135P - Isunakinra as Monotherapy and Combined with Nivolumab for Treatment Resistant Advanced Solid Tumours: Exploratory Effect Data, Tolerability, and Pharmacokinetics from a Dose Escalation Trial

Background

Inflammatory signalling by interleukin-1 receptor (IL-1R) family members promote neoplastic transformation, tumour growth, dissemination, and supportive cell recruitment. IL-1R1-inhibition is tumor suppressive and optimizes PD-1-inhibition in animals. Isunakinra, an anakinra-like IL-1R1 antagonist, blocks IL-1α/IL-1β 10-20x more potently in various assays. A safety, dose escalation trial with exploratory endpoints of isunakinra w/wo nivolumab in patients with advanced solid tumors is presented.

Methods

15 subjects recruited to escalating dose groups (3+3 per Dose-Limiting Toxicity criteria) with daily isunakinra SC at 15, 25 or 50 mg for 3 weeks was followed by combination treatment with flat dose nivolumab every 4 weeks for up to 28 weeks.

Results

15 patients accrued to the study, exposure totalling 1.584 doses. No DLT occurred, and no PD-1 immune reactions developed. Five mild, transient injection site reactions were reported. Ten serious events (hospitalizations) in 7 subjects were related to tumor progression. Decrease in circulating tumor cells: 35% (N=13) at week 4, 53% (N=10) at week 8 and 80% (N=5) at week 12. Best Overall Response (BoR) per RECIST 1.1 and ( irRC) assessable in 12 subjects: SD in 10 (8), PR in 1 (2), and PD in 1(2). Four subjects completed the trial with SD/SD or SD/PR. One subject (colon cancer, k-ras mut, MSS) with a pelvic mass close to CR at W28 with PR /PR granted extended study therapy continued to W64 without safety issues and the target lesion stable at 16 mm from W44. Baseline MDSC compositions varied at baseline. Isunakinra alone (W1 - W4) clearly impacted key naïve cell types in all patients. With nivolumab added (W4), equally clear but often contrasting effects were observed at W8 and W12. Mature cells were unaffected.

Conclusions

The RP2D for isunakinra + nivolumab is 50 mg SC per day. No serious events related to the combination therapy. Encouraging exploratory data with signs of tumour control in heavily pre-treated subjects along with currently obtained pharmacokinetic and safety profiles justifies exploring further CPI combinations in planned phase 2 studies.

Clinical trial identification

NCT04121442.

Legal entity responsible for the study

Buzzard Pharmaceuticals AB Buzzard Pharmaceuticals AB.

Funding

Buzzard Pharmaceuticals.

Disclosure

C. Becerra: Non-Financial Interests, Institutional, Principal Investigator: Buzzard Pharmaceuticals. H. Olivecrona: Non-Financial Interests, Personal, Coordinating PI: Buzzard Pharmaceuticals. M. de Château: Financial Interests, Institutional, Full or part-time Employment: Buzzard Pharmaceuticals. S.A. Paulson: Non-Financial Interests, Institutional, Local PI: Buzzard Pharmaceuticals.