Safety and efficacy of zinpentraxin alfa as monotherapy or in combination with ruxolitinib in myelofibrosis: stage I of a phase II trial

Abstract

Pentraxin 2 (PTX-2; serum amyloid P component), a circulating endogenous regulator of the inflammatory response to tissue injury and fibrosis, is reduced in patients with myelofibrosis (MF). Zinpentraxin alfa (RO7490677, PRM-151) is a recombinant form of PTX-2 that has shown preclinical antifibrotic activity and no dose-limiting toxicities in phase I trials. We report results from stage 1 of a phase II trial of zinpentraxin alfa in patients with intermediate-1/2 or high-risk MF. Patients (n=27) received intravenous zinpentraxin α weekly (QW) or every 4 weeks (Q4W), as monotherapy or an additional therapy for patients on stable-dose ruxolitinib. The primary endpoint was overall response rate (ORR; investigatorassessed) adapted from International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria. Secondary endpoints included modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) change, bone marrow (BM) MF grade reduction, pharmacokinetics, and safety. ORR at week 24 was 33% (n=9/27) and varied across individual cohorts (QW: 38% [3/8]; Q4W: 14% [1/7]; QW+ruxolitinib: 33% [2/6]; Q4W+ruxolitinib: 50% [3/6]). Five of 18 evaluable patients (28%) experienced a ≥50% reduction in MPN-SAF TSS, and six of 17 evaluable patients (35%) had a ≥1 grade improvement from baseline in BM fibrosis at week 24. Most treatment-emergent adverse events (AE) were grade 1-2, most commonly fatigue. Among others, anemia and thrombocytopenia were infrequent (n=3 and n=1, respectively). Treatment-related serious AE occurred in four patients (15%). Overall, zinpentraxin alfa showed evidence of clinical activity and tolerable safety as monotherapy and in combination with ruxolitinib in this open-label, non-randomized trial (clinicaltrials gov. Identifier: NCT01981850).

Figure 1.

Zinpentraxin alfa mechanism of action. DAMP: danger-associated molecular pattern.

Figure 2.

Percentage change from baseline in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score and palpable spleen size at week 24. (A) Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)^a; (B) palpable spleen size^b; all treated population. ^aData shown for 18 patients in total; 7 patients withdrew from the trial before week 24 and 2 patients had missing values at week 24. ^bData shown for 15 patients in total; 7 patients withdrew from the trial before week 24 and 5 patients had missing values at week 24. Q4W: every 4 weeks; QW: weekly.

Figure 3.

Effect of treatment with zinpentraxin alfa on hemoglobin and red blood cell transfusions. Mean hemoglobin (g/L) levels and proportion of patients with red blood cell (RBC) transfusions over time^a; all-treated population. *Zero transfusions recorded at scheduled time point. ^a(A and C) Time points are day 1, 8, 15, and 22 in each cycle, plus day 29 for cycle 6; (B and D) time points are day 1 and 15 in cycle 1, day 1 in cycles 2 to 5, and days 1 and 29 in cycle 6. Q4W: every 4 weeks; QW: weekly; Rux: ruxolitinib.

Figure 4.

Effect of treatment with zinpentraxin alfa on fibrocytes. (A) Mean fibrocyte count and percentage of fibrocytes as a proportion of total cells in the bone marrow (BM) at baseline and week 24^a (N=8); (B) representative fluorescence micrographs of BM biopsies of a patient at baseline and at week 24. In (A) data shown for 8 patients from a single center, who had each completed ≥12 cycles of treatment. Error bars represent standard error. In (B), depicted for 1 patient are DNA (Hoechst 33258; blue), CD45 (Opal 690; red), CD68 (Opal 520; green), and procollagen-I (Opal 570; white). Images are shown in pseudo-colors corresponding to individual channel intensities and as a composite of all 4 channels (Merge). Scale bar, 100 μm. Micrographs are provided at a resolution of 600 px/in. ^aIncludes 1 patient with data from week 20.

Figure 5.

Effect of treatment with zinpentraxin alfa on cytokines. Mean levels of selected cytokines across the treatment period from baseline (BSL) to week 130, showing a significant decrease over the course of treatment (N=5). Plasma was analyzed by combined 40- and 37-plex magnetic bead-based immunoassays. Graphs show mean levels of 8 selected cytokines of interest over time, over the period on treatment (time points T1–7 are defined in the Online Supplementary Figure S5). The data points in green denote significant (P<0.05) on treatment changes relative to BSL in the 5 patients. P values were calculated for each time point using an empirical Bayes moderated t test with a Benjamini & Hochberg adjustment for multiple testing.