A Randomized, Placebo-controlled, Double-blind Phase II Study Evaluating if Glucophage Can Avoid Liver Injury Due to Chemotherapy Associated Steatosis

NCT01523639 | Terminated Phase 2 DMC

• 3 other identifiers: G-LUCAS200084-6102011-001010-34
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 7

Brief Summary

This multicenter randomized, placebo-controlled phase II study will enroll 132 first-line palliative treated subjects with metastatic KRAS wild type CRC. Subjects with histologically confirmed, KRAS wild-type CRC without previous chemo-therapy for metastatic disease will be screened for this study. Approximately 10 sites in Austria will participate in the study. Subjects will be randomized in a ratio of 1:1 into two groups.

Conditions

Colorectal Cancer; Steatohepatitis

Keywords

liver injury; steatosis; KRAS-Wild-Type; metastatic colorectal cancer; metformin; placebo; chemotherapy

Outcome Measures

Primary Outcomes (1)

• Reduction in the chemotherapy-associated steatosis

  Reduction in the chemotherapy-associated steatosis, as assessed by the steatosis subcore of NAFLD activity score (NAS)

  up to 24 weeks

Secondary Outcomes (6)

• Progression Free Survival

  up to 30 months

• Overall Survival

  up to 30 months

• Safety assessment of all randomized subjects with at least one administration of study treatment

  up to 24 weeks

• Occured Adverse Events of all randomized subjects with at least one administration of study treatment

  up to 30 months

• Objective response rate (CR/PR)

  up to 24 weeks

Study Arms (2)

Metformin

ACTIVE COMPARATOR

FOLFIRI + cetuximab + metformin every 2 weeks for 12 cycles

Drug: Metformin/Placebo

Placebo

PLACEBO COMPARATOR

FOLFIRI + cetuximab + placebo every 2 weeks for 12 cycles

Drug: Metformin/Placebo

Interventions

Metformin/Placebo DRUG

The starting dose of Metformin/Placebo is 500 mg p.o. twice daily for 7 days (daily dose 1000 mg p.o.). Dose will be increased to 1000 mg p.o. twice daily at day 8 (daily dose 2000 mg p.o.) unless no toxicity ≥ 2 due to IMP occurs. Duration of treatment: 24 weeks

Also known as: Glucophage

Metformin; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed written informed consent
• Male or female \>= 18 years of age
• Diagnosis of histologically confirmed, KRAS "wild-type" adenocarcinoma of the colon or rectum
• Non-resectable metastatic colorectal carcinoma
• Either presence of at least one liver lesion measurable unidimensionally by CT scan or MRI or at least one resectable liver metastasis with non-resectable extrahepatic disease (as assessed within 3 weeks prior to randomisation)
• Subjects scheduled to receive cetuximab and FOLFIRI
• ECOG performance status of 0 - 1 at study entry
• Leukocytes \>= 3.0 x 10\^9/L and neutrophils \>= 1.5 x 10\^9/L, platelets \>= 100 x 10\^9/L, and hemoglobin \>= 8 g/dL
• Bilirubin \<= 1.5 x ULN
• ASAT and ALAT \<= 5 x ULN

You may not qualify if:

• Brain metastasis (if suspected, brain scan indicated)
• Previous chemotherapy for the currently existing metastatic disease
• Known or newly diagnosed diabetes
• Patients with ACS within the last three months
• Stage 3 or 4 heart failure defined according to the NYHA criteria
• Uncontrolled angina
• Contraindications to metformin (renal impairment \[eGFR \<45 mL/min/1.73m\^2\], known hypersensitivity to metformin, acute illness \[dehydration, severe infection, shock, acute cardiac failure\]), and suspected tissue hypoxia
• Surgery (excl. diagnostic biopsy, central venous catheter) or irradiation within 2 weeks prior to study entry defined as given written informed consent
• Concurrent chronic systemic immune therapy, chemotherapy, or hormone therapy not indicated in the study protocol
• Administration of any investigational agent(s) within 4 weeks prior to study entry,
• Previous exposure to EGFR-pathway targeting therapy
• Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease
• Known grade 3 or 4 allergic reaction to any of the components of the treatment
• Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma in situ of the cervix. (Subjects with a previous malignancy but without evidence of disease for \>= 5 years will be allowed to enter the trial)
• Pregnancy or lactation

Sponsors & Collaborators

• Austrian Breast & Colorectal Cancer Study Group: lead
• Merck Gesellschaft mbH, Austria: collaborator

Study Sites (7)

Medical University Graz, Oncology

Graz, Styria, 8036, Austria

Location

Medical University Innsbruck, Internal Medicine

Innsbruck, Tyrol, 6020, Austria

Location

Hospital St. Vinzenz

Zams, Tyrol, 6511, Austria

Location

Hospital BHS Ried

Ried, Upper Austria, 4910, Austria

Location

KH BHB Vienna

Vienna, 1021, Austria

Location

Med. Univ. Vienna, General Hospital Vienna

Vienna, 1090, Austria

Location

KH St. Josef KH

Vienna, 1130, Austria

Location

Related Publications (36)

• Colucci G, Maiello E, Leo S, Giuliani F, Pedicini A, Pezzella G, Valori V, Galetta D, Contillo A, Prete F. Biochemical modulation of fluorouracil with high dose methotrexate or folinic acid in advanced colorectal cancer patients. Gruppo Oncologico dell' Italia Meridionale (GOIM). Anticancer Res. 1994 Sep-Oct;14(5B):2157-62.

  PMID: 7840516 BACKGROUND

• Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000 Sep 28;343(13):905-14. doi: 10.1056/NEJM200009283431302.

  PMID: 11006366 BACKGROUND

• Scheithauer W, Kornek GV, Raderer M, Schull B, Schmid K, Kovats E, Schneeweiss B, Lang F, Lenauer A, Depisch D. Randomized multicenter phase II trial of two different schedules of capecitabine plus oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2003 Apr 1;21(7):1307-12. doi: 10.1200/JCO.2003.09.016.

  PMID: 12663719 BACKGROUND

• Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, Jandik P, Iveson T, Carmichael J, Alakl M, Gruia G, Awad L, Rougier P. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000 Mar 25;355(9209):1041-7. doi: 10.1016/s0140-6736(00)02034-1.

  PMID: 10744089 BACKGROUND

• Giacchetti S, Perpoint B, Zidani R, Le Bail N, Faggiuolo R, Focan C, Chollet P, Llory JF, Letourneau Y, Coudert B, Bertheaut-Cvitkovic F, Larregain-Fournier D, Le Rol A, Walter S, Adam R, Misset JL, Levi F. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2000 Jan;18(1):136-47. doi: 10.1200/JCO.2000.18.1.136.

  PMID: 10623704 BACKGROUND

• Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.

  PMID: 15175435 BACKGROUND

• Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408-17. doi: 10.1056/NEJMoa0805019.

  PMID: 19339720 BACKGROUND

• Adam R, Pascal G, Castaing D, Azoulay D, Delvart V, Paule B, Levi F, Bismuth H. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases? Ann Surg. 2004 Dec;240(6):1052-61; discussion 1061-4. doi: 10.1097/01.sla.0000145964.08365.01.

  PMID: 15570210 BACKGROUND

• Abdalla EK, Barnett CC, Doherty D, Curley SA, Vauthey JN. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg. 2002 Jun;137(6):675-80; discussion 680-1. doi: 10.1001/archsurg.137.6.675.

  PMID: 12049538 BACKGROUND

• Jaeck D, Oussoultzoglou E, Rosso E, Greget M, Weber JC, Bachellier P. A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases. Ann Surg. 2004 Dec;240(6):1037-49; discussion 1049-51. doi: 10.1097/01.sla.0000145965.86383.89.

  PMID: 15570209 BACKGROUND

• Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, Dousset B, Morel P, Soubrane O, Chaussade S, Mentha G, Terris B. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004 Mar;15(3):460-6. doi: 10.1093/annonc/mdh095.

  PMID: 14998849 BACKGROUND

• Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg. 2005 Jun;200(6):845-53. doi: 10.1016/j.jamcollsurg.2005.01.024.

  PMID: 15922194 BACKGROUND

• DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002 Feb;22(1):27-42. doi: 10.1055/s-2002-23204.

  PMID: 11928077 BACKGROUND

• Zorzi D, Laurent A, Pawlik TM, Lauwers GY, Vauthey JN, Abdalla EK. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg. 2007 Mar;94(3):274-86. doi: 10.1002/bjs.5719.

  PMID: 17315288 BACKGROUND

• Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA. Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy. J Clin Oncol. 1993 Dec;11(12):2386-90. doi: 10.1200/JCO.1993.11.12.2386.

  PMID: 8246027 BACKGROUND

• Parikh AA, Gentner B, Wu TT, Curley SA, Ellis LM, Vauthey JN. Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg. 2003 Dec;7(8):1082-8. doi: 10.1016/j.gassur.2003.08.005.

  PMID: 14675719 BACKGROUND

• Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21. doi: 10.1002/hep.20701.

  PMID: 15915461 BACKGROUND

• Vauthey JN, Pawlik TM, Ribero D, Wu TT, Zorzi D, Hoff PM, Xiong HQ, Eng C, Lauwers GY, Mino-Kenudson M, Risio M, Muratore A, Capussotti L, Curley SA, Abdalla EK. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006 May 1;24(13):2065-72. doi: 10.1200/JCO.2005.05.3074.

  PMID: 16648507 BACKGROUND

• Masi G, Loupakis F, Pollina L, Vasile E, Cupini S, Ricci S, Brunetti IM, Ferraldeschi R, Naso G, Filipponi F, Pietrabissa A, Goletti O, Baldi G, Fornaro L, Andreuccetti M, Falcone A. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg. 2009 Mar;249(3):420-5. doi: 10.1097/SLA.0b013e31819a0486.

  PMID: 19247029 BACKGROUND

• Sasaki M, Itatsu K, Minato H, Takamura H, Ohta T, Nakanuma Y. Flare-up of nonalcoholic steatohepatitis after hepatectomy resulted in hepatic failure in a patient with type 2 diabetes mellitus. Dig Dis Sci. 2007 Dec;52(12):3473-6. doi: 10.1007/s10620-006-9662-7. Epub 2007 Apr 3. No abstract available.

  PMID: 17404845 BACKGROUND

• Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003 May;37(5):1202-19. doi: 10.1053/jhep.2003.50193.

  PMID: 12717402 BACKGROUND

• Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005 Jul;129(1):113-21. doi: 10.1053/j.gastro.2005.04.014.

  PMID: 16012941 BACKGROUND

• Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, Musso A, De Paolis P, Capussotti L, Salizzoni M, Rizzetto M. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002 Jul;123(1):134-40. doi: 10.1053/gast.2002.34168.

  PMID: 12105842 BACKGROUND

• Pessaux P, Panaro F, Casnedi S, Zeca I, Marzano E, Bachellier P, Jaeck D, Chenard MP. Targeted molecular therapies (cetuximab and bevacizumab) do not induce additional hepatotoxicity: preliminary results of a case-control study. Eur J Surg Oncol. 2010 Jun;36(6):575-82. doi: 10.1016/j.ejso.2010.04.010. Epub 2010 May 7.

  PMID: 20452168 BACKGROUND

• Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin. 1999 Jan-Feb;49(1):33-64, 1. doi: 10.3322/canjclin.49.1.33.

  PMID: 10200776 BACKGROUND

• Köhne CH, Van Cutsem E, Wils J, et al. Irinotecan improves the activity of the AIO regimen in metastatic colorectal cancer: Results of EORTC GI Group study 40986. Proc AmSocClinOncol 2003;22:Abstract 1018

  BACKGROUND

• Tournigand C, Louvet C, Quinaux E et al. FOLFIRI followed by FOLFOX followed by FOLFIRI in metastatic colorectal cancer (MCRC): final results of a phase III study. Proc Am Soc Clin Oncol 2001;20:124a (Abstract 494)

  BACKGROUND

• Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, Landi B, Colin P, Louvet C, de Gramont A. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004 Jan 15;22(2):229-37. doi: 10.1200/JCO.2004.05.113. Epub 2003 Dec 2.

  PMID: 14657227 BACKGROUND

• de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000 Aug;18(16):2938-47. doi: 10.1200/JCO.2000.18.16.2938.

  PMID: 10944126 BACKGROUND

• Eric Van Cutsem et al., Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer - the influence of KRAS and BRAF biomarkers on outcome: Updated data from the CRYSTAL trial, ASCO GI 2010, Abstract # 281

  BACKGROUND

• Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001 Oct;108(8):1167-74. doi: 10.1172/JCI13505.

  PMID: 11602624 BACKGROUND

• Lin HZ, Yang SQ, Chuckaree C, Kuhajda F, Ronnet G, Diehl AM. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med. 2000 Sep;6(9):998-1003. doi: 10.1038/79697.

  PMID: 10973319 BACKGROUND

• Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, David E, Rizzetto M, Marchesini G. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005 May;100(5):1082-90. doi: 10.1111/j.1572-0241.2005.41583.x.

  PMID: 15842582 BACKGROUND

• Uygun A, Kadayifci A, Isik AT, Ozgurtas T, Deveci S, Tuzun A, Yesilova Z, Gulsen M, Dagalp K. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2004 Mar 1;19(5):537-44. doi: 10.1111/j.1365-2036.2004.01888.x.

  PMID: 14987322 BACKGROUND

• Angelico F, Burattin M, Alessandri C, Del Ben M, Lirussi F. Drugs improving insulin resistance for non-alcoholic fatty liver disease and/or non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005166. doi: 10.1002/14651858.CD005166.pub2.

  PMID: 17253544 BACKGROUND

• Duseja A, Das A, Dhiman RK, Chawla YK, Thumburu KT, Bhadada S, Bhansali A. Metformin is effective in achieving biochemical response in patients with nonalcoholic fatty liver disease (NAFLD) not responding to lifestyle interventions. Ann Hepatol. 2007 Oct-Dec;6(4):222-6.

  PMID: 18007551 BACKGROUND

Related Links

• Click here for more information about this study: open studies

MeSH Terms

Conditions

Colorectal Neoplasms; Fatty Liver

Interventions

Metformin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Birgit Gruenberger, MD

  Austrian Breast & Colorectal Cancer Study Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2012
• First Posted: February 1, 2012
• Study Start: April 1, 2012
• Primary Completion: November 1, 2013
• Study Completion: April 1, 2014
• Last Updated: December 19, 2018

Record last verified: 2018-12

Locations

AU (7)