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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Liver Carcinoma

Intervention / Treatment
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* Drug: AVE1642
* Drug: sorafenib
* Drug: erlotinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | Time Frame |
| --- | --- | --- |
| Anti tumoral activity |  | Every 2 cycles | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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monoclonal antibody, anti IGF1R