ASH News Daily 2016 - Issue 3 - A-22

ASH News Daily

Page A-22

Monday, December 5, 2016

Hemophilia
«« From Page A-3

hepatocytes. Dr. Amit C. Nathwani
and colleagues previously incorporated a course of steroids to rescue
FIX expression following AAV8mediated gene transfer in four of
six subjects treated at a dose of 2 ×
1012 vg/kg resulting in long-term
expression of FIX of approximately
5 percent. (Nathwani et al. N Engl
J Med. 2014;371:1994-2004). With
SPK-9001, you "get more bang for
your buck." By using the FIX-Padua
transgene there is increased FIX activity, so a lower vector dose can be
used to minimize the need for im-

munosuppression while still obtaining therapeutic FIX levels of around
30 percent. The optimal target FIX
level is unknown. "It is a balance between increasing the vector dose and
risking an immune response, versus
having a consistent and predictable
response with a lower dose."
Patients are not eligible for the
study if they have high neutralizing
antibodies to the AAV capsid. This
study reported a 40 percent rate of
pre-existing neutralizing antibodies
to the capsid, Spark-100, that is used
in this trial. "This is a vulnerability
of all the AAV trials and isn't specific to SPK-9001," said Dr. George.
Strategies to overcome the barrier

INDICATIONS AND USAGE
ADCETRIS is a CD30-directed antibody-drug conjugate indicated for the treatment of patients with classical
Hodgkin Lymphoma (HL) at high risk of relapse or progression as post-auto-HSCT consolidation.

CONTRAINDICATIONS
ADCETRIS is contraindicated with concomitant bleomycin due to pulmonary toxicity (e.g., interstitial
infiltration and/or inflammation).
WARNINGS AND PRECAUTIONS
Peripheral Neuropathy (PN)
ADCETRIS treatment causes a PN that is predominantly sensory. Cases of motor PN have also been
reported. ADCETRIS-induced PN is cumulative. In the relapsed classical HL and sALCL clinical trials,
54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution,
31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy,
51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms
of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation,
neuropathic pain, or weakness. Patients experiencing new or worsening PN may require a delay, change
in dose, or discontinuation of ADCETRIS.
Anaphylaxis and Infusion Reactions
Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during
infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS
and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should
be interrupted and appropriate medical management instituted. Patients who have experienced a prior
infusion-related reaction should be premedicated for subsequent infusions. Premedication may include
acetaminophen, an antihistamine, and a corticosteroid.
Hematologic Toxicities
Prolonged (≥1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with
ADCETRIS. Febrile neutropenia has been reported with treatment with ADCETRIS. Complete blood counts
should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered
for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops,
consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses.
Serious Infections and Opportunistic Infections
Serious infections and opportunistic infections such as pneumonia, bacteremia, and sepsis or septic
shock (including fatal outcomes) have been reported in patients treated with ADCETRIS. Patients should
be closely monitored during treatment for the emergence of possible bacterial, fungal or viral infections.
Tumor Lysis Syndrome
Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis
syndrome. Monitor closely and take appropriate measures.
Increased Toxicity in the Presence of Severe Renal Impairment
The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal
impairment compared to patients with normal renal function. Due to higher monomethyl auristatin E
(MMAE) exposure, ≥Grade 3 adverse reactions may be more frequent in patients with severe renal
impairment compared to patients with normal renal function. Avoid the use of ADCETRIS in patients with
severe renal impairment [creatinine clearance (CLcr) <30 mL/min].
Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment
The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe
hepatic impairment compared to patients with normal hepatic function. Avoid the use of ADCETRIS in
patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.
Hepatotoxicity
Serious cases of hepatotoxicity, including fatal outcomes, have occurred in patients receiving ADCETRIS.
Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin.
Cases have occurred after the first dose of ADCETRIS or after ADCETRIS rechallenge. Preexisting liver
disease, elevated baseline liver enzymes, and concomitant medications may also increase the risk.
Monitor liver enzymes and bilirubin. Patients experiencing new, worsening, or recurrent hepatotoxicity
may require a delay, change in dose, or discontinuation of ADCETRIS.
Progressive Multifocal Leukoencephalopathy
JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients.
First onset of symptoms occurred at various times from initiation of ADCETRIS therapy, with some
cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible
contributory factors include prior therapies and underlying disease that may cause immunosuppression.
Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central
nervous system abnormalities. Hold ADCETRIS dosing for any suspected case of PML and discontinue
ADCETRIS dosing if a diagnosis of PML is confirmed.
Pulmonary Toxicity
Events of noninfectious pulmonary toxicity including pneumonitis, interstitial lung disease, and acute
respiratory distress syndrome (ARDS), some with fatal outcomes, have been reported. Monitor patients for
signs and symptoms of pulmonary toxicity, including cough and dyspnea. In the event of new or worsening
pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious Dermatologic Reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), including fatal outcomes, have
been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate
medical therapy.

Gastrointestinal (GI) Complications
Fatal and serious GI complications including perforation, hemorrhage, erosion, ulcer, intestinal
obstruction, enterocolitis, neutropenic colitis, and ileus have been reported in ADCETRIS-treated
patients. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event
of new or worsening GI symptoms, perform a prompt diagnostic evaluation and treat appropriately.
Embryo-Fetal Toxicity
Based on the mechanism of action and findings in animals, ADCETRIS can cause fetal harm when
administered to a pregnant woman. There are no adequate and well-controlled studies of ADCETRIS in
pregnant women. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased
embryo viability and fetal malformations, in animals at maternal exposures that were similar to the
clinical dose of 1.8 mg/kg every 3 weeks. Advise females of reproductive potential to avoid pregnancy
during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS. If ADCETRIS
is used during pregnancy or if the patient becomes pregnant during ADCETRIS treatment, the patient
should be apprised of the potential risk to the fetus.
ADVERSE REACTIONS
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may
not reflect the rates observed in practice.
In a placebo-controlled trial of ADCETRIS in 329 patients with classical HL at high risk of relapse or progression
post-auto-HSCT, the most common adverse reactions (≥20%) in the ADCETRIS-treatment arm, regardless
of causality, were neutropenia, peripheral sensory neuropathy, thrombocytopenia, anemia, upper respiratory
tract infection, fatigue, peripheral motor neuropathy, nausea, cough, and diarrhea. The most common adverse
reactions occurring in at least 10% of patients, using the NCI CTC Version 4, are shown in Table 1.
Summary of Clinical Trial Experience in Classical HL Post-auto-HSCT Consolidation (Study 3)
ADCETRIS was studied in 329 patients with classical HL at high risk of relapse or progression post-autoHSCT in a randomized, double-blind, placebo-controlled clinical trial in which the recommended starting
dose and schedule was 1.8 mg/kg of ADCETRIS administered intravenously over 30 minutes every 3 weeks
or placebo for up to 16 cycles. Of the 329 enrolled patients, 327 (167 brentuximab vedotin, 160 placebo)
received at least one dose of study treatment. The median number of treatment cycles in each study arm
was 15 (range, 1-16) and 80 patients (48%) in the ADCETRIS-treatment arm received 16 cycles.
Standard international guidelines were followed for infection prophylaxis for herpes simplex virus (HSV),
varicella-zoster virus (VZV), and Pneumocystis jiroveci pneumonia (PCP) post-auto-HSCT. Overall, 312
patients (95%) received HSV and VZV prophylaxis with a median duration of 11.1 months (range, 0-20)
and 319 patients (98%) received PCP prophylaxis with a median duration of 6.5 months (range, 0-20).
Table 1: Most Commonly Reported (≥10% in the ADCETRIS arm) Adverse Reactions in Study 3
ADCETRIS
Total N = 167
% of patients
Adverse Reaction
Blood and lymphatic system disorders
Neutropenia*
Thrombocytopenia*
Anemia*
Nervous system disorders
Peripheral sensory neuropathy
Peripheral motor neuropathy
Headache
Infections and infestations
Upper respiratory tract infection
General disorders and administration site conditions
Fatigue
Pyrexia
Chills
Gastrointestinal disorders
Nausea
Diarrhea
Vomiting
Abdominal pain
Constipation
Respiratory, thoracic and mediastinal disorders
Cough
Dyspnea
Investigations
Weight decreased
Musculoskeletal and connective tissue disorders
Arthralgia
Muscle spasms
Myalgia
Skin and subcutaneous tissue disorders
Pruritus
Metabolism and nutrition disorders
Decreased appetite

Placebo
Total N = 160
% of patients

Any
Grade

Grade
3

Grade
4

Any
Grade

Grade
3

Grade
4

78
41
27

30
2
4

9
4
-

34
20
19

6
3
2

4
2
-

56
23
11

10
6
2

16
2
8

1
1
1

24
19
10

2
2
-

18
16
5

3
-

22
20
16
14
13

3
2
2
2
2

8
10
7
3
3

1
-

21
13

16
6

18
11
11

1
1

9
6
4

*Derived from laboratory values and adverse reaction data
Additional Important Adverse Reactions
Peripheral neuropathy
In Study 3, 67% of patients treated with ADCETRIS experienced any grade of neuropathy. The median time
to first onset of any grade was 14 weeks (range, 0.1-47), of Grade 2 was 27 weeks (range, 0.4-52) and of
Grade 3 was 34 weeks (range, 7-106). The median time from onset to resolution or improvement of any
grade was 23 weeks (range, 0.1-138), of Grade 2 was 24 weeks (range, 1-108) and of Grade 3 was 25
weeks (range, 2-98). Of the patients who reported neuropathy, 59% had complete resolution and 41% had
residual neuropathy (26% partial improvement, 15% no improvement) at the time of their last evaluation.
Infusion reactions
Two cases of anaphylaxis were reported in the dose-finding trials. In Study 3, infusion-related reactions
were reported in 25 patients (15%) in the ADCETRIS-treated arm and 3 patients (2%) in the placebo arm.
Grade 3 events were reported in 3 of the 25 ADCETRIS-treated patients who experienced infusion-related
reactions. No Grade 4 infusion-related reactions were reported. The most common adverse reactions (≥2%)
associated with infusion-related reactions were nausea (4%), chills (4%), dyspnea (2%), headache (2%),
pruritus (2%), rash (2%), back pain (2%), and vomiting (2%).
Pulmonary Toxicity
In a trial in patients with classical HL that studied ADCETRIS with bleomycin as part of a combination
regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported

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DOSAGE AND ADMINISTRATION
Dosage Recommendations
Administer ADCETRIS as an intravenous infusion over 30 minutes every 3 weeks.
For classical HL post-auto-HSCT consolidation treatment, initiate ADCETRIS treatment within 4-6 weeks
post-auto-HSCT or upon recovery from auto-HSCT. These patients should continue treatment until a
maximum of 16 cycles, disease progression, or unacceptable toxicity.
The recommended dose is 1.8 mg/kg up to 180 mg. Reduce the dose in patients with mild hepatic
impairment (Child-Pugh A) to 1.2 mg/kg up to 120 mg. Avoid use in patients with moderate (Child-Pugh B)
or severe (Child-Pugh C) hepatic impairment or severe renal impairment (CLcr <30 mL/min).
Dose Modification
Peripheral Neuropathy: For new or worsening Grade 2 or 3 neuropathy, dosing should be held until
neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral
neuropathy, ADCETRIS should be discontinued.
Neutropenia: The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to
baseline or Grade 2 or lower. Consider G-CSF prophylaxis for subsequent cycles in patients who experience
Grade 3 or 4 neutropenia in the previous cycle. In patients with recurrent Grade 4 neutropenia despite the
use of G-CSF prophylaxis, consider discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg.

Dr. Skeith has no relevant conflicts of
interest.

LASERS PRINTED AT

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

is that they are going to have more
choices," Dr. George stated, noting
that gene therapy has the potential
to have a huge impact for patients.
And if gene therapy holds to its
promise, said the presenter, "it's
hard to compete with a one-time
treatment that results in sustained
expression of the protein you're
lacking."
The current phase I/IIa trial of
SPK-9001 is continuing to enroll
patients over the next year, with
follow-up of subjects planned over
five years.

70%

ADCETRIS (brentuximab vedotin) for injection, for intravenous use
Brief Summary: see package insert for complete prescribing information
®

of neutralizing antibodies in hemophilia gene therapy trials deserve
further study.
Dr. Armand Keating reflected
on novel therapies, including SPK9001: "There's been a great deal of
innovation here that is based on existing biology and science. It's moving [the field] forward in an innovative way that's going to have a real
impact on patient care."
What does gene therapy mean
for the future of hemophilia care?
"What is really exciting in the realm
of hemophilia is that there are several novel therapeutics, gene therapy
being one of them, that show great
promise. What it means for patients

Table of Contents for the Digital Edition of ASH News Daily 2016 - Issue 3