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treatment because of AEs , and this was consistent across all cohorts , the researchers reported . Four participants discontinued treatment because of grade ≥3 pneumonia , which the authors said was possibly related to both ibrutinib and carfilzomib .
“ Despite known cardiac toxicities associated with carfilzomib and ibrutinib as individual agents , the cardiac AEs with the combination did not meet DLT criteria and were manageable with re-challenge or
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dose reduction ,” the researchers observed . Five patients ( 12 %) required an ibrutinib dose reduction , and eight ( 19 %) required a carfilzomib dose reduction .
The median time on study was 20.5 months for all patients ( range not reported ), and at the time of analysis , one patient remained on study . Other than AEs , reasons for treatment discontinuation included progressive disease ( n = 18 ; 42 %), patient withdrawal ( n = 6 ; 14 %), and
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investigator decision ( n = 5 ; 12 %).
Thirteen deaths occurred from progressive disease ( n = 8 ), infections ( n = 4 ), and metastatic non small – cell lung cancer ( n = 1 ). Two deaths related to infection occurred after subsequent anti-cancer therapy .
Of the 42 patients who were evaluable for response ( secondary endpoint ), the clinical benefit rate ( defined as at least a minimal response ) was 76 percent and the overall response rate ( defined as at least a
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partial response ) was 67 percent ( see TABLE on page 39 ). At the time of analysis , 29 percent of patients with a partial response or better ( n = 8 / 28 ) were alive and their disease had not progressed .
The overall progression-free survival ( PFS ) was 7.2 months ( range = 0.2-20.3 months ). In the expansion cohorts 2b and 3b , median PFS was 8.1 months ( range = 1.4-16.3 months ) and 6.4 months ( range = 0.2-20.3 months ). The median overall survival was not reached in any cohorts .
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ADYNOVATE [ Antihemophilic Factor ( Recombinant )]
Rx Only
Lyophilized Powder for Reconstitution for Intravenous Injection BRIEF SUMMARY : Consult the Full Prescribing Information for complete product information .
CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE , to the parent molecule ( ADVATE ), mouse or hamster protein , or excipients of ADYNOVATE ( e . g . Tris , mannitol , trehalose , glutathione , and / or polysorbate 80 ).
WARNINGS and PRECAUTIONS
Hypersensitivity Reactions Hypersensitivity reactions are possible with ADYNOVATE . Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with other recombinant antihemophilic factor VIII products , including the parent molecule , ADVATE . Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema , chest tightness , dyspnea , wheezing , urticaria , and pruritus . Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur .
Neutralizing Antibodies Formation of neutralizing antibodies ( inhibitors ) to factor VIII can occur following administration of ADYNOVATE . Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests . Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected , or if bleeding is not controlled with expected dose .
Monitoring Laboratory Tests
• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained .
• Monitor for the development of factor VIII inhibitors . Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present . If
USE IN SPECIFIC POPULATIONS expected factor VIII activity plasma levels are not attained , or if bleeding is not controlled with the expected dose of ADYNOVATE , use Bethesda Units ( BU ) to determine inhibitor levels .
ADVERSE REACTIONS
The most common adverse reactions ( ≥1 % of subjects ) reported in the clinical studies were headache and nausea .
Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice .
The safety of ADYNOVATE was evaluated in 237 previously treated patients ( PTPs ) and 6 previously untreated patients ( PUPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 3 completed multi-center , prospective , open label clinical studies and 4 ongoing clinical studies . The median duration of participation per subject was 401 ( min-max : 3-1034 ) days and the median number of exposure days to ADYNOVATE per subject was 111 ( min-max : 1-322 ). Following are the adverse reactions reported during clinical studies .
Adverse reactions reported for ADYNOVATE as shown by Percent of Subjects , Number of subjects (%, n ) ( N = 243 ) and Rate of AEs per 100 infusions ( N = 30865 ). Reported adverse reactions are listed by MedDRA System Organ Class followed by MedDRA Preferred Term . Gastrointestinal Disorders : Diarrhea ( 0.4 %, n = 1 ) ( 0.003 rate of AE ), Nausea ( 0.8 %, n = 2 ) ( 0.006 rate of AE ); Immune System Disorder : Hypersensitivity a ( 0.4 %, n = 1 ) ( 0.003 rate of AE ); Nervous System Disorders : Headache ( 2.1 %, n = 5 ) ( 0.026 rate of AE ); Skin and Subcutaneous Tissue Disorders , Rash ( 0.4 %, n = 1 ) ( 0.003 rate of AE ); and Vascular Disorders : Flushing ( 0.4 %, n = 1 ) ( 0.003 rate of AE ).
a
The event of hypersensitivity was a mild transient non-serious rash , occurring in one 2-year old patient who had developed a previous rash while on ADYNOVATE .
Immunogenicity The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3 completed and 4 ongoing clinical trials . Subjects consisted of adolescent and adult ( n = 148 with ≥150 prior EDs ) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs ( n = 32 ), ≥6 years of age with ≥150 prior EDs ( n = 57 )], and pediatric PUPs ( n = 6 ). In 191 adult and pediatric PTPs who were treated for at least 50 exposure days with
Patented : see www . shire . com / legal-notice / product-patents /
ADYNOVATE , the factor VIII inhibitor frequency was 0 ( 95 % CI of 0 to 0.019 ). Shire Lexington , MA 02421 USA Printed in USA Issued 11 / 2016 S40815 06 / 18
One PUP subject from an ongoing study , who received at least one infusion of ADYNOVATE , developed neutralizing antibodies to factor VIII .
Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII , PEGylated ( PEG ) -factor VIII , PEG and Chinese hamster ovary ( CHO ) protein using validated ELISA assays . The majority of subjects ( 238 / 243 ) with at least one infusion of ADYNOVATE did not develop a persistent binding antibody response to any of these antigens . Twenty-eight subjects in total showed pre-existing antibodies to factor VIII ( n = 3 ), PEG-factor VIII ( n = 25 ) and / or PEG ( n = 3 ) prior to the first exposure to ADYNOVATE . Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII ( n = 6 ), PEG-FVIII ( n = 8 ) at one or two consecutive study visits . Antibodies were transient and not detectable at subsequent visits . Five subjects showed positive results for binding antibodies at study completion or at the time of data cutoff . Binding antibodies that were detected prior to exposure to ADYNOVATE , that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters . There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data . No subject had pre-existing or treatment-emergent antibodies to CHO protein .
The detection of antibodies that are reactive to factor VIII is highly dependent on many factors , including : the sensitivity and specificity of the assay , sample handling , timing of sample collection , concomitant medications and underlying disease . For these reasons , comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading .
Pregnancy : Risk Summary There are no data with ADYNOVATE use in pregnant women to inform a drug-associated risk . Animal reproduction studies have not been conducted with ADYNOVATE . It is unknown whether ADYNOVATE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity . ADYNOVATE should be given to a pregnant woman only if clearly needed . In the U . S . general population , the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively .
Lactation : Risk Summary There is no information regarding the presence of ADYNOVATE in human milk , the effect on the breastfed infant , or the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for ADYNOVATE and any potential adverse effects on the breastfed infant from ADYNOVATE or from the underlying maternal condition .
Pediatric Use Safety and efficacy studies have been performed in 91 previously treated , pediatric patients age 1 year to < 18 years who received at least one dose of ADYNOVATE as part of routine prophylaxis , on-demand treatment of bleeding episodes , or perioperative management . Adolescent subjects age 12 to < 18 ( n = 25 ) were enrolled in the adult and adolescent safety and efficacy trial , and subjects < 12 years of age ( n = 66 ) were enrolled in a pediatric trial . The safety and efficacy of ADYNOVATE in routine prophylaxis and the treatment of bleeding episodes were comparable between children and adults . Pharmacokinetic studies in children (< 12 years ) have demonstrated higher clearance , a shorter half-life and lower incremental recovery of factor VIII compared to adults . Because clearance ( based on per kg body weight ) has been demonstrated to be higher in children (< 12 years ), dose adjustment or more frequent dosing based on per kg body weight may be needed in this population .
Geriatric Use Clinical studies of ADYNOVATE did not include subjects aged 65 and over .
© 2018 Shire US Inc ., Lexington , MA 02421 . All rights reserved . 1-800-828-2088 . SHIRE and the Shire Logo are registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates .
ADYNOVATE and ADVATE are registered trademarks of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc .
Adding ibrutinib to a standard backbone treatment “ resulted in promising and durable responses .”
In high-risk patients ( defined as those with either del17p and / or t [ 4 ; 14 ]), the median PFS was 8.1 months ( range = 1.1-15.6 months ), with an estimated one-year PFS rate of 30 percent , which , the authors highlighted , was similar to responses seen in patients with standard-risk disease . “ Additionally , the median PFS in patients refractory to prior IMiDs and proteasome inhibitors was 6.4 months ( range = 0.2-20.3 months ), with an estimated one-year PFS rate of 33 percent and was comparable with those who were not double-refractory .”
Adding ibrutinib to a standard backbone treatment of carfilzomib and dexamethasone “ resulted in promising and durable responses ,” the authors concluded , noting that this early-phase study is limited by its small patient population . An ongoing phase IIb study is assessing the pharmacodynamics of this combination . ●
The corresponding authors report no conflicts of interest . Pharmacyclics , an AbbVie Company , provided editorial support .
REFERENCE
Chari A , Larson S , Holkova B , et al . Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma . Leuk Lymphoma . 2018 April 4 . [ Epub ahead of print ]
July 2018