Phase I Study of Tq-B3101 in Pediatric Patients with Relapsed/Refractory Anaplastic Lymphoma Kinase Positive Anaplastic Large Cell Lymphoma

Background Anaplastic large cell lymphoma (ALCL) accounts for 10-30% of childhood lymphomas, and 90% of pediatric and adolescent patients (pts) are Anaplastic Lymphoma Kinase positive ALCL (ALK+ ALCL). The results of ADVL0912 (NCT00939770) and A8081013 (NCT01121588) studies suggest that the ALK inhibitor crizotinib has good efficacy and safety in the treatment of ALK+ALCL. The recommended pediatric dose of crizotinib is 280 mg/m² orally twice daily until disease progression or unacceptable toxicity. TQ-B3101 is a novel kinase inhibitor for ROS1, ALK, and c-MET kinases. After oral administration, TQ-B3101 undergoes deacetylation to form crizotinib. In animal models, TQ-B3101 significantly inhibited the phosphorylation of AKT and extracellular signal-regulated kinase 1/2 (ERK1/2) in ALK downstream signaling pathway in tumor tissue, with a longer inhibition time and stronger inhibition compared to equimolar crizotinib. This study aimed to explore the safety and efficacy of TQ-B3101 in pediatric patients with ALK+ ALCL.

Methods TQ-B3101-II-02 is an open-label, single-arm, phase I dose escalation and pharmacokinetic study. Eligible pts were 10 to 18 years of age with relapsed/refractory (R/R) ALK+ALCL. We used a 3+3 design to determine the maximum tolerated dose (MTD). The dose levels to be investigated were 200mg BID, 250mg BID, and 300mg BID. Dose-limiting toxicities (DLT) were defined in cycle one (28-day) as any grade 4 hematologic toxicity or any grade 3 non-hematologic toxicity, except for alopecia and electrolyte disturbances that resolved within 3 days. The primary endpoints were safety and pharmacokinetics (PK). Secondary endpoints included overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Responses were evaluated by investigators per the 2014 Lugano classification based on positron emission tomography/computed tomography (PET/CT) scans. This trial was registered at www.clinicaltrials.gov as # NCT04306887.

Results All seven patients enrolled were evaluable for toxicities and response, with four males/three females, a median age of 12 years (range, 10-14 years), a median weight of 40.0 kg (range, 32.9-68.0 kg), a median height of 152.0 cm (range, 143.5-169.5 cm), and a median body surface area (BSA) 1.27 m² (range, 1.15-1.73 m²). Three patients, three patients, and one patient with ALCL were treated at doses of 200mg, 250mg, and 300mg, respectively. The majority of patients (57.1%) had a median Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 1. Two patients had a refractory disease and five had relapsed disease. Histological diagnosis of ALK-positive ALCL was confirmed by immunohistochemistry. The area under the curve (AUC)_(0-t) of the three dose groups after the first administration were 492 ± 285, 606 ± 288, and 914 μg/L*h, respectively, and the AUC(0-t) after the last administration was 2311 ± 997, 3749 ± 407, 3311 μg/L*h. The in vivo exposure of deacetylated metabolites generated after a single dose was lower than that of crizotinib, and after 28 days of continuous dosing, the in vivo exposure was similar to that of crizotinib (BSA-adjusted dose). The most frequently reported treatment-related adverse events (TRAEs) were hypothyroidism (n = 6), vomit (n = 6), reduced neutrophil count (n = 6). Four pts (57.1%) had grade 3-4 TRAEs. No treatment-related death and DLTs were observed. The ORR was 100%, with four patients achieving complete response (CR) and three patients achieving a partial response (PR). The median time to respond was 1.9 months (range 1.8, 2.0). Six pts had a ≥ 60% tumor reduction. As of the cut-off date of July 22, 2022, the four pts with CR received TQ-B3101 beyond 20 cycles (range, 20-34 cycles) and remained progression-free at 18.7 to 27.9 months. The three pts with PR progressed after 3 to 4 cycles of treatment and discontinued TQ-B3101. One patient voluntarily withdrew from the study. All seven patients were still alive, with the longest survival time of more than 32 months.

Conclusion Our preliminary results suggest that TQ-B3101 has significant clinical activity in children with R/R ALK+ ALCL. Responses were durable and ongoing, and treatment was well tolerated. Further investigation is warranted to find the MTD and confirm the efficacy of TQ-B3101.

No relevant conflicts of interest to declare.