ASH Annual Meeting Preview
swath of institutions including academia , clinical trial specialists , representatives from industry , and the U . S . Food and Drug Administration ( FDA ), are as follows :
• Sumithra J . Mandrekar , PhD , Alliance Statistics and Data Center , Mayo Clinic , Rochester , Minnesota
• Laurie H . Sehn , MD , British Columbia Cancer Agency , Vancouver , BC , Canada
• Ann T . Farrell , MD , U . S . Food and Drug Administration , Bethesda , Maryland
• Stephanie Seremetis , MD , Novo Nordisk A / S , Plainsboro , New Jersey
Everyone will analyze , as a case study , a couple of recent drug approvals . We will also discuss how to move forward so that all constituencies can agree on how to achieve the goal of getting drugs to pass as quickly and as safely as possible .
Discuss the new trial designs that will be covered in this session – why were they implemented ? Granting accelerated approval to investigational
DARZALEX FASPRO ® ( daratumumab and hyaluronidase-fihj ) injection , for subcutaneous use Brief Summary of Full Prescribing Information
INDICATIONS AND USAGE Multiple Myeloma
DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma :
• in combination with bortezomib , melphalan and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant .
• in combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy .
• in combination with bortezomib , thalidomide , and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant .
• in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy .
• in combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor .
• as monotherapy , in patients who have received at least three prior lines of therapy including a proteasome inhibitor ( PI ) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent .
Light Chain Amyloidosis
DARZALEX FASPRO in combination with bortezomib , cyclophosphamide and dexamethasone is indicated for the treatment of adult patients with newly diagnosed light chain ( AL ) amyloidosis .
This indication is approved under accelerated approval based on response rate [ see Clinical Studies ( 14.1 ) in Full Prescribing Information ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial ( s ).
Limitations of Use
DARZALEX FASPRO is not indicated and is not recommended for the treatment of patients with light chain ( AL ) amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials [ see Warnings and Precautions ].
CONTRAINDICATIONS DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab , hyaluronidase or any of the components of the formulation [ see Warnings and Precautions and Adverse Reactions ].
WARNINGS AND PRECAUTIONS Hypersensitivity and Other Administration Reactions Both systemic administration-related reactions , including severe or life-threatening reactions , and local injection-site reactions can occur with DARZALEX FASPRO . Fatal reactions have been reported with daratumumab-containing products , including DARZALEX FASPRO [ see Adverse Reactions ].
Systemic Reactions In a pooled safety population of 832 patients with multiple myeloma ( N = 639 ) or light chain ( AL ) amyloidosis ( N = 193 ) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy , 9 % of patients experienced a systemic administration-related reaction ( Grade 2 : 3.5 %, Grade 3 : 0.8 %). Systemic administration-related reactions occurred in 8 % of patients with the first injection , 0.4 % with the second injection , and cumulatively 1 % with subsequent injections . The median time to onset was 3.2 hours ( range : 9 minutes to 3.5 days ). Of the 129 systemic administration-related reactions that occurred in 74 patients , 110 ( 85 %) occurred on the day of DARZALEX FASPRO administration . Delayed systemic administration-related reactions have occurred in 1 % of the patients .
Severe reactions included hypoxia , dyspnea , hypertension and tachycardia . Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms , such as bronchospasm , nasal congestion , cough , throat irritation , allergic rhinitis , and wheezing , as well as anaphylactic reaction , pyrexia , chest pain , pruritus , chills , vomiting , nausea , and hypotension .
Pre-medicate patients with histamine-1 receptor antagonist , acetaminophen and corticosteroids [ see Dosage and Administration ( 2.5 ) in Full Prescribing Information ]. Monitor patients for systemic administration-related reactions , especially following the first and second injections . For anaphylactic reaction or life-threatening ( Grade 4 ) administration-related reactions , immediately and permanently discontinue DARZALEX FASPRO . Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed ( defined as occurring the day after administration ) systemic administration-related reactions [ see Dosage and Administration ( 2.5 ) in Full Prescribing Information ].
Local Reactions In this pooled safety population , injection-site reactions occurred in 8 % of patients , including Grade 2 reactions in 0.6 %. The most frequent (> 1 %) injection-site reaction was injection site erythema . These local reactions occurred a median of 5.5 minutes ( range : 0 minutes to 6.5 days ) after starting administration of DARZALEX FASPRO . Monitor for local reactions and consider symptomatic management .
DARZALEX FASPRO ® ( daratumumab and hyaluronidase-fihj ) injection
Cardiac Toxicity in Patients with Light Chain ( AL ) Amyloidosis Serious or fatal cardiac adverse reactions occurred in patients with light chain ( AL ) amyloidosis who received DARZALEX FASPRO in combination with bortezomib , cyclophosphamide and dexamethasone [ see Adverse Reactions ]. Serious cardiac disorders occurred in 16 % and fatal cardiac disorders occurred in 10 % of patients . Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk . Patients with NYHA Class IIIB or IV disease were not studied .
Monitor patients with cardiac involvement of light chain ( AL ) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate .
Neutropenia Daratumumab may increase neutropenia induced by background therapy [ see Adverse Reactions ].
Monitor complete blood cell counts periodically during treatment according to manufacturer ’ s prescribing information for background therapies . Monitor patients with neutropenia for signs of infection . Consider withholding DARZALEX FASPRO until recovery of neutrophils . In lower body weight patients receiving DARZALEX FASPRO , higher rates of Grade 3-4 neutropenia were observed .
Thrombocytopenia Daratumumab may increase thrombocytopenia induced by background therapy [ see Adverse Reactions ].
Monitor complete blood cell counts periodically during treatment according to manufacturer ’ s prescribing information for background therapies . Consider withholding DARZALEX FASPRO until recovery of platelets .
Embryo-Fetal Toxicity Based on the mechanism of action , DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman . DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density . Advise pregnant women of the potential risk to a fetus . Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose [ see Use in Specific Populations ].
The combination of DARZALEX FASPRO with lenalidomide , thalidomide or pomalidomide is contraindicated in pregnant women , because lenalidomide , thalidomide or pomalidomide may cause birth defects and death of the unborn child . Refer to the lenalidomide , thalidomide or pomalidomide prescribing information on use during pregnancy .
Interference with Serological Testing Daratumumab binds to CD38 on red blood cells ( RBCs ) and results in a positive Indirect Antiglobulin Test ( Indirect Coombs test ). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration . Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient ’ s serum [ see References ( 15 )]. The determination of a patient ’ s ABO and Rh blood type are not impacted [ see Drug Interactions ].
Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO . Type and screen patients prior to starting DARZALEX FASPRO [ see Dosage and Administration ( 2.1 ) in Full Prescribing Information ].
Interference with Determination of Complete Response Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis ( SPE ) and immunofixation ( IFE ) assays used for the clinical monitoring of endogenous M-protein [ see Drug Interactions ]. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein .
ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling :
• Hypersensitivity and Other Administration Reactions [ see Warning and Precautions ].
• Cardiac Toxicity in Patients with Light Chain ( AL ) Amyloidosis [ see Warning and Precautions ].
• Neutropenia [ see Warning and Precautions ].
• Thrombocytopenia [ see Warning and Precautions ].
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 the clinical trials of another drug and may not reflect the rates observed in practice .
Newly Diagnosed Multiple Myeloma
In Combination with Bortezomib , Melphalan and Prednisone The safety of DARZALEX FASPRO with bortezomib , melphalan and prednisone was evaluated in a single-arm cohort of PLEIADES [ see Clinical Studies ( 14.1 ) in Full Prescribing Information ]. Patients received DARZALEX FASPRO 1,800 mg / 30,000 units administered subcutaneously once weekly from weeks 1 to 6 , once every 3 weeks from weeks 7 to 54 and once every 4 weeks starting with week 55 until disease progression or unacceptable toxicity ( N = 67 ) in combination with bortezomib , melphalan and prednisone . Among these patients , 93 % were exposed for 6 months or longer and 19 % were exposed for greater than one year .