Rovadicitinib in Patients with Hemophagocytic Lymphohistiocytosis: A Single Arm, Open-Label, Phase I Study

Introduction:

Rovadicitinib (TQ05105) is a novel, oral, small molecule JAK/ROCK inhibitor which inhibits cell proliferation, induces cell apoptosis and decreases inflammatory cytokines by affecting the JAK-STAT signaling pathway in preclinical studies. Rovadicitinib demonstrated significant clinical benefits in myelofibrosis patients for spleen response or improved symptom response (NCT04339400/NCT05020652). Here we report the primary results of the phase I study of rovadicitinib in patients with hemophagocytic lymphohistiocytosis (HLH) (NCT04326348).

Methods:

Subjects must be at least 18 years of age, eastern cooperative oncology group (ECOG) performance status of 0 to 3; life expectancy more than 3 months, diagnosed as new or relapsed HLH according to the HLH-2004 criteria and interrupt other HLH treatment before the first rovadicitinib treatment at least one week. To protect subjects safety, glucocorticoid without drug withdrawal, but can not increase dose level during the study period. Eligible patients received escalating doses of oral rovadicitinib 15 mg BID, 20 mg BID, 25 mg BID, 30 mg BID of each 28-day cycle, and a modified “3 + 3” design was used. Treatment continued until eight weeks, progressive disease, unacceptable toxicity or the subject was judged by the investigator to be ineligible to continue the study (whichever came first). The primary outcomes were the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The secondary end points were pharmacokinetic parameters and preliminary efficacy results.

Results:

Between July 17, 2020, and April 24, 2022, 11 patients were assessed for eligibility and enrolled. The median age was 39 years (IQR 26-61). 7 (64%) patients were male. 5 (45%) patients with EBV-HLH, 3 (27%) patients with MAS, 2 (18%) patients with unclear-HLH, 1 (9%) patient with lymphoma-HLH. All patients were treated with glucocorticoid, 3 (27%) patients were treated with DEP regimen. 8 (73%) patients with splenomegaly, 8 (73%) patients with ferritin increase, 7 (64%) patients with soluble CD25 increase, 6 (55%) patients with NK cell activity decrease, 6 (55%) patients with anemia. The median hemoglobin was 90 g/L (IQR 69-140) , the median blood platelet count was 195 x 10⁹/L (IQR 78-381), the median neutrophil count was 2.65 x 10⁹/L (IQR 0.94-15.02). The number of patients enrolled per dose level was two at 15 mg BID, four at 20 mg BID, three at 25 mg BID, and two at 30 mg BID. The dose-limiting toxicitie (DLT) and MTD had not been found. 91% (10/11) patients occurred treatment-emergent adverse events (TEAEs). The most common TEAEs were white blood cell count decrease (5/11, 45.5%), lymphocyte count decrease (5/11, 45.5%), anemia (4/11, 36.4%), platelet count decrease (3/11, 27.3%) and pyrexia (3/11, 27.3%). Grade ≥3 TEAEs were reported in 27.3% (3/11) patients, inclued white blood cell count decrease (2/11, 18.2%), lymphocyte count decrease (1/11, 9.1%) and pyrexia (1/11, 9.1%). There was no death related to rovadicitinib. TEAEs were generally manageable. Rovadicitinib and active metabolite TQ12550 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Terminal half-life about 3 h. No accumulation trend was noted. The overall response rate (ORR) was 54.5% (6/11) at week 8. Four subjects with HLH unresponsive to glucocorticoid therapy ORR was 100% when treated by rovadicitinib and glucocorticoid, included two subjects with macrophage activation syndrome (MAS). Given the safety profile, efficacy and pharmacokinetic parameters, 25 mg BID was identified as RP2D.

Conclusions:

Rovadicitinib was generally safe, well-tolerated in patients with HLH, and showed clinical activity when combined with glucocorticoid. Rovadicitinib combined with glucocorticoid may be a new treatment option for patients with HLH unresponsive to glucocorticoid therapy. Meanwhile, a phase Ib/II study is ongoing, aiming to assess the efficacy and safety of rovadicitinib in patients with MAS unresponsive to glucocorticoid therapy.