ASH News Daily 2013 - Day 3 - (Page B-26)
ASH News Daily
Page B-26
Monday, December 9, 2013
®
career-development
awardS
Scholar Award
«« From Page B-20
hematopoietic and vascular development. He was fortunate to have
Dr. John E. Dick, who inspired a
particular interest in hematopoietic stem cells, join his graduate
supervisory committee.
Dr. Tamplin is very grateful for
the tremendous support he has
received from his mentors and
the ASH Scholar Awards
program. He believes this
award will help him achieve
his career goal of establishing himself as an independent researcher in the field
of hematology and build his
own research group focused
on hematopoietic stem cell
development.
emy of Sciences
in Beijing, China.
He did his postdoctoral training
with Dr. Timothy Springer at
Harvard to study
the structure and
function of cell
adhesion molecules with the foJieqing Zhu, PhD
cus on integrins.
Jieqing Zhu, PhD
Dr. Zhu is an associate inDr. Zhu is intervestigator at the Blood Research ested in understanding the conforInstitute of BloodCenter of Wis- mational regulation of the platelet
consin. He received a PhD degree specific integrin αIIbβ3 (GPIIbIIIa)
in microbiology from the Institute that function as a critical receptor in
of Microbiology, Chinese Acad- thrombosis and hemostasis. With the
KYPROLIS™ (carfilzomib) for Injection
Brief Summary of Prescribing Information. Please see the KYPROLIS package insert
for full prescribing information.
INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple
myeloma who have received at least two prior therapies including bortezomib and an
immunomodulatory agent and have demonstrated disease progression on or within 60 days of
completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full
PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously
over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and
16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment
cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the
dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent
cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see
Dosage and Administration]. The dose is calculated using the patient's actual body surface area at
baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a
body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than
or equal to 20%.
Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma
Cycle 1
Week 1
Week 2
Week 3
Week 4
Day Day Days Day Day Days Day Day Days Days
2
3-7
8
9
10-14 15
16 17-21 22-28
1
KYPROLIS
No
20
20 20
No
20
20
No
No
20
(20 mg/m2):
Dosing
Dosing
Dosing Dosing
Cycles 2 and Beyonda
Week 1
Week 2
Week 3
Week 4
Day Day Days Day Day Days Day Day Days Days
2
3-7
8
9
10-14 15
16 17-21 22-28
1
KYPROLIS
27
No
27 27
No
27
27
No
No
27
Dosing
Dosing
Dosing Dosing
(27 mg/m2):
a If
previous cycle dosage is tolerated.
Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor
lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate
fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in
Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid.
Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS
administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor
patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone
Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of
KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to
27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions].
Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or
reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended
actions and dose modifications are presented in Table 2.
Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment
Hematologic Toxicity
* Grade 3a or 4 Neutropenia
* Grade 4 Thrombocytopenia
[see Warnings and Precautions]
Recommended Action
* Withhold dose.
* If fully recovered before next scheduled dose, continue
at same dose level.
* If recovered to Grade 2 neutropenia or Grade 3
thrombocytopenia, reduce dose by one dose level
(from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to
15 mg/m2).
* If tolerated, the reduced dose may be escalated to the
previous dose at the discretion of the physician.
Non-Hematologic Toxicity
Recommended Action
* Withhold until resolved or returned to baseline.
Cardiac Toxicity
Grade 3 or 4, new onset or worsening of: * After resolution, consider if restarting KYPROLIS at
a reduced dose is appropriate (from 27 mg/m2 to
* congestive heart failure;
20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).
* decreased left ventricular
* If tolerated, the reduced dose may be escalated to the
function;
previous dose at the discretion of the physician.
* or myocardial ischemia
[see Warnings and Precautions]
Pulmonary Hypertension
* Withhold until resolved or returned to baseline.
* Restart at the dose used prior to the event or reduced
[see Warnings and Precautions]
dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2
to 15 mg/m2), at the discretion of the physician.
* If tolerated, the reduced dose may be escalated to the
previous dose at the discretion of the physician.
* Withhold until resolved or returned to baseline.
Pulmonary Complications
* Consider restarting at the next scheduled treatment
* Grade 3 or 4
with one dose level reduction (from 27 mg/m2 to
[see Warnings and Precautions]
20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).
* If tolerated, the reduced dose may be escalated to the
previous dose at the discretion of the physician.
* Withhold until resolved or returned to baseline.
Hepatic Toxicity
* After resolution, consider if restarting KYPROLIS is
* Grade 3 or 4 elevation of
appropriate; may be reinitiated at a reduced dose (from
transaminases, bilirubin or other
27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2)
liver abnormalities
with frequent monitoring of liver function.
[see Warnings and Precautions)]
* If tolerated, the reduced dose may be escalated to the
previous dose at the discretion of the physician.
(continued)
support of the ASH Scholar Award,
Dr. Zhu will investigate the structural role of transmembrane domain
in integrin activation and signaling
and the mechanism of small molecular antagonists induced integrin
conformational change. His research
will help the hematology community better understand the correlation
between integrin structural regulation and cell signaling and how
to control integrin function under
pathologic conditions. He feels the
ASH Scholar Award is a tremendous
support in the field of hematology; it
will bridge the gap between the end
of his training and the emergence of
his NIH fundable project.
Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued)
* Withhold until renal function has recovered to Grade 1
Renal Toxicity
or to baseline and monitor renal function.
* Serum creatinine equal to or
* If attributable to KYPROLIS, restart at the next scheduled
greater than 2 × baseline
treatment at a reduced dose (from 27 mg/m2 to
[see Adverse Reactions]
20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).
* If not attributable to KYPROLIS, restart at the dose used
prior to the event.
* If tolerated, the reduced dose may be escalated to the
previous dose at the discretion of the physician.
* Withhold until resolved or returned to baseline.
Peripheral Neuropathy
* Restart at the dose used prior to the event or reduced
* Grade 3 or 4
dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2
[see Adverse Reactions]
to 15 mg/m2), at the discretion of the physician.
* If tolerated, the reduced dose may be escalated to the
previous dose at the discretion of the physician.
* Withhold until resolved or returned to baseline.
Other
* Grade 3 or 4 non-hematological * Consider restarting at the next scheduled treatment
with one dose level reduction (from 27 mg/m2 to
toxicities
20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).
* If tolerated, the reduced dose may be escalated to the
previous dose at the discretion of the physician.
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.
a
Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg
carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity
delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other
medicinal products. The intravenous administration line should be flushed with normal saline or 5%
Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not
be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution
and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial
preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the
date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The
reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete
preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial
from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL
Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize
foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution
of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow
solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution,
KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear,
colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted
product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and
Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.
6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted
KYPROLIS under various temperature and container conditions are shown in Table 3.
Table 3: Stability of Reconstituted KYPROLIS
Storage Conditions of Reconstituted
KYPROLIS
Stabilitya per Container
Syringe
IV Bag
(D5Wb)
Refrigerated (2°C to 8°C; 36°F to 46°F)
24 hours
24 hours
24 hours
Room Temperature (15°C to 30°C; 59°F to 86°F)
a
Vial
4 hours
4 hours
4 hours
Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.
WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial
Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New
onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or
myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g.,
cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of
patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or
4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk
assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and
IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities
uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater
risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH)
was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of
patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for
pulmonary hypertension until resolved or returned to baseline and consider whether to restart
KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary
Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea
occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage
dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see
Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were
characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial
flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness,
or angina. These reactions can occur immediately following or up to 24 hours after administration of
KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of
reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact
physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis
Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of
patients. Patients with multiple myeloma and a high tumor burden should be considered to be at
greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage
and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt
KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS
causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and
recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of
patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following
KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of
treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment
with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration].
Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been
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