Date: 2018-06-03
Type of
information: Presentation of results at a congress
phase: 1
Announcement: amendment to the study protocol
Company: AstraZeneca (UK) Innate Pharma (France)
Product: durvalumab (MEDI4736) and monalizumab (IPH2201/anti-NKG2A)
Action
mechanism:
- monoclonal antibody/immune checkpoint inhibitor. Monalizumab (IPH2201/anti-NKG2A) is a first-in-class humanized IgG4 antibody. NKG2A is a checkpoint receptor that inhibits anti-cancer functions of cytotoxic NK and T lymphocytes. NKG2A recognises HLA-E ligands, and by expressing HLA-E cancer cells can protect themselves from killing by CD94/NKG2A-positive NK-, NKT-, and T-cells (a/b and g/d). HLA-E is frequently up-regulated on cancer cells and this occurs in patients with different types of solid tumours or haematological malignancies. In some types of cancers, high-levels of HLA-E appear to confer poorer prognosis. IPH2201 blocks the inhibitory function of CD94/NKG2A, thereby unleashing NK and T cells to kill cancer cells, despite expression of HLA-E. IPH2201 enhances NK and T cell killing of a variety of cancer cell types. Hence, IPH2201 may potentially re-establish a broad anti-tumour response mediated by NK and T cells. Anti-NKG2A mAb may also enhance the cytotoxic potential of other therapeutic antibodies. In an ongoing single- and multiple-dose Phase I dose-escalation safety trial in patients with rheumatoid arthritis, IPH2201 appears to have a safe and well-tolerated profile at all doses tested.
- Monalizumab has been developed by Innate Pharma. This French biotech company has entered into a collaboration agreement with AstraZeneca in 2015 to accelerate and broaden the development of the antibody.
- Durvalumab (MEDI4736) is a human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. MEDI4736 blocks these signals, countering the tumour’s immune-evading tactics. This antibody is directed against B7-H1, have been shown to block the interaction between B7-H1 and its receptors, PD-1 and CD80 (B7-1). This blockade may help to overcome the immunosuppressive effects of B7-H1 on anti-tumor T cells.
Disease: advanced solid tumors
Therapeutic
area: Cancer - Oncology
Country: USA, Europe
Trial
details:
- This multicenter, open-label, dose-escalation and dose-expansion phase 1 study is evaluating the safety, tolerability, antitumor activity, PK, pharmacodynamics, and immunogenicity of durvalumab (MEDI4736) in combination with monalizumab (IPH2201) in adult subjects with selected advanced solid tumors. It will include up to 208 patients, and will be performed in the United States and in Europe. The rationale for this trial is based on the potential synergy in blocking several checkpoints expressed on tumor infiltrating immune cells. The checkpoints targeted by durvalumab and monalizumab are both upregulated in many cancers, suggesting they both contribute to tumor immune escape, and that simultaneous blockade of both inhibitory pathways may be necessary for fully unleashing effective anti-tumor immune responses. The primary endpoint of the study is safety, with antitumor efficacy being a key secondary endpoint. Other secondary endpoints include response duration, progression free survival, overall survival, pharmacokinetics, pharmacodynamics and immunogenicity of durvalumab and monalizumab given in combination. (NCT02671435)
Latest
news:
- • On June 4, 2018, Innate Pharma announced updated preliminary clinical data from an ongoing Phase I dose escalation and expansion study evaluating the safety and efficacy of the combination of monalizumab and durvalumab in patients with recurrent/metastatic microsatellite-stable colorectal cancer (MSS-CRC). In a poster presentation made at the Gastrointestinal (Colorectal) Cancer session, during the annual meeting of the American Society of Clinical Oncology (ASCO), the combination of monalizumab and durvalumab showed encouraging anti-tumor activity in this difficult-to-treat patient subset. “The preliminary data so far suggest that the combination of monalizumab and durvalumab
may hold promise in some patients with MSS-CRC, a population historically unresponsive to PD-1/L1 therapy”, said study investigator Neil H. Segal, MD., PhD., medical oncologist at Memorial Sloan Kettering Cancer Center, New York.
- Key findings from the MSS-CRC expansion cohort:
Updated preliminary clinical data on the expansion cohort of microsatellite-stable colorectal cancer patients (MSS-CRC) presented at ASCO are based on the cut-off date of April 23, 2018. Forty patients are evaluable for safety and 39, for efficacy. Thirty five (88%) patients had 2 or more prior lines of therapy for recurrent/metastatic disease. Efficacy data show an overall response rate (ORR) of 8%, with confirmed partial response in 3 patients (8%) and stable disease (SD) in 11 patients (28%), including 3 SD patients with tumor reduction who continued therapy for >200 days. The median duration of response was 16.1 weeks at the cutoff
date. Data demonstrated a disease control rate (DCR) of 31% at 16 weeks.
- The safety profile of the monalizumab and durvalumab combination was consistent with the monotherapy profiles of each agent. In the MSS-CRC expansion cohort, the most common treatment-related AE included arthralgia (7.5%), increased AST (7.5%), hypothyroidism (7.5%), pruritus (7.5%), and rash (7.5%). Grade 3/4 AE that occurred in three patients were limited to sepsis (n=1, Grade 4) and increased lipase (n=1, Grade 3), that both could be resolved, and increased AST (n=1, Grade 3).
- • On May 17, 2018, Innate Pharma announced preliminary data from an ongoing Phase I dose escalation and expansion study evaluating the safety and efficacy of the combination of monalizumab and durvalumab. Data show preliminary anti-tumor activity in patients with recurrent, metastatic colorectal
cancer, with 3 partial responses and 11 stable disease responses among 37 patients evaluable for efficacy, with a disease control rate of 24% at 16 weeks (data cut as of February 8, 2018). The data also showed a manageable toxicity profile.
- The Phase I dose escalation and expansion study enrolled a total of 55 patients. In the dose escalation part, 15 patients with selected solid tumors received durvalumab 1500 mg every 4 weeks in combination with monalizumab at increasing doses. In the expansion phase, 40 patients with microsatellite-stable colorectal cancer (MSS-CRC) were enrolled. 58% of patients in expansion had 3+ lines of prior therapy. These data were highlighted in an abstract (#3540) published online on May 16 by the American Society of Clinical Oncology (ASCO) in advance of its annual meeting in June.
- • On March 23, 2018, Innate Pharma announced that its partner MedImmune, AstraZeneca’s global biologics research and development arm, has amended the clinical trial protocol of the ongoing Phase I trial investigating the safety and
efficacy of monalizumab in combination with durvalumab, in patients with advanced solid tumors. The trial protocol has been expanded to add new expansion cohorts aiming at testing monalizumab in combination with durvalumab
and standard of care in patients with 1st- and 2nd-line, metastatic colorectal cancer (CRC).
- The dose-escalating part of the study has been completed, while the expansion cohorts in selected advanced solid tumors are ongoing.
- The primary objective of the new study arms will be safety, with Overall Response Rate (ORR) and Duration of Response (DOR), amongst others, as secondary outcome measures.
- • On February 8, 2016, Innate Pharma announced the start of a Phase I combination trial of the two checkpoint inhibitors monalizumab (antiNKG2A antibody) and durvalumab (anti-PD-L1 antibody). This trial is a multicenter, open-label, dose-escalation and cohort-expansion study to evaluate the safety, tolerability and antitumor activity of the combination in patients with selected advanced solid tumors. It will include up to 208 patients, and will be performed in the United States and in Europe. The rationale of the combination of the two immune checkpoints inhibitors durvalumab and monalizumab will be presented at a scientific meeting during 2016.
- This trial is part of a global co-development and commercialization agreement with AstraZeneca for monalizumab signed in April 2015. Five Phase I/II trials are now ongoing, testing monalizumab in a variety of solid and hematologic tumors, as a single-agent and in various combinations, exploring the clinical impact of monalizumab’s ability to stimulate direct tumor killing by cytotoxic NK and T cells, and different mechanisms of synergy with other immunomodulators, including T cell activators and ADCC-inducing antibodies.
Is
general: Yes
