Page 155 - Haematologica Vol. 109 - July 2024

ARTICLE - Sovleplenib Syk inhibitor in R/R B-cell tumors
Y. Song et al.
patient had received autologous hematopoietic stem cell transplant. As of data cutoff (April 30, 2021), all patients had discontinued treatment; most of them discontinued because of PD (N=44; 41.1%).
Safety/adverse events
Dose escalation
The median duration of exposure was 3.2 months and 92.6% of patients had a relative dose intensity between 80% and 110%.
One patient, two patients, and two patients treated with 200 mg q.d., 200 mg b.i.d., and 800 mg q.d., respectively, experienced dose-limiting toxicity (DLT) events (definitions of DLT are stated in the Online Supplementary Appendix): grade 3 amylase increased (200 mg q.d., dose interruption, resolved without supportive or concomitant treatment), grade 4 hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d., dose interruption, unknown out- come), grade 3 blood bilirubin increased and pneumonia (200 mg b.i.d., treatment discontinuation due to pneumo- nia, both events resolved with supportive or concomitant treatment), grade 3 febrile neutropenia (800 mg q.d., dose interruption, resolved with supportive or concomitant treat- ment), and grade 3 renal failure (800 mg q.d., treatment discontinuation, resolved with supportive or concomitant treatment). The maximum tolerated dose was determined as 600 mg q.d., and the SRC determined this as the rec- ommended dose for dose expansion on December 6, 2017. As of July 30, 2018, of 28 patients treated with 600 mg q.d., nine (32.1%) experienced grade ≥3 treatment-related AE (TRAE) during the first cycle of study treatment. In the exploratory analysis, patients who experienced treat- ment-related grade 3 AE had higher plasma exposure of sovleplenib and tended to have lower body weight (≤65 kg) versus those who experienced no drug-related grade ≥3 AE. In addition, drug exposure was body weight-dependent, evidenced by higher plasma sovleplenib concentration detected in patients with lower body weight. Therefore, weight-based dosing was introduced in the expansion cohort to reduce the risk of grade ≥3 AE in patients with lower body weight. The SRC recommended the RP2D of 600 mg q.d. in patients with a weight of >65 kg and 400 mg q.d. in those with a weight of ≤65 kg. If patients did not experience grade ≥2 AE at the starting dose of 400 mg q.d., after one or two treatment cycles the dose could be increased to 500 mg q.d. to maximize treatment efficacy. All (100%) patients experienced TEAE and, among them, 17 (63.0%) reported grade ≥3 TEAE. No fatal TEAE were re- ported. TEAE leading to treatment discontinuation occurred in five (18.5%) patients, including pneumonia in two (7.4%) patients (1 in 200 mg q.d. and 1 in 200 b.i.d.) and renal failure, malignant pleural effusion and anemia in one patient each. Pneumonia (1 patient in 200 mg b.i.d.), renal failure and anemia were considered possibly related to treatment, and the other TEAE were unlikely related. The event of malignant
pleural effusion was resolved with closed thoracentesis drainage. All (100%) patients had TRAE (Table 2); 13 (48.1%) patients had grade ≥3 TRAE. Five patients experienced treatment-related serious AE, including pneumonia (N=2; 200 mg q.d. and 200 mg b.i.d.), upper respiratory infection (N=1; 200 mg q.d.), blood bilirubin increased (N=1; 200 mg b.i.d.), interstitial lung disease (N=1; 600 mg q.d.), renal failure (N=1; 800 mg q.d.) and febrile neutropenia (N=1; 800 mg q.d.). All treatment-related serious AE were grade 3 and recovered/resolved with symptomatic treatment, dose modification and/or dose discontinuation. Thirteen (48.1%) patients reported TEAE leading to dose interruption or reduction; most common (≥2 patients) were neutrophil count decreased (18.5%), white blood cell count decreased (11.1%), blood bilirubin increased (7.4%), pneumonia (7.4%) and febrile neutropenia (7.4%).
Dose expansion
The median duration of exposure was 3.7 months (range, 0.1-35.7 months); 91.6% of patients had a relative dose intensity between 80% and 110%.
During dose expansion, 106 (99.1%) patients reported TEAE; among them, 105 (98.1%) were related to study drug (Table 2). The most common (≥30%) TRAE included neutrophil count decreased (60.7%), aspartate aminotransferase in- creased (51.4%), white blood cell count decreased (50.5%), alanine aminotransferase increased (44.9%), anemia (32.7%) and platelet count decreased (31.8%). The common grade ≥3 TRAE with an incidence of ≥5% included neutrophil count decreased (29.9%), pneumonia (12.1%), white blood cell count decreased (11.2%) and platelet count decreased (9.3%). Four (3.7%) patients (1 patient in cohort B and 3 patients in cohort D) experienced grade 1-2 blood lactate dehydrogenase increased; among these, two events were considered as treatment related. TEAE leading to death were reported in five (4.7%) patients, including one case each of sudden cardiac death, platelet count decreased, interstitial lung disease, pneumonia and acute kidney injury; all were considered treatment-related (possibly related). In addition, 20 (18.7%) patients experienced TEAE that led to treatment discontinuation, among which pneumonia (N=5; 4.7%) and interstitial lung disease (N=3; 2.8%) were most common. No notable difference was observed among cohorts for the incidence of TEAE leading to treatment discontinuation.
Tumor response
Dose escalation
Based on the EEAS (N=23), the overall ORR during dose escalation was 21.7% (95% CI: 7.5-43.7), where five patients (21.7%; 4 FL and 1 SLL) achieved partial response (PR), at 400 mg q.d. (1 PR), 600 mg q.d. (3 PR) and 200 mg b.i.d. (1 PR), and none achieved complete response (CR). In ad- dition, nine (39.1%) achieved stable disease (SD). Of five responders, median TTR (mTTR) was 3.6 months (95% CI:
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