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Genetically modified natural killer immune cells attack, kill leukemia cells
St. Jude lab studies shows that new genetic modification and culture techniques produce NK cells with significantly enhanced ability to eradicate leukemia cells
25-Mar-2005 - Natural killer (NK) immune system cells can be genetically modified to brandish a powerful "on-switch" that prompts them to aggressively attack and kill leukemic cells. This finding, from researchers at St. Jude Children's Research Hospital, suggests a way to improve the outcome of children who receive treatment for acute lymphoblastic leukemia (ALL) or other blood cancers.
Results of the St. Jude study are published in the current online issue of Blood.
The researchers demonstrated how to overcome significant technical hurdles that have until now slowed development of NK-based therapies for ALL, according to Dario Campana, M.D., Ph.D., a member of St. Jude Hematology-Oncology and Pathology, and senior author of the Blood report. Progress in adapting NK cells to the treatment of ALL had been significantly hampered because researchers were not able to grow large numbers of these immune cells in the laboratory, and because NK cells normally have only weak anti-leukemic activity.
The key breakthroughs made by the St. Jude team were the development of a laboratory technique for rapidly producing a large, pure population of NK cells from a small sample of blood; and developing a technique for genetically modifying NK cells so that they would become potent killers when they encountered leukemic cells.
In order to grow large populations of NK cells, the team started with samples of blood containing a variety of different immune system cells. They placed this sample into a dish containing a type of human leukemia cell called K562. Campana's team genetically modified the K562 cells so they carried on their surfaces many copies of two different proteins, 4-1BBL and IL-15. The genetically modified K562 cells quickly stimulated the expansion of the NK cell population to more than10,000 times their original number. The technique triggered growth of NK cells specifically, which greatly simplified the ability of the researchers to collect a pure population of these immune cells.
The researchers then genetically modified the growing NK cells so they carried on their surface an artificial receptor that made them particularly aggressive and effective killers that attacked only leukemic cells. A receptor is a protein that binds to a specific target molecule. The artificial receptor on the NK molecule was designed to recognize a protein called CD19, which is found on the surface of leukemic cells. When the receptor bound to CD19 on leukemic cells, it set off a reaction that super-charged the killing activity of the NK cell.
"By developing a technique for cultivating large numbers of NK cells from a small blood sample, we made it practical to consider them a potential treatment against many different types of cancer," Campana said. "By genetically modifying NK cells so they expressed the CD19 receptor, we made them specifically effective against ALL cells."
A potential clinical application for the technology developed in this study is in leukemia patients who are treated with hematopoietic (blood cell-forming) cell transplantation. In this case, NK cells will be derived from the transplant donor, expanded and genetically modified. These modified NK cells will then be infused into the patient after the transplant in order to eliminate residual leukemic cells. In another application, NK cells could be obtained from a patient while in remission and then reinfused after genetic modification if the patient suffers a resurgence of the leukemia.
"We look forward to seeing this strategy being added to the management of children with ALL," said Chihaya Imai, M.D., the postdoctoral student who did most of the work on this project.
Contact: Bonnie Cameron
[email protected]
901-495-4815
St. Jude Children's Research Hospital
###
The other author of this study is Shotaro Iwamoto, M.D., of St. Jude.
This work was supported in part by the National Cancer Institute and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.
Genzyme buys Bone Care
by Neal Bellucci
By signing a definitive agreement to acquire Bone Care International Inc., Genzyme Corp. welcomes a complementary line of products and a profitable commercial organization that will strengthen and diversify Genzymes renal business. The acquisition, the second major purchase for Genzyme in the past eight months, will be an all-cash transaction valued at $33 per fully diluted share, or about $600 million. With the closing of the deal expected in the third quarter, Genzyme predicts the transaction to be neutral in 2005 and accretive beyond.
Bone Care is a specialty pharmaceutical company engaged in the discovery, development, and commercialization of innovative therapeutic products to treat patients with debilitating conditions and life-threatening diseases.
One key component in the acquisition is Bone Cares Hectorol, a vitamin D2 pro-hormone product used to treat secondary hyperparathyroidism in patients on dialysis, where the drug can be used in tandem with Genzymes Renagel and other phosphate binders. Hectorol, comprising doxercalciferol, is available in intravenous form for patients on hemodialysis, and in oral forms primarily used by patients with earlier-stage chronic kidney disease. The drug is the first and only vitamin D2 analog approved to treat the continuum of chronic kidney disease.
Analysts at Prudential (prudential.com) believe that Hectorol should complement Renagel in the predialysis and dialysis settings. In addition, since Hectorol is only approved in the United States, international expansion of the drug should offer a growth opportunity for Genzyme, these analysts say. Based on the acquisition, Prudential raised its price target for Genzyme to $68 from $67, but maintained a neutral weight rating.
Hectorol comprises sevelamer. Sales reached $59 million for the nine months ended March 31, 2005. Based on strong third-quarter sales, Bone Care increased its revenue guidance April 26 to a range of $82 million to $83 million for fiscal year 2005, which ended June 30, 2005.
"We are tremendously excited for the opportunity to bring these products to Genzyme," says Henri A. Termeer, chairman and CEO, Genzyme (genzyme.com). "The addition of the Bone Care organization and the Hectorol brand will solidify and strengthen our growing renal business, while further broadening our overall product portfolio. This important therapy for patients with earlier stages of chronic kidney disease will provide Genzyme with valuable commercial experience and speed our entry into this much larger market."
The use of Renagel and Hectorol are each supported by a large and growing body of clinical evidence. The two products are well-positioned in the National Kidney Foundations K/DOQI guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Renagel, the only calcium-free, metal-free phosphate binder, controls serum phosphorus levels in patients with chronic kidney disease on hemodialysis. The National Kidney Foundations K/DOQI guidelines recommend sevelamer hydrochloride as a first-line treatment option to reduce phosphorus. Renagel has an established safety profile, is not systemically absorbed, and provides phosphorus control without the concerns of calcium or metal accumulation. Renagel is used by more than 350,000 people worldwide.
Hectorol capsules are a unique pro-hormone vitamin D2 analog formulation indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease stages 3, 4, and 5. Hectorol treats secondary hyperparathyroidism, a condition that impacts a significant number of patients with earlier stages of chronic kidney disease. This condition, if left untreated, can result in bone disease, muscle weakness, reduced immunity, cardiovascular disease, and increased mortality. Genzyme estimates that more than 500,000 patients in the United States with chronic kidney disease stage 3 and stage 4 have elevated parathyroid hormone levels above K/DOQI targets.
Beyond Renagels indication for patients on hemodialysis, Genzyme is developing a next-generation sevelamer for use in hyperphosphatemic patients in earlier stages of chronic kidney disease. Genzyme has begun enrolling patients in a short-term clinical trial of sevelamer carbonate to evaluate the products equivalence to Renagel and anticipates launching a study later this year to evaluate sevelamer carbonates potential to benefit hyperphosphatemic patients with earlier-stage chronic kidney disease.
Genzyme intends to integrate Bone Care into its own renal operations in the United States. In addition, Genzyme will begin immediate work on the registration of Hectorol outside the United States, with particular focus on Europe and Asia. At present, Hectorol is only sold in North America.
"Genzyme has recognized the potential of our strong growth platform and the value our employees bring to patients, clinicians, and shareholders," says Paul Berns, president and CEO, Bone Care (bonecare.com). "We believe that this merger is a tremendous opportunity to optimize Bone Cares global business potential."
In addition to Renagel, Genzyme developed and markets Fabrazyme, an enzyme replacement therapy for Fabry disease, a degenerative disorder that can lead to kidney failure; and Thymoglobulin, a polyclonal antibody product used to treat rejection of a kidney transplant. Genzyme is investigating future treatments focused on polycystic kidney disease and is working to improve renal patient care through support of basic research, disease-awareness initiatives, and treatment access programs.
Bone Care has an active development program for Hectorol and other vitamin D analogs in chronic kidney disease and a range of other diseases, including psoriasis and cancers of the prostate, breast, and colon.
In December 2004, Genzyme completed its acquisition of Ilex Oncology Inc. With the completion of that acquisition, Genzyme gained a cancer drug-development company with a growing marketed product, a second product nearing approval, and a third well into Phase II development. The stock-for-stock transaction was valued at about $1 billion.
The acquisition of Ilex created a solid foundation for Genzymes growing oncology business by adding an emerging commercial presence, a robust pipeline, and a highly regarded clinical-development organization to the company. These assets significantly augmented Genzymes existing research and development programs in oncology and helped to leverage Genzymes expertise in biologics manufacturing and targeted therapeutics.
"Genzyme has conducted important research in oncology for several years," says Duke Collier, executive VP, Genzyme. "With our acquisition of the cancer diagnostics business of Impath Inc. earlier this year, and now with this exciting acquisition of the therapeutics products and development experience of Ilex, Genzyme is taking major steps to build its presence in oncology."
Through the acquisition, Genzyme gained a strong and growing oncology product in Campath, which is indicated in the United States for the treatment of B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and have failed fludarabine therapy. Campath is the first and only monoclonal antibody approved by FDA for the treatment of patients with B-cell chronic lymphocytic leukemia and is being evaluated in a number of clinical trials to potentially expand its use in cancer and other disease areas, including a randomized Phase II trial versus Rebif in treating multiple sclerosis. Rebif is marketed by Serono Inc. (serono.com) and Pfizer Inc. (pfizer.com).
Genzyme gained clofarabine, a next-generation purine nucleoside analog that is believed to inhibit DNA production necessary for cancer cell growth. Clolar, comprising clofarabine, was approved by FDA Dec. 28, 2004, for the treatment of relapsed or refractory acute leukemia in children. Clolar is the first drug to be labeled initially for a pediatric leukemia in more than a decade. Clolar is being investigated for use in pediatric acute myelogenous leukemia and adult acute leukemia, as well as advanced solid tumors.
A second pipeline candidate, in Phase II clinical development, is ILX- 651, a synthetic analog of the natural substance dolastatin that has a unique mechanism of action targeting tubulin. ILX-651 complements Campath and Clolar in that it is directed at solid tumors rather than cancers of the blood. Genzyme has exclusive worldwide rights to ILX-651 in cancer.
For the first quarter of 2005, Genzyme increased revenue to $629.9 million, up from $491.3 million in 2004. GAAP net income was $95.6 million, or 36 cents per diluted share, compared with GAAP net income of $67.9 million, or 29 cents per diluted share, in the first quarter a year ago.
Non-GAAP net income, which excludes amortization and special items, rose to $131.1 million, compared with $85.6 million in first-quarter 2004. Non-GAAP earnings per share increased to 51 cents from 37 cents, including the impact of 18.5 million new shares associated with the acquisition of Ilex in December 2004.
GAAP earnings for the year are expected to increase to $1.72 to $1.78 per diluted share from previous guidance of $1.67 to $1.75. Non-GAAP earnings are expected to increase to $2.12 to $2.18 per diluted share from previous guidance of $2.08 to $2.16 per diluted share.
"We had an excellent first quarter, marked by strong product sales and a significant improvement in our gross margin," Mr. Termeer says. "We are raising our earnings guidance for the year based on this strong start and the greater clarity we have now about our momentum going forward."
Genzymes gross margin in the first quarter was 77% of revenue, up from 74% in the first quarter a year ago. This increase was driven by improved margins for the antiarthritic Synvisc, stemming from the acquisition of U.S. sales rights, along with improved margins for Renagel, and for enzyme-replacement products resulting from increased use of the companys manufacturing facilities.
Genzyme has grown from a small start-up to a diversified enterprise with annual revenue exceeding $2 billion and more than 7,000 employees in locations spanning the globe.
The companys products and services are focused on rare inherited disorders, kidney disease, orthopedics, cancer, transplant and immune diseases, and diagnostic testing.
DESCRIPTION - From Company product information
CLOLAR. For Intravenous Infusion (CLOLAR.;
clofarabine) contains clofarabine, a purine nucleoside
anti-metabolite. CLOLAR. (1 mg/mL) is supplied in a
20 mL, single-use vial. The 20 mL vial contains 20
mg clofarabine formulated in 20 mL unbuffered
normal saline (comprised of Water for Injection,
USP, and Sodium Chloride, USP). The pH range of
the solution is 4.5 to 7.5. The solution is clear and
practically colorless, and free from foreign matter.
The chemical structure of clofarabine is 2-chloro-9-
(2-deoxy-2-fluoro-s-D-arabinofuranosyl)-9H-purin-
6-amine. The molecular formula of clofarabine is
C10H11ClFN5O3 with a molecular weight of 303.68.
CLINICAL PHARMACOLOGY
Mechanism of Action
Clofarabine is sequentially metabolized intracellularly
to the 5f-monophosphate metabolite by
deoxycytidine kinase and mono- and di-phosphokinases
to the active 5f-triphosphate metabolite.
Clofarabine has high affinity for the activating
phosphorylating enzyme, deoxycytidine kinase,
equal to or greater than that of the natural substrate,
deoxycytidine. Clofarabine inhibits DNA
synthesis by decreasing cellular deoxynucleotide
triphosphate pools through an inhibitory action on
ribonucleotide reductase, and by terminating DNA
chain elongation and inhibiting repair through
incorporation into the DNA chain by competitive
inhibition of DNA polymerases. The affinity of clofarabine
triphosphate for these enzymes is similar
to or greater than that of deoxyadenosine triphosphate.
In preclinical models, clofarabine has
demonstrated the ability to inhibit DNA repair by
incorporation into the DNA chain during the repair
process. Clofarabine 5f-triphosphate also disrupts
the integrity of mitochondrial membrane, leading to
the release of the pro-apoptotic mitochondrial proteins,
cytochrome C and apoptosis-inducing factor,
leading to programmed cell death.
Clofarabine is cytotoxic to rapidly proliferating and
quiescent cancer cell types in vitro.
Human Pharmacokinetics
The population pharmacokinetics of CLOLAR.
were studied in 40 pediatric patients aged 2 to 19
years (21 males/19 females) with relapsed or
refractory acute lymphoblastic leukemia (ALL) or
acute myelogenous leukemia (AML). At the given
52 mg/m2 dose, similar concentrations were obtained
over a wide range of body surface areas (BSAs).
Clofarabine was 47% bound to plasma proteins, predominantly
to albumin. Based on non-compartmental
analysis, systemic clearance and volume of
distribution at steady-state were estimated to be
28.8 L/h/m2 and 172 L/m2, respectively. The terminal
half-life was estimated to be 5.2 hours. No apparent
difference in pharmacokinetics was observed
between patients with ALL and AML or between
males and females.
No relationship between clofarabine or clofarabine
triphosphate exposure and toxicity or response
was found in this population.
Based on 24-hour urine collections in the pediatric
studies, 49-60% of the dose is excreted in the urine
unchanged. In vitro studies using isolated human
hepatocytes indicate very limited metabolism (0.2%);
therefore, the pathways of non-renal elimination
remain unknown.
Although no clinical drug-drug interaction studies
have been conducted to date, on the basis of the in
vitro studies, cytochrome p450 inhibitors and inducers
are unlikely to affect the metabolism of clofarabine.
The effect of clofarabine on the metabolism of
cytochrome p450 substrates has not been studied.
The pharmacokinetics of clofarabine have not been
evaluated in patients with renal or hepatic dysfunction.
CLINICAL STUDIES
Sixty-six (66) pediatric ALL patients were exposed
to CLOLAR.. Fifty-eight (58) of the patients
received the recommended pediatric dose of
CLOLAR. 52 mg/m2 daily x 5 as an intravenous
infusion (IVI).
The safety and efficacy of CLOLAR. were evaluated
in pediatric patients with refractory or relapsed
hematologic malignancies in an open-label, doseescalation,
noncomparative study. The starting
dose of CLOLAR. was 11.25 mg/m2/day IVI daily x 5
and escalated to 70 mg/m2/day IVI daily x 5. This
dosing schedule was repeated every 2 to 6 weeks
depending on toxicity and response. Nine of 17 ALL
patients were treated with CLOLAR. 52 mg/m2
daily x 5. In the 17 ALL patients there were 2 complete
remissions (12.5%) and 2 partial remissions
(12.5%) at varying doses. Dose-limiting toxicities
(DLTs) in this study were reversible hyperbilirubinemia
and elevated transaminase levels and skin rash,
experienced at 70 mg/m2. As a result of this study, the
recommended dose for subsequent study in pediatric
patients was determined to be 52 mg/m2/day
for 5 days.
Single Arm Study in Pediatric ALL
A single arm study was conducted in relapsed/
refractory pediatric patients with ALL at a single
dose. All patients had disease that had relapsed
after and/or was refractory to two or more prior
therapies. Most patients, 46/49 (93.8%), had
received 2 to 4 prior regimens and 15/49 (30.6%) of
the patients had undergone at least 1 prior transplant.
The median age of the treated patients was 12
years. There were more males, 29/49 (59.2%), than
females, 20/49 (40.8%). Most of the patients were
either Caucasian (n=20, 40.8%) or Hispanic (n=20,
40.8%), with 12.2% African-American (n=6), and 6.1%
Other race (n=3). All patients received a dose of 52
mg/m2 daily x 5 IVI. There was no dose modification
during the remission induction phase of treatment
(maximum of 2 cycles). Doses could be modified
(reduced/delayed) during the post-induction phase.
There was no dose escalation. The planned study
endpoint was the rate of Complete Remission (CR),
defined as no evidence of circulating blasts or
extramedullary disease, an M1 bone marrow (<5%
blasts), and recovery of peripheral counts [platelets
> 100 x 109/L and absolute neutrophil count (ANC) >
1.0 x 109/L] and Complete Remission in the Absence
of Total Platelet Recovery (CRp), defined as meeting
all criteria for CR except for recovery of platelet
counts to > 100 x 109/L. Partial Response (PR) was also
determined, defined as complete disappearance of
circulating blasts, an M2 bone marrow (> 5% and
< 25% blasts), and appearance of normal progenitor
cells or an M1 bone marrow that did not qualify for CR
or CRp. Transplantation rate was not a study endpoint.
Response rates for these studies were determined
by an unblinded Independent Response Review
Panel (IRRP).
Table 1 summarizes results for the pediatric ALL
study. Responses were seen in both pre-B and
T-cell immunophenotypes of ALL. The median
cumulative dose was 540 mg (range 29-1905 mg) in
1 (42.9%), 2 (38.8%) or 3 or more (18.4%) cycles.
Table 1: Results in Pediatric ALL Study
Of the 15 responding pediatric ALL patients, 6 had
post-clofarabine bone marrow transplantation, so
that duration of response could not be determined.
In the 9 responding patients who were not transplanted,
the response durations for CR were 43, 50,
82, 93+, and 160+ days; for CRp the response duration
was 32 days; and for PR the response durations
were 7, 16, and 21 days.
INDICATIONS AND USAGE
CLOLAR. is indicated for the treatment of pediatric
patients 1 to 21 years old with relapsed or refractory
acute lymphoblastic leukemia after at least two
prior regimens. This use is based on the induction
of complete responses. Randomized trials demonstrating
increased survival or other clinical benefit
have not been conducted.
CONTRAINDICATIONS
None
Clofarabine
Responses n % 95% CI
CR 6 12.2 4.6 to 24.8
CRp 4 8.2 2.3 to 19.6
PR 5 10.2 3.4 to 22.2
n=49
WARNINGS
CLOLAR. should be administered under the supervision
of a qualified physician experienced in the use
of antineoplastic therapy. Suppression of bone marrow
function should be anticipated. This is usually
reversible and appears to be dose dependent. The
use of CLOLAR. is likely to increase the risk of
infection, including severe sepsis, as a result of
bone marrow suppression. Administration of
CLOLAR. results in a rapid reduction in peripheral
leukemia cells. For this reason, patients undergoing
treatment with CLOLAR. should be evaluated and
monitored for signs and symptoms of tumor lysis
syndrome, as well as signs and symptoms of
cytokine release (e.g., tachypnea, tachycardia,
hypotension, pulmonary edema) that could develop
into systemic inflammatory response syndrome
(SIRS)/ capillary leak syndrome, and organ dysfunction.
Physicians are encouraged to give continuous
IV fluids throughout the five days of
CLOLAR. administration to reduce the effects of
tumor lysis and other adverse events. Allopurinol
should be administered if hyperuricemia is expected.
CLOLAR. should be discontinued immediately in
the event of clinically significant signs or symptoms
of SIRS or capillary leak syndrome, either of which
can be fatal, and use of steroids, diuretics, and
albumin considered. CLOLAR. can be re-instituted
when the patient is stable, generally at a lower dose.
Severe bone marrow suppression, including neutropenia,
anemia, and thrombocytopenia, has been
observed in patients treated with CLOLAR.. At initiation
of treatment, most patients in the clinical
studies had hematological impairment as a manifestation
of leukemia. Because of the pre-existing
immunocompromised condition of these patients and
prolonged neutropenia that can result from treatment
with CLOLAR., patients are at increased risk for
severe opportunistic infections. Careful hematological
monitoring during therapy is important, and
hepatic and renal function should be assessed
prior to and during treatment with CLOLAR.
because of CLOLAR.fs predominantly renal excretion
and because the liver is a target organ for CLOLAR.
toxicity. The respiratory status and blood pressure
should be closely monitored during infusion of
CLOLAR..
Hepatic and Renal Impairment
CLOLAR. has not been studied in patients with
hepatic or renal dysfunction. Its use in such patients
should be undertaken only with the greatest caution.
Pregnancy . Teratogenic Effects: Pregnancy
Category D
CLOLAR. (clofarabine) may cause fetal harm when
administered to a pregnant woman.
Clofarabine was teratogenic in rats and rabbits.
Developmental toxicity (reduced fetal body weight
and increased post-implantation loss) and increased
incidences of malformations and variations (gross
external, soft tissue, skeletal and retarded ossification)
were observed in rats receiving 54 mg/m2/day
(approximately equivalent to the recommended
clinical dose on a mg/m2 basis), and in rabbits
receiving 12 mg/m2/day (approximately 23% of the
recommended clinical dose on a mg/m2 basis).
There are no adequate and well-controlled studies
in pregnant women using clofarabine. If this drug is
used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised
to avoid becoming pregnant while receiving treatment
with clofarabine.
PRECAUTIONS
Information for Patients and Caregivers
Physicians are advised to discuss the following
with patients to whom CLOLAR. will be administered
and patient caregivers, as appropriate.
Dehydration/Hypotension
Patients receiving CLOLAR. may experience vomiting
and diarrhea; they should therefore be advised
regarding appropriate measures to avoid dehydration.
Patients should be instructed to seek medical
advice if they experience symptoms of dizziness,
lightheadedness, fainting spells, or decreased urine
output. CLOLAR. administration should be stopped
if the patient develops hypotension for any reason
during the 5 days of administration. If hypotension
is transient and resolves without pharmacological
intervention, CLOLAR. treatment can be re-instituted,
generally at a lower dose.
Concomitant Medications
Since CLOLAR. is excreted primarily by the kidneys,
drugs with known renal toxicity should be
avoided during the 5 days of CLOLAR. administration.
In addition, since the liver is a known target
organ for CLOLAR. toxicity, concomitant use of
medications known to induce hepatic toxicity
should also be avoided. Patients taking medications
known to affect blood pressure or cardiac function
should be closely monitored during administration
of CLOLAR..
Pregnancy/Nursing
All patients should be advised to use effective contraceptive
measures to prevent pregnancy. Female
patients should be advised to avoid breast-feeding
during treatment with CLOLAR..
Laboratory Tests
Complete blood counts and platelet counts should
be obtained at regular intervals during CLOLAR.
therapy, and more frequently in patients who develop
cytopenias. In addition, liver and kidney function
should be monitored frequently during the 5 days of
CLOLAR. administration.
Drug Interactions
Although no clinical drug-drug interaction studies
have been conducted to date, on the basis of the in
vitro studies, cytochrome p450 inhibitors and inducers
are unlikely to affect the metabolism of clofarabine.
The effect of clofarabine on the metabolism of
cytochrome p450 substrates has not been studied.
Drug/Laboratory Tests Interactions
There are no known clinically significant interactions
of CLOLAR. with other medications or laboratory
tests. No formal drug/laboratory test interaction
studies have been conducted with CLOLAR..
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Carcinogenesis
Clofarabine has not been tested for carcinogenic
potential.
Mutagenesis
Clofarabine showed clastogenic activity in the in
vitro mammalian cell chromosome aberration
assay (CHO cells) and in the in vivo rat micronucleus
assay. It did not show evidence of mutagenic activity
in the bacterial mutation assay (Ames test).
Impairment of Fertility
Studies in mice, rats, and dogs have demonstrated
dose-related adverse effects on male reproductive
organs. Seminiferous tubule and testicular degeneration
and atrophy were reported in male mice
receiving intraperitoneal (IP) doses of 3 mg/kg/day
(9 mg/m2/day, approximately 17% of the recommended
clinical dose on a mg/m2 basis). The testes
of rats receiving 25 mg/kg/day (150 mg/m2/day,
approximately 3 times the recommended clinical
dose on a mg/m2 basis) in a 6-month IV study had
bilateral degeneration of the seminiferous epithelium
with retained spermatids and atrophy of interstitial
cells. In a 6-month IV dog study, cell degeneration
of the epididymis and degeneration of the seminiferous
epithelium in the testes were observed in
dogs receiving 0.375 mg/kg/day (7.5 mg/m2/day,
approximately 14% of the recommended clinical dose
on a mg/m2 basis). Ovarian atrophy or degeneration
and uterine mucosal apoptosis were observed in
female mice at 75 mg/kg/day (225 mg/m2/day,
approximately 4-fold of the recommended human
dose on a mg/m2 basis), the only dose administered to
female mice. The effect on human fertility is unknown.
Pregnancy
Teratogenic Effects: Pregnancy Category D
See WARNINGS.
Nursing Mothers
It is not known whether clofarabine or its metabolites
are excreted in human milk. Because of the
potential for tumorigenicity shown for clofarabine
in animal studies and the potential for serious
adverse reactions, women treated with clofarabine
should not nurse.
Other Special Population: Adults
Safety and efficacy have not been established in
adults. One study was performed in highly refractory
and/or relapsed adult patients with hematologic
malignancies. The Phase 2 dose of CLOLAR. was
determined to be 40 mg/m2/day administered as
a 1- to 2-hour IVI daily x 5 every 28 days.
ADVERSE REACTIONS
One hundred thirteen (113) pediatric patients with
ALL (67) or AML (46) were exposed to CLOLAR..
Ninety-six (96) of the pediatric patients treated in
clinical trials received the recommended dose of
CLOLAR. 52 mg/m2 daily x 5.
The most common adverse effects after CLOLAR.
treatment, regardless of causality, were gastrointestinal
tract symptoms, including vomiting, nausea,
and diarrhea; hematologic effects, including anemia,
leukopenia, thrombocytopenia, neutropenia, and
febrile neutropenia; and infection.
Table 2 lists adverse events by System Organ Class
regardless of causality, including severe or lifethreatening
events (NCI CTC grade 3 or grade 4),
reported in .10% of the 96 patients in the 52
mg/m2/day dose group. More detailed information
and follow-up of certain events is given below.
Table 2: Most Commonly Reported (.10% Overall)
Adverse Events by System Organ Class (N=96)
Table 2: Most Commonly Reported (.10% Overall)
Adverse Events by System Organ Class (N=96)
Table 2: Most Commonly Reported (.=10% Overall)
Adverse Events by System Organ Class (N=96)
1 Patients with more than one occurrence of the same
preferred term are counted only once.
Grade 4 includes deaths (Grade 5).
Cardiovascular
The most frequently reported cardiac disorder was
tachycardia (34%), which was, however, already
present in 27.4% of patients at study entry. Most of
the cardiac adverse events were reported in the first
2 cycles. Pericardial effusion was a frequent finding
in these patients on post-treatment studies, [19/55
(35%)]. The effusion was almost always minimal to
small and in no cases had hemodynamic significance.
Left ventricular systolic dysfunction (LVSD) was
also noted. Fifteen out of fifty-five patients [15/55
(27%)] had some evidence of LVSD after study
entry. In most cases where subsequent follow-up
data were available, the LVSD appeared to be transient.
The exact etiology for the LVSD is unclear
because of previous therapy or serious concurrent
illness.
Hepatic
Hepato-biliary toxicities were frequently observed in
pediatric patients during treatment with CLOLAR..
Grade 3 or 4 elevated aspartate aminotransferase
(AST) occurred in 38% of patients and grade 3 or 4
elevated alanine aminotransferase (ALT) occurred in
44% of patients. Grade 3 or 4 elevated bilirubin
occurred in 15% of patients, with 2 cases of grade
4 hyperbilirubinemia resulting in treatment discontinuation.
For patients with follow-up data, elevations in AST
and ALT were transient and typically of <2 weeks
duration. The majority of AST and ALT elevations
occurred within 1 week of CLOLAR. administration
and returned to baseline or . grade 2 within several
days. Although less common, elevations in bilirubin
appeared to be more persistent. Where follow-up
data are available, the median time to recovery
from grade 3 and grade 4 elevations in bilirubin to
. grade 2 was 6 days.
52mg/m2 (N=96)
Total Grade 3 Grade 4
N % n % n %
52mg/m2 (N=96)
Total Grade 3 Grade 4
N % n % n %
System Organ Class
Adverse Event1
Infections and Infestations (cont.)
Oral candidiasis 12 13 2 2 . .
Pneumonia NOS 10 10 5 5 2 2
Sepsis NOS 14 15 7 7 7 7
Staphylococcal
infection NOS 12 13 10 10 . .
Investigations
Weight decreased 10 10 1 1 . .
Metabolism and Nutrition Disorders
Anorexia 30 31 5 5 7 7
Appetite decreased
NOS 11 11 . . . .
Musculoskeletal, Connective Tissue and
Bone Disorders
Arthralgia 11 11 3 3 . .
Back pain 12 13 3 3 . .
Myalgia 13 14 . . . .
Pain in limb 28 29 5 5 . .
Nervous System Disorders
Dizziness
(except vertigo) 15 16 . . . .
Headache NOS 44 46 4 4 . .
Somnolence 10 10 1 1 . .
Tremor NEC 10 10 . . . .
Psychiatric Disorders
Anxiety NEC 21 22 2 2 . .
Depression NEC 11 11 1 1 . .
Irritability 11 11 1 1 . .
Renal and Urinary Disorders
Hematuria 16 17 2 2 . .
Respiratory, Thoracic and Mediastinal Disorders
Cough 18 19 . . . .
Dyspnea NOS 12 13 4 4 2 2
Epistaxis 30 31 14 15 . .
Pleural effusion 10 10 3 3 2 2
Respiratory distress 13 14 6 6 5 5
Skin and Subcutaneous Tissue Disorders
Contusion 11 11 1 1 . .
Dermatitis NOS 39 41 7 7 . .
Dry skin 10 10 1 1 . .
Erythema NEC 17 18 . . . .
52mg/m2 (N=96)
Total Grade 3 Grade 4
N % n % n %
System Organ Class
Adverse Event1
Blood and Lymphatic System Disorders
Febrile neutropenia 55 57 51 53 3 3
Neutropenia 10 10 3 3 7 7
Transfusion reaction 10 10 3 3 . .
Cardiac Disorders
Tachycardia NOS 33 34 6 6 . .
Gastrointestinal Disorders
Abdominal pain NOS 35 36 7 7 . .
Constipation 20 21 . . . .
Diarrhea NOS 51 53 10 10 . .
Gingival bleeding 14 15 7 7 1 1
Nausea 72 75 14 15 1 1
Sore throat NOS 13 14 . . . .
Vomiting NOS 80 83 8 8 1 1
General Disorders and Administration Site Conditions
Edema NOS 19 20 1 1 2 2
Fatigue 35 36 3 3 1 1
Injection site pain 13 14 1 1 . .
Lethargy 11 11 . . . .
Mucosal inflammation
NOS 17 18 3 3 . .
Pain NOS 18 19 6 6 1 1
Pyrexia 39 41 15 16 . .
Rigors 36 38 3 3 . .
Hepato-Biliary Disorders
Hepatomegaly 14 15 8 8 . .
Jaundice NOS 14 15 2 2 . .
Infections and Infestations
Bacteremia 10 10 10 10 . .
Cellulitis 11 11 9 9 . .
Herpes simplex 11 11 6 6 . .
System Organ Class
Adverse Event1
Skin and Subcutaneous Tissue Disorders (cont.)
Palmar-plantar
erythrodysesthesia
syndrome 12 13 4 4 . .
Petechiae 28 29 7 7 . .
Pruritus NOS 45 47 1 1 . .
Vascular Disorders
Flushing 17 18 . . . .
Hypertension NOS 11 11 4 4 . .
Hypotension NOS 28 29 12 13 7 7
Infection
At baseline, 47% of the patients had 1 or more concurrent
infections. A total of 85% of patients experienced
at least 1 infection after CLOLAR. treatment, including
fungal, viral and bacterial infections.
Renal
The most prevalent renal toxicity was elevated
creatinine. Grade 3 or 4 elevated creatinine
occurred in 6% of patients. Nephrotoxic medications,
tumor lysis, and tumor lysis with hyperuricemia
may contribute to renal toxicity.
Systemic Inflammatory Response Syndrome (SIRS)/
Capillary Leak Syndrome
Capillary leak syndrome or SIRS (signs and symptoms
of cytokine release, e.g., tachypnea, tachycardia,
hypotension, pulmonary edema) occurred in
4 pediatric patients overall (3 ALL, 1 AML). Several
patients developed rapid onset of respiratory distress,
hypotension, capillary leak (pleural and pericardial
effusions), and multi-organ failure. Close monitoring
for this syndrome and early intervention are recommended.
The use of prophylactic steroids (e.g., 100
mg/m2 hydrocortisone on Days 1 through 3) may be
of benefit in preventing signs or symptoms of SIRS
or capillary leak. Physicians should be alert to early
indications of this syndrome and should immediately
discontinue CLOLAR. administration if they occur
and provide appropriate supportive measures.
After the patient is stabilized and organ function
has returned to baseline, re-treatment with CLOLAR.
can be considered at a lower dose.
Overdosage
There were no known overdoses of CLOLAR.. The
highest daily dose administered to a human to date
(on a mg/m2 basis) has been 70 mg/m2/day x 5 days
(2 pediatric ALL patients). The toxicities included
in these 2 patients included grade 4 hyperbilirubinemia,
grade 2 and 3 vomiting, and grade 3 maculopapular
rash.
DOSAGE AND ADMINISTRATION
Recommended Dose
CLOLAR. should be diluted per instructions below
with 5% Dextrose Injection, USP, or 0.9% Sodium
Chloride Injection, USP, prior to intravenous infusion
(IVI).
The recommended pediatric dose and schedule is
52 mg/m2 administered by intravenous infusion (IVI)
over 2 hours daily for 5 consecutive days. Treatment
cycles are repeated following recovery or return to
baseline organ function, approximately every 2 to 6
weeks. The dosage is based on the patientfs body
surface area (BSA), calculated using the actual
height and weight before the start of each cycle. To
prevent drug incompatibilities, no other medications
should be administered through the same intravenous
line.
CLOLAR. has not been studied in patients with
hepatic or renal dysfunction. Its use in such patients
should be undertaken only with the greatest caution.
Physicians are encouraged to give continuous IV
fluids throughout the 5 days of CLOLAR. administration
to reduce the effects of tumor lysis and other
adverse events. The use of prophylactic steroids
(e.g., 100 mg/m2 hydrocortisone on Days 1 through
3) may be of benefit in preventing signs or symptoms
of SIRS or capillary leak (e.g., hypotension).
If patients show early signs or symptoms of SIRS or
capillary leak (e.g., hypotension), the physician
should immediately discontinue CLOLAR. administration
and provide appropriate supportive measures.
Close monitoring of renal and hepatic function during
the 5 days of CLOLAR. administration is advised. If
substantial increases in creatinine or bilirubin are
noted, physicians should immediately discontinue
administration of CLOLAR.. CLOLAR. should be
re-instituted when the patient is stable and organ
function has returned to baseline, possibly at a lower
dose. If hyperuricemia is anticipated (tumor lysis),
patients should prophylactically receive allopurinol.
STORAGE AND HANDLING
Vials containing undiluted CLOLAR. should be stored at
259C (779F); excursions permitted to 15-309C (59-869F).
CLOLAR. should be filtered through a sterile 0.2 ’Êm
syringe filter and then further diluted with 5%
Dextrose Injection, USP, or 0.9% Sodium Chloride
Injection, USP, prior to intravenous infusion (IVI). The
resulting admixture may be stored at room temperature,
but must be used within 24 hours of preparation.
HOW SUPPLIED
CLOLAR. is formulated at a concentration of 1 mg/mL
in sodium chloride (9 mg/mL), USP, and Water for
Injection, USP, quantity sufficient (qs) to 1 mL. CLOLAR.
is supplied in 20 mL flint vials in a box of 4 (NDC
58468-0100-2). The 20 mL flint vials contain 20 mL (20
mg) of solution. The pH range of the solution is 4.5 to
7.5. The solution is clear and practically colorless,
is preservative-free, and is free from foreign matter.
Rx only
U.S. Patents:
4,751,221; 4, 918,179; 5,384,310; 5,661,136; 6,680,382 B2.
Other patents pending.
NAME AND ADDRESS OF MANUFACTURER
Manufactured by:
AAI Development Services
Charleston, SC 29405
Manufactured for:
Genzyme Corporation
4545 Horizon Hill Blvd
San Antonio, TX 78229
Distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
c2005 Genzyme Corporation. All rights reserved.
Clolar is a trademark of Genzyme Corporation.
CLO/US/P001/0405
www.clolar.com
800-RX-CLOLAR
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