Activity of recombinant human interleukin-21 (rIL-21) in patients (pts) with stage IV malignant melanoma (MM) without prior treatment: clinical data from a phase IIa study

Background: IL-21 has a key role in cancer immunology. We have previously described a phase 1 study of rIL-21 in pts with advanced MM. We now report final clinical results from a phase 2a study in treatment-naïve pts with advanced MM. Methods: Open-label, two-stage phase 2a trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, measurement of anti-rIL-21 antibodies. Eligibility: unresectable MM, measurable disease by RECIST, no prior systemic therapy (adjuvant interferon permitted), adequate major organ function, good performance status, no significant autoimmune disease, life expectancy ≥4 months. rIL-21 was administered at 30 μg/kg/dose in cycles of 5 dosing days followed by 9 days of rest for 6 weeks (wks), followed by 2 wks off treatment. Further cycles were offered to pts without tumor progression causing symptoms and requiring other therapy. Only pts with PR or CR by RECIST at wk 16 were offered further treatment. Results: Stage 1 of the study comprised 14 pts. One confirmed CR was observed and as per protocol 10 more pts were accrued to stage 2 (total n=24: 10 female, 14 male). Best tumor response any time on study included 1 confirmed CR and 1 confirmed PR (both with lung mets) with overall RR 8.3%, 8 SD (33.3%) and 14 PD (58.3%). The pt with CR by wk 8 had PD 11 wks later. The pt with PR had SD at wk 8 but confirmed PR at wk 16. 6/8 pts with SD at wk 8 had progressed by wk 16. Another pt had CR in target lesions and SD in non-target, but PD in brain (overall PD). One pt had 9 cycles of treatment, 10 had 6, and 13 had 3–4. Treatment was well tolerated and safety was similar to the phase 1 trial. 8 pts had SAEs: hypersensitivity (1), hepatitis (1), fever (2), rigor (1), cellulitis (1), sinus tachycardia (1), cancer related pain (4). One pt withdrew due to adverse events at wk 8 and 3 pts had the dose reduced to 10 μg/kg. Conclusions: rIL-21 administered at 30 μg/kg/day in 5-day cycles every 2nd wk was well tolerated by pts with metastatic MM and confirmed responses by RECIST including one CR were observed. Future studies will evaluate potential for further anti-tumor activity at higher doses of rIL-21.