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.
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
