PDAC TREATMENT REGIMEN

Abstract

The human Interleukin 1 Receptor antagonist anakinra can be used in the treatment of pancreatic ductal adenocarcinoma (PDAC). The treatment involves administration of a daily dose of approximately at least 200 mg of anakinra to a patient in need thereof, for example to a patient who is undergoing a chemotherapy treatment regimen. The anakinra can be used in related treatment methods and corresponding pharmaceutical compositions.

Claims

1-31. (canceled)

32. A method of treatment of pancreatic ductal adenocarcinoma (PDAC), the method comprising: administering a therapeutically effective dose of at least approximately 200 mg of anakinra per day to a patient in need thereof.

33. The method of treatment of PDAC according to claim 32, wherein said patient is undergoing a PDAC treatment regimen.

34. The method of treatment of PDAC according to claim 32, wherein said patient is undergoing a PDAC treatment regimen and said regimen is a chemotherapy treatment regimen.

35. The method of treatment of PDAC according to claim 32, wherein a daily dose of at least approximately 200 mg of anakinra is administered at more than one separate administration occasion per day.

36. The method of treatment of PDAC according to claim 32, wherein a daily dose of at least approximately 200 mg of anakinra is administered as two doses per day of at least approximately 100 mg of anakinra each, administered at two separate administration occasions per day.

37. The method of treatment of PDAC according to claim 36, wherein said two separate administration occasions per day are at least approximately 8 hours apart.

38. The method of treatment of PDAC according to claim 36, wherein said two separate administration occasions per day are approximately 8-16 hours apart.

39. The method of treatment of PDAC according to claim 32, wherein said administration is subcutaneous administration or intravenous administration.

40. The method of treatment of PDAC according to claim 32, wherein said administration is subcutaneous administration.

41. The method of treatment of PDAC according to claim 32, wherein said PDAC is stage IV PDAC.

42. The method of treatment of PDAC according to claim 34, wherein said chemotherapy treatment regimen comprises days with administration of at least one chemotherapeutic agent and days without administration of the at least one chemotherapeutic agent, and wherein said anakinra is administered during days with and days without said administration of the at least one chemotherapeutic agent.

43. The method of treatment of PDAC according to claim 32, wherein said anakinra administration is continued after said patient has completed one or several chemotherapy treatment regimen(s).

44. The method of treatment of PDAC according to claim 32, wherein said patient is chemotherapy resistant.

45. The method of treatment of PDAC according claim 34, wherein said chemotherapy treatment regimen comprises administration of a therapeutically effective dose of at least one agent selected from the group consisting of actinomycin, all-trans retinoic acid, azacytidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemicitabine, hydroxyurea, idarubicin, imatinib, irinotecan, nanoliposomal irinotecan, leucovorin, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, nab-paclitaxel, pemetrexed, pembrolizumab, a platinum-based antineoplastic agent, teniposide, tioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine, and vindesine.

46. The method of treatment of PDAC according claim 34, wherein said chemotherapy treatment regimen is selected from the group consisting of regimens a), b), c), d), e), and f), wherein regimen a) is administration of leucovorin, fluorouracil, irinotecan, and oxaplatin; regimen b) is administration of gemcitabine and nab-paclitaxel; regimen c) is administration of pembrolizumab; regimen d) is administration of fluorouracil and oxaliplatin; regimen e) is administration of fluorouracil and irinotecan; and regimen f) is administration of fluorouracil and nanoliposomal irinotecan.

47. The method of treatment of PDAC according claim 45, wherein said chemotherapy treatment regimen comprises administration of gemcitabine and/or nab-paclitaxel.

48. The method of treatment of PDAC according to claim 45, wherein said chemotherapy treatment regimen comprises administration of gemcitabine and nab-paclitaxel.

49. The method of treatment of PDAC according to claim 48, wherein said administration of gemcitabine and nab-paclitaxel is on days 1, 8, and 15 of each 28-day cycle.

50. The method of treatment of PDAC according to claim 48, wherein said administration is intravenous administration of approximately 1,000 mg/m.sup.2 gemcitabine and approximately 125 mg/m.sup.2 nab-paclitaxel.

51. The method of treatment of PDAC according to claim 45, wherein said chemotherapy treatment regimen comprises administration of leucovorin, fluorouracil, irinotecan, and oxaliplatin.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0074] FIG. 1 is a schematical representation of the clinical study according to Example 1. Abbrevations in the figure are as follows: GNP: Gemcitabine+Nab-Paclitaxel.

EXAMPLES

Summary

[0075] The present Examples describe a clinical study that aims to assess the efficacy and safety of the hIL-1R antagonist anakinra as add-on to chemotherapy in the treatment of PDAC in patients. The present inventors have established a method of treatment comprising administering anakinra, which may be administered as a monotherapy or be administered in combination with a chemotherapeutic treatment regimen to a patient in need thereof. Table 2 shows the events schedule for the study according to Example 1.

TABLE-US-00002 TABLE 2 Schedule of events. Follow-up period 6 months Treatment period End of IMP Visit 4 visit Phone Visit 1.sup.1 Visit 2 Visit 3 and onwards 30 days call.sup.2 Baseline Day 15 Day 28 Every Progression after last Every Assessments (Day 1) (Week 2) (Week 4) 28 days visit intake of IMP 4 weeks Informed consent X Eligibility criteria X Medical and surgical X history, and demographics Physical examination X X X X X incl. neuro status Vital signs (BP, pulse, X X X X X X temperature, height, weight) assessment ECG X CT/MRI scan X X X Prior and concomitant X X X X X X medication Laboratory safety X X X X X X assessment, local.sup.3 Laboratory safety X X X X X X assessment, central.sup.3, 4 Randomization X Patient/caregiver IMP X injection training.sup.5 IMP administration X training IMP treatment stop  X.sup.6 GNP chemotherapy administration QoL EQORTC-QLQ- X X X X (X) C30 Adverse events X X X X X X SAEs.sup.7 X X X X X X X IMP tracking X X X X Survival status X X X X X X .sup.1Baseline visit will be performed during Day 1, possibility to pre-screen patients on Day −1; .sup.2Patients will be followed for SAEs and death events every 4 weeks up to maximum 6 months after date of confirmed progression; .sup.3Including CA19-9; .sup.4Including biomarkers; .sup.5To be administered at study site first time, then at home during the study treatment period (until progression); .sup.6IMP treatment will be stopped the same day as the patient has a confirmed disease progression according to the Investigator; .sup.7From signing of informed consent. After the follow-up visit only SAEs considered by the investigator to be related to study drug will be collected.

[0076] Abbreviations and definition of terms used herein:

TABLE-US-00003 Abbreviation Definition 5FU fluorouracil AE Adverse event BP Blood pressure CA Carbohydrate antigen CA 19-9 CA 19-9 is a tumor marker that may be helpful in pancreatic cancer. A drop in the CA 19-9 level after surgery (compared to the level before surgery) and low levels of CA 19-9 after pancreas surgery tend to predict a better prognosis. CI Confidence interval CT Computerized tomography ECOG PS A scale and criteria used by doctors and researchers to assess how a patient's disease is progressing. E. coli Escherichia coli EORTC Questionnaire developed to assess the quality of QLQ-C30 life of cancer patients. FOLFIRINOX A combination of cancer drugs that includes: leucovorin/folinic acid, fluorouracil, irinotecan, and oxaliplatin G-CSF Granulocyte colony stimulating factor GFR Glomerular Filtration Rate GNP Gemcitabine and nab-paclitaxel HR Hazard Ratio HER2 Human epidermal growth factor receptor 2 HgBA1c Hemoglobin A1c DSMBData Safety Monitoring Board IL-1 Interleukin-1 IL-1α Interleukin 1 alpha IL-1β Interleukin 1 beta IL-1R Interleukin-1 receptor IL-1RI Interleukin-1 receptor type I IL-1Ra Interleukin-1 receptor antagonist IMP Investigational medical product NAB Nanoparticle albumin-bound mPDAC Metastatic pancreatic ductal adenocarcinoma, also referred to as stage IV PDAC. Terms mPDAC and stage IV PDAC are used herein interchangeably. MRI Magnetic resonance imaging OS Overall survival PFS Progression free survival RECIST Standard way to measure how well a cancer patient responds to treatment SAE Serious adverse event SD Standard deviation SoC Standard of care TNM Diagnosis classification criteria. T: describes the size of the main tumor and whether it grows outside of the pancreas or in neighboring organs; N: describes extension to lymph nodes; and M: describes if the tumor has extended to distant organs ULN Upper limit of normal QoL Quality of life

Example 1

Clinical Study—Stage IV PDAC

[0077] The present Example relates to a randomized, double-blind, placebo-controlled, multicenter phase 2 study of anakinra as add-on to chemotherapy in the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC also referred to herein as stage IV PDAC). The main aim of the study is to evaluate the efficacy and safety of anakinra as add-on to chemotherapy in the treatment of mPDAC in adult, chemotherapy treatment-naïve patients. The primary objective is to demonstrate prolonged overall survival in patients with mPDAC receiving treatment with anakinra versus placebo, as add-on to chemotherapy. The primary endpoint is overall survival defined as the time from the date of randomization until death due to any cause. Furthermore, the study aims to demonstrate prolonged progression free survival in patients with mPDAC receiving treatment with anakinra versus placebo, as add-on to chemotherapy and to demonstrate efficacy of anakinra versus placebo, as add-on to chemotherapy in improving quality of life in patients with mPDAC.

[0078] Additionally, of interest is to evaluate early onset of efficacy of anakinra versus placebo, as add-on to chemotherapy in the treatment of mPDAC; to evaluate sustained efficacy of anakinra versus placebo, as add-on to chemotherapy in the treatment of mPDAC; to evaluate the effect of anakinra versus placebo, as add-on to chemotherapy on different aspects of quality of life (QoL) in patients with mPDAC; as well as to evaluate safety of anakinra as add-on to chemotherapy.

Example 1a

Study Design and Study Population

[0079] In Example 1a the design of the clinical study in described as well as the criteria relating to the study population.

[0080] Study design: A randomized, double-blind, placebo-controlled, multicenter phase 2 study of anakinra as add-on to chemotherapy in the treatment of mPDAC (stage IV PDAC) is conducted. Patients included are diagnosed with stage IV PDAC and are chemotherapy treatment-naïve and are histologically or cytologically confirmed to have mPDAC and exhibit acceptable bone marrow, liver and kidney status.

[0081] The study consists of a treatment period and a posttreatment follow-up period as illustrated in FIG. 1. Chemotherapy treatment-naïve patients with a confirmed diagnose of mPDAC who are suitable for a GNP (gemcitabine and nab-paclitaxel) regimen in the first line setting will be randomized at the baseline visit to either GNP+anakinra or GNP+placebo in a 1:1 ratio. Approximately 222 patients will be randomized in a 1:1 ratio to GNP+anakinra or GNP plus matching placebo. The total number of events that needs to be observed is 154.The randomization will be stratified at baseline by ECOG PS 0 (Yes; No); presence of liver metastasis (Yes; No) and elevated CA 19-9 levels (Yes; No).

[0082] The median PFS in the control group is assumed to be 5.5 months. If a median PFS in the placebo arm of 5.5 months and a median PFS of 7.5 months in the anakinra group are assumed, these assumptions will result in a HR of 0.71. To ensure a power of 80% in demonstrating efficacy if the true HR is 0.71, using a 1-sided alpha-level of 0.1, 154 death events need to be observed.

[0083] The enrolment period is exptected to be 12 months and final analysis is performed when the 154 events have occurred (approx. at 18 months). The study period is expected to be 24 months (the study will end 6 months after the date for Final analysis).

[0084] Anakinra (and matching placebo) will be given every calendar day as 2 subcutaneous injections, once in the morning and once in the evening, with a total daily anakinra dose of 200 mg. Anakinra, also referred to herein as investigational medical product (IMP), will be administered until disease progression.

[0085] Safety will be monitored throughout the study and three interim safety evaluations will be performed.

[0086] A Data Safety Monitoring Board (DSMB) will evaluate both safety data during the study and will keep the blinding towards the rest of the study team and sponsor.

[0087] Treatment period: Patients will start IMP treatment at Baseline and continue on IMP throughout the study. During the first month, patients will have study visits at the clinic every second week for assessments of vital signs, laboratory safety status, physical exam and QoL. Thereafter study visits will take place every 28 days and include the same assessments as above. A CT or MRI scan will be performed every 6 weeks. Table 2 gives an overview of the planned study visits.

[0088] Follow up period: Once the patient has a confirmed disease progression according to the Investigator, the treatment with anakinra will stop and patients will be unblinded and enter the Follow-up period. The Follow-up period comprises of an End of IMP visit approximately 30 days after last intake of IMP, where assessments on vital signs, laboratory status, adverse events, CT/MRI scan and physical examination including neurology status will occur. After that, patients will be followed for survival by phone calls every 4 weeks until 6 months after evaluation of primary endpoint.

[0089] Safety Analysis: Safety is evaluated according to Example 1c.

[0090] Study Population: The following inclusion and exclusion criteria apply:

[0091] Main inclusion criteria: A patient will be eligible for inclusion in this study if he or she meets all of the following criteria: 1. Histologically or cytologically confirmed diagnosis of mPDAC within 6 weeks before randomization; 2. Coexisting extra pancreatic distant metastasis; 3. Chemotherapy treatment-naïve patients suitable for a GNP treatment regimen in a first line setting; 4. Age ≥18 years old; 5. Life expectancy at least 3 months according to Investigator; 6. Measurable primary tumor in pancreas on imaging study at the time of diagnosis, according to the RECIST criteria, version 1.1; and 7. Signed informed consent.

[0092] Main exclusion criteria: A patient will be ineligible for inclusion in this study if he or she meets any of the following criteria: 1. Previous history of systemic chemotherapy; 2. History of malignancy, other than the current, within the past 5 years. Exceptions are basal cell skin cancer, carcinoma-in-situ of the cervix, and low-risk prostate cancer after curative therapy. 3. Existence of life-threatening co-morbidity; 4.Poor performance state (ECOG ≥2); 5. Severe bone marrow suppression (neutrophil count <1,500/mm3, hemoglobin <9 g/dL, platelet count <75,000/mm3); 6. Suspected severe liver dysfunction (Total bilirubin or prothrombin time >1.5 times upper reference limit); 7. Chronic kidney disease stages 4 and 5 (i.e. estimated GFR <30/ml/min/1.73 m.sup.2); 8. Pre-existence of grade 2 peripheral sensory neuropathy; 9. Existence of brain metastasis or meningeal carcinomatosis; 10. Known hypersensitivity to Escherichia coli-derived proteins, anakinra or any components of the product; 11. Exposure to an IL-1 or an IL-6 inhibitor within last 24 months; 12. Other severe and/or uncontrolled medical condition or other condition that according to the investigator could affect the participation of the patient in the study; 13. Known or suspected infection of hepatitis B, hepatitis C, tuberculosis, or HIV infection; 14. Pregnant or lactating women; 15. Any medical condition which in the opinion of the investigator makes the subject unsuitable for inclusion; 16. Enrollment in another concurrent clinical interventional study, or intake of an investigational drug, within three months prior to inclusion in this study; and 17. Foreseeable inability to cooperate with given instructions or study procedures.

[0093] Visit schedule and assessments: Patients are assessed at scheduled visits as shown in Table 2. A brief summary is as follows: Documentation and measurement of target and non-target tumor lesions by means of spiral CT or MRI is performed at baseline. Every 6 weeks after baseline, the tumor response is evaluated by means of spiral CT or MRI with the use of RECIST, version 1.1.

[0094] Safety is monitored by means of assessments by the investigators of serious and non-serious adverse events, laboratory testing performed at a central laboratory, dose modifications, dose delays, changes in type of chemotherapy regimen, and premature discontinuations of the study drug. Use of granulocyte colony stimulating factor (G-CSF) is also monitored.

[0095] Patients are followed for survival until death, patient withdrawal, or study closure.

[0096] Evaluation of patient reported outcomes by means of the questionnaire EORTC QLQ-C30 (a questionnaire developed to assess the quality of file of cancer patients) is performed at baseline and every 28 days thereafter. Serial measurements of cancer associated antigen 19-9 (CA19-9) and other biomarkers is also performed at baseline and every 28 days thereafter.

Example 1b

Inventive Treatment, Dose and Mode of Administration

[0097] Example 1b discloses the treatment administered and evaluated in the present clinical study, including the doses administered and treatment duration.

[0098] Treatment period first line: Patients in the treatment group (referred to as Arm A) are administered gemcitabine and nab-paclitaxel together with a daily dose 200 mg anakinra, administered as 100 mg b.i.d.

[0099] Anakinra, 100 mg subcutaneous (s.c.) injection, is administered twice daily and is given continuously, both during administration of chemotherapy and during the periods when chemotherapy is not given. Intravenous nab-paclitaxel (125 mg/m.sup.2) and gemcitabine (1000 mg/m.sup.2) is administered on days 1, 8 and 15 of each 28-day cycle. Gemcitabine is administered immediately after nab-paclitaxel.

[0100] Patient in the control group (referred to as Arm B) are administered gemcitabine and nab-paclitaxel together with a daily dose of placebo, administered mg b.i.d.

[0101] Placebo is administered twice daily by s.c. injection, and is given continuously, both during administration of chemotherapy and during the periods when chemotherapy is not given. Intravenous nab-paclitaxel (125 mg/m.sup.2) and gemcitabine (1000 mg/m.sup.2) is administered on days 1, 8 and 15 of each 28-day cycle. Gemcitabine is administered immediately after nab-paclitaxel.

[0102] Duration of treatment: Anakinra treatment starts on the first day of GNP administration. Anakinra is administered continuously until disease progression. Treatment with anakinra will be discontinued if intolerable toxicity is observed, if the patient withdraws from the study, or at the Investigator's discretion.

[0103] Treatment with GNP will discontinue if disease progression or intolerable toxicity is observed, if the patient withdraws from the study, or at the Investigator's discretion.

Example 1c

Safety and Efficacy Analyses

[0104] Example 1c describes the analyses of safety and efficacy as well as statistical methodology employed in the study.

[0105] Safety Analysis: Safety is evaluated by 3 predefined safety analyses will be performed by the Data Safety Monitoring Board (DSMB). The DSMB will evaluate safety data during the study and will keep the blinding towards the rest of the study team and sponsor.

[0106] The first safety analysis will be performed when 12 patients (approximately 6 patients on anakinra and 6 on placebo) have completed one GNP treatment cycle.

[0107] A second safety analysis will be performed when 40 patients (approximately 20 patients on anakinra and 20 on placebo) have completed two chemotherapy cycles.

[0108] A third safety analysis will be performed when 100 patients (approximately 50 patients on anakinra and 50 on placebo) have completed two chemotherapy cycles.

[0109] Additional evaluations of safety will be performed if required.

Study Objectives and Statistical Methods

[0110] Primary endpoint: As mentioned above, the primary objective is to demonstrate prolonged progression free survival in patients with mPDAC receiving treatment with anakinra versus placebo, as add-on to GNP. The primary endpoint is progression free survival defined as the time from the date of randomization to disease progression, or death due to any cause, whatever happens first. The primary endpoint is progression free survival defined as the time from the date of randomization to disease progression, assessed by Investigator in accordance with RECIST 1.1, or death due to any cause, whatever happens first. Any subject not known to have progressed at the time of analysis will be censored based on the last recorded date with an assessment documenting absence of progressive disease.

[0111] The primary endpoint will be analyzed using a stratified log rank test, with ECOG PS 0 (Yes or No); presence of liver metastasis (Yes or No); elevated (1.5×ULN) CA 19-9 levels (Yes or No) as stratification factors. The effect of treatment will be estimated by the HR (anakinra versus placebo) together with its corresponding 95% confidence interval (CI) and p-value.

[0112] Key secondary objectives and endpoints: Secondary objectives and endpoints include: 1.To evaluate overall survival in patients with mPDAC receiving treatment with anakinra versus placebo, as add-on to GNP (overall survival is defined as the time from the date of randomization until death due to any cause); 2. To evaluate the effect of anakinra versus placebo, as add-on to GNP chemotherapy on different aspects of QoL in patients with mPDAC (EORTC QLQ-C30 domain scores will be used); 3. To evaluate early onset of efficacy of anakinra versus placebo, as add-on to GNP chemotherapy in the treatment of mPDAC (Carbohydrate antigen 19-9 (CA 19-9) response rate, Objective response rate by investigator assessment in accordance with RECIST 1.1. All responses will be confirmed 8 weeks after onset of response, and time to treatment failure, defined as the time from the start of GNP chemotherapy treatment to the date of discontinuation hereof for any reason); 4. To evaluate safety of anakinra as add-on to GNP chemotherapy (Adverse events, vital signs and laboratory safety assessments, including severity and duration of neutropenia; Proportion of patients receiving GNP chemotherapy according to protocol; GNP cycles where patients receive G-CSF.). Additionally, the exploratory objective of the study is to explore the effect of anakinra as add-on to GNP chemotherapy on inflammation markers.

[0113] The analysis of key secondary endpoints may be performed according to be following:

[0114] The key secondary endpoint overall survival is defined as the time from the date of randomization until death due to any cause. Any subject not known to have died at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive.

[0115] The key secondary endpoints time to definitive deterioration 10 points) in each of the EORTC QLQ-C30 domain scores: fatigue, pain and loss of appetite may be analyzed using a stratified log rank test, with the same stratification factors as for the primary endpoint. The effect of treatment may be estimated by the HR (anakinra versus placebo) together with its corresponding confidence interval (CI) and p-value.

[0116] A multiple testing procedure, combining fixed sequence testing and Hochberg procedure, may be used to ensure an overall 1-sided significance level of 0.025 for the key secondary endpoints. A fixed sequential testing may be applied for the OS, the PFS and the three key QoL secondary endpoints: fatigue, pain and loss of appetite, i.e. the PFS will only be tested if the null hypothesis related to the OS is rejected and the QoL endpoints will only be tested if the null hypothesis related to the PFS is rejected. The Hochberg procedure may then be applied for the three key QoL secondary endpoints.

[0117] It is expected that administration of anakinra together with the chemotherapy as described above will result in a significant improvement of PDAC patient outcomes, such as stage IV PDAC patient outcomes, in comparison with the control group. Significant improvements are expected in one or several of the primary endpoint progression free survival and the key secondary endpoints overall survival listed above. The inventive treatment is expected to be tolerated well and fulfill safety requirements.

ITEMIZED LIST OF EMBODIMENTS

[0118] 1. Anakinra for use in the treatment of pancreatic ductal adenocarcinoma (PDAC), wherein said treatment comprises administration of a daily dose of at least approximately 200 mg, such as approximately 200 mg or at least 200 mg, anakinra to a patient in need thereof.

[0119] 2. Anakinra for use according to item 1, wherein said patient is undergoing a PDAC treatment regimen, such as a chemotherapy treatment regimen and/or a radiotherapy treatment regimen.

[0120] 3. Anakinra for use according to item 1 or 2, wherein said patient is undergoing a chemotherapy treament regimen.

[0121] 4. Anakinra for use according to any one of items 1-3, wherein said daily dose of at least approximately 200 mg, such as approximately 200 mg, anakinra is administered at more than one separate administration occasion per day.

[0122] 5. Anakinra for use according to any one of items 1-4, wherein said daily dose of at least approximately 200 mg, such as approximately 200 mg, anakinra is administered at least two separate administration occasions per day, such as at two separate administration occasions per day.

[0123] 6. Anakinra for use according to any one of items 1-5, wherein said daily dose of at least approximately 200 mg, such as approximately 200 mg, anakinra administered on at least two separate administration occasion per day is administered as two or more essentially equal doses per day.

[0124] 7. Anakinra for use according to any one of items 1-6, wherein said daily dose of at least approximately 200 mg, such as approximately 200 mg, anakinra administered on at least two separate administration occasion per day is administered as two doses per day of at least approximately 100 mg anakinra each, such as two doses of approximately 100 mg each, such as two doses of 100 mg anakinra each.

[0125] 8. Anakinra for use according to any one of items 5-7, wherein said at least two separate administration occasions per day are at least approximately 8 hours apart.

[0126] 9. Anakinra for use according to any one of items 5-8, wherein said at least two separate administration occasions per day are approximately 8-16 hours apart, such as approximately 9-15 hours apart, such as approximately 10-14 hours apart, such as approximately 11-13 hours apart, such as approximately 12 hours apart.

[0127] 10. Anakinra for use according to any one of items 5-9, wherein said at least two separate administration occasions per day are approximately 12 hours apart.

[0128] 11. Anakinra for use according to any one of items 1-10, wherein said administration is subcutaneous administration or intravenous administration.

[0129] 12. Anakinra for use according to item 11, wherein said administration is subcutaneous administration, such as subcutaneous self-administration.

[0130] 13. Anakinra for use according to item 11, wherein said administration is intravenous administration.

[0131] 14. Anakinra for use according to any one of items 1-13, wherein said PDAC is stage IV PDAC.

[0132] 15. Anakinra for use according to any one of items 1-14, wherein said treatment is preventive treatment of stage IV PDAC.

[0133] 16. Anakinra for use according to any one of items 2-15, wherein said chemotherapy treatment regimen comprises days with administration of at least one chemotherapeutic agent and days without administration of at least one chemotherapeutic agent, and wherein said anakinra is administered during days with and without said administration of at least one chemotherapeutic agent.

[0134] 17. Anakinra for use according to any one of items 2-16, wherein the patient is undergoing a chemotherapy treatment regimen and wherein

[0135] anakinra is administered continuously independent of the PDAC stage and/or identity of the chemotherapeutic agent.

[0136] 18. Anakinra for use according to any one of items 2-17, wherein the patient is undergoing a first line of chemotherapy treatment regimen.

[0137] 19. Anakinra for use according to any one of items 2-17, wherein the patient is undergoing a second or subsequent line of chemotherapy treatment regimen.

[0138] 20. Anakinra for use according to any one of items 1-19, wherein said anakinra administration is continued after said patient has completed one or several chemotherapy treatment regimen(s).

[0139] 21. Anakinra for use according to any one of items 1-2 and 4-15, wherein said patient is chemotherapy resistant.

[0140] 22. Anakinra for use according to any one of items 2-20, wherein said chemotherapy treatment regimen comprises administration of therapeutically effective dose of at least one agent selected for the group consisting of actinomycin, all-trans retinoic acid, azacytidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, nanoliposomal irinotecan, leucovorin, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, nab-paclitaxel, pemetrexed, pembrolizumab, platinum-based antineoplastic agents, teniposide, tioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine and vindesine, such as the group consisting of cisplatin, fluorouracil, gemcitabine, irinotecan, nanoliposomal irinotecan, leucovorin, nab-paclitaxel, oxaliplatin, pembrolizumab;

[0141] such as the group consisting of leucovorin, gemcitabine, nab-paclitaxel, cisplatin, fluorouracil, oxaliplatin and irinotecan;

[0142] such as the group consisting of gemcitabine, nab-paclitaxel, cisplatin, fluorouracil, oxaliplatin and irinotecan.

[0143] 23. Anakinra for use according item 22, wherein said chemotherapy treatment regimen is selected from the group consisting of regimens a), b), c), d), e) and f), such as the group consisting of regimens a) and b),

[0144] wherein

[0145] regimen a) is administration of leucovorin, fluorouracil, irinotecan and oxaplatin;

[0146] regimen b) is administration of gemcitabine and nab-paclitaxel;

[0147] regimen c) is administration of pembrolizumab;

[0148] regimen d) is administration of fluorouracil and oxaplatin;

[0149] regimen e) is administration of fluorouracil and irinotecan; and

[0150] regimen f) is administration of fluorouracil and nanoliposomal irinotecan.

[0151] 24. Anakinra for use according item 22 or 23, wherein said regimen comprises administration of gemcitabine or nab-paclitaxel.

[0152] 25. Anakinra for use according to any one of items 22-24, wherein said regimen comprises administration of gemcitabine and nab-paclitaxel.

[0153] 26. Anakinra for use according to item 25, wherein said administration of gemcitabine and nab-paclitaxel is on days 1, 8 and 15 of each 28-day cycle.

[0154] 27. Anakinra for use according to item 26, wherein said administration is intravenous administration of approximately 1000 mg/m.sup.2gemcitabine and approximately 125 mg/m.sup.2 nab-paclitaxel.

[0155] 28. Anakinra for use according item 22 or 23, wherein said regimen comprises administration of leucovorin, fluorouracil, irinotecan or oxaplatin.

[0156] 29. Anakinra for use according any one of items 22, 23 or 28, wherein said regimen comprises administration of leucovorin, fluorouracil, irinotecan and oxaplatin.

[0157] 30. Anakinra for use according to any one of items 1-29, wherein said PDAC is stage IV PDAC.

[0158] 31. A method of treatment of pancreatic ductal adenocarcinoma (PDAC), wherein said treatment comprises administering as therapeutically effective dose of at least approximately 200 mg, such as approximately 200 mg or at least 200 mg, anakinra per day to a patient in need thereof.

[0159] 32. Method of treatment of PDAC according to item 31, wherein wherein said patient is undergoing a PDAC treatment regimen, such as a chemotherapy treatment regimen and/or a radiotherapy treatment regimen.

[0160] 33. Method of treatment of PDAC according to item 31 or 32, wherein said patient is undergoing a chemotherapy treament regimen.

[0161] 34. Method of treatment of PDAC according to any one of items 31-33, wherein said daily dose of at least approximately 200 mg, such as approximately 200 mg, anakinra is administered at more than one separate administration occasion per day.

[0162] 35. Method of treatment of PDAC use according to any one of items 31-34, wherein said daily dose of at least approximately 200 mg, such as approximately 200 mg, anakinra is administered on at least two separate administration occasions per day, such as on two separate administration occasions per day.

[0163] 36. Method of treatment of PDAC according to any one of items 31-35, wherein said daily dose of at least approximately 200 mg anakinra administered on at least two separate administration occasion per day is administered as two or more essentially equal doses per day.

[0164] 37. Method of treatment of PDAC according to any one of items 31-36, wherein said daily dose of at least approximately 200 mg anakinra administered on at least two separate administration occasion per day is administered as two doses per day of at least approximately 100 mg anakinra each, such as two doses of approximately 100 mg each, such as two doses of 100 mg anakinra each.

[0165] 38. Method of treatment of PDAC according to any one of items 35-37, wherein said at least two separate administration occasions per day are at least approximately 8 hours apart.

[0166] 39. Method of treatment of PDAC according to any one of items 35-38, wherein said two separate administration occasions per day are approximately 8-16 hours apart, such as approximately 9-15 hours apart, such as approximately 10-14 hours apart, such as approximately 11-13 hours apart, such as approximately 12 hours apart.

[0167] 40. Method of treatment of PDAC according to any one of items 35-39, wherein said two separate administration occasions per day are approximately 12 hours apart.

[0168] 41. Method of treatment of PDAC according to any one of items 31-40, wherein said administration is subcutaneous administration or intravenous administration.

[0169] 42. Method of treatment of PDAC according to item 41, wherein said administration is subcutaneous administration, such as subcutaneous self-administration.

[0170] 43. Method of treatment of PDAC according to item 41, wherein said administration is intravenous administration.

[0171] 44. Method of treatment of PDAC according to any one of items 31-43, wherein said PDAC is stage IV PDAC.

[0172] 45. Method of treatment of PDAC according to any one of items 31-44, wherein said treatment is preventive treatment of stage IV PDAC.

[0173] 46. Method of treatment of PDAC according to any one of items 32-45, wherein said chemotherapy treatment regimen comprises days with administration of at least one chemotherapeutic agent and days without administration of at least one chemotherapeutic agent, and wherein said anakinra is administered during days with and without said administration of at least one chemotherapeutic agent.

[0174] 47. Method of treatment of PDAC according to any one of items 32-46, wherein the patient is undergoing a chemotherapy treatment regimen and wherein anakinra is administered continuously independent of the PDAC stage and/or identity of the chemotherapeutic agent.

[0175] 48. Method of treatment of PDAC according to any one of items 32-47, wherein the patient is undergoing a first line of chemotherapy treatment regimen.

[0176] 49. Method of treatment of PDAC according to any one of items 32-47, wherein the patient is undergoing a second or subsequent line of chemotherapy treatment regimen.

[0177] 50. Method of treatment of PDAC according to any one of items 31-49, wherein said anakinra administration is continued after said patient has completed a chemotherapy treatment regimen.

[0178] 51. Method of treatment of PDAC according to any one of items 31-32 and 34-45, wherein said patient is chemotherapy resistant.

[0179] 52. Method of treatment of PDAC according to any one of items 32-50, wherein said chemotherapy treatment regimen comprises administration of therapeutically effective dose of at least one agent selected for the group consisting of actinomycin, all-trans retinoic acid, azacytidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, nanoliposomal irinotecan, leucovorin, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, nab-paclitaxel, pemetrexed, pembrolizumab, platinum-based antineoplastic agents, teniposide, tioguanine, topotecan, valrubicin, vemurafenib, vinblastine, vincristine and vindesine,

[0180] such as the group consisting of cisplatin, fluorouracil, gemcitabine, irinotecan, nanoliposomal irinotecan, leucovorin, nab-paclitaxel, oxaliplatin, pembrolizumab;

[0181] such as the group consisting of leucovorin, gemcitabine, nab-paclitaxel, cisplatin, fluorouracil, oxaliplatin and irinotecan;

[0182] such as the group consisting of gemcitabine, nab-paclitaxel, cisplatin, fluorouracil, oxaliplatin and irinotecan.

[0183] 53. Method of treatment of PDAC according item 52, wherein said chemotherapy treatment regimen is selected from the group consisting of regimens a), b), c), d), e) and f), such as the group consisting of regimens a) and b),

[0184] wherein

[0185] regimen a) is administration of leucovorin, fluorouracil, irinotecan and oxaplatin;

[0186] regimen b) is administration of gemcitabine and nab-paclitaxel;

[0187] regimen c) is administration of pembrolizumab;

[0188] regimen d) is administration of fluorouracil and oxaplatin;

[0189] regimen e) is administration of fluorouracil and irinotecan; and

[0190] regimen f) is administration of fluorouracil and nanoliposomal irinotecan.

[0191] 54. Method of treatment of PDAC according item 52 or 53, wherein said regimen comprises administration of gemcitabine or nab-paclitaxel.

[0192] 55. Method of treatment of PDAC according to any one of items 52-54, wherein said regimen comprises administration of gemcitabine and nab-paclitaxel.

[0193] 56. Method of treatment of PDAC according to item 55, wherein said administration of gemcitabine and nab-paclitaxel is on days 1, 8 and 15 of each 28-day cycle.

[0194] 57. Method of treatment of PDAC according to item 56, wherein said administration is intravenous administration of approximately 1000 mg/m.sup.2gemcitabine and approximately 125 mg/m.sup.2 nab-paclitaxel.

[0195] 58. Method of treatment of PDAC according item 52 or 53, wherein said regimen comprises administration of leucovorin, fluorouracil, irinotecan or oxaplatin.

[0196] 59. Method of treatment of PDAC according any one of items 52, 53 or 58, wherein said regimen comprises administration of leucovorin, fluorouracil, irinotecan and oxaplatin.

[0197] 60. Method of treatment of PDAC according to any one of items 31-59, wherein said PDAC is stage IV PDAC.

[0198] 61. Use of anakinra for the manufacture of a medicament for the treatment of PDAC, wherein said treatment comprises administration of a daily dose of at least approximately 200 mg, such as approximately 200 mg, of anakinra to a patient in need thereof, such as wherein said treatment comprises administration of two doses per day of approximately at least 100 mg anakinra each, such as approximately 100 mg each, such as 100 mg each, to a patient in need thereof.

[0199] 62. The use of anakinra for the manufacture of a medicament for the treatment of PDAC according to item 61, wherein said patient is undergoing a chemotherapy treatment regimen, such as a chemotherapy treatment regimen as defined in any one of items 22-29.

[0200] 63. The use of anakinra for the manufacture of a medicament for the treatment of PDAC according to item 61 or 62, wherein said PDAC is stage IV PDAC.

[0201] 64. A pharmaceutical composition comprising anakinra for use according to any one of items 1-30 and at least one pharmaceutically acceptable excipient, diluent and/or carrier.

[0202] 65. The pharmaceutical composition comprising anakinra for use according to item 64, wherein said use is an add-on therapy to a PDAC treatment regimen, such as a chemotherapy treatment regimen.