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Advanced Hepatocellular CarcinomaPhase 2/3SS-HCCNCT00495846

GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma

A Phase 2/3 study testing Octreotide-LAR, Lanreotide Autogel and Locoregional treatments in people with Advanced Hepatocellular Carcinoma, run by Federico II University at 1 site in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The hepatocellular carcinoma (HCC) represents more than 5% of all human malignancies, with more than 500,000 deaths per year (1). In Campania region, mortality for HCC is 2 times higher than in the rest of Italy because of a higher locally prevalence of hepatitis-C virus infection. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Advanced Hepatocellular Carcinoma
What is being tested?
Octreotide-LAR, Lanreotide Autogel and Locoregional treatments
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
25 participants
Where
1 siteItaly
Study dates
Apr 2007to Dec 2008
Phase
Phase 2/3
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 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with cirrhosis without HCC in all liver function classes already receiving specific therapy for cirrhosis who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study
  • Patients with cirrhosis with multifocal HCC and clinical and/or radiological signs of persistence or recurrence of HCC in presence or absence of thrombosis of the portal vein, with a single nodule of > 6 cm in size or multiple nodules of > 3 cm in size who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study

Who cannot join

  • Age < 18 yrs or > 75 yrs
  • Pregnancy or lactation
  • Intolerance to somatostatin analogues
  • Treatment protocol:
  • In all patients fulfilling the inclusion criteria, treatment will begin with octreotide-LAR at a dose of 30 mg every 28 days or lanreotide autogel 120 mg every 28 days for 3 months.
  • After 28, 56 and 74 days (immediately before the next injection) all patients will be admitted to the Day Hospital of the IX Division of Internal Medicine of the D. Cotugno Hospital for the clinical examination, blood chemistry, blood sampling for the IGF axis analysis, and abdominal ultrasound. After 74 days, abdominal CT or MRI will also be performed.
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  • Then, in all survivors the interval between injection will be reduced to 21 days and follow up for the next 3 months will be done as stated before the day immediately preceding the injection.
  • Then, in the subsequent follow-up the interval between injection will be reduced to 14 days and all procedures will be repeated at monthly intervals.
  • All the patients fulfilling the inclusion criteria but refusing to participate to the study will be followed with the same methodology of those receiving the somatostatin analogues treatment.

Trial locations and contacts

1 site in 1 country.

Italy1 site

  • D. Cotugno Hospital

    Naples, 80131

Other trials in Italy

About this study

Official title: Treatment of Advanced Hepatocellular Carcinoma With Depot Somatostatin Analogues: a Pilot Prospective Study Based on Somatostatin Receptors Tumors Expression

The hepatocellular carcinoma (HCC) represents more than 5% of all human malignancies, with more than 500,000 deaths per year (1). In Campania region, mortality for HCC is 2 times higher than in the rest of Italy because of a higher locally prevalence of hepatitis-C virus infection.

Development of HCC in liver cirrhosis is associated with increased DNA synthesis and regeneration of hepatocytes (2). Hepatocyte growth factor, the transforming growth factor-α, the fibroblast growth factor are well studied (3,4) while the insulin-like growth factor system (IGF-I, IGF-II and their binding proteins) has been less investigated. IGF-I and IGF-II modulate growth, metabolism and cell differentiation and have specific receptors in the liver (5). IGF-I levels in the upper normal range have been associated with an increased risk to develop prostate cancer (6), breast cancer (7) and colon cancer (8). Some data report increased expression of IGF-II in HCC (9,10) and others suggest a role of increased IGF-I bioavailability in HCC (11). We reported increased IGF-I/IGFBP-3 ratio in patients with HCC compared with those with cirrhosis with a similar liver function, so suggesting increased IGF-I bioavailability in HCC (12).

Read more

There is no currently medical treatment for patients with advanced HCC which has a very poor prognosis (survival <6 months). Because of limited liver function, classical chemotherapy cannot be applied (13). In patients with HCC without cirrhosis, surgery is possible only in 5% while in those with cirrhosis first-line treatment is still questioned as survival is <50% three years after operation. Patients suitable for local resection of HCC are only those with Child-Pugh's "hyper A" liver function class, who are a minority (14-16). Percutaneous resection treatments may treat approximately 70%-90% of tumors with maximal diameters of <3 cm (15,17-19).

Somatostatin analogues are indicated in patients with neuroendocrine tumors expressing somatostatin receptors type 2 and 5 and has excellent safety profile. In advanced HCC, some studies demonstrated beneficial effects (20,21) while some others did not (22,23).

Only a few data are available on somatostatin receptor expression in HCC (24,25). Somatostatin analogues have also a clear-cut inhibitory effect on circulating IGF-I levels with a potential additional effect in delaying HCC progression.

Read the detailed description

Study objectives

  1. To evaluate relationships between GH/IGF-I and IGF-II axis and development and progression of HCC;
  2. To evaluate the expression of somatostatin receptor expression in biopsies of HCC by quantitative RT-PCR and immunohistochemistry and in vivo by octreoscan;
  3. To evaluate the efficacy of octreotide-LAR or lanreotide-autogel as compared to placebo on clinical symptoms, liver function, biological markers and tumor dimensions by ultrasonography in advanced HCC patients;
  4. To correlate the response to somatostatin analogues to somatostatin receptor expression in vitro and in vivo and suppression of the IGF-I and -II axis.

Study design

This is a pilot, open, prospective, monocentric study addressed to:

  1. patients with liver cirrhosis and multifocal HCC with or without portal vein invasion;
  2. patients with liver cirrhosis and single HCC nodule of >6 cm in size with or without portal vein invasion [principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)];
  3. patients with liver cirrhosis and more than 3 HCC nodules of > 3 cm in size with or without portal vein invasion [principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)];
  4. patients with cirrhosis without HCC.

Study protocol All enrolled subjects will be subjects to a baseline evaluation and a post-treatment evaluation according with the treatment protocol (see below).

  1. Clinical study in vivo diagnostic routine analysis (clinical evaluation, ECG, chest X-ray, blood chemistry, analysis of liver function, α-FP assay, CEA, liver ultrasonography and angio-ultrasonography, abdominal CT scan or MRI); blood sampling for GH, IGF-I, IGF-II, IGFBP-3, ALS, insulin, IGFBP-1 and IGFBP-2; whole body scintigraphy with radiolabeled octreotide (octreoscan) liver biopsy in patients in good clinical condition according with good clinical practice procedures. Biopsy will be performed under ultrasonography guidance with a 19G or 21G needle after local subcutaneous anesthesia (lidocaine 2%). Abdominal ultrasonography will followed biopsy to exclude hemorrage. The tissue sample will be stores at -80° until analysis.
  2. Morphological in vitro study the expression of somatostatin receptors will be performed by immunohistochemistry in sequential sections as well as by RT-PCR using specific primers for all receptors; the study includes an analysis of classical histology and immunohistochemical markers. The study includes positive and negative controls for an appropriate analysis of the results.

Study duration

The first study is a pilot study which expected number of patients fulfilling the inclusion criteria is 15 to address the issue of liver cirrhosis with HCC. The enrollment period will be of 12 months or shorter if the 15 patients are enrolled in a shorter time. The observational period is expected to be 3-12 months, according with previous studies. Treatment will be continued in all survivors even if the study will end after 12 months, according with previous studies. Subsequently, the study will proceed with a placebo-controlled randomized study according with the results obtained in the pilot study and will enroll 30-60 in case of patients with HCC without cirrhosis and 20-40 for patients with liver cirrhosis and HCC. All patients will be registered in dedicated CRF and data will be collected by investigators not involved in data analysis.

Withdrawal from the study

The causes of early study withdrawal will be recorded according with:

  1. adverse events;
  2. no treatment response or patients' clinical condition deterioration according with the investigator judgment;
  3. major protocol violation;
  4. patient's withdrawal of the consent.

Concomitant therapies All patients will continue all treatments as per investigator judgment. In case some therapy will be withdrawn this will be recorded in the CRF and analyzed as a potential beneficial effect of somatostatin analogues therapy.

Main outcome measures A) Efficacy parameters

For cirrhosis:

Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

For HCC:

Prolongation of the survival curve (>6 months) Stabilization or reduction of tumor size Reduction or disappearance of portal vein thrombosis Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

Expected results

The expected results are:

  1. Both cirrhotic and normal liver express somatostatin receptors. The different receptor pattern can suggest a role of this receptor subtype in HCC development. The correlation study can also give insight into any role of somatostatin receptors in differentiation, staging and prognosis of HCC.
  2. Treatment with somatostatin analogues will prolong survival in advanced HCC patients. This should occur according with liver function before starting the treatment. We expect that patients having tumors with high expression of SS-2 receptors on their HCC will have the longest survival.
Being tested
Octreotide-LAR, Lanreotide Autogel, Locoregional treatments
Keywords
Hepatocellular carcinoma, Somatostatin analogues, Somatostatin receptors, Octreotide, Lanreotide, IGF-I, IGF-II
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

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

  • Octreotide-LAR, Lanreotide AutogelDrug

    Also called Sandostatin-LAR, Ipstyl 120 mg, Somatuline Depot

    Octreotide-LAR intramuscular, dose of 30 mg every 28 days to increase up to 60 mg; lanreotide autogel 120 mg deep subcutaneous every 28 days for 3 months then uptitrated according with the protocol.

  • Locoregional treatmentsOther

Study groups in NCT00495846
Study groupRoleWhat they receive
AExperimental1. Patients with cirrhosis without HCC in all liver function classes already receiving specific therapy for cirrhosis who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study 2. Patients with cirrhosis with multifocal HCC and clinical and/or radiological signs of persistence or recurrence of HCC in presence or absence of trombosis of the portal vein, with a single nodule of >6 cm in size or multiple nodules of >3 cm in size who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study
Receives: Drug: Octreotide-LAR, Lanreotide Autogel
BOtherHistorical controls
Receives: Other: Locoregional treatments

What is being measured

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

  1. Prolongation of the survival curve (>6 months)

    Measured: 12 months

Secondary outcomes (2)

  1. Improvement of liver function, Reduction of biological markers of disease (if elevated before starting the treatment)

    Measured: 12 months

  2. Improvement of quality of life according with SF36 questionnaire

    Measured: 12 months

Timeline

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

  1. First posted3 Jul 2007 (estimated)
  2. Study startApr 2007
  3. Primary completionApr 2008
  4. Study completionDec 2008

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 2/3
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
25 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00495846
Sponsor's protocol ID
NeuroendoUnit-4
Acronym
SS-HCC
Status last verified
Aug 2009
First submitted
2 Jul 2007
Last updated
17 Aug 2009
Results posted
No
Data monitoring committee
Yes

Publications

  • Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol. 2003;38 Suppl 1:S136-49. doi: 10.1016/s0168-8278(02)00432-4. No abstract available.

    PubMed 12591191

  • Blanc P, Desprez D, Fabre JM, Pageaux G, Daures JP, Larrey D, Saint-Aubert B, Michel H, Maurel P. Contribution of primary cultures of adult human hepatocytes to the pathophysiology of hepatocellular carcinoma. J Hepatol. 1996 Nov;25(5):663-9. doi: 10.1016/s0168-8278(96)80236-4.

    PubMed 8938543

  • Burr AW, Hillan KJ, McLaughlin KE, Ferrier R, Chapman C, Mathew J, Burt AD. Hepatocyte growth factor levels in liver and serum increase during chemical hepatocarcinogenesis. Hepatology. 1996 Nov;24(5):1282-7. doi: 10.1002/hep.510240549.

    PubMed 8903411

  • Tomiya T, Fujiwara K. Serum transforming growth factor alpha level as a marker of hepatocellular carcinoma complicating cirrhosis. Cancer. 1996 Mar 15;77(6):1056-60. doi: 10.1002/(sici)1097-0142(19960315)77:63.0.co;2-f.

    PubMed 8635123

  • Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995 Feb;16(1):3-34. doi: 10.1210/edrv-16-1-3. No abstract available.

    PubMed 7758431

  • Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998 Jan 23;279(5350):563-6. doi: 10.1126/science.279.5350.563.

    PubMed 9438850

  • Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998 May 9;351(9113):1393-6. doi: 10.1016/S0140-6736(97)10384-1.

    PubMed 9593409

  • Giovannucci E, Pollak M, Platz EA, Willett WC, Stampfer MJ, Majeed N, Colditz GA, Speizer FE, Hankinson SE. Insulin-like growth factor I (IGF-I), IGF-binding protein-3 and the risk of colorectal adenoma and cancer in the Nurses' Health Study. Growth Horm IGF Res. 2000 Apr;10 Suppl A:S30-1. doi: 10.1016/s1096-6374(00)90014-5. No abstract available.

    PubMed 10984283

  • Nardone G, Romano M, Calabro A, Pedone PV, de Sio I, Persico M, Budillon G, Bruni CB, Riccio A, Zarrilli R. Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatology. 1996 Jun;23(6):1304-12. doi: 10.1002/hep.510230602.

    PubMed 8675143

  • Yang D, Faris R, Hixson D, Affigne S, Rogler CE. Insulin-like growth factor II blocks apoptosis of N-myc2-expressing woodchuck liver epithelial cells. J Virol. 1996 Sep;70(9):6260-8. doi: 10.1128/JVI.70.9.6260-6268.1996.

    PubMed 8709253

  • Buzzelli G, Dattolo P, Pinzani M, Brocchi A, Romano S, Gentilini P. Circulating growth hormone and insulin-like growth factor-I in nonalcoholic liver cirrhosis with or without superimposed hepatocarcinoma: evidence of an altered circadian rhythm. Am J Gastroenterol. 1993 Oct;88(10):1744-8.

    PubMed 8213718

  • Mattera D, Capuano G, Colao A, Pivonello R, Manguso F, Puzziello A, D'Agostino L. Increased IGF-I : IGFBP-3 ratio in patients with hepatocellular carcinoma. Clin Endocrinol (Oxf). 2003 Dec;59(6):699-706. doi: 10.1046/j.1365-2265.2003.01909.x.

    PubMed 14974910

  • Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999 Dec;30(6):1434-40. doi: 10.1002/hep.510300629.

    PubMed 10573522

  • Llovet JM, Fuster J, Bruix J; Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004 Feb;10(2 Suppl 1):S115-20. doi: 10.1002/lt.20034.

    PubMed 14762851

  • Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology. 1999 Mar;210(3):655-61. doi: 10.1148/radiology.210.3.r99fe40655.

    PubMed 10207464

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Octreotide-LAR, Lanreotide Autogel and Locoregional treatments in people with Advanced Hepatocellular Carcinoma, run by Federico II University at 1 site in Italy.

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 2 inclusion and 9 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: finished, as of the sponsor's last update on 17 Aug 2009. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined 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.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Prolongation of the survival curve (>6 months) (time frame: 12 months). 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 NCT00495846, which also lists 27 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 17 Aug 2009.

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