Innate Pharma : Opening of the Phase I/II trial of IPH2201 in combination with ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia

• Third trial opened in the Phase II clinical program of IPH2201 - program rollout on track
• Trial conducted in the United States with leading investigator at OSU

Innate Pharma SA (the 'Company' - Euronext Paris: FR0010331421 - IPH) today announced the opening of the Phase I/II trial of IPH2201, a first-in-class NKG2A checkpoint inhibitor, tested in combination with ibrutinib in patients with relapsed or refractory Chronic Lymphocytic Leukemia ('CLL'). This trial, which will include up to 45 patients, is multicentric and will be performed in the United States.

Pierre Dodion, Chief Medical Officer of Innate Pharma, said: 'HLA-E is expressed by CLL cells of virtually all patients. IPH2201 is a new checkpoint inhibitor targeting both T and NK cells and preventing their inhibition by HLA-E on tumor cells. In addition, ibrutinib has been demonstrated to create a favorable pro-inflammatory environment; this could result in a synergistic effect with the immunomodulating action of IPH2201'. He added: 'The Ohio State University Comprehensive Cancer Center is a leading center in developing new therapies to cure Chronic Lymphocytic Leukemia. It is a great opportunity for the development of IPH2201 to work with them'.

Pr. John Byrd, Director, and Dr Farrukh Awan, Principal Coordinating Investigator, both expert leaders in the field of CLL at the Division of Hematology, Department of Internal Medicine, Ohio State University, said: 'Ibrutinib represents a breakthrough medicine that was approved for the treatment of relapsed and del(17(p13.1) CLL in 2014. However, although ibrutinib induces a high response rate in patients with CLL, responses are rarely complete. Ultimately the disease progresses in a number of patients. Achieving complete responses would be of great interest to potentially prolong remission, and maybe eventually improve survival rate. Targeting the immune system in several novel ways is the rationale to combine IPH2201 and ibrutinib in this trial'.

This trial is part of a global co-development and commercialization agreement with AstraZeneca for IPH2201. Within this frame, Innate Pharma expects to have four trials opened by the end of 2015. In addition to the CLL trial, two Phase I/II studies are currently ongoing, testing IPH2201 as a single agent respectively in squamous cell carcinoma of the Head and Neck and in Ovarian cancer . The fourth trial, testing IPH2201 in combination cetuximab in patients with Head and Neck cancer, will start in the coming months.

The co-development plan also includes Phase II combination clinical trials with IPH2201 and durvalumab (MEDI4736), a PD-L1 immune checkpoint inhibitor, in solid tumors, which will be performed by AstraZeneca/MedImmune.

This Phase Ib/IIa study is a multicenter open label trial of the combination of IPH2201 and ibrutinib in patients with relapsed or refractory Chronic Lymphocytic Leukemia. Its primary objective is to evaluate the anti-leukemic activity of the combination and the primary endpoint for efficacy is complete response rate. The secondary objectives are to assess the safety of the combination of IPH2201 and ibrutinib. The trial will be performed in the United States under the coordination of leading investigators at the Ohio State University.

36 to 45 patients are planned to be enrolled. The trial is conducted in two parts:

• In the first part of the study, 12 to 24 patients will receive a combination of ibrutinib at the approved dosage and IPH2201; 4 dose levels of IPH2201 up to 10 mg/kg will be explored. Based on previous experience with IPH2201, these dosages are expected to induce saturation of the NKG2A receptor.
• In the second part of the study, IPH2201 at the dose selected in the dose-escalating part will be assessed in combination with ibrutinib during 26 cycles in up to 24 patients.

The rationale of this trial is based on the observation that HLA-E is expressed in virtually all patients with CLL, at higher levels compared to normal B cells (Veuillen, Aurran-Schleinitz et al. 2012). IPH2201 is a NGK2A checkpoint inhibitor that blocks the HLA-E driven inhibition of NK and CD8+ cells. By binding to NGK2A, IPH2201 restores the capability of those cells to destroy tumor cells. Furthermore, ibrutinib has been demonstrated to create a favorable pro-inflammatory environment; this could result in a synergistic effect with the immunotherapeutic action of IPH2201. Thus, treatment with IPH2201 in combination with ibrutinib may improve the quality of response above and beyond that achieved with ibrutinib alone and achieve complete responses; a higher rate of complete response should lead to improved overall survival.

In a Phase I dose-escalation safety trial, IPH2201 was found to be safe and well-tolerated.

CLL results from progressive accumulation of morphologically mature B lymphocytes in the blood, bone marrow and lymphatic tissues. In Western countries, CLL is the most common form of leukemia, accounting for about 25% of all leukemias. Incidence increases with age and the median age of diagnosis is 70 for males and 74 for females. It is estimated that 15,720 new cases will occur in 2014 in the US, causing 4,600 deaths (Siegel, Ma et al., 2014).

Ibrutinib, a first in class kinase inhibitor of BCR signaling, has been approved in 2014 for the treatment of patients with CLL who have received at least one prior therapy. Its approval was based on the safety and efficacy results of several trials which have shown mainly partial responses. The indication for ibrutinib was subsequently extended to include CLL with 17p deletion, irrespectively of the line of therapy.