First-in-Human Trial Shows AMG 330 Is Tolerable in Relapsed/Refractory AML

AMG 330, an anti-CD33 bispecific T-cell engager (BiTE®) antibody construct, was generally tolerable and demonstrated anti-leukemic activity in patients with pretreated relapsed/refractory acute myeloid leukemia (AML), according to results from a first-in-human trial presented at the 2018 ASH Annual Meeting.

The researchers also found that step-up dosing, pretreatment with corticosteroids, and the administration of tocilizumab and intravenous (IV) fluids also was an effective strategy for mitigating the risk of cytokine release syndrome (CRS) – a major expected toxicity of this type of treatment.

“Bispecific T-cell engager antibodies, as the term implies, have two targets – one on the surface of the leukemic cells and one on the surface of the T cells,” Farhad Ravandi-Kashani, MBBS, lead study investigator from The University of Texas MD Anderson Cancer Center in Houston, told ASH Clinical News. These agents have a different mechanism of action than prior antibodies, he continued. “These agents work by bringing the T cells to close proximity of the leukemic cells, allowing T-cell–mediated killing of the leukemic cells, so BiTEs rely more on the patient’s immune system to kill the leukemic cells.”

In this phase I, dose-escalation study, the researchers sought to establish the optimal dosing schedule of AMG 330 (which is designed to bind CD33 and CD3 proteins on T cells) in adults with AML that was relapsed and/or refractory to at least one treatment course.

Participants began treatment with “an extremely low dose of the drug,” Dr. Ravandi-Kashani said, “so, in the initial cohorts, we did not expect to see much activity.” The study included 12 dosing cohorts: The first thee cohorts included a single patient who received AMG 330 0.5 μg to 4 μg/day as a continuous IV infusion; subsequent cohorts comprised three to six patients who received AMG 330 10 μg to 240 μg/day.

Dosing followed a stepwise approach: If patients completed the first treatment cycle without experiencing dose-limiting toxicity, they received up to five additional treatment cycles, until clinical benefit.

As of June 14, 2018, data were evaluable for 35 patients, who had received a median of four prior treatments (range = 1-15 treatments).

A primary outcome of interest in this study was response to therapy, which was defined by the revised International Working Group criteria, as well as complete response (CR) with incomplete hematologic recovery (CRi).

Participants received a median of one cyle (range = 1-6 cycles) of AMG 330. Most patients (n=31; 89%) discontinued therapy, most commonly due to disease progression (n=24). Five patients discontinued because of adverse events (AEs) and two discontinued per request. Only one patient received and completed the maximum of six treatment cycles, while three patients were still receiving AMG 330 as of data presentation.

Twenty-three patients (66%) experienced serious AEs, and 15 of these were considered related to AMG 330 treatment. The most frequently reported serious AEs (observed in >1 patient) included:

  • CRS (n=11)
  • febrile neutropenia (n=6)
  • pneumonia (n=4)
  • leukopenia (n=3)
  • thrombocytopenia (n=2)
  • subdural hematoma (n=2)

One patient died due to disease progression; however, the patient death was not deemed related to the study drug.

Two patients developed severe CRS: one patient in the 10 μg/day and one in the 30 μg/day cohort. The administration of corticosteroids, vasopressors, and IV fluids, as well as the interruption of AMG 330 resolved CRS signs and symptoms in one day, the researchers noted.

The initial target dose (480 μg/day) was associated with dose-limiting toxicities, including grade 2 CRS and grade 4 ventricular fibrillation, leading investigators to reduce the target dose to 240 μg/day.

“In the latter cohorts, we have seen complete responses,” Dr. Ravandi-Kashani reported, at the following dose levels: 240 μg/day with a lead-in of 10 μg/day to 60 μg/day.

“One of the concerns with any drug that targets a marker that also is expressed on normal myeloid cells is that it can cause … cytopenias, but I think the occurrence of two complete responses in latter cohorts will alleviate that concern, at least for now.”

These results indicate that stepwise dosing of AMG 330 “is a viable strategy” in relapsed/refractory AML, Dr. Ravandi-Kashani concluded. “We hope that, with an increased number of patients treated and further adjustment of doses, we can get much higher responses.”

Limitations of the analysis include its lack of a randomized design, lack of a placebo control or treatment comparator group, and the small number of patients in the current cohort.

The authors report financial relationships with Amgen, the manufacturer of AMG 330 and the sponsor of this trial.

Reference

Ravandi D, Stein AS, Kantarjian HM, et al. A phase 1 first-in-human study of AMG 330, an anti-CD33 bispecific T-cell engager (BiTE®) antibody construct, in relapsed/refractory acute myeloid leukemia (R/R AML). Abstract #25. Presented at the 2018 ASH Annual Meeting, December 1, 2018; San Diego, CA.

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