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About
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.
Full 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 level 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 dose limiting toxicities (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 evaluable 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.
Enrollment
Sex
Ages
Volunteers
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)
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
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:
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.:
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, Bacillus Calmette-Guérin (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:
Note: Women of non-childbearing potential is defined as women who are physiologically and/or anatomically incapable of becoming pregnant, as now further described:
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 standard of care (SOC) anti-cancer.
Primary purpose
Allocation
Interventional model
Masking
10 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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