
Safety Issue:
Description:The Disease Control Rate (DCR) is calculated based on tumor response data [complete Response (CR) and Partial Response (PR) and Stable Disease (SD)] assessed at the local site using RECIST 1.1 Criteria of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine
Measure:Determine the Progression Free Survival (PFS) of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:Tumor response data from CT/MRI scans will be taken at screening visit and every 8 weeks throughout study treatment, an average of 6 months;
Safety Issue:
Description:The Progression Free Survival is defined as the time from the date of the first dose to the date of disease progression, assessed at the local site using RECIST 1.1 Criteria, of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine
Measure:Determine the Time To Response Rate (TTR) of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:Tumor response data from CT/MRI scans will be taken at screening visit and every 8 weeks throughout study treatment, an average of 6 months;
Safety Issue:
Description:The TIme To Response Rate is defined as the time from the date of the first dose to the date of first documented tumor response [Complete Response (CR) or Partial Response (PR)], assessed at the local site using RECIST 1.1 Criteria, of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine
Measure:Determine the Overall Survival (OS) of canakinumab, spartalizumab, nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer
Time Frame:Overall Survival assessment will be from first day of study treatment to subject's date of death, or until study closure, assessed up to 24 months; ;
Safety Issue:
Description:The Overall Survival is defined as the time from the date of the first dose to the date of death, due to any cause, of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine
Measure:Characterize the pharmacokinetics of canakinumab in patients with metastatic pancreatic cancer
Time Frame:Pharmacokinetic (PK) blood draws will be taken during cycles 1-6 for canakinumab analyte; Every cycle is 28-days, total estimated time is 6 months;
Safety Issue:
Description:Characterize the Descriptive Statistics (n, m (number of non-zero concentrations), mean, coefficient of variation CV%, SD, median, geometric mean, geometric CV%, minimum and maximum) of the Pharmacokinetic (PK) blood samples of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine;
Measure:Characterize the pharmacokinetics of spartalizumab in patients with metastatic pancreatic cancer
Time Frame:Pharmacokinetic (PK) blood draws will be taken during cycles 1-6 for spartalizumab analyte; Every cycle is 28-days, total estimated time is 6 months;
Safety Issue:
Description:Characterize the Descriptive Statistics (n, m (number of non-zero concentrations), mean, coefficient of variation CV%, SD, median, geometric mean, geometric CV%, minimum and maximum) of the Pharmacokinetic (PK) blood samples of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine;
Measure:Characterize the pharmacokinetics of nab-paclitaxel in patients with metastatic pancreatic cancer
Time Frame:Pharmacokinetic (PK) blood draws will be taken during cycles 1 and 2 for nab-paclitaxel analyte; Every cycle is 28-days, total estimated time is 2 months;
Safety Issue:
Description:Characterize the Descriptive Statistics (n, m (number of non-zero concentrations), mean, coefficient of variation CV%, SD, median, geometric mean, geometric CV%, minimum and maximum) of the Pharmacokinetic (PK) blood samples of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine;
Measure:Characterize the pharmacokinetics of gemcitabine in patients with metastatic pancreatic cancer
Time Frame:Pharmacokinetic (PK) blood draws will be taken during cycles 1 and 2 for gemcitabine analyte; Every cycle is 28-days, total estimated time is 2 months;
Safety Issue:
Description:Characterize the Descriptive Statistics (n, m (number of non-zero concentrations), mean, coefficient of variation CV%, SD, median, geometric mean, geometric CV%, minimum and maximum) of the Pharmacokinetic (PK) blood samples of patients treated with canakinumab, spartalizumab, nab-paclitaxel and gemcitabine;

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Pancreatic Cancer Action Network

Last Updated

October 2, 2020