Dose Escalation Study of Interleukin-7 (IL-7) and Bitherapy in HCV Genotype 1 or 4 Patients Resistant to Bitherapy Alone

This is a Phase I/IIa inter-patient dose-escalation study assessing weekly doses of Interleukin-7 (CYT107) in adult patients infected by virus genotype 1 or 4 of Hepatitis C and resistant to standard treatment with Peg-Interferon and Ribavirin (bitherapy).

The dose escalation is aimed at establishing the safety of a biologically active doses of CYT107 added to the combination therapy of pegylated interferon-alpha and ribavirin. At each dose level, study patients will receive one subcutaneous administration of CYT107 per week for a total of 4.

Groups of 6 patients will be entered at each dose level of CYT107. Three dose levels are planned.

Eligible patients initially receive bi-therapy for 6-10 weeks. Thereafter, CYT107 is added for a cycle of four weekly injections at a defined dose level while standard bi-therapy continues for 9 weeks after CYT107 treatment discontinuation. The patients are then followed on a regular basis until reaching 48 weeks after the CYT107 treatment. The duration of study is approximatively 60 weeks with 20-25 weeks of bi-therapy.

Participants will have 1 overnight hospitalization and 15 clinic visit on a period of 60 weeks.

During the visits the following may be done:

* medical history, physical examination, blood tests
* electrocardiograms (ECG)
* chest X-Ray
* liver/spleen imaging
* urine tests

• Interleukin-7 (Drug): 3 dose levels: 3, 10 \& 20 µg/kg. 4 administrations, 1 per week

Primary outcomes

• To evaluate at W 12 the safety of biologically active doses of CYT107 added to a combination therapy by pegylated interferon-alpha and ribavirin [12 weeks after the start of IL-7]

Secondary outcomes

• To characterize pharmacokinetics and pharmacodynamics of CYT107 [12 weeks after the start of IL-7]
• To evaluate in the context of a dose escalation strategy the potential anti-viral effect of CYT107 [12 weeks after the start of IL-7]
• To evaluate the immune specific response to HCV [12 weeks after the start of IL-7]
• To document the long-term safety and viral load variations [48 weeks after the start of IL-7]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Genotype 1 or 4 infected patients
* Age > 18 years
* Absence of viral response to previous treatments with pegylated interferon-alpha plus ribavirin defined as:

  * Absence of early viral response (EVR) with detectable HCV and with a decrease HCV RNA load < 2 logs, measured by a quantitative PCR tests after 12 weeks of treatment, as compared to baseline levels measured by a similar technique; or
  * Absence of end of treatment response defined by detectable HCV RNA at the end of treatment (24 weeks or 48 weeks)
* Metavir ≤ F3 assessed by biopsy in the last 12 months or by fibroscan if Fibroscan® result < 10 kPa in the last 6 months (biopsy can be avoided)

Exclusion Criteria:

* Active infection by HBV (positive HBs Ag or positive anti HBc antibodies with a detectable HBV DNA viral load).
* Infection by HIV-1 and /or HIV-2
* Apart from HCV infection, presence of active infection requiring a specific treatment or a hospitalization
* Other liver disease (notably from alcoholic, metabolic or immunological origin)
* Body mass index (BMI) > 30kg/m2
* Relapse after previous response to pegylated IFN alpha and ribavirin therapy
* Any history of malignancy apart from curatively treated basal cell carcinoma or in situ cervical carcinoma
* History of clinical autoimmune disease or active auto-immune disease
* History of severe asthma, presently on chronic medications
* Significant cardiac or pulmonary disease
* Prior solid organ or hematopoietic cell transplantation
* Dialyzed patient
* Inability to give informed consent

• Tilman Gerlach, Study chair, Hospital of San Gallen-Switzerland