Clinical trial NCT05132244: Monitoring and Managing Glucose Levels in People With Pancreatic Cancer
Official title: Pancreatic Cancer Glucose Assessment and Regulation Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Pancreatic Cancer
PDAC - Pancreatic Ductal Adenocarcinoma
Hyperglycemia
Keywords: FOLFIRINOX
Continuous Glucose Monitor
Feasibility
Glycemic management
Endocrinologist
Intensive glucose intervention
Pilot
Glucose control
Lead sponsor: British Columbia Cancer Agency
Sponsor class: OTHER
Collaborators: name: University of British Columbia
First posted: 2021-11-24
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will investigate whether or not it is feasible to closely monitor and manage glucose levels in people with pancreatic cancer. It will also investigate what impact glucose management may have on pancreatic cancer.

This is a pilot study that will use continuous glucose monitors (CGM) to monitor glucose levels in approximately 50 participants with pancreatic cancer. Participants will receive standard chemotherapy with a combination of up to four drugs to treat their pancreatic cancer: oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin (FOLFIRINOX). To treat high glucose levels, participants will be randomly assigned to one of two groups: Group 1 will receive anti-hyperglycemic treatment as guided by an endocrinologist with the aim of maintaining glucose levels between 4 and 10 mmol/L; Group 2 will receive anti-hyperglycemic treatment if their glucose levels are above 15 mmol/L, which is standard care. Participants in both Groups 1 and 2 will receive standard anti-hyperglycemic treatments: metformin, insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose co-transporter (SGLT2) inhibitors, and dipeptidyl peptidase 4 (DPP-4) inhibitors.

After 4 cycles of FOLFIRINOX, the CGM will be removed but any anti-hyperglycemic treatments will continue as needed. If participants discontinue treatment with FOLFIRINOX, they will continue to be followed for survival and subsequent anti-cancer therapy and will continue follow-up for glucose-related concerns at the discretion of their endocrinologist and/or medical oncologist.


Eligibility criteria: Inclusion Criteria:

* Histological/cytological diagnosis of pancreatic ductal adenocarcinoma (PDAC).
* Planned to undergo first-line systemic therapy with FOLFIRINOX.
* Age greater than or equal to 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* Adequate bone marrow and organ function as defined by the following laboratory values:

  1. Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9/L.
  2. Platelet count greater than or equal to 75 x 10\^9/L.
  3. Hemoglobin greater than or equal to 9.0 g/dL.
  4. Estimated glomerular filtration rate (GFR) by Cockroft-Gault equation OR 24 hour urine collection greater than or equal to 40 ml/min.
  5. Creatinine clearance greater than or equal to 40 mL/min using Cockcroft-Gault formula.
  6. Potassium within normal limits, or corrected with supplements.
  7. International normalized ratio (INR) less than or equal to 1.5.
  8. Total serum bilirubin less than or equal to 2 x upper limit of normal (ULN) (any elevated bilirubin should be asymptomatic at enrollment) except for participants with documented Gilbert's syndrome who may only be included if the total bilirubin less than or equal to 3 x ULN or direct bilirubin less than or equal to 1.5 x ULN).
  9. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 x ULN (or less than or equal to 5 x ULN if liver metastases are present).
* Able to understand and voluntarily sign the informed consent form.
* Able to comply with the study visit schedule and other protocol requirements.
* Able to swallow oral medications and has no contraindications to subcutaneous insulin injections.
* Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 at baseline.
* Life expectancy of more than 90 days as judged by the study doctor.

Exclusion Criteria:

* Absence of distant or lymph node metastases. Participants with borderline resectable or locally advanced PDAC are not eligible.
* Received prior systemic therapy (chemotherapy or any other anti-cancer agent) for treatment of metastatic PDAC. Participants who received adjuvant chemotherapy after surgical resection of early stage disease are eligible.
* Currently receiving anti-cancer therapy (chemotherapy or any other anti-cancer agent).
* Not fit for combination chemotherapy as judged by the study doctor.
* Presence of brain metastases.
* Known diagnosis of type I diabetes where strict glucose control and close Endocrinology follow-up is already indicated.
* Known diagnosis of type II diabetes and already followed by Endocrinologist.
* Female participants with a positive pregnancy test.
* Participants who are not safe to include in the study as judged by the study doctor for any medical or non-medical reason.
* Unable to comply with study assessments and follow-up.

Primary outcomes:
measure: Frequency of glucose levels maintained within range in Arm 1 compared to Arm 2
timeFrame: From the Cycle 4 FOLFIRINOX treatment date to the Cycle 5 FOLFIRINOX treatment date (each cycle is typically 14 days).
Secondary outcomes:
measure: Overall response rate (ORR) in each study arm, as defined by RECIST 1.1
timeFrame: From the date of the screening scan (within 28 days of first dose) until the date of confirmed progression, withdrawal, date of death, or end of study, whichever comes first, assessed up to 43 months.
measure: Progression-free survival (PFS) in each study arm from the initiation of FOLFIRINOX
timeFrame: From the date of first dose of FOLFIRINOX until the date of confirmed progression, withdrawal, date of death, or end of study, whichever comes first, assessed up to 43 months.
measure: Overall survival (OS) in each study arm from the initiation of FOLFIRINOX
timeFrame: From the date of first dose of FOLFIRINOX until the date of death or end of study, whichever comes first, assessed up to 43 months.
Other outcomes:
measure: Overall response rate (ORR) in each study arm, as defined by RECIST 1.1 and stratified by prognostic and metabolic gene expression subtypes of PDAC
timeFrame: From the date of the screening scan (within 28 days of first dose) until the date of confirmed progression, withdrawal, date of death, or end of study, whichever comes first, assessed up to 43 months.
measure: Progression-free survival (PFS) in each study arm stratified by prognostic and metabolic gene expression subtypes of PDAC from the initiation of FOLFIRINOX
timeFrame: From the date of first dose of FOLFIRINOX until the date of confirmed progression, withdrawal, date of death, or end of study, whichever comes first, assessed up to 43 months.
measure: Overall survival (OS) in each study arm stratified by prognostic and metabolic gene expression subtypes of PDAC from the initiation of FOLFIRINOX
timeFrame: From the date of first dose of FOLFIRINOX until the date of death or end of study, whichever comes first, assessed up to 43 months.
measure: Overall response rate (ORR) in each study arm, as defined by RECIST 1.1 and stratified by clinical features (i.e. type 2 diabetes), pathological profiles, and genomic profiles
timeFrame: From the date of the screening scan (within 28 days of first dose) until the date of confirmed progression, withdrawal, date of death, or end of study, whichever comes first, assessed up to 43 months.
measure: Progression-free survival (PFS) in each study arm stratified by clinical features (i.e. type 2 diabetes), pathological profiles, and genomic profiles from the initiation of FOLFIRINOX
timeFrame: From the date of first dose of FOLFIRINOX until the date of confirmed progression, withdrawal, date of death, or end of study, whichever comes first, assessed up to 43 months.
measure: Overall survival (OS) in each study arm stratified by clinical features (i.e. type 2 diabetes), pathological profiles, and genomic profiles from the initiation of FOLFIRINOX
timeFrame: From the date of first dose of FOLFIRINOX until the date of death or end of study, whichever comes first, assessed up to 43 months.
measure: Amount of insulin, measured in molar, for participants in each study arm from screening until the end of study visit
timeFrame: From the date of screening blood sample collection until the date of the end of study blood sample collection (an average of 6 months).
measure: Amount of proinsulin, measured in molar, for participants in each study arm from screening until the end of study visit
timeFrame: From the date of the screening blood sample collection until the date of the end of study blood sample collection (an average of 6 months).
measure: Amount of C-peptide, measured in molar, for participants in each study arm from screening until the end of study visit
timeFrame: From the date of the screening blood sample collection until the date of the end of study blood sample collection (an average of 6 months).
measure: Amount of circulating biomarkers, measured in molar, for participants in each study arm from screening until the end of study visit
timeFrame: From the date of the screening blood sample collection until the date of the end of study blood sample collection (an average of 6 months).
Locations:
city: Vancouver
country: Canada
facility: British Columbia Cancer
state: British Columbia
Study officials:
affiliation: BC Cancer
name: Daniel Renouf, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Becker S, Dossus L, Kaaks R. Obesity related hyperinsulinaemia and hyperglycaemia and cancer development. Arch Physiol Biochem. 2009 May;115(2):86-96. doi: 10.1080/13813450902878054.
citation: Dawson DW, Hertzer K, Moro A, Donald G, Chang HH, Go VL, Pandol SJ, Lugea A, Gukovskaya AS, Li G, Hines OJ, Rozengurt E, Eibl G. High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. Cancer Prev Res (Phila). 2013 Oct;6(10):1064-73. doi: 10.1158/1940-6207.CAPR-13-0065. Epub 2013 Aug 13.
citation: Harris D, Barts A, Connors J, Dahl M, Elliott T, Kong J, Keane T, Thompson D, Stafford S, Ur E, Sirrs S. Glucocorticoid-induced hyperglycemia is prevalent and unpredictable for patients undergoing cancer therapy: an observational cohort study. Curr Oncol. 2013 Dec;20(6):e532-8. doi: 10.3747/co.20.1499.
citation: Hart AR, Kennedy H, Harvey I. Pancreatic cancer: a review of the evidence on causation. Clin Gastroenterol Hepatol. 2008 Mar;6(3):275-82. doi: 10.1016/j.cgh.2007.12.041.
citation: Hassan MM, Bondy ML, Wolff RA, Abbruzzese JL, Vauthey JN, Pisters PW, Evans DB, Khan R, Chou TH, Lenzi R, Jiao L, Li D. Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol. 2007 Dec;102(12):2696-707. doi: 10.1111/j.1572-0241.2007.01510.x. Epub 2007 Aug 31.
citation: Hjartaker A, Langseth H, Weiderpass E. Obesity and diabetes epidemics: cancer repercussions. Adv Exp Med Biol. 2008;630:72-93. doi: 10.1007/978-0-387-78818-0_6.
citation: Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer. 2005 Jun 6;92(11):2076-83. doi: 10.1038/sj.bjc.6602619.
citation: Karasinska JM, Topham JT, Kalloger SE, Jang GH, Denroche RE, Culibrk L, Williamson LM, Wong HL, Lee MKC, O'Kane GM, Moore RA, Mungall AJ, Moore MJ, Warren C, Metcalfe A, Notta F, Knox JJ, Gallinger S, Laskin J, Marra MA, Jones SJM, Renouf DJ, Schaeffer DF. Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer. Clin Cancer Res. 2020 Jan 1;26(1):135-146. doi: 10.1158/1078-0432.CCR-19-1543. Epub 2019 Sep 3.
citation: Kawada K, Toda K, Sakai Y. Targeting metabolic reprogramming in KRAS-driven cancers. Int J Clin Oncol. 2017 Aug;22(4):651-659. doi: 10.1007/s10147-017-1156-4. Epub 2017 Jun 24.
citation: Kenner BJ, Chari ST, Maitra A, Srivastava S, Cleeter DF, Go VL, Rothschild LJ, Goldberg AE. Early Detection of Pancreatic Cancer-a Defined Future Using Lessons From Other Cancers: A White Paper. Pancreas. 2016 Sep;45(8):1073-9. doi: 10.1097/MPA.0000000000000701.
citation: Kleeff J, Costello E, Jackson R, Halloran C, Greenhalf W, Ghaneh P, Lamb RF, Lerch MM, Mayerle J, Palmer D, Cox T, Rawcliffe CL, Strobel O, Buchler MW, Neoptolemos JP. The impact of diabetes mellitus on survival following resection and adjuvant chemotherapy for pancreatic cancer. Br J Cancer. 2016 Sep 27;115(7):887-94. doi: 10.1038/bjc.2016.277. Epub 2016 Sep 1.
citation: Koorstra JB, Hustinx SR, Offerhaus GJ, Maitra A. Pancreatic carcinogenesis. Pancreatology. 2008;8(2):110-25. doi: 10.1159/000123838. Epub 2008 Apr 1.
citation: Kopp JL, von Figura G, Mayes E, Liu FF, Dubois CL, Morris JP 4th, Pan FC, Akiyama H, Wright CV, Jensen K, Hebrok M, Sander M. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell. 2012 Dec 11;22(6):737-50. doi: 10.1016/j.ccr.2012.10.025. Epub 2012 Nov 29.
citation: Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K; International Agency for Research on Cancer Handbook Working Group. Body Fatness and Cancer--Viewpoint of the IARC Working Group. N Engl J Med. 2016 Aug 25;375(8):794-8. doi: 10.1056/NEJMsr1606602. No abstract available.
citation: Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004 Mar 27;363(9414):1049-57. doi: 10.1016/S0140-6736(04)15841-8.
citation: McCarty MF. Insulin secretion as a determinant of pancreatic cancer risk. Med Hypotheses. 2001 Aug;57(2):146-50. doi: 10.1054/mehy.2001.1316.
citation: Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology. 2008 Apr;134(4):981-7. doi: 10.1053/j.gastro.2008.01.039. Epub 2008 Jan 18.
citation: Pleasance E, Titmuss E, Williamson L, Kwan H, Culibrk L, Zhao EY, Dixon K, Fan K, Bowlby R, Jones MR, Shen Y, Grewal JK, Ashkani J, Wee K, Grisdale CJ, Thibodeau ML, Bozoky Z, Pearson H, Majounie E, Vira T, Shenwai R, Mungall KL, Chuah E, Davies A, Warren M, Reisle C, Bonakdar M, Taylor GA, Csizmok V, Chan SK, Zong Z, Bilobram S, Muhammadzadeh A, D'Souza D, Corbett RD, MacMillan D, Carreira M, Choo C, Bleile D, Sadeghi S, Zhang W, Wong T, Cheng D, Brown SD, Holt RA, Moore RA, Mungall AJ, Zhao Y, Nelson J, Fok A, Ma Y, Lee MKC, Lavoie JM, Mendis S, Karasinska JM, Deol B, Fisic A, Schaeffer DF, Yip S, Schrader K, Regier DA, Weymann D, Chia S, Gelmon K, Tinker A, Sun S, Lim H, Renouf DJ, Laskin J, Jones SJM, Marra MA. Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes. Nat Cancer. 2020 Apr;1(4):452-468. doi: 10.1038/s43018-020-0050-6. Epub 2020 Apr 13.
citation: Polonsky KS. Dynamics of insulin secretion in obesity and diabetes. Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S29-31. doi: 10.1038/sj.ijo.0801273.
citation: Sharma A, Chari ST. Pancreatic Cancer and Diabetes Mellitus. Curr Treat Options Gastroenterol. 2018 Dec;16(4):466-478. doi: 10.1007/s11938-018-0197-8.
citation: Sharma A, Smyrk TC, Levy MJ, Topazian MA, Chari ST. Fasting Blood Glucose Levels Provide Estimate of Duration and Progression of Pancreatic Cancer Before Diagnosis. Gastroenterology. 2018 Aug;155(2):490-500.e2. doi: 10.1053/j.gastro.2018.04.025. Epub 2018 Apr 30.
citation: Shlomai G, Neel B, LeRoith D, Gallagher EJ. Type 2 Diabetes Mellitus and Cancer: The Role of Pharmacotherapy. J Clin Oncol. 2016 Dec 10;34(35):4261-4269. doi: 10.1200/JCO.2016.67.4044. Epub 2016 Nov 7.
citation: Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12.
citation: Templeman NM, Flibotte S, Chik JHL, Sinha S, Lim GE, Foster LJ, Nislow C, Johnson JD. Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan. Cell Rep. 2017 Jul 11;20(2):451-463. doi: 10.1016/j.celrep.2017.06.048.
citation: Tsujimoto T, Kajio H, Sugiyama T. Association between hyperinsulinemia and increased risk of cancer death in nonobese and obese people: A population-based observational study. Int J Cancer. 2017 Jul 1;141(1):102-111. doi: 10.1002/ijc.30729. Epub 2017 Apr 22.
citation: Wang F, Qi XM, Wertz R, Mortensen M, Hagen C, Evans J, Sheinin Y, James M, Liu P, Tsai S, Thomas J, Mackinnon A, Dwinell M, Myers CR, Bartrons Bach R, Fu L, Chen G. p38gamma MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis. Cancer Res. 2020 Aug 15;80(16):3251-3264. doi: 10.1158/0008-5472.CAN-19-3281. Epub 2020 Jun 24.
citation: Wang M, Li J, Lim GE, Johnson JD. Is dynamic autocrine insulin signaling possible? A mathematical model predicts picomolar concentrations of extracellular monomeric insulin within human pancreatic islets. PLoS One. 2013 Jun 14;8(6):e64860. doi: 10.1371/journal.pone.0064860. Print 2013.
citation: Yan L, Raj P, Yao W, Ying H. Glucose Metabolism in Pancreatic Cancer. Cancers (Basel). 2019 Sep 29;11(10):1460. doi: 10.3390/cancers11101460.
citation: Yuan C, Rubinson DA, Qian ZR, Wu C, Kraft P, Bao Y, Ogino S, Ng K, Clancy TE, Swanson RS, Gorman MJ, Brais LK, Li T, Stampfer MJ, Hu FB, Giovannucci EL, Kulke MH, Fuchs CS, Wolpin BM. Survival among patients with pancreatic cancer and long-standing or recent-onset diabetes mellitus. J Clin Oncol. 2015 Jan 1;33(1):29-35. doi: 10.1200/JCO.2014.57.5688. Epub 2014 Nov 17.
citation: Zhang AMY, Magrill J, de Winter TJJ, Hu X, Skovso S, Schaeffer DF, Kopp JL, Johnson JD. Endogenous Hyperinsulinemia Contributes to Pancreatic Cancer Development. Cell Metab. 2019 Sep 3;30(3):403-404. doi: 10.1016/j.cmet.2019.07.003. Epub 2019 Aug 1. No abstract available.