Patent Application
20220275101
This application contains a sequence listing, which is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file name “JBI6479USNP1SEQLIST.txt” creation date of Jan. 20, 2022 and having a size of 24 KB. The sequence listing submitted via EFS-Web is part of the specification and is herein incorporated by reference in its entirety.
The present invention relates to methods of treating light chain amyloidosis using an approved drug product comprising daratumumab and hyaluronidase in combination with bortezomib, cyclophosphamide and dexamethasone. Also described are methods for achieving a complete hematologic response in light chain amyloidosis patients and methods of selling or offering for sale an approved drug product comprising daratumumab and hyaluronidase for the treatment of light chain amyloidosis.
B-cell malignancies include B-cell chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, hairy cell leukemia, primary effusion lymphoma and AIDS-related Non-Hodgkin's Lymphoma. B-cell malignancies comprise more than 85% of diagnosed lymphomas.
Multiple myeloma (MM) is characterized by the latent accumulation of secretory plasma cells in bone marrow with a low proliferative index and an extended life span. The disease ultimately attacks bones and bone marrow, resulting in multiple tumors and lesions throughout the skeletal system. Approximately 1% of all cancers and slightly more than 10% of all hematologic malignancies can be attributed to multiple myeloma. Incidence of multiple myeloma increases in the aging population, with the median age at time of diagnosis being about 61 years.
Light chain amyloidosis (AL) (also called systemic amyloidosis) is a clonal plasma cell disorder in which fragments of misfolded immunoglobulin light chains are deposited in tissues. Monoclonal plasma cells in the bone marrow produce the misfolded immunoglobulin light chains that accumulate in tissues and cause toxicity in vital organs leading to organ failure and death (Comenzo et al., Leukemia 26:2317-25, 2012). The clinical features depend on the organs involved; amyloidosis frequently manifests in kidneys, heart, skin, nervous system and in soft tissues, such as the tongue (Merlini and Belotti, NEJM, 349:583-596, 2003), resulting in albuminuria and renal failure, heart failure, arrhythmias, risk of sudden cardiac death, hepatomegaly, bloating, early satiety, paresthesias, dysthesias, orthostatic hypotension, constipation, or diarrhea (Chaulagain and Comenzo; Curr Hematol Malig Rep 8:291-8, 2013).
CD38 is a multifunctional protein having function in receptor-mediated adhesion and signaling as well as mediating calcium mobilization via its ecto-enzymatic activity, catalyzing formation of cyclic ADP-ribose (cADPR) and ADPR. CD38 mediates cytokine secretion and activation and proliferation of lymphocytes (Funaro et al., J Immunol 145:2390-6, 1990; Terhorst et al., Cell 771-80, 1981; Guse et al., Nature 398:70-3, 1999). CD38, via its NAD glycohydrolase activity, also regulates extracellular NAD+ levels, which have been implicated in modulating the regulatory T-cell compartment (Adriouch et al., 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In addition to signaling via Ca2+, CD38 signaling occurs via crosstalk with antigen-receptor complexes on T- and B-cells or other types of receptor complexes, e.g., MHC molecules, involving CD38 in several cellular responses, but also in switching and secretion of IgG1. CD38 is expressed on various malignant cells.
Currently recognized treatments for AL include various chemotherapeutic agents with or without autologous stem cell transplantation. The chemotherapeutic agents include a combination regimen of bortezomib, cyclophosphamide and dexamethasone. However, the disease remains largely incurable. Thus, there is a need for additional therapeutics for AL.
The invention provides a method of achieving confirmed hematologic complete response (HemCR) in an adult patient with light chain amyloidosis (AL), the method comprising administering to the adult patient an approved drug product comprising daratumumab and hyaluronidase
The invention also provides a method of treating AL comprising administering an approved drug product containing daratumumab and hyaluronidase to an adult patient with AL in an amount that is described in a drug product label for the drug product.
The invention also provides a method of selling an approved drug product comprising daratumumab and hyaluronidase, the method comprising selling such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating AL.
The invention also provides a method of offering for sale an approved drug product comprising daratumumab and hyaluronidase, the method comprising offering for sale such drug product, wherein a drug product label for a reference listed drug for such drug product includes instructions for treating AL.
The invention also provides a method of selling an approved drug product comprising daratumumab and hyaluronidase, the method comprising selling such drug product, wherein the drug product label for a reference listed drug for such drug product comprises HemCR data.
The invention also provides a method of offering for sale an approved drug product comprising daratumumab and hyaluronidase, said method comprising offering for sale such drug product, wherein the drug product label for a reference listed drug for such drug product comprises HemCR data.
“DARZALEX FASPRO” is a sterile, preservative-free, colorless to yellow, and clear to opalescent solution for subcutaneous injection use supplied as individually packaged single-dose vials providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase per 15 mL.
“CD38” refers to the human CD38 protein (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1). Human CD38 has an amino acid sequence shown in GenBank accession number NP_001766 and in SEQ ID NO: 1. It is well known that CD38 is a single pass type II membrane protein with amino acid residues 1-21 representing the cytosolic domain, amino acid residues 22-42 representing the transmembrane domain, and residues 43-300 representing the extracellular domain of CD38.
“Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen-binding fragments, bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds as well as multimers thereof (for example IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
“Biosimilar” (of an approved reference product/biological drug, i.e., reference listed drug) refers to a biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components with no clinically meaningful differences between the biosimilar and the reference product in terms of safety, purity and potency, based upon data derived from (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biosimilar. The biosimilar may be an interchangeable product that may be substituted for the reference product at the pharmacy without the intervention of the prescribing healthcare professional. To meet the additional standard of “interchangeability,” the biosimilar is to be expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. The biosimilar utilizes the same mechanisms of action for the proposed conditions of use to the extend the mechanisms are known for the reference product. The condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product. The route of administration, the dosage form, and/or the strength of the biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure and potent. The biosimilar may include minor modifications in the amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.
“Complementarity determining regions (CDR)” are “antigen binding sites” in an antibody. CDRs may be defined using various terms: (i) Complementarity Determining Regions (CDRs), three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3) are based on sequence variability (Wu and Kabat, J Exp Med 132:211-50, 1970; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). (ii) “Hypervariable regions”, “HVR”, or “HV”, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3) refer to the regions of an antibody variable domains which are hypervariable in structure as defined by Chothia and Lesk (Chothia and Lesk, Mol Biol 196:901-17, 1987). The International ImMunoGeneTics (IMGT) database (http://www_imgt_org) provides a standardized numbering and definition of antigen-binding sites. The correspondence between CDRs, HVs and IMGT delineations is described in Lefranc et al., Dev Comparat Immunol 27:55-77, 2003. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia or IMGT, unless otherwise explicitly stated in the specification.
“Drug product” or “approved drug product” is product that contains an active pharmaceutical ingredient that has been approved for marketing for at least one indication by a governmental authority, e.g., the Food and Drug Administration or the similar authority in other countries. In the present invention, DARZALEX FASPRO is an approved drug product. The approved drug product could also be a biosimilar drug product, a Biologic License Application drug product or a supplemental Biologic License Application drug product
“Monoclonal antibody” refers to an antibody population with single amino acid composition in each heavy and each light chain, except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain. Monoclonal antibodies typically bind one antigenic epitope, except that multispecific monoclonal antibodies bind two or more distinct antigens or epitopes. Bispecific monoclonal antibodies bind two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific, or monovalent, bivalent or multivalent. A multispecific antibody, such as a bispecific antibody or a trispecific antibody is included in the term monoclonal antibody.
“Recombinant” includes antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means.
“Epitope” refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be composed of contiguous and/or discontiguous amino acids that form a conformational spatial unit. For a discontiguous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3-dimensional space through the folding of the protein molecule.
“In combination with” means that two or more therapeutics are administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.
“Pharmaceutical composition” refers to a product that results from combining an anti-CD38 antibody and a hyaluronidase and includes both fixed and non-fixed combinations. Pharmaceutical composition typically includes a pharmaceutically acceptable carrier. “Fixed combinations” refers to a single pharmaceutical composition comprising the anti-CD38 antibody and the hyaluronidase administered simultaneously in the form of a single entity or dosage.
“Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
The term “Reference Listed Drug (RID)” is a drug product to which new generic versions are compared to show that they are bioequivalent 21 CFR 314.3(b)) It is also a medicinal product that has been granted marketing authorization by a Member State of the European Union or by the Commission on the basis of a completed dossier, i.e., with the submission of quality, pre-clinical and clinical data in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC and to which the application for marketing authorization for a generic/hybrid medicinal product refers, by demonstration of bioequivalence, usually through the submission of the appropriate bioavailability studies.
“Treat” or “treatment” refers to therapeutic treatment wherein the object is to slow down (lessen) an undesired physiological change or disease, such as the development or spread of tumor or tumor cells, or to provide a beneficial or desired clinical outcome during treatment. Beneficial or desired clinical outcomes include alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, lack of metastasis, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” may also mean prolonging survival as compared to expected survival if a subject was not receiving treatment. Those in need of treatment include those subjects already with the undesired physiological change or disease well as those subjects prone to have the physiological change or disease.
“Therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics include, for example, improved well-being of the patient, reduction in a tumor burden, arrested or slowed growth of a tumor, and/or absence of metastasis of cancer cells to other locations in the body and, in the case of patients with AL, a confirmed hematologic complete response (HemCR) rate based on negative serum and urine immunofixation, involved free light chain level decrease to less than the upper limit of normal, and normal free light chain ratio.
“About” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.
The invention provides a pharmaceutical composition comprising an anti-CD38 antibody and a hyaluronidase.
The pharmaceutical composition is useful for subcutaneous administration of the anti-CD38 antibody to a subject in need of anti-CD38 antibody therapy, such as a subject having a cancer, for example a CD38-positive hematological malignancy. Without wishing to be bound by any particular theory, subcutaneous administration of the anti-CD38 antibody may have reduced infusion related reactions when compared to the intravenous administration of the anti-CD38 antibody.
In some embodiments, the pharmaceutical composition is a fixed combination.
In some embodiments, the pharmaceutical composition is a non-fixed combination.
In some embodiments, the hyaluronidase is rHuPH20 having the amino acid sequence of SEQ ID NO: 22, namely residues 36-482 of wild type human hyaluronidase.
rHuPH20 is a recombinant hyaluronidase (HYLENEX® recombinant) and is described in Int. Pat. Publ. No. WO2004/078140.
Hyaluronidase is an enzyme that degrades hyaluronic acid (EC 3.2.1.35) and lowers the viscosity of hyaluronan in the extracellular matrix, thereby increasing tissue permeability.
Enzymatic activity of hyaluronidase, including rHuPH20 can be defined by units per mL (U/mL) or by total enzyme activity in a particular formulation (U).
The standard definition for one unit (U) of enzyme activity is the amount of enzyme that catalyzes the reaction of 1 nmol of substrate per minute.
In some embodiments, the anti-CD38 antibody in the pharmaceutical composition competes for binding to CD38 with an antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5.
In some embodiments, the anti-CD38 antibody in the pharmaceutical composition binds at least to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).
In some embodiments, the anti-CD38 antibody in the pharmaceutical composition comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2, a HCDR3, a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 of SEQ ID NOs: 6, 7 and 8, 9, 10 and 11, respectively.
In some embodiments, the anti-CD38 antibody in the pharmaceutical composition comprises the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5.
In some embodiments, the anti-CD38 antibody in the pharmaceutical composition comprises a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13.
The invention also provides a pharmaceutical composition comprising an anti-CD38 antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 and a hyaluronidase rHuPH20 of SEQ ID NO: 22, wherein the anti-CD38 antibody concentration in the pharmaceutical composition is about 120 mg/mL.
The invention also provides a pharmaceutical composition comprising an anti-CD38 antibody comprising the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively, and the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively and the hyaluronidase rHuPH20 of SEQ ID NO: 22, wherein the anti-CD38 antibody concentration in the pharmaceutical composition is about 120 mg/mL.
The invention also provides a pharmaceutical composition comprising about 1,800 mg of the anti-CD38 antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5, and about 30,000 U of the hyaluronidase rHuPH20 of SEQ ID NO: 22, wherein the anti-CD38 antibody concentration in the pharmaceutical composition is about 120 mg/mL.
The pharmaceutical compositions of the invention further comprise a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable carriers are solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, such as salts, buffers, antioxidants, saccharides, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, or combinations thereof.
The invention also provides a pharmaceutical composition comprising about 120 mg/mL of the anti-CD38 antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 and 2000 U/mL rHuPH20 (SEQ ID NO: 22) in about 10 mM L-histidine, 300 mM sorbitol, 0.04% w/v polysorbate-20 (PS-20), and about 1 mg/mL L-Methionine, pH 5.6.
The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.
The invention provides methods of treating light chain amyloidosis (AL) with an approved drug product. The invention also provides methods for increasing HemCR comprising administering an approved drug product.
The anti-CD38 antibody used in the methods of treatment of the invention is daratumumab. Daratumumab comprises the heavy chain variable region (VH) and the light chain variable region (VL) amino acid sequences shown in SEQ ID NOs: 4 and 5, respectively, the HCDR1, the HCDR2 and the HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively, the LCDR1, the LCDR2 and the LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively, and is of IgG1/κ subtype and described in U.S. Pat. No. 7,829,693. Daratumumab heavy chain amino acid sequence is shown in SEQ ID NO: 12 and light chain amino acid sequence shown in SEQ ID NO: 13.
The hyaluronidase used in the methods of treatment of the invention is rHuPH20 having the amino acid sequence of SEQ ID NO: 22, namely residues 36-482 of wild type human hyaluronidase. rHuPH20 is a recombinant hyaluronidase (HYLENEX® recombinant) and is described in Int. Pat. Publ. No. WO2004/078140.
Hyaluronidase is an enzyme that degrades hyaluronic acid (EC 3.2.1.35) and lowers the viscosity of hyaluronan in the extracellular matrix, thereby increasing tissue permeability.
Enzymatic activity of hyaluronidase, including rHuPH20 can be defined by units per mL (U/mL) or by total enzyme activity in a particular formulation (U).
The standard definition for one unit (U) of enzyme activity is the amount of enzyme that catalyzes the reaction of 1 nmol of substrate per minute.
The invention also provides a method of treating AL, comprising administering to a subject in need thereof an approved drug product comprising the anti-CD38 antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5 and the hyaluronidase rHuPH20 (SEQ ID NO: 22) subcutaneously for a time sufficient to treat the subject, wherein the anti-CD38 antibody concentration in the approved drug product is about 120 mg/mL.
The invention also provides a method of treating AL, comprising administering to a subject in need thereof an approved drug product comprising about 1,800 mg of the anti-CD38 antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5, and about 30,000 U of the hyaluronidase rHuPH20 (SEQ ID NO: 22) for a time sufficient to treat the subject, wherein the anti-CD38 antibody concentration in the pharmaceutical composition is about 120 mg/mL.
The invention also provides a method of treating AL, comprising administering to a subject in need thereof an approved drug product comprising about 120 mg/mL of the anti-CD38 antibody comprising the VH of SEQ ID NO: 4 and the VL of SEQ ID NO: 5, and 2000 U/mL rHuPH20 (SEQ ID NO: 22) in about 10 mM L-histidine, about 300 mM sorbitol, about 0.04% w/v polysorbate-20 (PS-20), and about 1 mg/mL L-Methionine, about pH 5.6 for a time sufficient to treat the subject.
The anti-CD38 antibodies in the pharmaceutical compositions of the invention may induce killing of CD38-expressing tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or modulation of CD38 enzymatic activity. The anti-CD38 antibodies in the pharmaceutical compositions of the invention may also mediate anti-tumor efficacy by their immunomodulatory effects by inducing CD4+ and CD8+ T cell proliferation, and/or by relieving inhibition of inflammatory responses mediated by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs).
“Antibody-dependent cellular cytotoxicity”, “antibody-dependent cell-mediated cytotoxicity” or “ADCC” is a mechanism for inducing cell death that depends upon the interaction of antibody-coated target cells with effector cells possessing lytic activity, such as natural killer cells, monocytes, macrophages and neutrophils via Fc gamma receptors (FcγR) expressed on effector cells. For example, NK cells express FcγRIIIa, whereas monocytes express FcγRI, FcγRII and FcvRIIIa. Death of the antibody-coated target cell, such as CD38-expressing cells, occurs as a result of effector cell activity through the secretion of membrane pore-forming proteins and proteases. To assess ADCC activity of an antibody that specifically binds CD38, the antibody may be added to CD38-expressing cells in combination with immune effector cells, which may be activated by the antigen antibody complexes resulting in cytolysis of the target cell. Cytolysis is generally detected by the release of label (e.g. radioactive substrates, fluorescent dyes or natural intracellular proteins) from the lysed cells. Exemplary effector cells for such assays include peripheral blood mononuclear cells (PBMC) and NK cells. Exemplary target cells include Tregs or MDSCs expressing CD38. In an exemplary assay, target cells are labeled with 20 μCi of 51Cr for 2 hours and washed extensively. Cell concentration of the target cells may be adjusted to 1×106 cells/ml, and anti-CD38 antibodies at various concentrations are added. Assays are started by adding target cells at an effector:target cell ratio of 40:1. After incubation for 3 hr at 37° C. assays are stopped by centrifugation, and 51Cr release from lysed cells are measured in a scintillation counter. Percentage of cellular cytotoxicity may be calculated as % maximal lysis which may be induced by adding 3% perchloric acid to target cells.
“Antibody-dependent cellular phagocytosis” (“ADCP”) refers to a mechanism of elimination of antibody-coated target cells by internalization by phagocytic cells, such as macrophages or dendritic cells. ADCP may be evaluated by using Tregs or MDSCs expressing CD38 as target cells engineered to express GFP or other labeled molecule. Effctor:target cell ratio may be for example 4:1. Effector cells may be incubated with target cells for 4 hours with or without anti-CD38 antibody. After incubation, cells may be detached using accutase. Macrophages may be identified with anti-CD11 b and anti-CD14 antibodies coupled to a fluorescent label, and percent phagocytosis may be determined based on % GFP fluorescent in the CD11+CD14+ macrophages using standard methods.
“Complement-dependent cytotoxicity”, or “CDC”, refers to a mechanism for inducing cell death in which an Fc effector domain of a target-bound antibody binds and activates complement component C1q which in turn activates the complement cascade leading to target cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes.
The pharmaceutical composition of the methods of the invention are administered in combination with a second therapeutic regimen.
The second therapeutic regimen is bortezomib, cyclophosphamide and dexamethasone administered at dosages recommended for the treatment of AL on a 28-day cycle.
The dosages of the second therapeutic regimen are bortezomib (available as VELCADE®) administered at 1.3 mg/m2, cyclophosphamide administered at 300-500 mg/m2 and dexamethasone administered at 20-40 mg dosages on days 1, 8, 15 and 22 of each 28-day cycle.
The pharmaceutical composition of the methods of the invention may be administered simultaneously or sequentially with the second therapeutic regimen.
The second therapeutic regimen may be administered orally or intravenously with the pharmaceutical composition of the methods of the invention.
The pharmaceutical compositions of the invention are administered as a fixed combination, e.g., as a unit dosage form (or dosage unit form). Fixed combinations may be advantageous for ease of administration and uniformity of dosage.
The pharmaceutical composition of the invention may be administered in a total volume of about 15 mL.
The pharmaceutical compositions of the invention may be administered once weekly for eight weeks, followed by once in two weeks for 16 weeks, followed by once in four weeks.
The pharmaceutical composition of the invention may be administered subcutaneously to the abdominal region.
Subcutaneous administration may be accomplished using a device. The device may be a syringe, a prefilled syringe, an auto-injector, either disposable or reusable, a pen injector, a patch injector, a wearable injector or an ambulatory syringe infusion pump with subcutaneous infusion sets.
While having described the invention in general terms, the embodiments of the invention will be further disclosed in the following examples that should not be construed as limiting the scope of the claims.
Full Prescribing Information
Indications and Usage
1) Multiple Myeloma
DARZALEX FASPRO is indicated for the treatment of adult patients with multiple myeloma:
2) 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)]. 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 (5.2)].
Dosage and Administration
3) Important Dosing Information
4) Recommended Dosage for Multiple Myeloma
The recommended dose of DARZALEX FASPRO is 1,800 mg/30,000 units (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously over approximately 3-5 minutes. Tables 1, 2, 3, and 4 provide the recommended dosing schedule when DARZALEX FASPRO is administered as monotherapy or as part of a combination therapy.
Monotherapy and in Combination with Lenalidomide and Dexamethasone (D-Rd)
Use the dosing schedule provided in Table 1 when DARZALEX FASPRO is administered:
aFirst dose of the every-2-week dosing schedule is given at Week 9
bFirst dose of the every-4-week dosing schedule is given at Week 25
When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.2) and the prescribing information for dosage recommendations for the other drugs.
In Combination with Bortezomib, Melphalan and Prednisone (D-VMP)
Use the dosing schedule provided in Table 2 when DARZALEX FASPRO is administered in combination with bortezomib, melphalan and prednisone (6-week cycle).
aFirst dose of the every-3-week dosing schedule is given at Week 7
bFirst dose of the every-4-week dosing schedule is given at Week 55
When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.1) and the prescribing information for dosage recommendations for the other drugs.
In Combination with Bortezomib, Thalidomide, and Dexamethasone (D-VTd)
Use the dosing schedule in Table 3 when DARZALEX FASPRO is administered in combination with bortezomib, thalidomide, and dexamethasone (4-week cycle).
aFirst dose of the every-2-week dosing schedule is given at Week 9
bFirst dose of the every-2-week dosing schedule is given at Week 1 upon re-initiation of treatment following ASCT
When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs.
In Combination with Bortezomib and Dexamethasone (D-Vd)
Use the dosing schedule in Table 4 when DARZALEX FASPRO is administered in combination with bortezomib and dexamethasone (3-week cycle).
aFirst dose of the every-3-week dosing schedule is given at Week 10
bFirst dose of the every-4-week dosing schedule is given at Week 25
When DARZALEX FASPRO is administered as part of a combination therapy, see the prescribing information for dosage recommendations for the other drugs.
5) Recommended Dosage for Light Chain Amyloidosis
In Combination with Bortezomib, Cyclophosphamide and Dexamethasone (D-VCd)
Use the dosing schedule provided in Table 5 when DARZALEX FASPRO is administered in combination with bortezomib, cyclophosphamide and dexamethasone (4-week cycle).
aFirst dose of the every-2-week dosing schedule is given at Week 9
bFirst dose of the every-4-week dosing schedule is given at Week 25
When DARZALEX FASPRO is administered as part of a combination therapy, see Clinical Studies (14.2) and the prescribing information for dosage recommendations for the other drugs.
6) Administration
If a dose of DARZALEX FASPRO is missed, administer the dose as soon as possible and adjust the dosing schedule to maintain the dosing interval.
7) Recommended Concomitant Medications
Pre-Medication
Administer the following pre-medications 1-3 hours before each dose of DARZALEX FASPRO:
Post-Medication
Administer the Following Post-Medications:
If the patient does not experience a major systemic administration-related reaction after the first 3 doses of DARZALEX FASPRO, consider discontinuing the administration of corticosteroids (excluding any background regimen-specific corticosteroid).
For patients with a history of chronic obstructive pulmonary disease, consider prescribing short and long-acting bronchodilators and inhaled corticosteroids. Following the first 4 doses of DARZALEX FASPRO, consider discontinuing these additional post-medications, if the patient does not experience a major systemic administration-related reaction.
Prophylaxis for Herpes Zoster Reactivation
Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after starting DARZALEX FASPRO and continue for 3 months following the end of treatment [see Adverse Reactions (6.1)].
8) Dosage Modifications for Adverse Reactions
No dose reductions of DARZALEX FASPRO are recommended. Consider withholding DARZALEX FASPRO to allow recovery of blood cell counts in the event of myelosuppression [see Warnings and Precautions (5.3, 5.4)].
9) Preparation and Administration
DARZALEX FASPRO should be administered by a healthcare provider.
To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is DARZALEX FASPRO for subcutaneous use. Do not administer DARZALEX FASPRO intravenously.
DARZALEX FASPRO is ready to use.
Preparation
Storage
Administration
10) Dosage Forms and Strengths
Injection: 1,800 mg daratumumab and 30,000 units hyaluronidase per 15 mL (120 mg and 2,000 units/mL) colorless to yellow and clear to opalescent solution in a single-dose vial.
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 (5.1) and Adverse Reactions (6.3)].
Warnings and Precautions
11) 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.
Systemic Reactions
In a pooled safety population of 683 patients with multiple myeloma (N=490) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 10% of patients experienced a systemic administration-related reaction (Grade 2: 3.5%, Grade 3: 1%). Systemic administration-related reactions occurred in 9% 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 117 systemic administration-related reactions that occurred in 66 patients, 100 (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)]. 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)].
Local Reactions
In this pooled safety population, injection-site reactions occurred in 9% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 4.7 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.
12) 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 (6.1)]. 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.
13) Neutropenia
Daratumumab may increase neutropenia induced by background therapy [see Adverse Reactions (6.1)].
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.
14) Thrombocytopenia
Daratumumab may increase thrombocytopenia induced by background therapy [see Adverse Reactions (6.1)].
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.
15) 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 (8.1, 8.3)].
The combination of DARZALEX FASPRO with lenalidomide is contraindicated in pregnant women, because lenalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.
16) 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 (7.1)].
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)].
17) 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 (7.1)]. 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:
18) 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 (D-VMP) was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.1)]. 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.
Serious adverse reactions occurred in 39% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia and pyrexia. Fatal adverse reactions occurred in 3% of patients.
Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 4.5% of patients. The adverse reaction resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient was neutropenic sepsis.
Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 51% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included thrombocytopenia, neutropenia, anemia, and pneumonia.
The most common adverse reactions (≥20%) were upper respiratory tract infection, constipation, nausea, fatigue, pyrexia, peripheral sensory neuropathy, diarrhea, cough, insomnia, vomiting, and back pain.
Table 6 summarizes the adverse reactions in patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) in PLEIADES.
7#
3*
1#
1#
3#
3#
1#
6#
3#
aUpper respiratory tract infection includes nasopharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, tonsillitis, upper respiratory tract infection, and viral pharyngitis.
bPneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, pneumonia, and pneumonia bacterial.
cAbdominal pain includes abdominal pain, and abdominal pain upper.
dFatigue includes asthenia, and fatigue.
eEdema peripheral includes edema, edema peripheral, and peripheral swelling.
fCough includes cough, and productive cough.
#Only grade 3 adverse reactions occurred.
Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) included:
Table 7 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) in PLEIADES.
aDenominator is based on the safety population treated with D-VMP (N = 67).
Relapsed/Refractory Multiple Myeloma
In Combination with Lenalidomide and Dexamethasone
The safety of DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) was evaluated in a single-arm cohort of PLEIADES [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity (N=65) in combination with lenalidomide and dexamethasone. Among these patients, 92% were exposed for 6 months or longer and 20% were exposed for greater than one year.
Serious adverse reactions occurred in 48% of patients who received DARZALEX FASPRO. Serious adverse reactions in >5% of patients included pneumonia, influenza and diarrhea. Fatal adverse reactions occurred in 3.1% of patients.
Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 11% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 1 patient were pneumonia and anemia.
Dosage interruptions due to an adverse reaction occurred in 63% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruptions in >5% of patients included neutropenia, pneumonia, upper respiratory tract infection, influenza, dyspnea, and blood creatinine increased.
The most common adverse reactions (≥20%) were fatigue, diarrhea, upper respiratory tract infection, muscle spasms, constipation, pyrexia, pneumonia, and dyspnea.
Table 8 summarizes the adverse reactions in patients who received DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) in PLEIADES.
aFatigue includes asthenia, and fatigue.
bUpper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection viral, rhinitis, sinusitis, upper respiratory tract infection, and upper respiratory tract infection bacterial.
cPneumonia includes lower respiratory tract infection, lung infection, and pneumonia.
dBronchitis includes bronchitis, and bronchitis viral.
eDyspnea includes dyspnea, and dyspnea exertional.
fCough includes cough, and productive cough.
#Only grade 3 adverse reactions occurred.
Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) included:
Table 9 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) in PLEIADES.
aDenominator is based on the safety population treated with D-Rd (N = 65).
Monotherapy
The safety of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA [see Clinical Trials (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity. Among patients receiving DARZALEX FASPRO, 37% were exposed for 6 months or longer and 1% were exposed for greater than one year.
Serious adverse reactions occurred in 26% of patients who received DARZALEX FASPRO. Fatal adverse reactions occurred in 5% of patients. Fatal adverse reactions occurring in more than 1 patient were general physical health deterioration, septic shock, and respiratory failure.
Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received DARZALEX FASPRO. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than 2 patients were thrombocytopenia and hypercalcemia.
Dosage interruptions due to an adverse reaction occurred in 26% of patients who received DARZALEX FASPRO. Adverse reactions requiring dosage interruption in >5% of patients included thrombocytopenia.
The most common adverse reaction (≥20%) was upper respiratory tract infection. Table 10 summarizes the adverse reactions in COLUMBA.
6@
aUpper respiratory tract infection includes acute sinusitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, and upper respiratory tract infection.
bPneumonia includes lower respiratory tract infection, lung infection, pneumocystis jirovecii pneumonia, and pneumonia.
cFatigue includes asthenia, and fatigue.
dInfusion reactions includes terms determined by investigators to be related to infusion.
eCough includes cough, and productive cough.
fDyspnea includes dyspnea, and dyspnea exertional.
#Only grade 3 adverse reactions occurred.
@Grade 5 adverse reactions occurred.
Clinically relevant adverse reactions in <10% of patients who received DARZALEX FASPRO included:
Table 11 summarizes the laboratory abnormalities in COLUMBA.
aDenominator is based on the safety population treated with DARZALEX FASPRO (N = 260) and Intravenous Daratumumab (N = 258).
Light Chain Amyloidosis
In Combination with Bortezomib, Cyclophosphamide and Dexamethasone
The safety of DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (D-VCd) was evaluated in ANDROMEDA [see Clinical Studies (14.2)]. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity or a maximum of 2 years. Among patients who received D-VCd, 74% were exposed for 6 months or longer and 32% were exposed for greater than one year.
Serious adverse reactions occurred in 43% of patients who received DARZALEX FASPRO in combination with VCd. Serious adverse reactions that occurred in at least 5% of patients in the D-VCd arm were pneumonia (9%), cardiac failure (8%), and sepsis (5%). Fatal adverse reactions occurred in 11% of patients. Fatal adverse reactions that occurred in more than one patient included cardiac arrest (4%), sudden death (3%), cardiac failure (3%), and sepsis (1%).
Permanent discontinuation of DARZALEX FASPRO due to an adverse reaction occurred in 5% of patients. Adverse reactions resulting in permanent discontinuation of DARZALEX FASPRO in more than one patient were pneumonia, sepsis, and cardiac failure.
Dosage interruptions (defined as dose delays or skipped doses) due to an adverse reaction occurred in 36% of patients who received DARZALEX FASPRO. Adverse reactions which required a dosage interruption in ≥3% of patients included upper respiratory tract infection (9%), pneumonia (6%), cardiac failure (4%), fatigue (3%), herpes zoster (3%), dyspnea (3%), and neutropenia (3%).
The most common adverse reactions (≥20%) were upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.
Table 12 below summarizes the adverse reactions in patients who received DARZALEX FASPRO with VCd in ANDROMEDA.
1#
2#
4#
#Only grade 3 adverse reactions occurred.
aUpper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinovirus infection, sinusitis, tonsillitis, tracheitis, upper respiratory tract infection, upper respiratory tract infection bacterial, and viral upper respiratory tract infection.
bPneumonia includes lower respiratory tract infection, pneumonia, pneumonia aspiration, and pneumonia pneumococcal.
cDyspnea includes dyspnea, and dyspnea exertional.
dCough includes cough, and productive cough.
eArrhythmia includes atrial flutter, atrial fibrillation, supraventricular tachycardia, bradycardia, arrhythmia, bradyarrhythmia, cardiac flutter, extrasystoles, supraventricular extrasystoles, ventricular arrhythmia, ventricular extrasystoles, atrial tachycardia, ventricular tachycardia
fInjection site reactions includes terms determined by investigators to be related to daratumumab injection.
Clinically relevant adverse reactions not included in Table 12 and occurred in patients who received DARZALEX FASPRO with bortezomib, cyclophosphamide and dexamethasone (D-VCd) included:
Table 13 summarizes the laboratory abnormalities in patients who received DARZALEX FASPRO with VCd in ANDROMEDA.
Cardiac Adverse Reactions in Light Chain (AL) Amyloidosis
Among patients who received DARZALEX FASPRO in combination with VCd, 72% of patients had baseline cardiac involvement with Mayo Cardiac Stage I (3%), Stage II (46%) and Stage III (51%). Serious cardiac disorders occurred in 16% of patients (8% of patients with Mayo Cardiac Stage I and II and 28% of patients with Stage III). Serious cardiac disorders in >2% of patients included cardiac failure (8%), cardiac arrest (4%) and arrhythmia (4%). Fatal cardiac disorders occurred in 10% of patients (5% of patients with Mayo Cardiac Stage I and II and 19% of patients with Stage III) who received DARZALEX FASPRO in combination with VCd. Fatal cardiac disorders that occurred in more than one patient in the D-VCd arm included cardiac arrest (4%), sudden death (3%), and cardiac failure (3%).
19) Immunogenicity
As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other daratumumab products or other hyaluronidase products may be misleading.
In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, less than 1% of 633 patients developed treatment-emergent anti-daratumumab antibodies.
In patients with multiple myeloma and light chain (AL) amyloidosis who received DARZALEX FASPRO as monotherapy or as part of a combination therapy, 7% of 628 patients developed treatment-emergent anti-rHuPH20 antibodies. The anti-rHuPH20 antibodies did not appear to affect daratumumab exposure. None of the patients who tested positive for anti-rHuPH20 antibodies tested positive for neutralizing antibodies.
20) Postmarketing Experience
The following adverse reactions have been identified with use of intravenous daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System: Anaphylactic Reaction
Gastrointestinal: Pancreatitis
21) Drug Interactions
22) Effects of Daratumumab on Laboratory Tests
Interference with Indirect Antiglobulin Tests (Indirect Coombs Test)
Daratumumab binds to CD38 on RBCs and interferes with compatibility testing, including antibody screening and cross matching. Daratumumab interference mitigation methods include treating reagent RBCs with dithiothreitol (DTT) to disrupt daratumumab binding [see References (15)] or genotyping. Since the Kell blood group system is also sensitive to DTT treatment, supply K-negative units after ruling out or identifying alloantibodies using DTT-treated RBCs.
If an emergency transfusion is required, administer non-cross-matched ABO/RhD-compatible RBCs per local blood bank practices.
Interference with Serum Protein Electrophoresis and Immunofixation Tests
Daratumumab may be detected on serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for monitoring disease monoclonal immunoglobulins (M protein). False positive SPE and IFE assay results may occur for patients with IgG kappa myeloma protein impacting initial assessment of complete responses by International Myeloma Working Group (IMWG) criteria. In DARZALEX FASPRO-treated patients with persistent very good partial response, where daratumumab interference is suspected, consider using a FDA-approved daratumumab-specific IFE assay to distinguish daratumumab from any remaining endogenous M protein in the patient's serum, to facilitate determination of a complete response.
Use in Specific Populations
23) Pregnancy
Risk Summary
DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. The assessment of associated risks with daratumumab products is based on the mechanism of action and data from target antigen CD38 knockout animal models (see Data). There are no available data on the use of DARZALEX FASPRO in pregnant women to evaluate drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted.
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, loss, 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 DARZALEX FASPRO and lenalidomide is contraindicated in pregnant women, because lenalidomide may cause birth defects and death of the unborn child. Lenalidomide is only available through a REMS program. Refer to the lenalidomide prescribing information on use during pregnancy.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
Immunoglobulin G1 (IgG1) monoclonal antibodies are transferred across the placenta. Based on its mechanism of action, DARZALEX FASPRO may cause depletion of fetal CD38 positive immune cells and decreased bone density. Defer administering live vaccines to neonates and infants exposed to daratumumab in utero until a hematology evaluation is completed.
Data
Animal Data
DARZALEX FASPRO for subcutaneous injection contains daratumumab and hyaluronidase. Mice that were genetically modified to eliminate all CD38 expression (CD38 knockout mice) had reduced bone density at birth that recovered by 5 months of age. Data from studies using CD38 knockout animal models also suggest the involvement of CD38 in the regulation of humoral immune responses (mice), feto-maternal immune tolerance (mice), and early embryonic development (frogs).
No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on embryo-fetal development in pregnant mice given 330,000 U/kg hyaluronidase subcutaneously daily during organogenesis, which is 45 times higher than the human dose.
There were no effects on pre- and post-natal development through sexual maturity in offspring of mice treated daily from implantation through lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.
24) Lactation
Risk Summary
There is no data on the presence of daratumumab and hyaluronidase in human milk, the effects on the breastfed child, or the effects on milk production. Maternal immunoglobulin G is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. Because of the potential for serious adverse reactions in the breastfed child when DARZALEX FASPRO is administered with lenalidomide and dexamethasone, advise women not to breastfeed during treatment with DARZALEX FASPRO. Refer to lenalidomide prescribing information for additional information.
Data
Animal Data
No systemic exposure of hyaluronidase was detected in monkeys given 22,000 U/kg subcutaneously (12 times higher than the human dose) and there were no effects on post-natal development through sexual maturity in offspring of mice treated daily during lactation with 990,000 U/kg hyaluronidase subcutaneously, which is 134 times higher than the human doses.
25) Females and Males of Reproductive Potential
DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
With the combination of DARZALEX FASPRO with lenalidomide, refer to the lenalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential.
Contraception
Advise females of reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose. Additionally, refer to the lenalidomide labeling for additional recommendations for contraception.
26) Pediatric Use
Safety and effectiveness of DARZALEX FASPRO in pediatric patients have not been established.
27) Geriatric Use
Of the 291 patients who received DARZALEX FASPRO as monotherapy for relapsed and refractory multiple myeloma, 37% were 65 to <75 years of age, and 19% were 75 years of age or older. No overall differences in effectiveness of DARZALEX FASPRO have been observed between patients ≥65 years of age and younger patients. Adverse reactions that occurred at a higher frequency (≥5% difference) in patients ≥65 years of age included upper respiratory tract infection, urinary tract infection, dizziness, cough, dyspnea, diarrhea, nausea, fatigue, and peripheral edema. Serious adverse reactions that occurred at a higher frequency (≥2% difference) in patients ≥65 years of age included pneumonia.
Clinical studies of DARZALEX FASPRO as part of a combination therapy for patients with multiple myeloma did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.
Of the 193 patients who received DARZALEX FASPRO as part of a combination therapy for light chain (AL) amyloidosis, 35% were 65 to <75 years of age, and 10% were 75 years of age or older. Clinical studies of DARZALEX FASPRO as part of a combination therapy for patients with light chain (AL) amyloidosis did not include sufficient numbers of patients aged 65 and older to determine whether effectiveness differs from that of younger patients. Adverse reactions that occurred at a higher frequency in patients ≥65 years of age were peripheral edema, asthenia, pneumonia and hypotension.
No clinically meaningful differences in the pharmacokinetics of daratumumab were observed in geriatric patients compared to younger adult patients [see Clinical Pharmacology (12.3)].
Description
Daratumumab is an immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody that binds to the CD38 antigen. Daratumumab is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. The molecular weight of daratumumab is approximately 148 kDa.
Hyaluronidase (recombinant human) is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is a glycosylated single-chain protein produced by Chinese Hamster Ovary cells containing a DNA plasmid encoding for a soluble fragment of human hyaluronidase (PH20). Hyaluronidase (recombinant human) has a molecular weight of approximately 61 kDa.
DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection is a sterile, preservative-free, colorless to yellow, and clear to opalescent solution supplied in a single-dose vial for subcutaneous administration.
Each DARZALEX FASPRO 15 mL single-dose vial contains 1,800 mg of daratumumab and 30,000 units of hyaluronidase, L-histidine (4.9 mg), L-histidine hydrochloride monohydrate (18.4 mg), L-methionine (13.5 mg), polysorbate 20 (6 mg), sorbitol (735.1 mg), and Water for Injection, USP.
Clinical Pharmacology
28) Mechanism of Action
CD38 is a transmembrane glycoprotein (48 kDa) expressed on the surface of hematopoietic cells, including clonal plasma cells in multiple myeloma and light chain (AL) amyloidosis, as well as other cell types. Surface CD38 has multiple functions, including receptor mediated adhesion, signaling, and modulation of cyclase and hydrolase activity. Daratumumab is an IgG1κ human monoclonal antibody (mAb) that binds to CD38 and inhibits the growth of CD38 expressing tumor cells by inducing apoptosis directly through Fc mediated cross linking as well as by immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). A subset of myeloid derived suppressor cells (CD38+MDSCs), regulatory T cells (CD38+Tregs) and B cells (CD38+Bregs) are decreased by daratumumab.
Hyaluronan is a polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase increases permeability of the subcutaneous tissue by depolymerizing hyaluronan. In the doses administered, hyaluronidase in DARZALEX FASPRO acts locally. The effects of hyaluronidase are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.
29) Pharmacodynamics
NK cells express CD38 and are susceptible to daratumumab mediated cell lysis. Decreases in absolute counts and percentages of total NK cells (CD16+CD56+) and activated (CD16+CD56dim) NK cells in peripheral whole blood and bone marrow were observed with DARZALEX FASPRO treatment.
Cardiac Electrophysiology
DARZALEX FASPRO as a large protein has a low likelihood of direct ion channel interactions. There is no evidence from non-clinical or clinical data to suggest that DARZALEX FASPRO has the potential to delay ventricular repolarization.
Exposure-Response Relationship
The exposure-response relationship and time course of pharmacodynamics of DARZALEX FASPRO have not been fully characterized.
30) Pharmacokinetics
Following the recommended dose of DARZALEX FASPRO 1,800 mg/30,000 units, Cmax increased 4.8-fold and AUC0-7 days increased 5.4-fold from the 1st dose to the 8th dose.
Table 14 lists the observed mean (±SD) maximum trough concentrations (Ctrough) after the 8th dose, simulated median (5th-95th percentiles) maximum Ctrough after the 8th dose, simulated median (5th-95th percentiles) Cmax after the 8th dose, and simulated median (5th-95th percentiles) area under the curve (AUC0-7day) after the 8th dose following DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously in patients with multiple myeloma or light chain (AL) amyloidosis.
aGeometric mean ratio between 1,800 mg SC and 16 mg/kg was 108% (90% CI: 96, 122) in patients with multiple myeloma
bSource: MMY3012 Primary Analysis Clinical Study Report
cSource: AMY3001 Primary Analysis Clinical Study Report
dSource: Population Pharmacokinetics and Exposure-response Analysis Report for Subcutaneously Administered Daratumumab in Multiple Myeloma Subjects
eSource: Population Pharmacokinetics and Exposure-response Analysis Report for Daratumumab Subcutaneous Administration for the Treatment of Subjects with AL Amyloidosis
Absorption
At the recommended dose of DARZALEX FASPRO 1,800 mg/30,000 units, the absolute bioavailability is 69%, with peak concentrations occurring around 3 days (Tmax) in patients with multiple myeloma. Peak concentrations occurred around 4 days in patients with light chain (AL) amyloidosis.
Distribution
The estimated mean (coefficient of variation, CV) volume of distribution for the central compartment is 5.2 L (37%) and peripheral compartment was 3.8 L in patients with multiple myeloma. The estimated mean volume of distribution was 10.8 L (28%) in patients with light chain (AL) amyloidosis.
Elimination
Daratumumab is cleared by parallel linear and nonlinear saturable target mediated clearances. The estimated mean (CV %) linear clearance of daratumumab is 119 mL/day (59%) in patients with multiple myeloma and is 210 mL/day (42%) in patients with light chain (AL) amyloidosis. The estimated mean (CV %) elimination half-life associated with linear clearance is 20 days (22%) in patients with multiple myeloma and 28 days (74%) in patients with light chain (AL) amyloidosis.
Specific Populations
The following population characteristics have no clinically meaningful effect on the pharmacokinetics of daratumumab in patients administered DARZALEX FASPRO as monotherapy or as combination therapy: sex, age (33 to 92 years), renal impairment [Creatinine clearance (CLcr) 15 to 89 mL/min as determined by the Cockcroft-Gault formula], and mild hepatic impairment (total bilirubin 1 to 1.5 times ULN and AST>ULN). The effect of moderate and severe hepatic impairment on daratumumab pharmacokinetics is unknown.
Racial or Ethnic Groups
Of 190 patients with light chain (AL) amyloidosis who received DARZALEX FASPRO and had a maximum Ctrough after the 8th dose, African-Americans (4%) had 24% higher daratumumab mean maximum Ctrough after the 8th dose compared to that of Whites (83%) and Asians (10%) had 16% higher mean maximum Ctrough after the 8th dose compared to that of Whites. The difference in exposure between that of Asians and Whites could be explained in part by differences in body size. The effect of African-American race on exposure and related safety and efficacy of daratumumab is unknown.
Body Weight
In patients with multiple myeloma who received DARZALEX FASPRO 1,800 mg/30,000 units as monotherapy, the mean maximum Ctrough after the 8th dose was 12% lower in the higher body weight (BW) group (>85 kg), while the mean maximum Ctrough after the 8th dose was 81% higher in the lower BW group (≤50 kg) compared to the corresponding BW groups in the intravenous daratumumab arm.
In patients with light chain (AL) amyloidosis who received DARZALEX FASPRO 1,800 mg/30,000 units in combination and had a maximum Ctrough after the 8th dose, the mean maximum Ctrough after the 8th dose was 22% lower in the higher BW group (>85 kg), while the mean maximum Ctrough was 37% higher in the lower BW group (≤50 kg) compared to the patients with body weight of 51-85 kg.
Nonclinical Toxicology
31) Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or genotoxicity studies have been conducted with daratumumab. No animal studies have been performed to evaluate the potential effects of daratumumab on reproduction or development, or to determine potential effects on fertility in males or females.
No carcinogenicity, genotoxicity, or fertility studies were conducted for recombinant human hyaluronidase. There were no effects on reproductive tissues and function and no systemic exposure of hyaluronidase in monkeys given 22,000 U/kg/week subcutaneously (12 times higher than the human dose) for 39 weeks. As hyaluronidase is a recombinant form of the endogenous human hyaluronidase, no carcinogenicity, mutagenesis, or effects on fertility are expected.
Clinical Studies
32) Newly Diagnosed Multiple Myeloma
In Combination with Bortezomib, Melphalan and Prednisone
The efficacy of DARZALEX FASPRO with bortezomib, melphalan and prednisone (D-VMP) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. Eligible patients were required to have newly diagnosed multiple myeloma who are ineligible for transplant. 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; bortezomib 1.3 mg/m2 subcutaneously twice weekly on Weeks 1, 2, 4 and 5 for the first 6-week cycle (Cycle 1; 8 doses), followed by once weekly on Weeks 1, 2, 4 and 5 for eight more 6-week cycles (Cycles 2-9; 4 doses per cycle); and melphalan 9 mg/m2 and prednisone 60 mg/m2 orally on Days 1 to 4 of the nine 6-week cycles (Cycles 1-9). The major efficacy outcome measure was overall response rate (ORR).
A total of 67 patients received DARZALEX FASPRO with VMP. The median age was 75 years (range: 66 to 86); 46% were male; 69% were White, 8% Asian, and 2% Black or African American; and 33% had ISS Stage I, 45% had ISS Stage II, and 22% had ISS Stage III disease.
Efficacy results are summarized in Table 15.
aBased on treated patients
33) Relapsed/Refractory Multiple Myeloma
In Combination with Lenalidomide and Dexamethasone
The efficacy of DARZALEX FASPRO with lenalidomide and dexamethasone (D-Rd) was evaluated in a single-arm cohort of PLEIADES (NCT03412565), a multi-cohort, open-label trial. Patients received DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or unacceptable toxicity with lenalidomide 25 mg once daily orally on Days 1-21 of each 28-day cycle; and dexamethasone 40 mg per week (or a reduced dose of 20 mg per week for patients >75 years or BMI <18.5). The major efficacy outcome measure was ORR.
A total of 65 patients received DARZALEX FASPRO with Rd. The median age was 69 years (range: 33 to 82 years); 69% were male; 69% were White, and 3% Black or African American; and 42% had ISS Stage I, 30% had ISS Stage II, and 28% had ISS Stage III disease. Patients had received a median of 1 prior line of therapy. A total of 52% of patients had a prior ASCT; 95% of patients received a prior PI; 59% received a prior immunomodulatory agent, including 22% who received prior lenalidomide; and 54% of patients received both a prior PI and immunomodulatory agent.
Efficacy results are summarized in Table 16.
aBased on treated patients
Monotherapy
The efficacy of DARZALEX FASPRO as monotherapy was evaluated in COLUMBA (NCT03277105), an open-label, randomized, non-inferiority study. Eligible patients were required to have relapsed or refractory multiple myeloma who had received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who were double-refractory to a proteasome inhibitor and an immunomodulatory agent. Patients were randomized to receive DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously or daratumumab 16 mg/kg administered intravenously; each administered once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until unacceptable toxicity or disease progression. The major efficacy outcome measures were ORR by the IMWG response criteria and maximum Ctrough at pre-dose Cycle 3 Day 1 [see Clinical Pharmacology (12.3)]. Randomization was stratified by body weight, myeloma type, and number of prior lines of therapy.
A total of 522 patients were randomized: 263 to the DARZALEX FASPRO arm and 259 to the intravenous daratumumab arm. The median age was 67 years (range: 33 to 92 years); 55% were male; and 78% were White, 14% Asian, and 3% Black or African American. The median weight was 73 kg (range: 29 to 138). Patients had received a median of 4 prior lines of therapy. A total of 51% of patients had a prior ASCT; 100% of patients received both a PI and an immunomodulatory agent. Forty-nine percent of patients were refractory both a PI and an immunomodulatory agent. Eighty-two percent of patients were refractory to their last line of prior systemic therapy.
The results show that DARZALEX FASPRO 1,800 mg/30,000 units administered subcutaneously is non-inferior to daratumumab 16 mg/kg administered intravenously in terms of ORR and maximum trough concentration [see Clinical Pharmacology (12.3)]. Median progression-free survival was 5.6 months in the DARZALEX FASPRO arm and 6.1 months in the intravenous daratumumab arm. ORR results are provided in Table 17.
5 (1.9%)
7 (2.7%)
aBased on intent-to-treat population.
34) Light Chain Amyloidosis
In Combination with Bortezomib, Cyclophosphamide and Dexamethasone
The efficacy of DARZALEX FASPRO with VCd was evaluated in ANDROMEDA (NCT03201965), an open-label, randomized, active-controlled trial. Eligible patients were required to have newly diagnosed light chain (AL) amyloidosis with at least one affected organ, measurable hematologic disease, Cardiac Stage I-IIIA (based on European Modification of Mayo 2004 Cardiac Stage), and NYHA Class I-IIIA. Patients with NYHA Class IIIB and IV were excluded. Patients were randomized to receive bortezomib 1.3 mg/m2 administered subcutaneously, cyclophosphamide 300 mg/m2 (max dose 500 mg) administered orally or intravenously, and dexamethasone 40 mg (or a reduced dose of 20 mg for patients >70 years or body mass index <18.5 or who have hypervolemia, poorly controlled diabetes mellitus or prior intolerance to steroid therapy) administered orally or intravenously on Days 1, 8, 15, and 22 of each 28-day cycle with or without DARZALEX FASPRO 1,800 mg/30,000 units subcutaneously once weekly from weeks 1 to 8, once every 2 weeks from weeks 9 to 24 and once every 4 weeks starting with week 25 until disease progression or a maximum of two years. When DARZALEX FASPRO and dexamethasone were administered on the same day, dexamethasone 20 mg was administered before DARZALEX FASPRO with the remaining dose of dexamethasone administered after DARZALEX FASPRO if applicable. The major efficacy outcome measure was confirmed hematologic complete response (HemCR) rate based on Consensus Criteria as determined by the Independent Review Committee (negative serum and urine immunofixation, involved free light chain level decrease to less than the upper limit of normal, and normal free light chain ratio). Randomization was stratified by Cardiac Stage (European Modification of Mayo 2004 Cardiac Stage) countries that typically offer autologous stem cell transplant (ASCT) for patients with light chain (AL) amyloidosis, and renal function.
A total of 388 patients were randomized: 195 to D-VCd and 193 to VCd. The median patient age was 64 years (range: 34 to 87 years); 58% were male; 76% White, 17% Asian, and 3% Black or African American; 23% had light chain (AL) amyloidosis Cardiac Stage I, 40% had Stage II, and 37% had Stage IIIA. The median number of organs involved was 2 (range: 1-6) and 66% of patients had 2 or more organs involved. Vital organ involvement was: cardiac 71%, renal 59% and hepatic 8%. The majority (79%) of patients had lambda free light chain disease.
Efficacy results are summarized in Table 18.
aBased on intent-to-treat population
bp-value from Cochran Mantel-Haenszel Chi-Squared test.
cMajor organ deterioration-PFS defined as hematologic progression, major organ (cardiac or renal) deterioration or death
The median time to HemCR was 59 days (range: 8 to 299 days) in the D-VCd arm and 59 days (range: 16 to 340 days) in the VCd arm. The median time to VGPR or better was 17 days (range: 5 to 336 days) in the D-VCd arm and 25 days (range: 8 to 171 days) in the VCd arm. The median duration of HemCR had not been reached in either arm.
The median follow-up for the study is 11.4 months. Overall survival (OS) data were not mature. A total of 56 deaths were observed [N=27 (13.8%) D-VCd vs. N=29 (15%) VCd group].
How Supplied/Storage and Handling
DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj) injection is a sterile, preservative-free, colorless to yellow, and clear to opalescent solution for subcutaneous use supplied as individually packaged single-dose vials providing 1,800 mg of daratumumab and 30,000 units of hyaluronidase per 15 mL (NDC 57894-503-01).
Store DARZALEX FASPRO vials in a refrigerator at 2° C. to 8° C. (36° F. to 46° F.) in the original carton to protect from light.
Do not freeze or shake.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Hypersensitivity and Other Administration Reactions
Advise patients to seek immediate medical attention for any of the following signs and symptoms of systemic administration-related reactions: itchy, runny or blocked nose; chills, nausea, throat irritation, cough, headache, shortness of breath or difficulty breathing [see Warnings and Precautions (5.1)].
Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis
Advise patients to immediately contact their healthcare provider if they have signs or symptoms of cardiac adverse reactions [see Warnings and Precautions (5.2)].
Neutropenia
Advise patients to contact their healthcare provider if they have a fever [see Warnings and Precautions (5.3)].
Thrombocytopenia
Advise patients to contact their healthcare provider if they have bruising or bleeding [see Warnings and Precautions (5.4)].
Embryo-Fetal Toxicity
Advise pregnant women of the potential hazard to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to avoid becoming pregnant during treatment with DARZALEX FASPRO and for at least 3 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
Advise patients that lenalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide is only available through a REMS program [see Use in Specific Populations (8.1, 8.3)].
Interference with Laboratory Tests
Advise patients to inform their healthcare provider, including personnel at blood transfusion centers, that they are taking DARZALEX FASPRO, in the event of a planned transfusion [see Warnings and Precautions (5.6)].
Advise patients that DARZALEX FASPRO can affect the results of some tests used to determine complete response in some patients and additional tests may be needed to evaluate response [see Warnings and Precautions (5.7)].
Hepatitis B Virus (HBV) Reactivation
Advise patients to inform healthcare providers if they have ever had or might have a hepatitis B infection and that DARZALEX FASPRO could cause hepatitis B virus to become active again [see Adverse Reactions (6.1)].
Product of Switzerland
Manufactured by:
Janssen Biotech, Inc.
Horsham, Pa. 19044
U.S. License Number 1864
This application claims priority to U.S. Provisional Application Ser. No. 63/147,323, filed 9 Feb. 2021, the entire contents of which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63147323 | Feb 2021 | US |
