Sarclisa Drug Information
Generic name: ISATUXIMAB
CD38-directed Cytolytic Antibody [EPC]
Uses of Sarclisa
is indicated: in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy. in combination with bortezomib, lenalidomide, and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT). SARCLISA is a CD38-directed cytolytic antibody indicated: in combination with pomalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 2 prior therapies including lenalidomide and a proteasome inhibitor. in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy. in combination with bortezomib, lenalidomide and dexamethasone, for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplant (ASCT).
Dosage & Administration of Sarclisa
| Cycle 1 (28-day cycle) | Days 1, 8, 15, and 22 (weekly) |
|---|---|
| Cycle 2 and beyond (28-day cycles) | Days 1, 15 (every 2 weeks) |
Side Effects of Sarclisa
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. Relapsed and/or Refractory Multiple Myeloma Combination treatment with pomalidomide and dexamethasone (Isa-Pd) The safety of SARCLISA was evaluated in ICARIA-MM, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and dexamethasone (Isa-Pd) (n=152) or pomalidomide and dexamethasone (Pd) (n=149) . Among patients receiving Isa-Pd, 66% were exposed to SARCLISA for 6 months or longer and 24% were exposed for greater than 12 months or longer.
Serious adverse reactions occurred in 62% of patients receiving Isa-Pd. Serious adverse reactions in >5% of patients who received Isa-Pd included pneumonia (26%), upper respiratory tract infections (7%), and febrile neutropenia (7%). Fatal adverse reactions occurred in 11% of patients (those that occurred in more than 1% of patients were pneumonia and other infections ). Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 7% of patients who received Isa-Pd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Pd were infections (2.6%). SARCLISA alone was discontinued in 3% of patients due to infusion-related reactions.
Dosage interruptions due to an adverse reaction occurred in 31% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (28%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, pneumonia, and diarrhea. Table 4 summarizes the adverse reactions in ICARIA-MM. Table 4: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Pomalidomide, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in ICARIA-MM Trial Adverse Reactions SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd) Pomalidomide + Dexamethasone (Pd) (N=152) (N=149) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) CTCAE version 4.03 General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and drug hypersensitivity. 38 1.3 1.3 0 0 0 Infections Upper respiratory tract infection Upper respiratory tract infection includes bronchiolitis, bronchitis, bronchitis viral, chronic sinusitis, fungal pharyngitis, influenza-like illness, laryngitis, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tracheitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. 57 9 0 42 3.4 0 Pneumonia Pneumonia includes atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, candida pneumonia, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal, and pneumocystis jirovecii pneumonia. 31 22 3.3 23 16
Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea, dyspnea exertional, and
dyspnea at rest. 17 5 0 12 1.3 0 Gastrointestinal disorders Diarrhea 26 2 0 19 0.7 0 Nausea 15 0 0 9 0 0 Vomiting 12 1.3 0 3.4 0 0 Table 5 summarizes the hematology laboratory abnormalities in ICARIA-MM. Table 5: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Pd versus Pd in ICARIA-MM Laboratory Parameter SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd) Pomalidomide + Dexamethasone (Pd) (N=152) (N=149) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) The denominator used to calculate the percentages was based on the safety population. Hemoglobin decreased 99 32 0 97 28 0 Neutrophils decreased 96 24 61 92 38 31 Lymphocytes decreased 92 42 13 92 35 8 Platelets decreased 84 14 16 79 9 15 Combination treatment with carfilzomib and dexamethasone (Isa-Kd) The safety of SARCLISA was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously weekly in the first cycle, and every two weeks thereafter, in combination with carfilzomib and dexamethasone (Isa-Kd) (n=177) or carfilzomib and dexamethasone (Kd) (n=122) . Among patients receiving Isa-Kd, 68% were exposed to SARCLISA for 12 months or longer and 51% were exposed for greater than 18 months.
Serious adverse reactions occurred in 59% of patients receiving Isa-Kd. The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients). Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%). SARCLISA alone was discontinued in 0.6% of patients due to infusion-related reactions.
Dosage interruptions due to an adverse reaction occurred in 33% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (30%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain. Table 6 summarizes the adverse reactions in IKEMA. Table 6: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Carfilzomib, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in IKEMA Adverse Reactions SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd) Carfilzomib + Dexamethasone (Kd) (N=177) (N=122) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) General disorders and administration site conditions Infusion-related reaction Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity. 46 0.6 0 3.3 0 0 Fatigue Fatigue includes fatigue and asthenia. 42 5 0 32 3.3 0 Infections Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. 67 9 0 57 7 0 Pneumonia Pneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis. 36 19 3.4 30 15
Bronchitis Bronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic
and tracheobronchitis. 24 2.3 0 13 0.8 0 Vascular disorders Hypertension Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. 37 20 0.6 32 18
Respiratory, thoracic and mediastinal disorders Dyspnea Dyspnea includes dyspnea and dyspnea exertional.
29 5 0 24 0.8 0 Cough Cough includes cough, productive cough, and allergic cough. 23 0 0 15 0 0 Gastrointestinal disorders Diarrhea 36 2.8 0 29 2.5 0 Vomiting 15 1.1 0 9 0.8 0 Table 7 summarizes the hematology laboratory abnormalities in IKEMA. Table 7: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Kd versus Kd in IKEMA Laboratory Parameter SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd) Carfilzomib + Dexamethasone (Kd) (N=177) (N=122) All Grades (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%) The denominator used to calculate the percentage was based on the safety population. Hemoglobin decreased 99 22 0 99 20 0 Lymphocytes decreased 94 52 17 95 43 14 Platelets decreased 94 19 11 88 16 8 Neutrophils decreased 55 18 1.7 43 7
Newly Diagnosed Multiple Myeloma not Eligible for Autologous Stem Cell Transplant Combination
treatment with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) The safety of SARCLISA was evaluated in IMROZ, a randomized, open-label clinical trial in patients with newly diagnosed multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously on day 1, 8, 15, 22, and 29 in the first 42-day cycle, followed by every two weeks from cycle 2 to 4 (42-day cycles), followed by every two weeks from cycle 5 to 17 (28-day cycles), and then on day 1 from cycle 18 and onwards (28-day cycles), in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) (n=263) or bortezomib, lenalidomide, and dexamethasone (VRd) (n= 181) . In IMROZ, median duration of exposure to treatment was 53 (range: 0.5–69) months in patients treated with Isa-VRd and 31 (range 0.6–67) months in patients treated with VRd. Serious adverse reactions occurred in 71% of patients receiving Isa-VRd.
The serious adverse reaction in > 5% of patients who received Isa-VRd was pneumonia (30%). Fatal adverse reactions occurred in 11% of patients with Isa-VRd (those occurring in more than 1% of patients were pneumonia (5%). Permanent discontinuation of treatment due to an adverse reaction occurred in 22.8% of patients treated with Isa-VRd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-VRd were infections (8%). SARCLISA alone was discontinued in 2.3% of patients. Dosage interruptions due to an adverse reaction occurred in 21% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion related reaction (21%). The most common adverse reactions (≥20%) were upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) were decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils.
Table 8 summarizes the adverse reactions in IMROZ. Table 8: Adverse Reactions (≥ 20%) in Patients Receiving SARCLISA, Bortezomib, Lenalidomide, and Dexamethasone in IMROZ IMROZ study Adverse Reactions SARCLISA + Bortezomib + Lenalidomide + Dexamethasone (N=263) Bortezomib + Lenalidomide + Dexamethasone (N=181) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Includes other related terms 65 4.6 57 Includes 1 patient (0.6%) with fatal URTI. 6 Pneumonia Pneumonia includes Atypical pneumonia, Bronchopulmonary aspergillosis, COVID-19 pneumonia, Lower respiratory tract infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia influenzal, Pneumonia klebsiella, Pneumonia legionella, Pneumonia parainfluenzae viral, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia viral, Pulmonary sepsis. 45 Includes 14 patients (5%) with fatal pneumonia. 26 31 Includes 4 patients (2.2%) with fatal pneumonia. 19 COVID-19 COVID-19 includes COVID-19 infections other than COVID-19 pneumonia. 22 0.8 17 Includes 2 patients (1.1%) with fatal COVID-19.
General disorders and administration site conditions Fatigue Fatigue includes Fatigue, Asthenia, or
Malaise. 55 11 50 9 Edema peripheral 33 0 33
Infusion-related reaction 24 0.4 1.1 0 Gastrointestinal disorders Diarrhea 55 8 49
8 Constipation 36 2.3 41
Nervous system disorders Peripheral sensory neuropathy 54 7 61 6 Eye disorders
Cataract 38 16 25 11 Musculoskeletal and connective tissue disorders Musculoskeletal pain 38 4.2 33
Skin and subcutaneous tissue disorders Rash Rash includes Dermatitis, Dermatitis acneiform, Dermatitis
allergic, Dermatitis atopic, Dermatitis exfoliative generalized, Drug eruption, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Skin exfoliation, Skin hyperpigmentation, Skin lesion, Skin reaction, and Toxic skin eruption. 32 5 34 5 Psychiatric disorders Insomnia 22 3.8 24
Table 9 summarizes the hematology laboratory abnormalities in
IMROZ. Table 9: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-VRd Versus VRd in IMROZ Laboratory parameter SARCLISA + Bortezomib + Lenalidomide + Dexamethasone The denominator used to calculate the rate is based on the number of patients with a baseline value and at least one post-baseline value. Bortezomib + Lenalidomide + Dexamethasone All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Decreased hemoglobin 99 17 98 16 Decreased leukocytes 97 32 88 17 Decreased lymphocytes 95 60 92 53 Decreased platelets 95 30 85 28 Decreased neutrophils 87 54 80 37 Description of Selected Adverse Reactions Cardiac failure In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary edema) was reported in 7% of patients with the Isa-Kd group (grade ≥3 in 4%) and in 7% of patients with the Kd group (grade ≥3 in 4.1%). Serious cardiac failure was observed in 4% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. See the current prescribing information for carfilzomib for more information.
Warnings & Cautions for Sarclisa
Infusion-Related Reactions Serious infusion-related reactions including life-threatening anaphylactic reactions have occurred with
SARCLISA treatment. Severe signs and symptoms included cardiac arrest, hypertension, hypotension, bronchospasm, dyspnea, angioedema, and swelling. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), infusion-related reactions occurred in 206 patients (35%). Among these 206 patients, 92% experienced infusion-related reactions during the first infusion and 12% after the first cycle.
The most common symptoms (≥5%) of an infusion-related reaction included dyspnea and cough. Grade 1 infusion-related reactions were reported in 6% of patients, grade 2 in 28%, and grade 3 or 4 in 1.2%. Anaphylactic reactions occurred in less than 1% of patients. The total incidence of SARCLISA infusion interruptions was less than 1% and the incidence of patients with at least one SARCLISA infusion interruption due to infusion-related reactions was 26%. The median time to first SARCLISA infusion interruption was 61 minutes (range 4 to 240 minutes). SARCLISA was discontinued in 1% of patients due to infusion-related reactions.
To decrease the risk and severity of infusion-related reactions, premedicate patients prior to SARCLISA infusion with acetaminophen, H2 antagonists, diphenhydramine, or equivalent, and dexamethasone . Monitor vital signs frequently during the entire SARCLISA infusion. For patients with grade ≥2 reactions, interrupt SARCLISA infusion and provide appropriate medical management. For patients with grade 2 or grade 3 reactions, if symptoms improve to grade ≤1, restart SARCLISA infusion at half of the initial infusion rate, with supportive care as needed, and closely monitor patients.
If symptoms do not recur after 30 minutes, the infusion rate may be increased to the initial rate, and then increased incrementally, as shown in Table 3 . In case symptoms do not improve to grade ≤1 after interruption of SARCLISA infusion, persist or worsen despite appropriate medications, or require hospitalization, permanently discontinue SARCLISA and institute appropriate management. Permanently discontinue SARCLISA if an anaphylactic reaction or life-threatening (grade 4) infusion-related reaction occurs and institute appropriate management.
Infections
SARCLISA can cause severe, life-threatening, or fatal infections. In patients who received SARCLISA at the recommended dose in ICARIA-MM, IKEMA, and IMROZ (N=592), serious infections, including opportunistic infections, occurred in 46% of patients, grade 3 or 4 infections occurred in 43%, and fatal infections occurred in 4.7%. The most common type of serious infection reported was pneumonia (32%). Monitor patients for signs and symptoms of infection prior to and during treatment with SARCLISA and treat appropriately. Administer prophylactic antimicrobials according to guidelines .
Neutropenia
SARCLISA can cause neutropenia. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), neutropenia based on laboratory values occurred in 81%, with grade 3 or 4 occurring in 52%. Neutropenic infections occurred in 12% of patients, with grade 3 or 4 in 4.9%, and febrile neutropenia in 4% . Monitor complete blood cell counts periodically during treatment. If needed, use antibacterial and antiviral prophylaxis during treatment . Monitor patients with neutropenia for signs of infection.
In case of grade 4 neutropenia delay SARCLISA dose until neutrophil count recovery to at least 1 × 10 9 /L, and provide supportive care with growth factors, according to institutional guidelines. No dose reductions of SARCLISA are recommended.
Second Primary Malignancies
The incidence of second primary malignancies, during treatment and post-treatment, is increased in patients treated with SARCLISA-containing regimens. In clinical trials (ICARIA-MM, IKEMA, and IMROZ), in patients treated with SARCLISA (N=592), second primary malignancies occurred in 71 patients (12%). In ICARIA-MM, at a median follow-up time of 52 months, second primary malignancies occurred in 7% of patients in the Isa-Pd arm and in 2% of patients in the Pd arm. In IKEMA study, at a median follow-up time of 57 months, second primary malignancies occurred in 10% of patients in the Isa-Kd arm and in 8% of patients in the Kd arm.
In IMROZ study, at a median follow-up time of 60 months, second primary malignancies occurred in 16% of patients in the Isa-VRd arm and in 9% of patients in the VRd arm. The most common (≥1%) second primary malignancies in ICARIA-MM, IKEMA, and IMROZ (N=592) included skin cancers (7% with SARCLISA-containing regimens and 3.1% with comparative regimens) and solid tumors other than skin cancer (4.6% with SARCLISA-containing regimens and 2.9% with comparative regimens). Patients with non-melanoma skin cancer continued treatment after resection of the skin cancer, except 2 patients on the Isa-VRd arm and 1 patient on the VRd arm of the IMROZ study. Monitor patients for the development of second primary malignancies.
Laboratory Test Interference Interference with Serological Testing (Indirect Antiglobulin Test)
SARCLISA binds to CD38 on red blood cells (RBCs) and may result in a false positive indirect antiglobulin test (indirect Coombs test). This interference with the indirect Coombs test may persist for approximately 6 months after the last infusion of SARCLISA. The indirect antiglobulin test was positive during Isa-Pd treatment in 68% of the tested patients, and during Isa-Kd treatment in 63% of patients. In patients with a positive indirect antiglobulin test, blood transfusions were administered without evidence of hemolysis. ABO/RhD typing was not affected by SARCLISA treatment.
Before the first SARCLISA infusion, conduct blood type and screen tests on SARCLISA-treated patients. Consider phenotyping prior to starting SARCLISA treatment. If treatment with SARCLISA has already started, inform the blood bank that the patient is receiving SARCLISA and SARCLISA interference with blood compatibility testing can be resolved using dithiothreitol-treated RBCs.
If an emergency transfusion is required, non–cross-matched ABO/RhD-compatible RBCs can be given as per local blood bank practices . Interference with Serum Protein Electrophoresis and Immunofixation Tests SARCLISA is an IgG kappa monoclonal antibody that can be incidentally detected on both serum protein electrophoresis and immunofixation assays used for the clinical monitoring of endogenous M-protein. This interference can impact the accuracy of the determination of complete response in some patients with IgG kappa myeloma protein .
Embryo-Fetal Toxicity
Based on the mechanism of action, SARCLISA can cause fetal harm when administered to a pregnant woman. SARCLISA may cause fetal immune cell depletion and decreased bone density. Advise pregnant women of the potential risk to a fetus.
Advise females with reproductive potential to use an effective method of contraception during treatment with SARCLISA and for 5 months after the last dose . The combination of SARCLISA with pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide or lenalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy.
Drug Interactions with Sarclisa
Laboratory Test Interference Interference with Serological Testing
SARCLISA, an anti-CD38 antibody, may interfere with blood bank serologic tests with false positive reactions in indirect antiglobulin tests (indirect Coombs tests), antibody detection (screening) tests, antibody identification panels, and antihuman globulin crossmatches in patients treated with SARCLISA . Interference with Serum Protein Electrophoresis and Immunofixation Tests SARCLISA may be incidentally detected by serum protein electrophoresis and immunofixation assays used for the monitoring of M-protein and may interfere with accurate response classification based on International Myeloma Working Group (IMWG) criteria . In patients with persistent very good partial response, where interference is suspected, consider using an FDA-cleared isatuximab-irfc-specific IFE assay to distinguish isatuximab from any remaining endogenous M protein in the patient's serum to facilitate determination of a complete response.
Pregnancy Safety for Sarclisa
Pregnancy Risk Summary SARCLISA can cause fetal harm when administered to a pregnant woman. The assessment of isatuximab-irfc-associated risks is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data ). There are no available data on SARCLISA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction toxicity studies have not been conducted with isatuximab-irfc.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, miscarriage, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
The combination of SARCLISA and pomalidomide or lenalidomide is contraindicated in pregnant women because pomalidomide and lenalidomide may cause birth defects and death of the unborn child. Refer to the pomalidomide or lenalidomide prescribing information on use during pregnancy. Pomalidomide and lenalidomide are only available through a REMS program.
Clinical Considerations Fetal/neonatal reactions Immunoglobulin G1 monoclonal antibodies are known to cross the placenta. Based on its mechanism of action, SARCLISA may cause depletion of fetal CD38-positive immune cells and decreased bone density. Defer administration of live vaccines to neonates and infants exposed to SARCLISA in utero until a hematology evaluation is completed.
Data Animal data Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density which recovered 5 months after birth. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in regulating humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).
Pediatric Use of Sarclisa
Pediatric Use The safety and effectiveness of SARCLISA in pediatric patients have not been established. The safety and efficacy of SARCLISA in combination with chemotherapy were assessed, but not established, in an open-label study (ACT15378, ISAKIDS, NCT03860844) in 62 pediatric patients aged 1.4 years to < 17 years with relapsed or refractory T-acute lymphoblastic leukemia (T-ALL), B-acute lymphoblastic leukemia (B-ALL), or acute myeloid leukemia (AML). No new safety signals were observed in pediatric patients in this trial. Body weight adjusted clearance at steady state and volume of distribution of isatuximab in pediatric patients were within the range of values that were observed in adults.
Contraindications for Sarclisa
is contraindicated in patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients . Patients with severe hypersensitivity to isatuximab-irfc or to any of its excipients.
Clinical Studies of Sarclisa
Relapsed and/or Refractory Multiple Myeloma ICARIA-MM The efficacy and safety of SARCLISA in combination with pomalidomide and dexamethasone (Isa-Pd) were evaluated in ICARIA-MM (NCT02990338), a multicenter, multinational, randomized, open-label, 2-arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma. Patients had received at least two prior therapies including lenalidomide and a proteasome inhibitor. Patients were eligible for inclusion if they had an Eastern Cooperative Oncology Group (ECOG) status of 0–2, platelets ≥75,000 cells/mm 3, absolute neutrophil count ≥1 × 10 9 /L, creatinine clearance ≥30 mL/min/1.73 m 2 (MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN. A total of 307 patients were randomized in a 1:1 ratio to receive either SARCLISA in combination with pomalidomide and dexamethasone (Isa-Pd, 154 patients) or pomalidomide and dexamethasone (Pd, 153 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity.
SARCLISA 10 mg/kg was administered as an intravenous infusion weekly in the first cycle and every two weeks thereafter. Pomalidomide 4 mg was taken orally once daily from day 1 to day 21 of each 28-day cycle. Dexamethasone (orally or intravenously) 40 mg (20 mg for patients ≥75 years of age) was given on days 1, 8, 15, and 22 for each 28-day cycle.
Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 67 years (range 36–86), 20% of patients were ≥75 years; 79% of patients were White, 12% Asian, and 1% Black or African American; 10% of patients entered the study with a history of COPD or asthma. The proportion of patients with renal impairment (creatinine clearance <60 mL/min/1.73 m 2 ) was 34%. The International Staging System (ISS) stage at study entry was I in 37%, II in 36% and III in 25% of patients.
Overall, 20% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14) and t(14;16) were present in 12%, 8% and 2% of patients, respectively. The median number of prior lines of therapy was 3 (range 2–11). All patients received a prior proteasome inhibitor, all patients received prior lenalidomide, and 56% of patients received prior stem cell transplantation; the majority of patients (93%) were refractory to lenalidomide, 76% to a proteasome inhibitor, and 73% to both an immunomodulator and a proteasome inhibitor. The median duration of treatment was 41 weeks for Isa-Pd group compared to 24 weeks for Pd group.
The efficacy of SARCLISA was based upon progression-free survival (PFS). PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria. The improvement in PFS represented a 40% reduction in the risk of disease progression or death in patients treated with Isa-Pd. Efficacy results are presented in Table 10 and Kaplan-Meier curve for PFS is provided in Figure 1. Table 10: Efficacy of SARCLISA in Combination with Pomalidomide and Dexamethasone versus Pomalidomide and Dexamethasone in the Treatment of Multiple Myeloma (ICARIA-MM) Endpoint SARCLISA + Pomalidomide + Dexamethasone N=154 Pomalidomide + Dexamethasone N=153 Progression-Free Survival Median (months) 11.53 6.47 Hazard ratio Stratified-on age (<75 years versus ≥75 years) and number of previous lines of therapy (2 or 3 vs >3) according to IRT. 0.596 p-value (stratified log-rank test) 0.0010 Overall Response Rate sCR, CR, VGPR and PR were evaluated by the IRC using the IMWG response criteria.
Responders (sCR+CR+VGPR+PR) n (%) Estimated using Clopper-Pearson method. 93 54 p-value (stratified Cochran-Mantel-Haenszel) <0.0001 Stringent Complete Response (sCR) + Complete Response (CR) n (%) 7 3 Very Good Partial Response (VGPR) n (%) 42 10 Partial Response (PR) n (%) 44 41 The median time to first response in responders was 35 days in the Isa-Pd group versus 58 days in the Pd group. The median duration of response was 13.3 months (95% CI: 10.6-NR) in the Isa-Pd group versus 11.1 months (95% CI: 8.5-NR) in the Pd group. At a median follow-up time of 52.4 months, final median overall survival was 24.6 months in the Isa-Pd group and 17.7 months in the Pd group (HR=0.776; 95% CI: 0.594 to 1.015). Figure 1: Kaplan-Meier Curves of PFS – ITT Population – ICARIA-MM (assessment by the IRC) Figure 1 IKEMA The efficacy and safety of SARCLISA in combination with carfilzomib and dexamethasone were evaluated in IKEMA (NCT03275285), a multicenter, multinational, randomized, open-label, 2-arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma.
Patients had received one to three prior lines of therapy. Patients were eligible for inclusion if they had an ECOG status of 0–2, platelets ≥50,000 cells/mm 3, absolute neutrophil count ≥1 × 10 9 /L, creatinine clearance ≥15 mL/min/1.73 m 2 (MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN. A total of 302 patients were randomized in a 3:2 ratio to receive either SARCLISA in combination with carfilzomib and dexamethasone (Isa-Kd, 179 patients) or carfilzomib and dexamethasone (Kd, 123 patients). Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity. SARCLISA 10 mg/kg was administered as an intravenous infusion weekly in the first cycle and every two weeks thereafter.
Carfilzomib was administered as an intravenous infusion at the dose of 20 mg/m 2 on days 1 and 2; 56 mg/m 2 on days 8, 9, 15, and 16 of cycle 1; and at the dose of 56 mg/m 2 on days 1, 2, 8, 9, 15, and 16 for subsequent cycles of each 28-day cycle. Dexamethasone (intravenously on the days of isatuximab-irfc and/or carfilzomib infusions, and orally on the other days) 20 mg was given on days 1, 2, 8, 9, 15, 16, 22, and 23 for each 28-day cycle. On the days where both SARCLISA and carfilzomib were administered, dexamethasone was administered first, followed by SARCLISA infusion, then followed by carfilzomib infusion.
Overall, demographic and disease characteristics at baseline were similar between the two treatment groups. The median patient age was 64 years (range 33–90), 9% of patients were ≥75 years, 71% were White, 17% Asian, and 3% Black or African American. The proportion of patients with renal impairment (eGFR<60 mL/min/1.73 m 2 ) was 24% in the Isa-Kd group versus 15% in the Kd group.
The International Staging System (ISS) stage at study entry was I in 53%, II in 31%, and III in 15% of patients. Overall, 24% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), t(14;16) were present in 11%, 14%, and 2% of patients, respectively. In addition, gain(1q21) was present in 42% of patients.
The median number of prior lines of therapy was 2 (range 1–4) with 44% of patients who received 1 prior line of therapy. Overall, 90% of patients received prior proteasome inhibitors, 78% received prior immunomodulators (including 43% who received prior lenalidomide), and 61% received prior stem cell transplantation. Overall, 33% of patients were refractory to prior proteasome inhibitors, 45% were refractory to prior immunomodulators (including 33% refractory to lenalidomide), and 21% were refractory to both a proteasome inhibitor and an immunomodulator.
The median duration of treatment was 80 weeks for the Isa-Kd group compared to 61 weeks for the Kd group. The efficacy of SARCLISA was based upon PFS. PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. The improvement in PFS represented a 45% reduction in the risk of disease progression or death in patients treated with Isa-Kd compared to patients treated with Kd.
Efficacy results are presented in Table 11 and Kaplan-Meier curves for PFS are provided in Figure 2. Table 11 Results are based on a prespecified interim analysis., Median follow-up time 20.7 months. : Efficacy of SARCLISA in Combination with Carfilzomib and Dexamethasone versus Carfilzomib and Dexamethasone in the Treatment of Multiple Myeloma (IKEMA) Endpoint SARCLISA + Carfilzomib + Dexamethasone N=179 Carfilzomib + Dexamethasone N=123 NR: not reached. Progression-Free Survival PFS results were assessed by the IRC based on central laboratory data for M-protein and central radiologic imaging review using the IMWG criteria. A comparison is considered statistically significant if the p-value is <0.008 (efficacy boundary). Median (months) NR 20.27 Hazard ratio Stratified on number of previous lines of therapy (1 versus >1) and R-ISS (I or II versus III versus not classified) according to IRT. 0.548 p-value (stratified log-rank test) 0.0032 Overall Response Rate sCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria.
Responders (sCR+CR+VGPR+PR) n (%) Estimated using Clopper-Pearson method. 155 102 p-value (stratified Cochran-Mantel-Haenszel) 0.3859 Complete Response (CR) n (%) 71 34 Very Good Partial Response (VGPR) n (%) 59 35 Partial Response (PR) n (%) 25 33 Figure 2: Kaplan-Meier Curves of PFS – ITT Population – IKEMA (assessment by the IRC) At a median follow-up time of 44.0 months, final PFS analysis showed a median PFS of 41.7 months for Isa-Kd group compared to 20.8 months for Kd group, with a hazard ratio of 0.594 (95.4% CI: 0.424 to 0.832). Final complete response, determined using a FDA-cleared isatuximab-irfc-specific IFE assay , was 44.1% in Isa-Kd group compared to 28.5% in Kd group. At a median follow-up time of 57 months, median overall survival was not reached in the Isa-Kd group (95% CI: 52.172–NR) and was 50.6 months in Kd group (95% CI: 38.932–NR) (HR=0.855; 95% CI: 0.608–1.202). Figure 2 Newly Diagnosed Multiple Myeloma IMROZ The efficacy of SARCLISA in combination with bortezomib, lenalidomide, and dexamethasone was evaluated in IMROZ (NCT03319667), a multicenter, international, randomized, open-label, 2-arm, phase 3 study in patients with newly diagnosed multiple myeloma who are not eligible for stem cell transplantation. Patients were eligible for inclusion if they had an Eastern Cooperative Oncology Group (ECOG) status of 0 or 1, platelets ≥70,000 cells/mm 3, absolute neutrophil count ≥1 × 10 9 /L, creatinine clearance ≥30 mL/min/1.73 m 2 (MDRD formula), AST ≤3 × ULN, and ALT ≤3 × ULN. A total of 446 patients were randomized in a 3:2 ratio to receive either SARCLISA in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd, 265 patients) or bortezomib, lenalidomide, and dexamethasone (VRd, 181 patients). Treatment was administered in both groups during 4 cycles of 42-days each for the induction period.
After completion of cycle 4, patients entered the continuous treatment period starting from cycle 5, in which 28-day cycles were administered up to disease progression or unacceptable toxicity. During the continuous treatment period, patients of the Isa-VRd group received SARCLISA in combination with lenalidomide, and dexamethasone (Isa-Rd), and patients in the VRd group received lenalidomide, and dexamethasone (Rd). During the induction period (cycle 1 to 4, 42-day cycles), SARCLISA 10 mg/kg was administered as an intravenous infusion on day 1, 8, 15, 22, and 29, in the first cycle and on day 1, 15, and 29, from cycle 2 to 4. Bortezomib was administered subcutaneously at the dose of 1.3 mg/m 2 on days 1, 4, 8, 11, 22, 25, 29, and 32 of each cycle. Lenalidomide was administered orally at the dose of 25 mg/day from day 1 to 14 and from day 22 to 35 of each cycle.
Dexamethasone (intravenously on the days of SARCLISA infusions, and orally on the other days) 20 mg/day was given on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, and 33 of each cycle. During the continuous treatment period (from cycle 5, 28-day cycles), SARCLISA 10 mg/kg was administered as an IV infusion on day 1 and 15 from cycle 5 to 17, and on day 1 from cycle 18. Lenalidomide was administered orally at the dose of 25 mg/day from day 1 to 21 of each cycle. Dexamethasone (intravenously on the days of SARCLISA infusions, and orally on the other days) 20 mg/day was given on days 1, 8, 15, and 22 of each cycle.
The median patient age was 72 years (range 55–80), 28% of patients were ≥75 years; 72% of patients were White, 11% Asian, and 0.9% Black or African American. The proportion of patients with renal impairment (eGFR<60 mL/min/1.73m 2 ) was 29%. The Revised International Staging System (R-ISS) stage at study entry was I in 23%, II in 64%, and III in 10% of patients. Overall, 17% of patients had high-risk chromosomal abnormalities at study entry; del(17p), t(4;14), and t(14;16) were present in 5%, 9% and 2% of patients, respectively.
In addition, 1q21+ was present in 37% of patients. The efficacy of SARCLISA was established based upon progression-free survival (PFS). PFS results were assessed by an Independent Response Committee based on central laboratory data for M-protein and central radiologic imaging review using the International Myeloma Working Group (IMWG) criteria. The improvement in PFS represented a 40% reduction in the risk of disease progression or death in patients treated with Isa-VRd.
Efficacy results are presented in Table 12 and Kaplan-Meier curves for PFS are provided in Figure 3: Table 12 – Efficacy Results of SARCLISA in combination with bortezomib, lenalidomide, and dexamethasone versus bortezomib, lenalidomide, and dexamethasone (IMROZ) Endpoint SARCLISA + bortezomib + lenalidomide + dexamethasone N =265 Bortezomib + lenalidomide + dexamethasone N = 181 NR: not reached. Median follow-up time=60 months. Progression-Free Survival Based on ITT population.
Median (months) NR 54.34 Hazard ratio Stratified by age (<70 years vs ≥70 years) and Revised International Staging System (R-ISS) stage (I or II vs. III or not classified) according to IRT. 0.60 p-value (Stratified Log-Rank test) A comparison is considered statistically significant if the p-value is <0.0148. 0.0009 Overall Response Rate sCR, CR, VGPR, and PR were evaluated by the IRC using the IMWG response criteria. Responders (sCR+CR+VGPR+PR) N(%) Estimated using Clopper-Pearson method. 242 167 Stringent Complete Response (sCR) N(%) 29 10 Complete Response (CR) N(%) 169 106 Very Good Partial Response (VGPR) N(%) 38 34 Partial Response (PR) N(%) 6 17 CR or better (sCR and CR) Other efficacy endpoints of CR and MRD negativity CR were tested hierarchically after PFS. N(%) 198 116 p-value (Stratified Cochran-Mantel-Haenszel) 0.0160 Minimal Residual Disease (MRD) MRD negativity rate Patients achieved both MRD negativity (threshold of 10 -5 ) and response of CR or better.
Based on a sensitivity level of 10 -5 by the next-generation sequencing assay (clonoSEQ). N(%) 147 74 p-value (Stratified Cochran-Mantel-Haenszel) 0.0026 Number of patients with CR or better (sCR and CR) 198 116 MRD negativity rate in patients with CR or better N(%) 147 74 Median overall survival was not reached for either treatment group. At a median follow-up time of 60 months, 26% of patients in the Isa-VRd group and 32.6% of patients in the VRd group had died (HR=0.78; 95% CI: 0.55 to 1.1). Figure 3 – Kaplan-Meier Curves of PFS – ITT population – IMROZ Figure 3
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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