A Phase I/II Study of IPH1101 (BrHPP), Specific Agonist of Vã9Vä2 T Lymphocytes, in Combination with Rituximab Re-Treatment in Patients with Follicular Lymphoma. Interim Phase I Data.

Background: Unconventional γδ T lymphocytes are innate immunity effectors bearing very strong anti-tumoral activity. Previous studies have documented that malignant B cells are highly sensitive to γδ T cells mediated cellular toxicity. IPH1101 is a chemically-synthesized, specific antigen for γδ T cells: IPH1101 triggers the synthesis of pro-inflammatory cytokines by γδ T cells - inducing the recruitment of other cell effectors and facilitating implementation of an adaptive response - and potentiates the direct cytotoxic activity of γδ T cells against a large number of tumor B-cell lines. Also, IPH1101-activation of γδ T cells in the presence of low doses of IL-2 leads to their proliferation and differentiation into effectors capable of mediating ADCC. ADCC is the main known molecular mechanism underlying rituximab bioactivity. Increasing the number and the activation of killer lymphocytes mediating ADCC is crucial for therapeutic potency and deserves to be tested in a clinical trial. The purpose of this study is to assess the clinical efficacy, the biological activity, and the safety of the association of IPH1101 with low doses of IL-2, combined to a standard rituximab re-treatment, in patients with Follicular Lymphoma.

Method: This is an open label, multinational study consisting of a Phase I like dose-escalation part, followed by Phase II part. Here are reported the Phase I part results. The study population is patients presenting Follicular non-Hodgkin’s Lymphoma, relapsing after 1 or 2 lines of previous therapy, with at least 1 rituximab-containing line. Rituximab (375 mg/m²) was administered 4 times weekly. IPH1101 (750 mg/m2) was administered i.v. three times (every 3 weeks), the first administration being one day after the second rituximab infusion. IL-2 courses consisted in s.c. daily administrations for 5 days, starting on the same day of each IPH1101 administration. All patients participating in this Phase I like period were to be enrolled sequentially with an interval of at least 15 days for evaluation of potential dose limiting toxicity (DLT) occurrence.

Results: Six patients were part of the phase I: 3 at IL-2 dose level of 4 MIU and 3 at IL-2 dose level 8 MIU, the targeted dose. No patient presented a DLT as defined in the protocol. One patient treated at the dose level of 8 MIU withdrew the study treatment after the second administration of IL-2 of cycle 2 mainly due to grade 3 asthenia (SAE) and grade 2 vomiting and epigastralgia. At dose level IL-2 of 4 MIU, 2 SAEs were reported: a grade 3 hypotension and a grade 3 ALAT elevation. Most reported adverse events were mild or moderate, mainly nausea, IL-2 injection site reaction, vomiting, diarrhoea, and grade 1 or 2 pyrexia. Their frequency was higher in the cohort treated with 8 MIU of IL2. Pharmacology of IPH1101/IL-2 in this phase I part, based on a weekly monitoring of blood γδ T cells and on dosages of early released plasma cytokines, shows γδ T cells are very efficiently expanded, in an IL-2 dose-dependent fashion and with slow return to baseline. Pro-inflammatory cytokines are released at each IPH1101/IL-2 injections. No unexpected immuno-biological event was reported.

Conclusion: These observations showing a good safety and immuno-biological efficacy profile of the combination of rituximab, IPH1101 and low dose IL-2, have allowed the start of the Phase II part of the study with IPH1101/ IL-2 dose of 8 MIU combined with rituximab in patients with follicular lymphoma. The recruitment is ongoing.