Dose Finding Study of AVE1642 in Patients With Advanced or Metastatic Liver Carcinoma

Dose-finding, Safety, Pharmacokinetic and Pharmacodynamic Study of AVE1642, an Anti-Insulin-like Growth Factor-1 Receptor (IGF-1R/CD221) Monoclonal Antibody, Administered as Single Agent and in Combination With Other Anti Cancer Therapies (Sorafenib or Erlotinib) in Patients With Advanced Liver Carcinoma

The primary objective of the study is to select the dose of AVE1642 to be administered in patients with liver carcinoma not eligible for local treatment.

The secondary objectives of the study are:

• To evaluate the safety profile of AVE1642 as single agent and the safety profile of combinations with other anti-cancer therapies of interest in liver carcinoma , including detection of immunogenicity.
• To evaluate pharmacokinetics and pharmacodynamics profiles of AVE1642 as single agent or any PK interactions when given in combination with other anti-cancer therapies.
• To assess the preliminary clinical activity in terms of response rate (Complete response + Partial response), duration of responses, stabilisation rate and duration of stabilisation, according to RECIST criteria.
• To assess the biological activity at the tumor level.

Study Overview

• Status: Terminated
• Conditions: Liver Carcinoma
• Intervention / Treatment: Drug: AVE1642; Drug: sorafenib; Drug: erlotinib

Detailed Description

AVE1642 will be administered as an IV infusion on day 1 and then every 3 weeks for at least 2 infusions for evaluability requirements. Curative and / or prophylactic management of allergic reactions during infusion will be implemented when needed. The duration of the study for one patient will include a period for inclusion of up to 2 weeks, at least 2 cycles of treatment in dose escalation step (one cycle of AVE1642 alone and at least one cycle of AVE1642 in combination) and at least one cycle of the combination in the extension cohort, followed, when possible, by a minimum of 30-day follow-up after the last drug administration, in order to detect any potential immunogenicity. In the second step, the patients will continue treatment until disease progression, unacceptable toxicity or willingness to stop.

The expected enrolment period is 15 months with at least 30 day follow-up after the last patient treated.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France
    • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients not eligible for surgical resection, liver transplantation, local ablation techniques or chemoembolisation and with histologically proven liver carcinoma whenever possible or combination of radiologically documented hypervascular liver tumour and α foeto protein level ≥ 400 ng/ml
• Signed and dated approved patient informed consent form prior to enrollment into the study

Exclusion Criteria:

• ECOG performance status > 2

• Inadequate organ function:

  • Neutrophils (ANC) < 1,500/mm3
  • Hemoglobin < 10g/dl
  • Platelets < 100,000/mm3
  • Total bilirubin > 1.5 x ULN
  • ASAT, ALAT > 3 x ULN
  • Creatininemia > 1.5 x ULN (or ≥ 2.0 mg/dl)
  • INR > 1.6
  • Liver cirrhosis Child Pugh B or C (score > 6)
  • HbA1C > 8%
• No measurable or evaluable tumoral lesion
• Patients not eligible for sorafenib therapy and for whom this therapy cannot be postponed by 3 weeks (during AVE1642 single treatment period) in dose escalation part
• Prior exposure to an anti-IGF-1R class compound

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level -1; 0.5 mg/kg AVE1642 single agent at cycle 1 with sorafenib at cycle 2	Drug: AVE1642; intravenous infusion; Drug: sorafenib; oral intake; Other Names: Nevaxar
Experimental: Dose Level 1; 1 mg/kg AVE1642 single agent at cycle 1 with sorafenib at cycle 2	Drug: AVE1642; intravenous infusion; Drug: sorafenib; oral intake; Other Names: Nevaxar
Experimental: Dose Level 2; 3 mg/kg AVE1642 single agent at cycle 1 with sorafenib at cycle 2	Drug: AVE1642; intravenous infusion; Drug: sorafenib; oral intake; Other Names: Nevaxar
Experimental: Dose Level 3; 6 mg/kg AVE1642 single agent at cycle 1 with sorafenib at cycle 2	Drug: AVE1642; intravenous infusion; Drug: sorafenib; oral intake; Other Names: Nevaxar
Experimental: Dose Level 4; 12 mg/kg AVE1642 single agent at cycle 1 with sorafenib at cycle 2	Drug: AVE1642; intravenous infusion; Drug: sorafenib; oral intake; Other Names: Nevaxar
Experimental: Dose Level 5; 18 mg/kg AVE1642 single agent at cycle 1 with sorafenib at cycle 2	Drug: AVE1642; intravenous infusion; Drug: sorafenib; oral intake; Other Names: Nevaxar
Experimental: Combination cohort 1; AVE1642 selected dose in combination with sorafenib	Drug: AVE1642; intravenous infusion; Drug: sorafenib; oral intake; Other Names: Nevaxar
Experimental: Combination cohort 2; AVE1642 selected dose in combination with erlotinib	Drug: AVE1642; intravenous infusion; Drug: erlotinib; oral intake; Other Names: Tarceva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose-limiting toxicities (DLT) based on grade = or > 3 hematological or non-hematological toxicity and on fasting hyperglycemia	Cycle 1 and cycle 2 (6 weeks)

Secondary Outcome Measures

Outcome Measure	Time Frame
Anti tumoral activity	Every 2 cycles

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Principal Investigator: Olivier Rosmorduc, Professor, Hôpital St Antoine, 184 rue du Faubourg St Antoine, 75012 Paris - France

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): November 1, 2009
• Study Completion (Actual): November 1, 2009

Study Registration Dates

• First Submitted: November 13, 2008
• First Submitted That Met QC Criteria: November 13, 2008
• First Posted (Estimate): November 14, 2008

Study Record Updates

• Last Update Posted (Estimate): August 4, 2010
• Last Update Submitted That Met QC Criteria: August 3, 2010
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: monoclonal antibody, anti IGF1R
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Sorafenib
• Other Study ID Numbers: TED10630; EudraCT 2008-000809-10