on behalf of the CLWP of the EBMT This randomized-controlled trial studied the efficacy of palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, ± s.d. ¼ 8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving palifermin (60 mg/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, palifermin was unable to reduce OM or OM-related patient's burden in MM transplant patients.

The purpose of our study was to compare long-term safety outcomes (overall survival, disease progression, and incidence of secondary malignancies) between palifermin and placebo in the prevention of oral mucositis in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation (HSCT). Patients were enrolled between 1997 and 2005 into 4 phase I to III studies (3 double-blind placebo-controlled and 1 open-label) conducted at 31 sites in Australia, Europe, and the United States. Survival outcomes (overall survival, progression-free survival) were compared using hazard ratios (HRs) estimated with a Cox model that included treatment group, baseline age, disease type, Eastern Cooperative Oncology Group performance status, country, and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with a chi-square test. A total of 672 patients were randomized into the studies (428 palifermin and 244 placebo). The median follow-up time for subjects alive at last visit was 7.9 years (range, .1 to 14.9) for palifermin and 8.8 years (range, .1 to 14.8) for placebo. Palifermin-treated patients had overall survival (HR, 1.01; 95% confidence interval [CI], .78 to 1.31; P = .921) and progression-free survival times (HR, 1.04; 95% CI, .83 to 1.31; P = .733) that were comparable with placebo-treated patients. Secondary malignancies were reported by 13% of palifermin-treated patients versus 11% of placebo patients (P = .477). Breakdown into secondary hematological malignancies (7% versus 6%) or solid tumors (6% versus 6%) did not suggest any differences between the treatment groups. After a follow-up of up to 15 years, comparable long-term safety outcomes (overall survival, progression-free survival, and incidence of secondary malignancies) were observed for palifermin- and placebo-treated patients undergoing autologous HSCT.

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e14580 Background: Interleukin-1 is a master cytokine produced by macrophages (IL-1 β) and released upon cell death (IL-1 α). IL-1 upregulates other cytokines in the tumor microenvironment (i.e. IL-6 and IL-8), drives chronic non-resolving inflammation in the tumor, induces cancer cell invasion and metastasis (EMT), has profound effects on immune cells and cancer associated fibroblasts and can attract granulocytic myeloid suppressor cells to the tumor (PMN-MDSC), that in turn inhibit cytotoxic T cell responses. Isunakinra is a small recombinant protein resembling IL-1Ra, with an inhibitory potency 10-20 times higher, that binds to the IL1-R1 and blocks activation of the receptor by both IL-1α and IL-1β. We conducted a phase I dose escalation study with isunakinra as monotherapy and in combination with a PD-1 inhibitor in patients with locally advanced or metastatic solid tumors that had exhausted all treatment options. Methods: Enrolled patients with refractory metastatic solid tumor, ECOG 0-2, on a 3 + 3 dose-escalation trial at three dose levels of isunakinra (15, 25 or 50 mg). Isunakinra was self-administered once daily SC for three weeks followed by 4 additional weeks in combination with nivolumab Q4W at 480 mg, flat dose to complete the DLT period of 7 weeks. Thereafter, isunakinra/nivolumab was continued until week 28. Primary endpoints: DLTs, safety, and pharmacokinetics. Secondary endpoints: tumor and immune monitoring. Results: Enrolled fifteen patients with metastatic or unresectable locally advanced solid tumors (colorectal, pancreatic, triple-negative BC, anal, prostatic, CCA, and appendix) that had received 2-5 prior lines of therapy. Seven SAE occurred in three rapidly deteriorating subjects, all disease related hospitalizations, leading to study withdrawal during the DLT period. No DLTs, irAE or predefined laboratory deviations occurred in any subject. The highest dose, 50 mg, was selected as RP2D. Twelve subjects completed visit week 8, six of them week 12, and four completed the trial. One patient with metastatic colon cancer (MSS, KRAS mut, high TMB) was granted extended treatment for PR and continued response at end of study. Isunakinra exposure totaled 1575 daily doses, 81% during combination with nivolumab, t 1/2 5 hours with no accumulation over time. At 50mg of isunakinra, plasma levels where well above 100 ng/mL, a target for complete IL-1 inhibition. Conclusions: Isunakinra is safe and well-tolerated in combination with standard dose nivolumab. Ongoing expansion cohorts and future studies will explore the safety and efficacy of isunakinra in specific tumors and with other immunotherapy combinations. Clinical trial information: NCT04121442 .