"AMG 330 is a CD33 BiTE® molecule under investigation in an ongoing, open-label phase I dose-escalation study and has shown preliminary activity and acceptable safety in relapsed/refractory AML patients."
AMG 330 was safe and tolerable with the most common and expected adverse event (AE) being cytokine release syndrome (CRS) when used in patients with relapsed/refractory acute myeloid leukemia (AML)according to preliminary results from an open label phase I dose escalation study presented at the 2020 ASCO Virtual Scientific Program.1
AMG 330 is a canonical BiTE®(Bispecific T-cell engager) molecule that binds to CD3+ T cells and CD33+ AML blasts, which results in T-cell activation and cytotoxicity toward AML blasts.2
"CD33 is expressed on AML blasts in approximately 99% of AML cases and is used as a target tumor antigen," the researchers wrote. "AMG 330 is a CD33 BiTE® molecule under investigation in an ongoing, open-label phase I dose-escalation study and has shown preliminary activity and acceptable safety in relapsed/refractory AML patients."
Across all doing schedules, all patients reported a treatment-emergent adverse event (AE) of any grade. In total, 90% of patients reported an AMG 330-related AE of any grade, including CRS (67%), skin disorders (58%), elevated liver function (25%), gastrointestinal disorders (30%), blood and lymphatic disorders (23%), metabolism and nutrition disorders (18%), respiratory disorders (17%), nervous system disorders (17%), and musculoskeletal disorders (13%). Grade 3 or higher AEs included CRS (15%), skin disorders (10%), elevated liver function (5%), febrile neutropenia (17%), and decreased appetite (2%).
"AMG 330 was safe and tolerable in relapsed/refractory AML patients, with (cytokine release syndrome [CRS]) as the most frequent expected mode of toxic action-based toxicity, and without unexpected toxicities to date," Farhad Ravandi-Kashani, MD, Department of Leukemia, Division of Cancer Medicine, The Universtiy of Texas MD Anderson Cancer Center, said during a presentation.
CRS, which occurred in a dose/schedule-dependent manner, was reversible and most events occurred within 24 hours of administration of the triggering AMG 330 dose. Of note, higher grades of CRS were also seen in patients with higher leukemic burden at baseline and with higher Effector:Target ratio. The frequency and severity of CRS depended on the dose schedule and the targeted dose level, as well as higher levels of cytokines released in response to AMG 330 treatments. "At later cohorts, the frequency and severity of CRS may be mitigated by early use of tocilizumab (Actemra)," Ravandi-Kashani said.
Eight patients responded to AMG 330 treatment including 3 patients with a complete response (CR), 4 patients with complete remission with incomplete hematologic recovery (CRi), and 1 patient with morphologic leukemia free state (MLFS). For those who experienced CR/CRi, the minimal efficacious dose was established at 120 µg/day.
Responses were observed after the first cycle and sustained for a median of 38.5 days (range, 14-121) during the on-study period. Of note, following Cri, 1 patient treated in cohort 15 was bridged to allogenic hematopoietic stem cell transplant (HSCT).
Of those with a CR/CRi (17%), 57% had an adverse cytogenetic risk profile, compared with non-responders. Lower leukemic burden in the blood and bone marrow was associated with a higher likelihood of patients responded to AMG 330; however, there was no correlation between CD33 expression on AML blasts at baseline and patient responses to the agent.
In total, 20% of patients with less than 4 prior therapies and 14% of patients who received 4 or more lines of therapy responded to AMG 330 treatment. Among responders, 43% received 4 or more prior lines of therapy. Moreover, those with a higher number of prior therapies showed a trend toward decreased Effector:Target ratio and increased PD-1 expression on their T cells. "Higher Effector:Target ratio and lower PD-1 expression on T cells at baseline showed a trend towards better clinical response," Ravandi-Kashani said.
The researchers aimed to establish safety and tolerability of AMG 330 and to identify the phase II recommended dose. Patients were included in the study if they were aged ≥18 years; had a confirmed relapsed or refractory AML diagnosis; ≥1 prior therapies, including HSCT; had > 5% blasts in bone marrow, and ECOG score of ≤ 2.
AMG 330 was evaluated as a continuous IV infusion using a 3+3 design. Response was assessed per revised IWG criteria. Each cycle (2–4 weeks duration) was followed by an infusion-free interval.
The researchers evaluated AMG 330 as a continuous intravenous (IV) infusion in a 14-28 days cycle using a 3+3 design. AMG 330 was administered on 4 schedules (0–3 dose steps) prior to the target dose (0.5–720 µg/day). To evaluate clinical pharmacokinetics, the researchers analyzed serum concentrations of AMG 330 using a validated, GLP compliant, electro-chemiluminescence assay. Pharmacokinetics were characterized using a non-compartmental and population-based approach using non-linear effects modeling.
AMG 330 was administered on 4 schedules (0–3 dose steps) prior to the target dose (0.5–720 µg/day). Dose steps were implemented in the dose schedule design based on the adverse event (AE) profile. "The optimized schedule of AMG 330 administration using dose steps allowed for higher targeted dose levels with improved drug exposure," Ravandi-Kashani explained.
The researchers examined relationships between AMG 330 exposures, baseline characteristics with efficacy, and incidence of cytokine release syndrome (CRS).
As of December 10, 2019, 55 patients were enrolled in 16 cohorts. Patients were a median age of 58 years, and the majority were white (77%), male (55%), and responded to prior therapies (73%) – with 48% receiving a median 4 or more therapies before. Moreover, 45% of patients had prior HSCT.
Ravandi-Kashani noted that the AMG 330 dose escalation study is continuing to accrue patients to the next target dose level.