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Colorectal CancerPhase 2G-LUCASNCT01523639

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

A Phase 2 study of Colorectal Cancer and Steatohepatitis, run by Austrian Breast & Colorectal Cancer Study Group at 7 sites in Austria.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Colorectal Cancer, Steatohepatitis
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
8 participants
Where
7 sitesAustria
Study dates
Apr 2012to Apr 2014
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 10Show fewer
  • 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

Who cannot join

  • 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
Show all 18Show fewer
  • 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
  • Inadequate contraception (male or female patients) if of childbearing or procreative potential
  • Known drug abuse/ alcohol abuse
  • Legal incapacity or limited contractual capacity Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

Austria7 sites

  • Medical University Graz, Oncology

    Graz, Styria, 8036

  • Medical University Innsbruck, Internal Medicine

    Innsbruck, Tyrol, 6020

  • Hospital BHS Ried

    Ried, Upper Austria, 4910

  • KH BHB Vienna

    Vienna, 1021

  • Med. Univ. Vienna, General Hospital Vienna

    Vienna, 1090

  • KH St. Josef KH

    Vienna, 1130

  • Hospital St. Vinzenz

    Zams, Tyrol, 6511

Other trials in Austria

About this study

Official title: A Randomized, Placebo-controlled, Double-blind Multicenter Phase II Study to Investigate the Protectivity and Efficacy of Metformin Against Steatosis in Combination With FOLFIRI and Cetuximab in Subjects With First-line Palliative Treated, KRAS-Wild-Type, Metastatic Colorectal Cancer

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.

Read the detailed description

This multicenter randomized, placebo-controlled phase II study will enroll 132 first-line palliative treated subjects with metastatic KRAS wild type CRC.

Wild-type KRAS is required for study entry. Further target-related parameters, based on current scientific knowledge may be assessed.

Subjects are randomized to Arm A or Arm B Arm A: FOLFIRI in combination with cetuximab and metformin Arm B: FOLFIRI in combination with cetuximab and placebo

A liver biopsy of hepatic metastasis and normal liver tissue is planned before the first cycle and at the end of treatment; with regard to the primary study objective, these subjects are evaluable.

Both efficacy and safety data will be collected. The investigators will assess response to treatment every 8 weeks based on imaging.

Following permanent treatment cessation, subjects will be followed-up for survival.

One interim analysis for futility (54 evaluable patients) and in addition two safety analysis for evaluation of reported adverse events between the two treatment groups will be performed at two different timepoints (20 evaluable patients/54 evaluable patients).

Being tested
Metformin/Placebo
Keywords
liver injury, steatosis, KRAS-Wild-Type, metastatic colorectal cancer, metformin, placebo, chemotherapy
Medical subject headings
Colorectal Neoplasms, Fatty Liver

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Metformin/PlaceboDrug

    Also called Glucophage

    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

Study groups in NCT01523639
Study groupRoleWhat they receive
MetforminActive comparatorFOLFIRI + cetuximab + metformin every 2 weeks for 12 cycles
Receives: Drug: Metformin/Placebo
PlaceboPlacebo comparatorFOLFIRI + cetuximab + placebo every 2 weeks for 12 cycles
Receives: Drug: Metformin/Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Reduction in the chemotherapy-associated steatosis

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

    Measured: up to 24 weeks

Secondary outcomes (6)

  1. Progression Free Survival

    PFS will be evaluated after final study visits. Subjects who terminate the study before their scheduled final study visits will be censored.

    Measured: up to 30 months

  2. Overall Survival

    OS will be evaluated after final study visits. Subjects who terminate the study before their scheduled final study visits will be censored.

    Measured: up to 30 months

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

    All subjects who received at least one dose of IMP. Additional safety analyses of reported AEs will be performed after the evaluation of 20 and 54 patients (between the 2 treatment groups) at the time of interim analysis.

    Measured: up to 24 weeks

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

    All subjects who received at least one dose of IMP. Additional safety analyses of reported AEs will be performed after the evaluation of 20 and 54 patients (between the 2 treatment groups) at the time of interim analysis.

    Measured: up to 30 months

  5. Objective response rate (CR/PR)

    Objective response rate (CR/PR), as assessed by RECIST criteria, version 1.1

    Measured: up to 24 weeks

  6. Reduction in chemo-therapy associated steatohepatitis (CASH)

    Reduction in chemo-therapy associated steatohepatitis (CASH) as assessed by NAS

    Measured: up to 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Feb 2012 (estimated)
  2. Study startApr 2012
  3. Primary completionNov 2013
  4. Study completionApr 2014

Why it stopped: Prematurely due to slow recruitment (07/08/2013). Newly defined study end=LPLV=05/11/2013. ABCSG guaranteed completed treatment period for ethical reasons.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
8 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01523639
Sponsor's protocol ID
G-LUCAS
Other IDs
200084-610, 2011-001010-34
Acronym
G-LUCAS
Status last verified
Dec 2018
First submitted
26 Jan 2012
Last updated
19 Dec 2018
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 7840516

  • 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.

    PubMed 11006366

  • 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.

    PubMed 12663719

  • 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.

    PubMed 10744089

  • 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.

    PubMed 10623704

  • 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.

    PubMed 15175435

  • 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.

    PubMed 19339720

  • 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.

    PubMed 15570210

  • 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.

    PubMed 12049538

  • 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.

    PubMed 15570209

  • 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.

    PubMed 14998849

  • 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.

    PubMed 15922194

  • 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.

    PubMed 11928077

  • 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.

    PubMed 17315288

  • 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.

    PubMed 8246027

Questions about this trial

What is this clinical trial studying?

A Phase 2 study of Colorectal Cancer and Steatohepatitis, run by Austrian Breast & Colorectal Cancer Study Group at 7 sites in Austria.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 19 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Prematurely due to slow recruitment (07/08/2013). Newly defined study end=LPLV=05/11/2013. ABCSG guaranteed completed treatment period for ethical reasons.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Reduction in the chemotherapy-associated steatosis (time frame: up to 24 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01523639, which also lists 36 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2018.

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G-LUCAS Clinical Trial NCT01523639 | AzTrials