San Diego, CA—In a first-in-human study of a novel bispecific T-cell engager (BiTE), AMG 420, when administered at a daily dose of 400 mcg, this novel drug induced responses in 7 of 10 patients with heavily pretreated multiple myeloma in a phase 1 clinical trial, according to results presented at ASH 2018.
Among patients who responded to treatment with this new BiTE, which targets B-cell maturation antigen (BCMA), 4 patients had no detectable cancer, said Max S. Topp, MD, Department Head, Department of Internal Medicine, University Hospital Würzburg, Germany.
Responses were observed at lower dose levels, but most patients showed robust responses starting at 400 mcg daily, Dr Topp said. Based on positive results from this dose-escalation study, the FDA granted AMG 420 a fast-track designation status.
In the study, AMG 420 was administered for up to 10 cycles to 42 patients, depending on their response. Single-patient cohorts received treatment with 0.2 to 1.6 mcg daily during the run-in phase, followed by cohorts of 3 to 6 patients who received 3.2 mcg to 800 mcg daily doses of this new BiTE. Patients received treatment in 4-week cycles, followed by 2 weeks off.
The “off-the-shelf” nature of the anti-BCMA BiTE platform is considered an advantage in that patients do not have to wait several weeks to receive treatment, but this platform requires continuous infusion for 4 weeks of every 6-week cycle.
Overall, 11 patients had objective responses at the data cutoff point. After the cutoff point, 2 additional responses were recorded, for an objective overall response rate (ORR) of 31% (13 of 42 patients). The ORR was 70% in patients who received the daily 400-mcg dose. In addition to the 4 patients who achieved complete responses with the 400-mcg daily dose, another 3 patients had complete responses using lower daily doses of AMG 420.
In the overall cohort, 4 patients had partial responses at the data cutoff, and 2 additional patients had partial responses after data cutoff. The median time to any response was 1.4 months, and the median time to best response was 2.8 months. Overall, 6 patients were still responding at 7.5 months of follow-up.
Study participants had multiple myeloma for a median of 5.4 years. During that time, they received a median of 4 therapies and up to 13. Overall, 11 (26%) patients had previously received daratumumab (Darzalex), 4 (10%) had received elotuzumab (Empliciti), and 35 (83%) had had a transplant. In addition, 55% of patients had disease refractory to immunomodulatory drugs, 45% had disease refractory to a proteasome inhibitor, and 31% had disease refractory to both.
The maximum tolerated dose of AMG 420 was 400 mcg daily. A dose-limiting peripheral polyneuropathy was reported with the 400-mcg daily dose, but this was resolved after intravenous immunoglobulin and corticosteroid treatment.
At the 800-mcg daily dose, 2 of 3 patients had dose-limiting grade 3 events—cytokine release syndrome and peripheral polyneuropathy.
“To our surprise, it took us many, many cohorts…until we hit the ceiling in defining [dose-limiting side effects]. In this study, 800 mcg was deemed to be intolerable for the patients,” Dr Topp said.
Serious adverse events were reported in 48% of patients, including 17 who required hospitalization, 4 of whom had a prolonged hospitalization. Treatment-related serious adverse events included 2 cases of grade 3 peripheral polyneuropathy and 1 case of grade 3 edema.
Of the 16 patients who had cytokine release syndrome, 13 cases were grade 1. No grade 3 or 4 central nervous system events were reported.
Of the 42 patients, 12 had infections, 7 of which were grade 3. Pneumonia (7%) and central venous catheter line infections (7%) were the most common serious infections.