CLINICAL NEWS
Latest & Greatest
FDA Approves
Betrixaban for Venous
Thromboembolism
The U.S. Food and Drug Administration
(FDA) has approved betrixaban for the
prophylaxis of venous thromboembolism
(VTE) in adults hospitalized for an acute
medical illness who are at risk for throm-
boembolic complications (related to lim-
ited mobility or other risk factors for VTE).
Betrixaban is now the fifth FDA-approved
oral anticoagulant on the market.
The decision was based on data
from the phase III APEX trial – a
double-blind, international study that
randomized 7,513 patients to receive
either extended-duration betrixaban
(betrixaban 160 mg orally on day 1, then
80 mg daily for 35-42 days, followed by
a placebo injection once-daily for 6-14
days) or short-duration enoxaparin
(enoxaparin 40 mg subcutaneously once-
daily for 6-14 days followed by an oral
placebo pill once-daily for 35-42 days).
Patients in the betrixaban arm
experienced fewer VTE events (including
asymptomatic or symptomatic proximal
deep vein thrombosis, non-fatal
pulmonary embolism, or VTE-related
death): 4.4 percent versus 6 percent
(relative risk = 0.75, 95% CI 0.61-0.91).
One or more adverse events (AEs)
occurred in 54 percent of patients
receiving betrixaban, compared with 52
percent receiving enoxaparin. The most
common AEs (observed in ≥5% of pa-
tients) associated with betrixaban were
involved bleeding. Treatment discon-
tinuation related to AEs was reported
in 2.4 percent of patients receiving
betrixaban and 1.2 percent of patients
receiving enoxaparin, and bleeding was
the most common reason for treatment
discontinuation.
The drug can be administered only to
patients who have received at least one full
dose of intravenous (IV) rituximab. The
approval offers patients a subcutaneous
route of rituximab administration that
shortens administration time from several
hours to five to seven minutes. The new
product also allows for flat dosing.
Its indications cover the following
previously approved indications for IV
rituximab:
• relapsed/refractory FL, as a single agent
• previously untreated FL, in combi-
nation with firstline chemotherapy;
and, in patients achieving a complete
or partial response to rituximab in
combination with chemotherapy, as
single-agent maintenance therapy
• non-progressing (including stable
disease) FL, as a single agen t
after firstline cyclophosphamide,
vincristine, and prednisone
chemotherapy
• previously untreated DLBCL, in
combination with cyclophosphamide,
doxorubicin, vincristine, prednisone,
or other anthracycline-based
chemotherapy regimens
• previously untreated and previously
treated CLL, in combination with
fludarabine and cyclophosphamide
The approval was based on multiple
randomized clinical trials in which
rituximab and hyaluronidase demon-
strated rituximab trough concentration
(C trough ) levels that were non-inferior
to IV rituximab 375 mg/m 2 and IV
rituximab 500 mg/m 2 . Efficacy and
safety outcomes were also comparable
between the two products.
The FDA has approved the subcutane-
ous injection formula of rituximab and
hyaluronidase for the treatment of adults
with follicular lymphoma (FL), diffuse
large B-cell lymphoma (DLBCL), or
chronic lymphocytic leukemia (CLL).
ASHClinicalNews.org
Source: Seattle Genetics press release, June 19, 2017.
Pembrolizumab Trials
Halt Enrollment After
Patient Deaths
The FDA placed a clinical hold on three
trials evaluating the PD-1 inhibitor
pembrolizumab in patients with multiple
myeloma (MM) following reports of
patient deaths and a review of the Data
Monitoring Committee.
Two trials have been placed on full
clinical hold:
• KEYNOTE-183: Patients with
relapsed/refractory MM received
pomalidomide and low-dose
dexamethasone with or without
pembrolizumab.
Source: U.S. Food and Drug Administration news release, June 22, 2017.
Source: U.S. Food and Drug Administration news release, June 23, 2017.
FDA Approves
Rituximab and
Hyaluronidase
Combination for
Several Lymphomas
The manufacturer reached the deci-
sion after a review of unblinded data
from the randomized, double-blind,
placebo-controlled CASCADE study
and consultation with the Independent
Data Monitoring Committee. Patients
assigned to receive vadastuximab
talirine in combination with hypometh-
ylating agents (HMAs; azacitidine or
decitabine) had higher rates of death
(including fatal infections) than those
in the control arm (in which patients
received only HMAs).
The drug’s manufacturer also noted
that no new deaths appeared to be asso-
ciated with hepatotoxicity, an AE linked
to the four patient deaths that led to a
clinical hold in December 2016. The hold
was lifted in March 2017.
Calling the results “disappointing and
unexpected,” the manufacturer intends
to consult with the FDA to determine
future plans for the drug.
All Clinical Trials of
Vadastuximab Talirine
Suspended Following
Patient Deaths
Seattle Genetics, Inc., announced the
discontinuation of the phase III CASCADE
trial of vadastuximab talirine (also known
as SGN-CD33A) in older patients with
newly diagnosed with acute myeloid
leukemia (AML) amid rising concerns
about patient deaths. It is also suspend-
ing patient enrollment and treatment in
all vadastuximab talirine clinical trials.
• KEYNOTE-185: Patients with newly
diagnosed and treatment-naïve MM
who were ineligible for autologous
hematopoietic cell transplantation
received lenalidomide and low-dose
dexamethasone with or without
pembrolizumab.
One trial has been placed on partial
clinical hold:
• KEYNOTE-023: Patients who
received prior anti-MM treatment
with an immunomodulatory
treatment (lenalidomide,
pomalidomide, or thalidomide)
received pembrolizumab in
combination with lenalidomide
and dexamethasone.
More deaths were observed in the
pembrolizumab-treated arms of
KEYNOTE-183 and KEYNOTE-185,
which led to a pause in new patient
enrollment. The FDA determined
that available data indicated that
the risks of pembrolizumab plus
immunomodulatory treatment
outweighed any potential benefits.
All patients enrolled in
KEYNOTE-183 and KEYNOTE-185
and those in the pembrolizumab
cohort of KEYNOTE-023 will
discontinue investigational treatment
with pembrolizumab, but the clinical
hold does not apply to other studies
evaluating pembrolizumab treatment.
Sources: Merck press release, June 12, 2017, and July 5, 2017.
NIH Will Not Cap
Funding to Individual
Laboratories
The National Institutes of Health (NIH) is
dropping its controversial proposal to limit
grant funding to individual laboratories. The
agency announced the plan in May 2017,
with a goal of freeing up funding for young-
er researchers and correcting an imbalance
in the distribution of research funds.
However, many in the research com-
munity pushed back on the proposal,
claiming that the limits would discourage
collaboration and divert funding from
talented, proven investigators. Following
the criticism, NIH announced that it will
instead increase support for early-career
principal investigators through its Next
Generation Researchers Initiative. The
agency will designate $210 million in
funding in 2017 and increase that to
approximately $1.1 billion per year after
five years.
The increased budget will benefit
first-time grant applicants, labs losing
NIH support, and mid-career scientists
(those with ≤10 years of experience as a
principal investigator).
NIH Director Francis Collins, MD,
PhD, said the new funding would be a
result of a “reprioritization of funds,” but no
further details were provided. “We are shift-
ing toward a bold, more focused approach
to bolster support to early- and mid-career
investigators while we continue to work
with experts on approaches to evaluate our
research portfolio,” Dr. Collins wrote in a
statement on the agency’s website.
Visit grants.nih.gov/ngri.htm for
more information on Next Generation
Researchers Initiative grants. ●
Sources: The Boston Globe, June 8, 2017; National Institutes of Health
Director’s Blog post, June 8, 2017.
ASH Clinical News
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