CLINICAL NEWS
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 toler-
able and demonstrated anti-leukemic activity in
patients with 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 dos-
ing, 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 sur-
face of the leukemic cells and one on the surface
of the T cells,” lead study investigator Farhad
Ravandi-Kashani, MBBS, from the University
of Texas MD Anderson Cancer Center, told ASH
Clinical News. These agents have a different mech-
anism of action [from those of] prior antibodies,
he continued. “They 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 on leukemia cells 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 in-
cluded 12 dosing cohorts: The first three cohorts
each included a single patient who received
AMG 330 at 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 pa-
tients completed the first treatment cycle without
experiencing dose-limiting toxicity, they received
up to five additional treatment cycles, until clini-
cal benefit or futility.
At the time of presentation, data were evalu-
able for 40 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.
Participants received a median of one cycle
(range = 1-6 cycles) of AMG 330. Most patients
(n=35; 87.5%) discontinued therapy, most com-
monly due to disease progression (n=27). Six
patients discontinued because of adverse events
(AEs) and two discontinued per request. Only
three patients (7.5%) completed five cycles of
treatment.
Twenty-nine patients (73%) experienced
serious AEs, and 17 AEs were considered related
ASHClinicalNews.org
to AMG 330 treatment. The most frequently
reported serious AEs (observed in >1 patient)
included:
• CRS (n=11)
• febrile neutropenia (n=7)
• pneumonia (n=4)
• leukopenia (n=4)
• pyrexia (n=3)
• thrombocytopenia (n=3)
• subdural hematoma (n=2)
For patients who developed CRS, the researchers
noted, the administration of corticosteroids, vaso-
pressors, and IV fluids, as well as the interruption
of AMG 330, resolved CRS signs and symptoms
in an average of one day.
One patient died on study due to disease
progression, and another patient died due to
intracranial hemorrhage; however, neither death
was deemed related to the study drug.
The initial target dose (480 μg/day) was as-
sociated 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
CRs,” Dr. Ravandi-Kashani reported, including
two patients with CRs at a target dose of 240 μg/
day, with a lead-in dose 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 CRs in latter
cohorts will alleviate that concern, at least for
now,” he noted.
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.
Attendees browse the exhibit hall.
Selinexor Induces
Deep Responses in
Refractory Multiple
Myeloma
More than one-quarter of patients with refractory
multiple myeloma (MM) responded to treatment with a
combination of selinexor and low-dose dexamethasone,
according to results from the pivotal STORM Part 2 trial
presented at the 2018 ASH Annual Meeting. Further,
responses occurred rapidly and most patients achieved
stable disease with this oral combination regimen.
“A growing number of patients are exposed to the
proteasome inhibitors [bortezomib and carfilzomib], im-
munomodulatory agents, and the anti-CD38 monoclonal
antibody daratumumab,” lead investigator Ajai Chari,
MD, from Mount Sinai School of Medicine in New York,
said during his presentation. “But eventually these pa-
tients develop penta-exposed and triple class–refractory
myeloma and have a dismal prognosis.”
In the STORM Part 2 trial, investigators evaluated the
safety and efficacy of selinexor, a first-in-class selective
inhibitor of XPO1, with low-dose dexamethasone in 122
heavily pretreated patients. All participants had been
previously treated and had disease that was refractory to
bortezomib, carfilzomib, lenalidomide, pomalidomide,
daratumumab, an alkylator, and glucocorticoids.
The inclusion criteria were “relatively permissive,” Dr.
Chari noted, although patients were required to have a
creatinine clearance ≥20 mL/min, absolute neutrophil
count ≥1,000/mm 3 , platelets ≥75,000/mm 3 , and hemoglo-
bin ≥8.5 g/dL.
Participants’ median age was 65 years (range = 40-86
years) and more than half (53%) had high-risk cytoge-
netics. The median number of prior lines of therapy was
seven (range = 3-18), with 29.5 percent having received at
least nine prior therapies.
“Patients had rapidly progressive disease and were se-
quencing through many lines of therapy in a short time,”
Dr. Chari reported. He noted that two patients (1.6%)
had disease that progressed even after treatment with
chimeric antigen receptor T-cell therapy.
In STORM, patients were treated with twice-weekly
selinexor 80 mg and dexamethasone 20 mg in 28-day
cycles. “Due to aggressiveness of this disease and based
on preclinical data from phase I studies, STORM treat-
ment begins with high doses of selinexor to obtain rapid
disease control,” Dr. Chari explained.
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