WO2023240180A1 - Méthodes de traitement d'un trouble prolifératif des lymphocytes b - Google Patents

Méthodes de traitement d'un trouble prolifératif des lymphocytes b Download PDF

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WO2023240180A1
WO2023240180A1 PCT/US2023/068121 US2023068121W WO2023240180A1 WO 2023240180 A1 WO2023240180 A1 WO 2023240180A1 US 2023068121 W US2023068121 W US 2023068121W WO 2023240180 A1 WO2023240180 A1 WO 2023240180A1
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zanubrutinib
patient
patients
coadministration
dose
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PCT/US2023/068121
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English (en)
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Ying Ou
Jason Paik
Tommi Salmi
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Beigene Switzerland Gmbh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • kits for treating a patient having a B-cell proliferative disorder particularly methods of prolonging progression-free survival time of a patient having chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL), comprising administering to the patient an effective amount of zanubrutinib.
  • CLL/SLL chronic lymphocytic leukemia/ small lymphocytic lymphoma
  • B-cell receptor signaling pathway is not only essential for normal B-cell development but is also implicated in the survival and proliferation of malignant B cells. Inhibition of B-cell receptor signaling has recently been established as an effective approach for management of B-cell malignancies.
  • Bruton tyrosine kinase (BTK) is a key component of the B- cell receptor signaling pathway, and the first-generation BTK inhibitor, ibrutinib, has become a standard of care in frontline and previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), previously treated mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM).
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • MCL mantle cell lymphoma
  • WM Waldenstrom macroglobulinemia
  • Zanubrutinib is a highly specific next-generation BTK inhibitor with favorable oral bioavailability, as shown in preclinical studies. Compared with ibrutinib, zanubrutinib has shown greater selectivity for BTK and fewer off-target effects in multiple in vitro enzymatic and cellbased assays, zanubrutinib, ibrutinib, and other active BTK inhibitors covalently bind cysteine 481 in the adenosine triphosphate-binding pocket of BTK, and display varying affinities (depending on specificity of the individual drug) for related and unrelated adenosine triphosphate-binding kinases that contain a sterically available cysteine at this position, including epidermal growth factor receptor (EGFR), human EGFR-2 (HER2), human EGFR-4 (HER4), interleukin-2-inducible T-cell kinase (ITK), bone marrow tyrosine
  • Off-target inhibition likely contributes to the toxicides reported in patients treated with ibrutinib, such as diarrhea and rash (toxicides associated with EGFR inhibition), bleeding or bruising, and atrial fibrillation, and those that are not seen in patients with congenital X-linked agammaglobulinemia due to germline mutations in the BTK gene; a more specific BTK inhibitor may have fewer toxicides.
  • PFS progression-free survival
  • Oxidative metabolism by the CYP3A4 and CYP3A5 members of the CYP3A enzyme subfamily plays a dominant role in the elimination of a large number of drugs, and it can be difficult to maintain therapeutically effective blood plasma levels of drugs which are metabolized by these enzymes, e.g., zanubrutinib. Also, for some drugs, the metabolic by-products of CYP3A-mediated metabolism are highly toxic and can result in severe side effects.
  • CYP3A inducers can be used to improve the therapeutic efficacy of drugs, e.g., zanubrutinib, metabolized by CYP3A.
  • a method of treating a patient having a B-cell proliferative disorder comprising administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, wherein the patient is characterized by being administered with a moderate CYP3A inducer.
  • zanubrutinib is administered at a dose of about 320 mg twice a day, or at a total daily dose of 640 mg.
  • the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • the zanubrutinib is administered at a dose of about 320 mg twice a day, which has a total daily dose of about 640 mg.
  • the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL).
  • the B-cell proliferative disorder is small lymphocytic lymphoma (SLL).
  • the B-cell proliferative disorder is Waldenstrom macroglobulinemia (WM). In one embodiment, the B-cell proliferative disorder is mantle cell lymphoma (MCL). In one embodiment, the B-cell proliferative disorder is marginal zone lymphoma (MZL). In one embodiment, the B-cell proliferative disorder is follicular lymphoma (FL). In one embodiment, the moderate CYP3A inducer is rifabutin, bosentan, phenobarbital, efavirenz, etravirine, modafinil, or nafcillin. In one embodiment, the patient is characterized by a 17p deletion (del(17p)) mutation or TP53 mutation.
  • the administration prolongs the progression-free survival (PFS) time of the patient as compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the administration causes lower rate of atrial fibrillation and/or flutter as compared to the rate of atrial fibrillation and/or flutter of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • FIG. 1 depicts the pharmacokinetics (PK) study design of Example 1.
  • FTGs. 2A-2B depict arithmetic mean (+SD) plasma concentrations of zanubrutinib after administration of zanubrutinib alone and after coadministration of zanubrutinib with rifabutin on a (FIG. 2A) linear and (FIG. 2B) semi -logarithmic scale. SD, standard deviation.
  • FIG. 3 depicts the Independent-Review Committee Assessment of the Progression- Free Survival in intent-to-treat (ITT) Populations. Noninferiority 1-sided P ⁇ 0.0001.
  • FIG. 4 depicts the Independent-Review Committee Assessment of the Progression- Free Survival in del(17p)/7P53 Mutation Populations.
  • FIG. 5 depicts the Study Schema of Example 2.
  • FIG. 6 depicts the Participant Disposition and Study Flow.
  • FIG. 7 is for Investigator-assessed ORR
  • FIG. 8 is for IRC-assessed ORR. All subgroups, with the exception of complex karyotype were prespecified. Rate difference (zanubrutinib minus ibrutinib) and 95% CI were unstratified for subgroups.
  • Bulky disease is derived from any target lesion longest diameter >5 cm.
  • ECOG Eastern Cooperative Oncology Group
  • IGHV immunoglobulin heavy chain variable region
  • ORR overall response rate.
  • FIG. 9 depicts the Investigator Assessment of the Progression-Free Survival in ITT Populations.
  • FIG. 10 depicts the Investigator Assessment of the Progression-Free Survival in del(17p)/7P53 Mutation Populations.
  • FIG. 11 depicts the overall survival.
  • FIG. 14 depicts the time-to-treatment failure.
  • FIG. 20 depicts the Study Schema of Example 3. Abbreviations: CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; SLL, small lymphocytic lymphoma; WM, Waldenstrom macroglobulinemia.
  • FIG. 21 depicts the Study CONSORT diagram of Example 3. Abbreviations: bid: twice daily, qd: once daily. COVID-19: coronavirus disease 2019.
  • FIG. 22 depicts the recurrence and change in severity of ibrutinib- and acalabrutinib- intol erance events on zanubrutinib.
  • ibrutinib-related intolerance events arthritis, bone pain, bronchitis, embolism, irregular heart rate, malaise, pericardial effusion, pleural effusion, pneumonia, psoriasis, pyrexia, sinusitis, subcutaneous abscess, supraventricular tachycardia, transaminases increased, ventricular extrasystoles, vertigo, and vomiting
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • FIG. 23 depicts Formula (EAIR).
  • Zanubrutinib or “zanubrutinib” refers to the compound having the name of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[l,5- a]pyrimidine-3-carboxamide, or the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer, enantiomer, isotopologue, solvate, or prodrug thereof.
  • Zanubrutinib is disclosed and claimed, along with pharmaceutically acceptable salts thereof, and also as solvates thereof, as being useful as an inhibitor of BTK activity, particularly in treatment of cancer, in WO2014173289, the entire disclosure of which is incorporated herein by reference.
  • Zanubrutinib is compound 27b in WO2014173289 and Compound 1 in WO2018033853, the entire disclosure of which is incorporated herein by reference.
  • Zanubrutinib can be prepared as described in WO2014173289 and WO2018033853.
  • zanubrutinib is a hydrate.
  • a solid form of zanubrutinib is used for the treatment provided herein.
  • a crystal form of zanubrutinib is used for the treatment provided herein.
  • an amorphous form of zanubrutinib is used for the treatment provided herein.
  • a freebase of zanubrutinib is used for the treatment provided herein.
  • an oxalate form of zanubrutinib is used for the treatment provided herein.
  • Form A of zanubrutinib described in WO2018033853 is used for the treatment provided herein.
  • CYP3A inducer refers to any chemical entity that increases the normal function of the Cytochrome P450 3A (CYP3A) subfamily of genes and proteins.
  • the CYP3A inducer can increase the action of the CYP3A gene or the CYP3A protein/enzyme.
  • CYP3A inducers include, but are not limited to, armodafinil, apalutamide, bexarotene, bosentan, carbamazepine, cenobamate, dabrafenib, dexamethasone, dipyrone, efavirenz, elagolix, enzalutamide, eslicarbazepine, estradiol, Etravirine, ivosidenib, lumacaftor, lorlatinib, mitapivat, mitotane, mobocertinib, modafinil, nafcillin, pexidartinib, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, rufmamide, sotorasib, St.
  • the CYP3A inducer is a moderate CYP3A inducer, examples of which include, but are not limited to rifabutin, bexarotene, bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, efavirenz, a combination of elagolix, estradiol, and norethindrone, eslicarbazepine, etravirine, lorlatinib, mitapivat, modafinil, or nafcillin, pexidartinib, phenobarbital, primidone, rifapentine, sotorasib.
  • rifabutin include, but are not limited to rifabutin, bexarotene, bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, efavirenz, a combination of elagolix, estradiol, and
  • the moderate CYP3A inducer is rifabutin, bosentan, cenobamate, dabrafenib, efavirenz, etravirine, lorlatinib, pexidartinib, phenobarbital, primidone, or sotorasib.
  • a moderate CYP3A inducer is phenobarbital.
  • BTK inhibitor refers to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK).
  • BTK inhibitors include, but are not limited to, those described above: ibrutinib, acalabrutinib, evobrutinib, fenebrutinib, poseltinib, vecabrutinib, tirabrutinib, spebrutinib, and zanubrutinib.
  • progression-free survival refers to the length of time from the beginning of the treatment to the first disease progression or death, whichever occurs first.
  • the PFS can be during or after the treatment of a disease, such as cancer, during which a patient can live with the disease, but the disease does not get worse.
  • a “PFS event” refers to the first disease progression or death observed in a patient under treatment of a disease. PFS can be measured using methods known in the art in view of the present disclosure.
  • progress! on -free survival probability and “progression-free survival rate” are interchangeable. They refer to the probability of a patient stays PFS event free during or after a treatment, or the PFS event-free rate in a patient population that are receiving or have received a treatment.
  • ibrutinib refers to the compound having the name of l-[(3R)-3-[4- amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl]- 1 -piperidinyl]-2-propen- 1 -one, and the following structure:
  • acalabrutinib refers to the compound having the name of 4- ⁇ 8- amino-3 -[(2S)- 1 -(but-2-ynoyl)pyrrolidin-2-yl]imidazo[ 1 ,5-a]pyrazin- 1 -yl) ⁇ -N-(pyridine-2- yl)benzamide, and the following structure:
  • treating refers to therapeutic therapy.
  • treating means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • prevention is not an absolute term. Prophylactic therapy is appropriate, for example, when a subject is considered at high risk for developing cancer, such as when a subject has a strong family history of cancer or when a subject has been exposed to a carcinogen.
  • the term “effective amount” means that amount of a drug or pharmaceutical agent that elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • Zanubrutinib disclosed herein may contain one or more chiral atoms, or may otherwise be capable of existing as enantiomers. Accordingly, the compounds of this invention include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also, it is understood that all tautomers and mixtures of tautomers are included within the scope of zanubrutinib.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, compounds of formula (I) or a salt thereof and a solvent. Also, it is understood that zanubrutinib may be presented, separately or both, as solvates.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, dimethyl sulforide, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water (i.e., a hydrate).
  • Zanubrutinib may have the ability to crystallize in more than one form, a characteristic, which is known polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of zanubrutinib.
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • Techniques for characterizing crystal forms and amorphous solids include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), singlecrystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies.
  • TGA thermal gravimetric analysis
  • DSC differential scanning calorimetry
  • XRPD X-ray powder diffractometry
  • IR infrared
  • Raman spectroscopy solid-state and solution nuclear magnetic resonance (NMR) spectroscopy
  • optical microscopy hot stage optical microscopy
  • SEM scanning electron microscopy
  • PSA
  • the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values.
  • the value of an XRPD peak position may vary by up to ⁇ 0.2° 20 (or ⁇ 0.2 degrees 20) while still describing the particular XRPD peak.
  • the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
  • Suitable pharmaceutically acceptable base addition salts of the compounds provided herein include, but are not limited to, those well-known in the art, see for example, Remington ’s Pharmaceutical Sciences, 18 th eds., Mack Publishing, Easton PA (1990) o Remington: The Science and Practice of Pharmacy, 19 th eds., Mack Publishing, Easton PA (1995).
  • stereoisomer or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the zanubrutinib and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the zanubrutinib and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the zanubrutinib and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the zanubrutinib and less than about 3% by weight of the other stereoisomers of the compound.
  • the compounds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.
  • stereomerically pure forms of such compounds are encompassed by the embodiments disclosed herein.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein.
  • isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley -Tnterscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.
  • the compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof.
  • the compounds are isolated as either the E or Z isomer. In other embodiments, the compounds are a mixture of the E and Z isomers.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • subject includes an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig, in one embodiment a mammal, in another embodiment a human.
  • an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig, in one embodiment a mammal, in another embodiment a human.
  • zanubrutinib While it is possible that, for use in therapy, zanubrutinib, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include zanubrutinib, and one or more pharmaceutically acceptable carriers, diluents, or excipients. Zanubrutinib is as described above.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical composition including admixing a zanubrutinib with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Such elements of the pharmaceutical compositions utilized may be presented in separate pharmaceutical combinations or formulated together in one pharmaceutical composition.
  • the invention further provides a pharmaceutical composition containing zanubrutinib and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Zanubrutinib described above may be utilized in any of the compositions described above.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose depends on the condition being treated, the route of administration and the age, weight, and condition of the patient. Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
  • Zanubrutinib may be administered by any appropriate route. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It is appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that zanubrutinib may be compounded together in a pharmaceutical composition.
  • routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It is appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination and the cancer to be treated. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that zanubrutin
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • kit refers to a pharmaceutical composition or a composition that is used to administer zanubrutinib according to the disclosure.
  • the kit can contain zanubrutinib in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions.
  • a kit of parts comprising components: zanubrutinib in association with a pharmaceutically acceptable excipients, diluents, or carrier.
  • the kit can also be provided with instruction, such as dosage and administration instructions.
  • dosage and administration instructions can be of the kind that are provided to a doctor, for example by a drug product label, or they can be of the kind that are provided by a doctor, such as instructions to a patient.
  • dose as used herein is understood to mean a dose that is intended to either slowly raise plasma or blood concentration levels of the compound to a therapeutically effective level, or to maintain such a therapeutically effective level.
  • zanubrutinib and a moderate CYP3A inducer can be used in coordinated fashion but such a use does not necessarily mean that zanubrutinib is used in the combination or coadministration with the moderate CYP3A inducer.
  • zanubrutinib and the moderate CYP3A inducer can be administered simultaneously, consecutively, or sequentially.
  • the concomitant administration of zanubrutinib and the moderate CYP3A inducer refers to that zanubrutinib and the moderate CYP3A inducer can be administered simultaneously, consecutively, or sequentially.
  • zanubrutinib and the moderate CYP3A inducer have separate dosing regimens, such as, one therapeutically active agent can be administered once a day while the other therapeutically active agent can be administered multiple times a day, or the different therapeutic agents can be dosed on different days.
  • the use of a moderate CYP3A inducer is used to identify a patient population.
  • “assessing a patient receiving a moderate CYP3A inducer as to whether administration of the moderate CYP3A inducer can be avoided” refers to a step of determining if the patient has an alternative option to replace the moderate CYP3A inducer or a method by which the patient may stop receiving the moderate CYP3A inducer. Such an alternative option or method would not lead to the deterioration of the patient condition. If such an alternative option or method is not available to the patient, it is determined that the administration of the moderate CYP3 A inducer cannot be avoided.
  • a method of treating a patient having a B-cell proliferative disorder comprising administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, wherein the patient is characterized by being administered with a moderate CYP3A inducer.
  • Also provided herein is a method of treating or delaying progression of a B-cell proliferative disorder in a patient, the method comprising administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 320 mg twice a day, or at a total daily dose of about 640 mg, wherein the patient is characterized by being administered with a moderate CYP3A inducer; and the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • Also provided herein is a method of treating or delaying progression of a B-cell proliferative disorder in a patient comprising determining whether the patient is being treated with a moderate CYP3 A inducer; and if the patient is being treated with a moderate CYP3A inducer, administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 320 mg twice a day, or at a total daily dose of about 640 mg; wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM mantle cell lymphoma
  • MZL marginal zone lympho
  • a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer comprising assessing the patient as to whether administration of the moderate CYP3A inducer can be avoided; and if the administration of the moderate CYP3A inducer cannot be avoided, administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 320 mg twice a day, or at a total daily dose of about 640 mg; wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM mantle cell lymphoma
  • Also provided herein is a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer, the method comprising concomitantly administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 320 mg twice a day, or at a total daily dose of about 640 mg, and the moderate CYP3A inducer; wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL follicular lymph
  • Also provided herein is a method of treating or delaying progression of a B-cell proliferative disorder in a patient comprising determining whether the patient is being treated with a moderate CYP3 A inducer; and if the patient is being treated with a moderate CYP3A inducer, concomitantly administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 320 mg twice a day, or at a total daily dose of about 640 mg; and the moderate CYP3A inducer; wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM man
  • Also provided herein is a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer, the method comprising assessing the patient as to whether administration of the moderate CYP3A inducer can be avoided; and if the administration of the moderate CYP3A inducer cannot be avoided, concomitantly administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 320 mg twice a day, or at a total daily dose of about 640 mg, and the moderate CYP3A inducer; wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL
  • Also provided herein is a method of treating or delaying progression of a B-cell proliferative disorder in a patient, the method comprising administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, wherein the patient is characterized by being administered with a moderate CYP3A inducer.
  • zanubrutinib or a pharmaceutically acceptable salt thereof, for use in treating or preventing a B-cell proliferative disorder.
  • zanubrutinib or a pharmaceutically acceptable salt thereof, for use as a medicament in the treatment of a B-cell proliferative disorder.
  • zanubrutinib is administered at a dose of about 320 mg twice a day (BID), or at a total daily dose of about 640 mg. In one embodiment, zanubrutinib is administered at a dose of about 320 mg twice a day (BID).
  • zanubrutinib is administered at a dose of about 80 mg BID, about 90 mg BID, about 100 mg BID, about 110 mg BID, about 120 mg BID, about 130 mg BID, about 140 mg BID, about 150 mg BID, about 160 mg BID, 170 mg BID, about 180 mg BID, about 190 mg BID, about 200 mg BID, about 210 mg BID, about 220 mg BID, about 230 mg BID, about 240 mg BID, about 250 mg BID, about 260 mg BID, about 270 mg BID, about 280 mg BID, about 290 mg BID, about 300 mg BID, about 310 mg BID, about 320 mg BID, about 330 mg BID, about 340 mg BID, about 350 mg BID, about 360 mg BID, about 370 mg BID, about 380 mg BID, about 390 mg BID, about 400 mg BID, about 410 mg BID, about 420 mg BID, about 430 mg
  • zanubrutinib is administered at a dose of about 540 mg QD, about 550 mg QD, about 560 mg QD, about 570 mg QD, about 580 mg QD, about 590 mg QD, about 600 mg QD, about 610 mg QD, about 620 mg QD, about 630 mg QD, about 640 mg QD, about 650 mg QD, about 660 mg QD, about 670 mg QD, about 680 mg QD, about 690 mg QD, about 700 mg QD, about 710 mg QD, about 720 mg QD, about 730 mg QD, or about 740 mg
  • the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • the zanubrutinib is administered at a dose of about 320 mg twice a day.
  • the zanubrutinib is administered at a total daily dose of about 640 mg.
  • the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • the B-cell proliferative disorder is small lymphocytic lymphoma (SLL).
  • SLL small lymphocytic lymphoma
  • the B-cell proliferative disorder is Waldenstrom macroglobulinemia (WM).
  • the B-cell proliferative disorder is mantle cell lymphoma (MCL).
  • the B-cell proliferative disorder is marginal zone lymphoma
  • the B-cell proliferative disorder is follicular lymphoma (FL).
  • the B-cell proliferative disorder is Diffuse Large B-Cell
  • the B-cell proliferative disorder is Diffuse Large B-Cell Lymphoma (DLBCL) with CD79B mutation. In one embodiment, the B-cell proliferative disorder is Diffuse Large B-Cell Lymphoma (DLBCL) characterized by CD79B mutation.
  • the patient is assessed as to whether administration of the moderate CYP3A inducer should be avoided, and if the administration of the moderate CYP3A inducer should not be avoided, the patient is administered with the moderate CYP3 A inducer and zanubrutinib.
  • the patient is assessed as to whether administration of the moderate CYP3A inducer can be avoided, and if the administration of the moderate CYP3A inducer cannot be avoided, the patient is administered with the moderate CYP3 A inducer and zanubrutinib.
  • the moderate CYP3 A inducer is rifabutin, bosentan, efavirenz, etravirine, modafinil, or nafcillin.
  • the moderate CYP3A inducer is rifabutin, bosentan, efavirenz, etravirine, modafinil, phenobarbital, or nafcillin.
  • the moderate CYP3A inducer is rifabutin, or efavirenz.
  • the moderate CYP3A inducer is rifabutin.
  • the patient is characterized by being administered with rifabutin at 300 mg per day.
  • the moderate CYP3A inducer is Bexarotene, Bosentan, Cenobamate, Dabrafenib, Dexamethasone, Dipyrone, Efavirenz, Elagolix, estradiol, Eslicarbazepine, Etravirine, Lorlatinib, Mitapivat, Modafinil, Nafcillin, Pexidartinib, Rifabutin, Rifapentine, or Sotorasib.
  • a moderate CYP3A inducer is phenobarbital.
  • the patient is characterized by a 17p deletion (del(17p)) mutation.
  • the patient is characterized by a TP53 mutation.
  • the administration prolongs the progression-free survival (PFS) time of the patient as compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the progression-free survival (PFS) time of the patient is longer compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily
  • the administration causes lower rate of atrial fibrillation and/or flutter as compared to the rate of atrial fibrillation and/or flutter of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the administration prolongs the progression-free survival (PFS) time of the patient as compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily; wherein the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • the progression-free survival (PFS) time of the patient is longer compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the patient was treated with ibrutinib or acalabrutinib but discontinued the treatment prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof.
  • the patient is intolerant to ibrutinib or acalabrutinib.
  • the patient has all of the factors:
  • the PFS of the patient is prolonged to more than about 1 month, more than about 6 months, more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, or more than about 5 years. In one embodiment, the PFS of the patient is prolonged to more than about 6 months, more than about 1 year, or more than about 2 years. In one embodiment, the PFS of the patient is prolonged to more than about 1 year, or more than about 2 years. In one embodiment, the PFS of the patient is prolonged for more than about 1 month, more than about 6 months, more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, or more than about 5 years. In one embodiment, the PFS of the patient is prolonged for more than about 6 months, more than about 1 year, or more than about 2 years. Tn one embodiment, the PFS of the patient is prolonged for more than about 1 year, or more than about 2 years.
  • the PFS of the patient is prolonged for more than about 1 month, more than about 6 months, more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, or more than about 5 years longer compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily. In one embodiment, the PFS of the patient is prolonged for more than about 6 months, more than about
  • the PFS of the patient is prolonged for more than about 1 year, or more than about 2 years longer compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily. In one embodiment, the PFS of the patient is prolonged for more than about 1 year, or more than about 2 years longer compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily. In one embodiment, the PFS of the patient is prolonged for more than about
  • the PFS of the patient is extended to more than about 20 months, more than about 25 months, more than about 30 months, more than about 35 months, more than about 40 months, more than about 45 months, more than about 50 months, more than about 55 months, more than about 60 months, more than about 65 months, more than about 70 months, more than about 75 months, more than about 80 months, or more than about 85 months.
  • the patient further does not have Hemorrhage, infection, Cytopenia, Second Primary Malignancies, Cardiac Arrhythmias, or Embryo-Fetal Toxicity.
  • the patient further does not have Hemorrhage, opportunistic infection, Cytopenia, skin cancer, atrial fibrillation, atrial flutter, or pregnancy.
  • Also provided here is a method of treating a patient having a B-cell proliferative disorder, the method comprising concomitantly administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, and a CYP3A inducer.
  • the dose of zanubrutinib is increased by 2-fold in the presence of a moderate CYP3A inducer.
  • the patient is assessed as to whether administration of the moderate CYP3A inducer can be avoided, and if the administration of the moderate CYP3A inducer cannot be avoided, the patient is administered the moderate CYP3 A inducer and zanubrutinib.
  • a method of determining a therapeutic dosage of zanubrutinib, or a pharmaceutically acceptable salt thereof, in the treatment of a patient with a B-cell proliferative disorder comprising: a) obtaining a suitable cell or tissue sample from the patient; b) identifying the cytochrome P450 enzymatic genotype of the patient; c) assessing the patient’s medical history for a history of smoking or use of medications that act as inducers of CYP3A; and d) administering 320 mg of zanubrutinib twice daily to a patient determined to require a moderate CYP3A inducer.
  • a method of treating a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer comprising administering 320 mg of zanubrutinib, or a pharmaceutically acceptable salt thereof, twice daily to the patient.
  • the moderate CYP3A inducer is administered before, concurrently with, or after zanubrutinib, or a pharmaceutically acceptable salt thereof.
  • a method of treating a patient with a B-cell proliferative disorder comprising administering an adjusted dose of zanubrutinib, or a pharmaceutically acceptable salt thereof, wherein the adjusted dose is 320 mg of zanubrutinib twice daily when the patient is receiving a moderate CYP3 A inducer.
  • Also provided herein is a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer the method comprising assessing the patient as to whether administration of the moderate CYP3A inducer can be avoided; and if the administration of the moderate CYP3A inducer cannot be avoided, concomitantly administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 320 mg twice a day, and a moderate CYP3A inducer; wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL); and the moderate CYP3A inducer is rifabutin, bosentan, efavi
  • PFS progression-free survival
  • the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • the administration causes lower rate of atrial fibrillation and /or flutter as compared to the rate of atrial fibrillation and /or flutter of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the patient has relapsed or refractory CLL or SLL.
  • the patient was treated with ibrutinib or acalabrutinib but discontinued the treatment prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof.
  • the patient has a 17p deletion (del(17p)).
  • the administration prolongs the PFS time of the patient to be more than about 1 month, more than about 6 months, more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, or more than about 5 years.
  • the administration prolongs the PFS time of the patient to be more than about 20 months, more than about 25 months, more than about 30 months, more than about 35 months, more than about 40 months, more than about 45 months, more than about 50 months, more than about 55 months, more than about 60 months, more than about 65 months, more than about 70 months, more than about 75 months, more than about 80 months, or more than about 85 months.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 160 mg of zanubrutinib twice a day.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 320 mg of zanubrutinib once a day.
  • the method further comprises assessing baseline risk of tumor lysis syndrome (TLS) in the patient, monitoring TLS during the PFS time, and treating TLS when it occurs.
  • TLS tumor lysis syndrome
  • the patient is administered with a moderate CYP3A inducer.
  • the severe bleeding disorder is hemophilia A, hemophilia B, or von Willebrand disease.
  • the patient further does not have Hemorrhage, opportunistic infection, Cytopenia, skin cancer, atrial fibrillation, atrial flutter, Tumor Lysis Syndrome, or pregnancy.
  • the patient further does not have Tumor Lysis Syndrome.
  • the clinically significant cardiovascular condition is selected from the group consisting of:
  • the moderate or severe hepatic impairment is Child-Pugh class B or C.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • zanubrutinib (a) assessing baseline risk of tumor lysis syndrome (TLS) in the patient; (b) orally administering to the patient zanubrutinib or a pharmaceutically acceptable salt thereof at a dose of 160 mg of zanubrutinib twice a day or 320 mg of zanubrutinib once a day; and
  • the administration results in a progression-free survival (PFS) rate of at least 75%, such as 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or any number in between thereof, as measured at 24 months.
  • PFS progression-free survival
  • the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • the administration prolongs the PFS time as compared to the PFS time of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the administration causes lower rate of atrial fibrillation and /or flutter as compared to the rate of atrial fibrillation and /or flutter of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the patient has relapsed or refractory CLL or SLL.
  • the patient was treated with ibrutinib or acalabrutinib but discontinued the treatment prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof
  • the patient has a 17p deletion (del(17p)).
  • the administration prolongs the PFS time of the patient to be more than about 1 month, more than about 6 months, more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, or more than about 5 years.
  • the administration prolongs the PFS time of the patient to be more than about 20 months, more than about 25 months, more than about 30 months, more than about 35 months, more than about 40 months, more than about 45 months, more than about 50 months, more than about 55 months, more than about 60 months, more than about 65 months, more than about 70 months, more than about 75 months, more than about 80 months, or more than about 85 months.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 160 mg of zanubrutinib twice a day.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 320 mg of zanubrutinib once a day.
  • the patient is administered with a moderate CYP3A inducer.
  • the severe bleeding disorder is hemophilia A, hemophilia B, or von Willebrand disease.
  • the clinically significant cardiovascular condition is selected from the group consisting of:
  • the moderate or severe hepatic impairment is Child-Pugh class B or C.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • TLS tumor lysis syndrome
  • c monitoring TLS and treating TLS when it occurs, wherein the administration results in a progression-free survival (PFS) rate of at least 75% as measured at 24 months, and the administration prolongs the PFS time and causes lower rate of atrial fibrillation and/or flutter as compared to the PFS time and rate of atrial fibrillation and/or flutter, respectively, of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily, wherein the patient is optionally administered with a moderate CYP3A inducer.
  • PFS progression-free survival
  • the administration results in a progression-free survival (PFS) rate of at least 75%, such as 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or any number in between thereof, as measured at 24 months.
  • PFS progression-free survival
  • the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • the patient was treated with ibrutinib or acalabrutinib but discontinued the treatment prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof.
  • the patient has a 17p deletion (del(17p)).
  • the administration prolongs the PFS time of the patient to be more than about 1 month, more than about 6 months, more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, or more than about 5 years.
  • the administration prolongs the PFS time of the patient to be more than about 20 months, more than about 25 months, more than about 30 months, more than about 35 months, more than about 40 months, more than about 45 months, more than about 50 months, more than about 55 months, more than about 60 months, more than about 65 months, more than about 70 months, more than about 75 months, more than about 80 months, or more than about 85 months.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 160 mg of zanubrutinib twice a day.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 320 mg of zanubrutinib once a day.
  • the patient is administered with a moderate CYP3A inducer.
  • the severe bleeding disorder is hemophilia A, hemophilia B, or von Willebrand disease.
  • the clinically significant cardiovascular condition is selected from the group consisting of:
  • the moderate or severe hepatic impairment is Child-Pugh class B or C.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • a method of treating a patient having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) comprising orally administering to the patient zanubrutinib or a pharmaceutically acceptable salt thereof at a dose of 160 mg of zanubrutinib twice a day or 320 mg of zanubrutinib once a day, wherein the patient is further administered with a moderate CYP3A inducer.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • the patient has a 17p deletion (del(17p)), and the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • the patient has a 17p deletion (del(17p)), and the patient meets all of the following criteria prior to the initial administration of zanubrutinib or the pharmaceutically acceptable salt thereof:
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • the administration causes lower rate of atrial fibrillation and /or flutter as compared to the rate of atrial fibrillation and /or flutter of a comparable patient orally administered with ibrutinib at a dose of 420 mg once daily.
  • the patient has relapsed or refractory CLL or SLL.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 160 mg of zanubrutinib twice a day.
  • the zanubrutinib or the pharmaceutically acceptable salt thereof is administered at a dose of 320 mg of zanubrutinib once a day.
  • the severe bleeding disorder is hemophilia A, hemophilia B, or von Willebrand disease.
  • the patient further does not have Hemorrhage, opportunistic infection, Cytopenia, skin cancer, atrial fibrillation, atrial flutter, Tumor Lysis Syndrome, or pregnancy.
  • the patient further does not have Tumor Lysis Syndrome.
  • the clinically significant cardiovascular condition is selected from the group consisting of:
  • the moderate or severe hepatic impairment is Child-Pugh class B or C.
  • kits comprising zanubrutinib and means for improving progression-free survival (PFS) probability of a patient having chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), wherein said patient is relapsed or refractory to at least 1 prior therapy for CLL or SLL.
  • PFS progression-free survival
  • a method of treating a patient having B-cell malignancy comprising administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 160 mg twice a day or about 320 mg once a day, wherein the patient is intolerant to a BTK inhibitor other than zanubrutinib.
  • a method of treating a patient having B-cell malignancy comprising administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a dose of about 160 mg twice a day or about 320 mg once a day, wherein the patient is intolerant to ibrutinib or acalabrutinib.
  • the patient has all of the factors:
  • the patient does not have any one of the medical conditions:
  • the PFS probability of the patient is about 83.8 % after about 18- month treatment.
  • the patient does not have del(17p)/Z7’53 mutation.
  • the patient has del(17p)/7P53 mutation.
  • the zanubrutinib is administered at a dose of about 160 mg twice a day.
  • the zanubrutinib is administered at a dose of about 320 mg once a day.
  • the patient further does not have Hemorrhage, opportunistic infection, Cytopenia, skin cancer, atrial fibrillation, atrial flutter, Tumor Lysis Syndrome, or pregnancy.
  • the patient further does not have Tumor Lysis Syndrome.
  • the PFS of the patient is extended to more than about 1 month, more than about 6 months, more than about 1 year, more than about 2 years, more than about 3 years, more than about 4 years, or more than about 5 years.
  • the PFS of the patient is extended is more than about 20 months, more than about 25 months, more than about 30 months, more than about 35 months, more than about 40 months, more than about 45 months, more than about 50 months, more than about 55 months, more than about 60 months, more than about 65 months, more than about 70 months, more than about 75 months, more than about 80 months, or more than about 85 months.
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • the B-cell malignancy is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • the B-cell malignancy is small lymphocytic lymphoma (SLL).
  • SLL small lymphocytic lymphoma
  • the B-cell malignancy is Waldenstrom macroglobulinemia
  • the B-cell malignancy is mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • the B-cell malignancy is marginal zone lymphoma (MZL).
  • a method of treating or delaying progression of a B-cell proliferative disorder in a patient comprising administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 640 mg, wherein the patient is characterized by being administered with a moderate CYP3A inducer; and the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • a method of treating or delaying progression of a B-cell proliferative disorder in a patient comprising selecting the patient who is being treated with a moderate CYP3A inducer; and administering to the selected patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 640 mg, wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer comprising assessing the patient as to whether administration of the moderate CYP3A inducer can be avoided; selecting the patient who cannot avoid being treated with a moderate CYP3A inducer; and administering to the selected patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 640 mg, wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL
  • a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer comprising concomitantly administering to the patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 640 mg, and the moderate CYP3A inducer, wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • a method of treating or delaying progression of a B-cell proliferative disorder in a patient comprising selecting the patient who is being treated with a moderate CYP3A inducer; and concomitantly administering to the selected patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 640 mg; and the moderate CYP3A inducer, wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • FL follicular lympho
  • a method of treating or delaying progression of a B-cell proliferative disorder in a patient receiving a moderate CYP3A inducer comprising assessing the patient as to whether the patient who can avoid being treated with the moderate CYP3A inducer; selecting the patient who cannot avoid being treated with the moderate CYP3 A inducer; and concomitantly administering to the selected patient zanubrutinib, or a pharmaceutically acceptable salt thereof, at a total daily dose of about 640 mg, and the moderate CYP3A inducer, wherein the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia (WM), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or follicular lymphoma (FL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM mantle cell
  • the moderate CYP3A inducer is rifabutin, bosentan, efavirenz, etravirine, modafinil, phenobarbital or nafcillin.
  • the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL).
  • the moderate CYP3A inducer is rifabutin.
  • the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL), and the moderate CYP3A inducer is rifabutin.
  • zanubrutinib is administered at a dose of about 320 mg twice a day; the B-cell proliferative disorder is chronic lymphocytic leukemia (CLL); and the moderate CYP3A inducer is rifabutin.
  • CLL chronic lymphocytic leukemia
  • BTK Bruton tyrosine kinase
  • Zanubrutinib a second-generation covalent BTK inhibitor, was designed to maximize BTK receptor occupancy and minimize off-target kinase inhibition.
  • Prior pharmacokinetic (PK), safety, efficacy, and exposure-response analyses support the recommended 320 mg total daily dose of zanubrutinib (160 mg twice daily BID or 320 mg once daily QD with or without food) for the approved indications.
  • Previous PK data demonstrate that zanubrutinib is rapidly absorbed and eliminated after oral administration with a median time to peak plasma concentration (Tmax) of 2 hours and a mean terminal elimination half-life (t 1/2) of 2-4 hours.
  • Tmax median time to peak plasma concentration
  • t 1/2 mean terminal elimination half-life
  • Hepatically, enzymatic metabolism via cytochrome P450, family 3, subfamily A (CYP3A) is considered the primary route of zanubrutinib metabolism.
  • zanubrutinib After multiple-dose administrations of zanubrutinib at doses ranging from 40 mg to 320 mg QD and 160 mg BID, there is a dose proportional increase in the maximum concentration (Cmax) and the area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity (AUCO-co); additionally, limited systemic accumulation is observed, which is consistent with the observed tl/2 of zanubrutinib.
  • CYP3A enzymes in zanubrutinib metabolism, studies have been conducted to explore the interactions between zanubrutinib and various CYP3A modulators.
  • zanubrutinib Coadministration of zanubrutinib with the strong CYP3A inhibitor itraconazole resulted in a 2.6-fold and 3.8-fold increase in zanubrutinib Cmax and AUCO-co, respectively.
  • a strong CYP3A inducer such as rifampin
  • zanubrutinib with moderate or strong CYP3A inducers should be avoided.
  • multiple treatments including, but not limited to, antibacterial and/or antifungal agents, may often be administered in conjunction with zanubrutinib to manage opportunistic infections in patients with B-cell malignancies.
  • Some of these agents may be CYP3A inducers, and thus it is essential to further elucidate the PK profde of zanubrutinib when coadministered with CYP3A inducers.
  • Rifabutin a moderate CYP3A inducer
  • Rifabutin is a first-line therapeutic alternative to the strong CYP3A inducer rifampin and is a clinically relevant anti-infective agent used in patients with B-cell malignancies.
  • Other known moderate CYP3A inducers including, but not limited to, efavirenz and etravirine, are indicated for the treatment of HIV infection.
  • patients are on chronic usage of anti-seizure medications, which are often moderate inducers.
  • phenobarbital a moderate CYP inducer
  • zanubrutinib In the patient population in which usage of CYP3 A inducers can’t be stopped, stopping zanubrutinib treatment may not be a viable option.
  • zanubrutinib can be the optimal cancer treatment for those patients, and/or stopping zanubrutinib treatment may encourage development of drug resistance or relapse.
  • Rifabutin is primarily metabolized by CYP3A enzymes, and multiple doses of rifabutin were associated with induction of enzymes of the CYP3A subfamily. Following a single oral dose of 300 mg, rifabutin was readily absorbed with a Tmax ranging from 2-4 hours and was slowly eliminated from plasma with a mean tl/2 of 45 (standard deviation, 17) hours (range: 16-69 hours). Although the systemic levels of rifabutin after multiple doses decreased by 38% due to auto-induction, its tl/2 remained unchanged. To achieve maximal induction of CYP3A, 300 mg rifabutin QD was administered for 8 days to reach steady-state.
  • zanubrutinib and rifabutin were administered after an overnight fast of 8-10 hours. Each dose of zanubrutinib and rifabutin was administered orally with approximately 240 mL of room temperature water. When zanubrutinib and rifabutin were administered concurrently (on day 11), an additional amount (up to 240 mL) of room temperature water was allowed to be administered.
  • Noncompartmental analysis was conducted using Phoenix® WinNonlinTM version 8.1 (Certara USA, Inc., Princeton, New Jersey, USA).
  • PK parameters were derived for zanubrutinib alone and in combination with rifabutin, including AUC, Cmax, Tmax, 11/2, apparent total oral clearance (CL/F), and apparent volume of distribution during the terminal elimination phase (Vd/F).
  • Plasma samples were collected to assess single-dose zanubrutinib PK on day 1 and after coadministration with rifabutin on day 11 at the following timepoints: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 36 hours postdose.
  • Plasma concentrations of zanubrutinib were determined using a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method by XenoBiotic Laboratories, Tnc. (Plainsboro, NJ, United States) Protein precipitation was utilized to extract the analyte and internal standard from human plasma containing dipotassium ethylenediaminetetraacetic acid (K2EDTA) as an anticoagulant.
  • K2EDTA dipotassium ethylenediaminetetraacetic acid
  • the calibration range was 1.00- 1000 ng/mL for the plasma zanubrutinib concentration, with a lower limit of quantification of 1.00 ng/mL.
  • Safety was assessed by monitoring and recording of adverse events (AEs), serious adverse events (SAEs), clinical laboratory tests, physical examinations, and vital signs. Safety was measured by the incidence, timing, and severity of treatment-emergent adverse events (TEAEs), according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0).
  • TEAE treatment-emergent adverse events
  • NCI CTCAE v5.0 National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0
  • a TEAE was defined as an AE that started during or after the first dose or started before the first dose and increased in severity after the first dose. AEs were classified based on MedDRA Version 24.0.
  • the study sample size was based on precedent set by other PK studies of a similar nature and was not based on power calculations. It was aimed to enroll 15 volunteers to ensure that at least 12 volunteers completed the study.
  • the safety analysis set included all patients who received >1 dose of zanubrutinib. Safety and tolerability were assessed, when applicable, by incidence, severity, change from baseline values, and abnormal values for all relevant parameters such as AEs, laboratory parameters, vital signs, and physical examination.
  • the GMRs of PK parameters of zanubrutinib with and without coadministration of rifabutin and the associated 90% confidence interval (CI) was constructed based on the least squares mean (LSM) and intra-subject coefficient of variation (CV) from a mixed effects model of log-transformed PK parameters.
  • LSM least squares mean
  • CV intra-subject coefficient of variation
  • GLSM geometric least squares mean
  • GLSM geometric least squares mean
  • Within-subject CV was calculated as 100 x square root[exp(mean square error from the analysis model)-l].
  • N number of volunteers
  • n number of volunteers with valid observation
  • SD standard deviation
  • zanubrutinib After administration of zanubrutinib alone (day 1) and coadministration with 300 mg rifabutin (day 11), zanubrutinib was rapidly absorbed with a median Tmax of 1.5 and 2.0 hours postdose, respectively (FIGs. 2A-2B).
  • the zanubrutinib arithmetic mean tl/2 was similar when zanubrutinib was administered alone (7.2 hours) compared to when zanubrutinib was coadministered with rifabutin (7.0 hours; Table 2).
  • the GLSM for AUCO-t, AUCO-co, and Cmax values were lower when zanubrutinib was coadministered with rifabutin than when zanubrutinib was administered alone, with GLSM ratios of 0.57 (90% CI: 0.53-0.61), 0.56 (90% CI: 0.53-0.59), and 0.52 (90% CI: 0.44-0.61) for AUC0- t, AUCO-co, and Cmax, respectively (Table 3). Additionally, as assessed from the geometric CV, within-subject variability was low for zanubrutinib, with values of 10.7%, 7.0%, and 23.2% for AUCO-t, AUCO-co, and Cmax, respectively (Table 3).
  • AUCo-co area under the concentration-time curve from time zero to infinity
  • AUCo-t area under the concentration-time curve from time zero to the time of the last quantifiable concentration (Tiast)
  • CLZF apparent oral clearance
  • Cmax maximum observed concentration
  • CV coefficient of variation (%)
  • n number of volunteers with valid observations
  • N number of volunteers
  • ti/2 apparent terminal elimination half-life
  • Tiast time of the last quantifiable concentration
  • Tmax time of the maximum observed concentration, Vd/F, apparent volume of distribution.
  • Patients with B-cell malignancies are at an increased risk of infection due to immune defects associated with disease.
  • the current therapies to treat opportunistic infections, such as mycobacterial infections include rifampin and rifabutin.
  • An exemplary moderate CYP3A inducer is rifabutin, bosentan, efavirenz, etravirine, modafinil, or nafcillin.
  • Rifabutin coadministration with the index CYP3A substrate midazolam demonstrated moderate induction potential, resulting in AUCO-co and Cmax GMRs of 0.31 (90% CI: 0.27, 0.35) and 0.47 (90% CI: 0.42, 0.51), respectively. Since many anticancer agents are metabolized by CYP3A and rifabutin is a moderate CYP3A inducer, rifabutin may be considered a clinically relevant anti-infective agent in patients with B-cell malignancies. This study was conducted to elucidate the DDI potential of zanubrutinib when coadministered with rifabutin specifically.
  • results of this study provided useful information for the evaluation of clinical DDI between rifabutin and zanubrutinib and management of clinical DDIs for zanubrutinib when a moderate CYP3A inducer is coadministered.
  • results from this study help determine the appropriate dose recommendation of zanubrutinib when coadministered with moderate CYP3A inducers.
  • Results of the current study showed less than a two-fold reduction of systemic exposures of zanubrutinib after coadministration of zanubrutinib with rifabutin, a moderate CYP3A inducer, compared with administration of zanubrutinib alone. No new safety signals were identified. Single doses of 320 mg zanubrutinib administered alone or coadministered with 300 mg rifabutin were well tolerated in healthy volunteers in this study.
  • zanubrutinib with a moderate CYP3A inducer, e.g., rifabutin, resulted in a decrease in zanubrutinib exposures by approximately 44% for AUCO-t and AUC0 -co, and 48% for Cmax, respectively, compared with administration of zanubrutinib alone.
  • Zanubrutinib under the brand name Brukinsa, was approved by FDA for treating Mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia (WM), marginal zone lymphoma (MZL) on November 14, 2019, August 31, 2021, and September 12, 2021, respectively, at 160 mg twice a day or 320 mg once a day.
  • MCL Mantle cell lymphoma
  • WM macroglobulinemia
  • MZL marginal zone lymphoma
  • the FDA approved label can be downloaded from the FDA database, e.g., https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213217s0051bl.pdf (last visit December 16, 2022).
  • This study demonstrated an approximately 2-fold reduction in zanubrutinib exposure (i.e., 1.8-fold decrease in exposure for AUCO-t and AUC0-co, and 1.9-fold for Cmax) when zanubrutinib was coadministered in a patient receiving a moderate CYP3A inducer, e g., rifabutin.
  • the moderate CYP3 A inducer induced the metabolism of zanubrutinib and resulted in a decrease in the effect of zanubrutinib.
  • the reduced efficacy may or may not be safely compensated for by increasing the amount of zanubrutinib to be administered to a patient.
  • an increased metabolism of zanubrutinib may also lead to increased toxicity if the increased metabolism is accompanied by an increase in exposure to a toxic metabolite.
  • patients may not comply with their treatment regimens for a moderate CYP3A inducer, including by not taking the moderate CYP3A inducer or skipping one or more doses of the moderate CYP3A inducer.
  • Such non-compliance thereby enhances exposure to zanubrutinib compared to existing use. The enhanced exposure may lead to the safety concern.
  • Example 2 addressed concerns regarding the safety of zanubrutinib when it is administered at a higher dose, e.g., 320 mg twice a day (a total daily dose of 640 mg).
  • this study result demonstrated a non-inferior safety profile of the patients receiving 160 mg twice a day of zanubrutinib with a moderate or stronger CYP3A inhibitor when compared to the patients receiving 160 mg of zanubrutinib twice a day without coadministration of a moderate or stronger CYP3A inhibitor even though there was a 2 to 3-fold increase (AUC and Cmax) over therapeutic exposure range of zanubrutinib when used with strong or moderate CYP3A inhibitors (ie., with zanubrutinib exposure equivalent or higher than 640 mg total daily dose).
  • 123 patients received a dose of 320 mg zanubrutinib daily with a moderate or stronger CYP3A inhibitor.
  • the percentage of the 123 patients with at least 1 TEAE is non-inferior when compared to that of the patients receiving 160 mg of zanubrutinib twice a day without coadministration of a moderate or stronger CYP3A inhibitor.
  • this study result suggested a non-inferior safety profde of the patients receiving 320 mg twice a day of zanubrutinib when compared to the patients receiving 160 mg twice a day of zanubrutinib.
  • Such a study result solved the safety concern in Example 1.
  • the assessment includes patients with B-cell malignancies treated with single-agent zanubrutinib studies.
  • the list of studies included in this analysis Studies BGB-311 l-AU-003, BGB-3111-1002, BGB-3111-205, BGB-3111-206, BGB-3111-210, BGB-3111-214, and BGB-3111-302. Key design features of these studies are summarized in Table 5.
  • TEAEs treatment-emergent adverse events
  • AEs adverse events
  • AESI AEs of special interest
  • AE adverse event
  • AU Australia
  • BID twice a day
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • CZ Czech Republic
  • DE Germany
  • DLBCL diffuse large B-cell lymphoma (subdiagnosis of NHL); ES, Spain; EU, European Union
  • FL follicular lymphoma (subdiagnosis of NHL); FR, France
  • HCL hairy cell leukemia
  • IRC Independent Review Committee
  • IT Italy
  • LPL lymphoplasmacytic lymphoma
  • MALT mucosa-associated lymphoid tissue
  • MCL mantle cell lymphoma (subdiagnosis of NHL); MRR, major response rate
  • MZL marginal zone lymphoma (subdiagnosis of NHL); nGCB, nongerminal center B-cell (subdiagnosis of DLBCL); NHL, non-Hodgkin’s lymphoma; NL, Netherlands
  • the analyses were performed in patients who had received at least one concomitant treatment with moderate or strong CYP3A inhibitors while on a total daily dose up to 320 mg zanubrutinib, including patients on a reduced dose of zanubrutinib. Patients who did not take any dose of zanubrutinib during the CYP3 A inhibitor treatment period were not included in the analyses.
  • Concomitant medications were defined as medications that (1) started before the first dose of zanubrutinib and were continuing at the first dose date of zanubrutinib, or (2) started on or after the first dose date of zanubrutinib up to 30 days after the patient’s last dose of study treatment or initiation of a new anticancer therapy.
  • Prior to Coadministration Period This period extends from the date of the first dose of zanubrutinib to the date of the first coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor. All TEAEs occurring on the first day of coadministration were summarized in this period, since in many cases, the CYP3A inhibitor may have been initiated as treatment for such TEAEs. These events were also to be reviewed and described.
  • Coadministration Period This period extends from the date of the second day of coadministration of zanubrutinib and a moderate or strong CYP3 A inhibitor to either 30 days from end of coadministration, end of study date, death date, initiation of a new anticancer therapy, or data cutoff date, whichever came first.
  • the “During” period starts on Day 2 of coadministration to avoid capture of events in which the CYP3A inhibitor was used to treat an AE (e g., voriconazole was given to treat a fungal infection).
  • Coadministration Period begins at 30 days after the end of coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor to either 30 days after last dose of zanubrutinib (permanent discontinuation), end of study date, death date, initiation of a new anticancer therapy, or data cutoff date, whichever came first.
  • time between the coadministration periods was included in this “after” period.
  • a TEAE was defined as an AE with onset date or increase in severity level on or after the first dose of zanubrutinib and within 30 days after the last dose of zanubrutinib (permanent discontinuation) or initiation of a new anticancer therapy (if collected), whichever came first. Only those AEs that were treatment emergent were included in summary tables.
  • a treatment-related AE is an AE that was noted by the investigator as related, possibly related, probably related to study drug, or with missing causal relationship.
  • Adverse events were graded by the investigators using National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 and coded to the Medical Dictionary for Regulatory Activities (MedDRA v22.0 or higher) Lowest Level Terms closest to the verbatim term.
  • NCI-CTCAE National Cancer Institute- Common Terminology Criteria for Adverse Events
  • MedDRA Lowest Level Terms closest to the verbatim term.
  • the linked MedDRA Preferred Term (PT) and primary System Organ Class (SOC) were also to be captured in the database.
  • TEAEs were also to be summarized by SOC and PT.
  • a patient reporting the same TEAE more than once within the same period was counted only once when calculating incidence 1) within a given SOC, and 2) within a given SOC and PT combination.
  • the maximum CTCAE toxicity grade and strongest causal relationship to study drug for the event was used in the incidence calculations for each study period.
  • AESIs > Grade 3 AESIs, serious AESIs, fatal AESIs, AESIs leading to zanubrutinib dose reduction, AESIs leading to zanubrutinib treatment interruption, and AESIs leading to zanubrutinib discontinuation were summarized by category, PT, and study period.
  • the AESIs are prospectively defined TEAEs that are consistent with the known and theoretical toxicity profile for the class of Bruton tyrosine kinase (BTK) inhibitors.
  • the categories and criteria that define each category of AESI are shown in Table 6.
  • EAIR EAIR per event
  • TEAEevent represented if “patient” experienced the event (1) or not (0)
  • tevemj represented the time when the first TEAE occurred (non-censored data) or total duration of exposure if no event occurred (censored data).
  • Table 7 Duration of Study Periods and Dose in the During Coadministration Period
  • N number of patients receiving a planned dose of 320 mg daily and having at least 1 coadministration of zanubrutinib and a strong or moderate CYP3A inhibitor.
  • the Prior to Coadministration Period is defined as the period from the first dose date of zanubrutinib to the first date of the coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor.
  • the During Coadministration Period is defined as the period from the second day of the coadministration of zanubrutinib and a moderate or strong CYP3 A inhibitor to the date of the end of the coadministration + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • the After Coadministration Period is defined as the period from the end of the coadministration of zanubrutinib and a moderate or strong CYP3 A inhibitor + 31 days to the last dose of zanubrutinib (end of treatment) + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • N number of patients receiving a planned dose of 320 mg daily and having at least
  • a The Prior to Coadministration Period is defined as the period from the first dose date of zanubrutinib to the first date of the coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor.
  • the During Coadministration Period is defined as the period from the second day of the coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor to the date of the end of the coadministration + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • c The After Coadministration Period is defined as the period from the end of the coadministration of zanubrutinib and a moderate or strong CYP3 A inhibitor + 31 days to the last dose of zanubrutinib (end of treatment) + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • Adverse event grades are evaluated based on NCI-CTCAE (Version 4.03).
  • Table 9 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term in > 10% of Patients in Any Study Period
  • CYP cytochrome P450
  • MedDRA Medical Dictionary for Regulatory Activities
  • TEAE treatment-emergent adverse event.
  • N number of patients receiving a planned dose of 320 mg daily and having at least 1 coadministration of zanubrutinib and a strong or moderate CYP3A inhibitor.
  • the Prior to Coadministration Period is defined as the period from the first dose date of zanubrutinib to the first date of the coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor.
  • the During Coadministration Period is defined as the period from the second day of the coadministration of zanubrutinib and a moderate or strong CYP3 A inhibitor to the date of the end of the coadministration + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • the After Coadministration Period is defined as the period from the end of the coadministration of zanubrutinib and a moderate or strong CYP3 A inhibitor + 31 days to the last dose of zanubrutinib (end of treatment) + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • Table 10 Treatment-Emergent Adverse Events of Grade 3 or Higher by System Organ Class and Preferred Term in > 2% of Patients
  • CYP cytochrome P450
  • MedDRA Medical Dictionary for Regulatory Activities
  • NCI-CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • TEAE treatment-emergent adverse event.
  • N number of patients receiving a planned dose of 320 mg daily and having at least 1 coadministration of zanubrutinib and a strong or moderate CYP3A inhibitor.
  • a The Prior to Coadministration Period is defined as the period from the first dose date of zanubrutinib to the first date of the coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor.
  • the During Coadministration Period is defined as the period from the second day of the coadministration of zanubrutinib and a moderate or strong CYP3A inhibitor to the date of the end of the coadministration + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • the After Coadministration Period is defined as the period from the end of the coadministration of zanubrutinib and a moderate or strong CYP3 A inhibitor + 31 days to the last dose of zanubrutinib (end of treatment) + 30 days, end of study, death, initiation of a new anticancer therapy, or data cutoff, whichever comes first.
  • the CYP3 inhibitors administered included antibiotics (clarithromycin, ciprofloxacin), antifungals (voriconazole), and calcium blockers (diltiazem).
  • Atrial Fibrillation and Flutter The percentage of patients with both atrial fibrillation and flutter was higher in the After Coadministration Period (4.7%) than in the Prior to Coadministration and During Coadministration Periods (1.7% and 1.4%, respectively).
  • the EAIR of this AESI in the Prior to Coadministration, During Coadministration, and After Coadministration Periods was 0.13 per 100 person-months, 0.33 per 100 person-months, and 0.23 per 100 person-months, respectively.
  • the percentage of patients in each study period with an AESI by PT of atrial fibrillation was 1.7%, 1.4%, and 2.8%, respectively, while the PT of atrial flutter was reported in 0.0%, 0.0%, and 1.9% of patients, respectively.
  • PT 1 patient had a serious event of atrial fibrillation in the Prior to Coadministration Period
  • Grade 3 was lower in the During Coadministration Period (1.4%) compared with the Prior to Coadministration Period (4.2%) and After Coadministration Period (5.6%).
  • the EAIR of second primary malignancies for AESIs Grade 3 was 0.32 per 100 person-months, 0.33 per 100 person-months, and 0.27 per 100 person-months for the Prior to Coadministration, During Coadministration, and After Coadministration Periods, respectively.
  • the only second primary malignancy PTs Grade 3 that occurred in > 1 patient in any study period were basal cell carcinoma (2 (1.7%) patients, 0 (0.0%) patients, and 1 (0.9%) patients, respectively) and squamous cell carcinoma of skin (2 (1.7%) patients, 0 (0.0%) patients, and 1 (0.9%) patients, respectively).
  • One of these patients had lymphoma transformation that was considered by the investigator to be related to study treatment and was considered by the sponsor as progression of the disease under study.
  • the other patient had skin squamous cell carcinoma recurrent considered to be not related to study treatment by the investigator.
  • the EAIRs of skin cancers AESIs in the Prior to Coadministration was 0.69 per 100 person-months, 0.17 per 100 person-months, and 0.41 per 100 person-months, respectively; for AESIs Grade 3, it was 0.26 per 100 person-months, 0.00 per 100 person- months, and 0.13 per 100 person-months; and for SAEs, it was 0.26 per 100 person-months, 0.00 per 100 person-months, and 0.04 per 100 person-months.
  • the percentage of patients with opportunistic infection AESIs was similar in the During Coadministration Period and the After Coadministration Period but higher in the Prior to Coadministration Period.
  • the percentage of patients with an opportunistic infection AESI and the EAIRs of these events in the Prior to Coadministration, During Coadministration, and After Coadministration Periods were 8.4% (0.64 per 100 person-months), 2.9% (0.67 per 100 person- months), and 2.8% (0.13 per 100 person-months), respectively.
  • the percentage of patients with an opportunistic infection AESI Grade 3 was slightly lower in the During Coadministration Period (3 (2.2%) patients) and After Coadministration Period (1 (0.9%) patient) compared with the Prior to Coadministration Period (6 (5.0%) patients).
  • the EAIRs were 0.38 per 100 person-months, 0.50 per 100 person-months, and 0.04 per 100 person-months for the Prior to Coadministration, During Coadministration, and After Coadministration Periods, respectively.
  • one patient had Grade 4 meningitis cryptococcal and encephalitis fungal, which both were assessed as related to study treatment; one patient had Grade 3 bronchopulmonary aspergillosis assessed as not related to study treatment; and one patient had Grade 5 Scedosporium infection, which was assessed as not related to study treatment.
  • the percentage of patients with an anemia AESI was lower in the During Coadministration Period compared with the other 2 periods.
  • the percentage of patients with an anemia AESI in the Prior to Coadministration, During Coadministration, and After Coadministration Periods was 12.6%, 7.2%, and 10.3%, respectively.
  • the EAIR of anemia AESIs was 1.07 per 100 person-months, 1.91 per 100 person-months, and 0.53 per 100 person- months, respectively.
  • the percentage of patients with anemia AESIs Grade 3 was similar in the Prior to Coadministration, During Coadministration, and After Coadministration Periods (6.7%, 6.5%, and 3.7%, respectively).
  • the EAIRs were 0.54 per 100 person-months, 1.70 per 100 person- months, and 0.18 per 100 person-months, respectively.
  • One patient had an AEST of anemia leading to dose interruption in the During Coadministration Period.
  • One patient had a TEAE of anemia leading to treatment discontinuation in the After Coadministration Period.
  • the percentage of patients with an AESI of neutropenia was lower in the During Coadministration and After Coadministration Periods compared with the Prior to Coadministration Period.
  • the percentages of patients with an AESI of neutropenia and EAIRs in the Prior to Coadministration, During Coadministration, and After Coadministration Periods were 28.6% (2.72 per 100 person-months), 17.4% (5.43 per 100 person-months), and 16.8% (0.92 per 100 person-months), respectively.
  • neutropenia The AESIs of neutropenia reported by PT were neutropenia (17.6%, 8.0%, and 9.3%, respectively), neutrophil count decreased (11.8%, 8.0%, and 7.5%, respectively), febrile neutropenia (1.7%, 2.9%, and 3.7%, respectively), and neutropenic sepsis (0.8%, 0.0%, and 0.0%, respectively).
  • Neutropenia is an on-target effect of zanubrutinib, and it has not been shown to be associated with higher rate of infections compared to ibrutinib in head-to-head study BGB-3 H l- 302.
  • 10 cases were concurrent with an infection (within 14 days of neutropenia).
  • 3 concurrent infections were Grade 3, while 4 infections were serious (including 1 Grade 1 event). All 10 concurrent infections resolved except one fatal case.
  • the majority of the concurrent infections with neutropenia were nonserious, Grade 1 or 2, and were reported as resolved.
  • neutropenia (1.7%, 0.0%, and 0.9%, respectively
  • febrile neutropenia (0.8%, 0.0%, and 1.9%, respectively
  • neutrophil count decreased (0.8%, 0.0%, and 0.0%, respectively).
  • One patient had an AESI of neutropenia that led to treatment discontinuation in the After Coadministration Period.
  • a similar percentage of patients had a serious AESI of neutropenia in the Prior to Coadministration, During Coadministration, and After Coadministration Periods (3.4%, 4.3%, and 3.7%, respectively).
  • the EAIRs for serious neutropenia AESIs were 0.26 per 100 person-months, 1.11 per 100 person-months, and 0.18 per 100 person-months, respectively.
  • the percentage of patients with an AESI of thrombocytopenia was similar in the Prior to Coadministration, During Coadministration, and After Coadministration Periods (9.2%, 6.5%, and 8.4%, respectively).
  • the EAIRs were 0.79 per 100 person-months, 1.52 per 100 person- months, and 0.41 per 100 person-months, respectively.
  • Treatment-emergent AEs of thrombocytopenia reported by PT were thrombocytopenia (6.7%, 4.3%, and 3.7%, respectively) and platelet count decreased (3.4%, 2.2%, and 4.7%, respectively).
  • This report summarizes the assessment of the integrated safety data from 7 singleagent zanubrutinib studies for B-cell malignancies.
  • the analysis included 138 patients who had coadministration of zanubrutinib and strong and moderate CYP3A inhibitors out of 835 patients from the 7 studies.
  • the number of patients experiencing a TEAE and the EAIRs of AESIs did not show any trend for safety concerns across the 3 study periods (Prior to Coadministration, During Coadministration, and After Coadministration Periods).
  • the median duration of coadministration was approximately 2 months, and the majority of the patients (89.1%) received a full dose of 320 mg zanubrutinib daily during the Coadministration Period.
  • the EAIRs did not show a clear trend of increase in AESIs during the Coadministration Period. Most of the EAIRs of AESIs were similar across the 3 periods except for cytopenia (including anemia, neutropenia, and thrombocytopenia) and atrial fibrillation and flutter. Only 1 case of thrombocytopenia in the During Coadministration Period led to treatment discontinuation, and no cases of atrial fibrillation and flutter led to treatment discontinuation.
  • Adverse events of special interest are those that are known to be associated with the class of BTK inhibitors.
  • the AESI patterns in this analysis appear to be generally consistent with the known safety profile of zanubrutinib trials.
  • Neutropenia reported during the coadministration of a CYP3A inhibitor and zanubrutinib was not associated with more Grade 3, serious, or fatal concurrent infections.
  • TEAEs leading to death, treatment discontinuation, or dose reduction were generally consistent with the known safety profile of zanubrutinib.
  • 90% of the patients in the Coadministration Period in this analysis were treated with a 320 mg once daily zanubrutinib dose, prior to the implementation of the dose modification guideline in the current zanubrutinib prescribing information.
  • the current dose modification guidelines in the zanubrutinib label ie, 80 mg once daily with strong CYP3A inhibitors and 80 mg twice daily with moderate CYP3A inhibitors
  • this safety study surprisingly showed the non-inferior safety profiles at zanubrutinib exposures 2 to 3 -fold higher (equivalent to a total daily dose of 640 mg or higher) than therapeutic exposure of zanubrutinib (320 mg total daily dose). Therefore, the overall benefit-risk profile remains favorable when zanubrutinib is concomitantly prescribed with a CYP3A inhibitor.
  • Rate of PR-L or higher was assessed as a secondary efficacy endpoint considering the finding that treatment with BTK inhibitors may lead to lymphocytosis due to redistribution of leukemia cells from lymphoid compartment to blood. Tn these instances, treatment-related transient progressive lymphocytosis was not a sign of treatment failure or disease progression and has no bearing on treatment outcome.
  • Randomization was stratified by age ( ⁇ 65 years versus > 65 years), geographic region (China versus non-China), refractory status (yes or no), and del[17p]/TP53 mutation status (present or absent). Patients from China will comprise no more than 20% of the study population.
  • Treatment with zanubrutinib and ibrutinib was open label. Study treatment must commence within 5 days after randomization/treatment assignment and was continued until disease progression, unacceptable toxicity, treatment consent withdrawal, or study termination. Each cycle consists of 28 days. Based on enrollment prediction, the study duration was approximately 7 years.
  • CLL/SLL status assessments of CLL/SLL status to be performed during the study include disease- related constitutional symptoms, physical examination of lymph nodes, liver, and spleen; laboratory studies; bone marrow examination, genetic alterations in the tumor cells (including del[17p], del[l lq], 12q+, and immunoglobulin variable region heavy chain [IGHV] mutation analysis); computed tomography (CT) scan of neck, chest, abdomen, and pelvis with contrast; and patient-reported outcomes (PROs; European quality of life 5-dimensions 5-levels health questionnaire (EQ-5D-5L) and European Organisation for Research and Treatment of Cancer quality of life cancer core questionnaire (EORTC QLQ-C30)).
  • CT computed tomography
  • PROs European quality of life 5-dimensions 5-levels health questionnaire
  • EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer quality of life cancer core questionnaire
  • Imaging of the neck, chest, abdomen, and pelvis and any other disease sites by CT with contrast was performed as indicated in until disease progression, death, lost to follow-up, withdrawal of consent, or end of study, whichever occurs first.
  • a blood sample was obtained from patients receiving zanubrutinib who have progressive disease (PD) confirmed by independent central review.
  • AEs was graded for severity per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03.
  • DMC Data Monitoring Committee
  • FIG. 5 was Study Schema.
  • ALPINE enrolled 652 patients with relap sed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Patients were randomized 1 :1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity.
  • Randomization was stratified by age ( ⁇ 65 years versus > 65 years), geographic region (China versus non-China), refractory status (yes or no), and del[17p]/TP53 mutation status (present versus absent).
  • ORR interim analysis was scheduled approximately 12 months after the enrollment of the first 415 patients.
  • ORR final analysis was scheduled approximately 12 months after enrollment completion.
  • BID denotes twice daily
  • CLL denotes chronic lymphocytic leukemia
  • ORR denotes overall response rate
  • PFS denotes progression-free survival
  • QD denotes once daily
  • R/R denotes relapsed/refractory
  • SLL small lymphocytic lymphoma
  • Treatment with zanubrutinib and treatment with ibrutinib was open label; however, the assessment of ORR by independent central review (primary endpoint) was blinded.
  • CLL/SLL requiring treatment as defined by at least 1 of the following criteria: a. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia b. Massive (> 6 cm below left costal margin), progressive, or symptomatic splenomegaly c. Massive nodes (> 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy d. Progressive lymphocytosis with an increase of > 50% over a 2-month period or lymphocyte-doubling time of ⁇ 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months.
  • lymphocyte-doubling time should not be used as a single parameter to define treatment indication.
  • factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL e.g., infection
  • e. Autoimmune anemia and/or thrombocytopenia that was poorly responsive to corticosteroids or other standard therapy
  • Constitutional symptoms defined as any 1 or more of the following disease-related symptoms or signs: i. Unintentional weight loss of > 10% within the previous 6 months ii. Significant fatigue (ie, inability to work or perform usual activities) iii. Fevers > 100.5°F or 38°C for > 2 weeks without other evidence of infection iv. Night sweats for > 1 month without evidence of infection
  • Patient must have adequate organ function defined as: a. Creatinine clearance > 30 mL/min (as estimated by the Cockcroft-Gault equation or the Modification of Diet in Renal Disease [MDRD] equation, or as measured by nuclear medicine scan or 24-hour urine collection) b. Aspartate aminotransferase/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ⁇ 2.5 x upper limit of normal unless due to CLL/SLL c. Serum total bilirubin ⁇ 2.0 x upper limit of normal (unless documented Gilbert’s syndrome)
  • Each patient eligible to participate in this study must NOT meet any of the following exclusion criteria: Known prolymphocytic leukemia or history of, or currently suspected, Richter’s transformation (biopsy based on clinical suspicion may be needed to rule out transformation) Clinically significant cardiovascular disease including the following: a. Myocardial infarction within 6 months before screening b. Unstable angina within 3 months before screening c. New York Heart Association class III or IV congestive heart failure d. History of clinically significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes) e.
  • arrhythmias e.g., sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes
  • HBcAb hepatitis B virus
  • HCV hepatitis C virus
  • Samples was shipped to the designated bioanalytical lab for quantification of plasma zanubrutinib concentrations using a validated method.
  • a complete physical examination includes an assessment of systems per standard of care at the study site and as clinically indicated by symptoms.
  • a 12-lead ECG was performed locally in triplicate at screening for all subjects. Subjects should be in the semi-recumbent or supine position.
  • Bone marrow biopsy was required during the Screening period. Thereafter, bone marrow examination was required for patients with baseline marrow involvement who meet clinical and laboratory criteria for CR or CRi, and need bone marrow examination to confirm CR or CRi (MRD assessment may also be performed on the bone marrow or blood at this time). Patients who were otherwise complete responders, but show bone marrow involvement, should recheck bone marrow as clinically indicated, but at a minimum at least once per year until CR or CRi was confirmed. Patients should also undergo bone marrow biopsy in the setting of progression of cytopenias unrelated to autoimmune cytopenias or study treatment in order to confirm PD. All the bone marrow samples was collected and reviewed by a pathologist from the central pathology laboratory.
  • the primary endpoint was ORR (PR or higher, defined as CR/CRi + PR + nodular PR) determined by independent central review using the “modified” 2008 IWCLL guidelines with modification for treatment-related lymphocytosis for patients with CLL and per Lugano Classification for non-Hodgkin lymphoma (NHL) for patients with SLL.
  • ORR PR or higher, defined as CR/CRi + PR + nodular PR
  • PFS defined as the time from randomization to the date of first documentation of disease progression or death, whichever occurs first, determined by independent central review
  • Duration of response defined as the time from the date that response criteria were first met to the date that disease progression was objectively documented or death, whichever occurs first, determined by independent central review
  • Time to treatment failure defined as time from randomization to discontinuation of study drug due to any reason
  • Rate of PR-L or higher defined as the proportion of patients who achieve a CR/CRi + PR + nodular PR + PR-L determined by independent central review
  • Safety parameters including AEs, SAEs, clinical laboratory tests, physical exams, and vital signs
  • the Intent-to-Treat Analysis Set includes all randomized patients.
  • the Intent-to-Treat Analysis Set was the primary analysis set for efficacy analyses.
  • the Safety Analysis Set includes all patients who received any dose of study drug. Patients was included in the treatment group corresponding to the actual treatment received. The Safety Analysis Set was used for all safety analyses.
  • the Per-protocol Analysis Set includes patients who received any dose of study drug and had no major protocol deviations. Criteria for exclusion from the Per-protocol Analysis Set was determined and documented before the database lock for the primary analysis. For the primary analysis of non-inferiority testing in ORR by independent central review, the Per- protocol Analysis Set was used as the secondary population.
  • the PK Analysis Set includes all zanubrutinib-treated patients who have at least 1 post-dose drug concentration.
  • Concomitant medications was assigned an 11 -di it code using the World Health Organization Drug Dictionary drug codes. Concomitant medications was further coded to the appropriate Anatomical Therapeutic Chemical code indicating therapeutic classification. Prior and concomitant medications was summarized and listed by drug and drug class in the Clinical Study Report for this protocol. Prior medications was defined as medications that started before the first dose of study drug, whether continuing at or stopped at the first dose of study drug. Concomitant medications was defined as medications that (1) started before the first dose of study drug and were continuing at the time of the first dose of study drug, or (2) started on or after the date of the first dose of study drug up to 30 days after the patient’s last dose.
  • a Cochran-Mantel-Haenszel test for response ratio adjusting for the 4 randomization stratification factors (age [ ⁇ 65 years versus > 65 years], geographic region (China versus nonChina), refractory status [yes or no], and del[17p]/TP53 status [present versus absent]) was performed for the hypothesis testing.
  • the p-value from the test was compared against the monitoring boundaries for the non-inferiority testing (Table 11) and used for the primary inference.
  • the treatment effect in ORR and its 95% Wald confidence interval (CI) was estimated, and the Clopper-Pearson 95% Cis was calculated for ORR for each treatment group.
  • the monitoring boundaries for the non-inferiority and superiority tests were based on the O’Brien- Fleming boundary approximated by the Lan-DeMets spending function and were listed in Table 11 and Table 12. The monitoring boundaries was adjusted based on the actual information fraction (number of subjects for ORR) observed up to the data cutoff. Deviation from the scheduled interim analysis will not affect the overall type I error.
  • ORR overall response rate
  • ORR overall response rate
  • a non-inferiority margin of 0.8558 in response ratio was derived using the 95% to 95% fixed margin approach (FDA Guidance for Industry Non-inferiority 2016).
  • the ibrutinib effect over ofatumumab represented by the ratio of response rate (PR or higher) was 10.43 with a 95% CI of (5.2, 21.0) based on the independent review committee assessment.
  • the ibrutinib effect over chlorambucil represented by the ratio of response rate (PR or higher) was 2.33 with a 95% CI of (1.83, 2.97) based on the independent review committee assessment.
  • the ibrutinib effect in response rate ratio was estimated as 2.7392 with a 95% CI of (2.1781, 3.4450).
  • Ml was 2.1781, the lower bound of the 95% CI. Since the effect sizes of ibrutinib were over active controls in both studies (ofatumumab and chlorambucil, respectively), rather than placebos, the choice of Ml was very conservative and results in a narrow margin.
  • Table 13 and Table 14 include the monitoring boundaries of the PFS non-inferiority and superiority tests at the interim (assuming 93 PFS events) and the final analysis.
  • the monitoring boundaries were based on O’Brien-Fleming boundary approximated by the Lan-DeMets spending function.
  • the monitoring boundaries was adjusted based on the actual information fraction (number of events for PFS) observed up to the data cutoff. Deviation from the scheduled interim analysis did not affect the overall type I error.
  • HR hazard ratio
  • PFS progression-free survival
  • HR hazard ratio
  • PFS progression-free survival
  • the non-inferiority margin of 1.3319 was derived using the 95%-95% fixed margin method based on a meta-analysis of the RESONATE and RESONATE 2 studies.
  • the estimated PFS HR for ibrutinib versus chlorambucil was 0.16 with a 95% CI of (0.09, 0.28).
  • the estimated PFS HR for ibrutinib versus ofatumumab was 0.106 with a 95% CI of (0.073, 0.153).
  • the pooled HR was estimated as 0.120 with a 95% CI of (0.088, 0.163).
  • control arm effect (Ml) was -0.163 in HR and 1.814 in log HR. Requiring 84.2% of Ml to be retained in zanubritinib, a non- inferiority margin of 1.3319 for the HR (zanubrutinib/ibrutinib) was generated.
  • PFS The distribution of PFS including median and other quartiles, and PFS rate at selected timepoints, was estimated using the Kaplan-Meier method for each arm.
  • PFS was calculated as the time from the date of the randomization to the date of the first documentation of disease progression or death due to any cause, regardless of the use of subsequent anticancer therapy prior to the documented PD or death. PFS for the patients without a documented PD or death was censored at the last disease assessment.
  • the HR for PFS by investigator assessment and its 95% CI was estimated from a stratified Cox regression using the four randomization stratification factors (age [ ⁇ 65 years versus > 65 years], geographic region (China vs non-China), refractory status [yes or no], and del[17p]/TP53 status [present versus absent]). Kaplan-Meier method was used to estimate the distribution of PFS for each treatment group.
  • PFS was calculated as the time from the date of randomization to the date of first documentation of disease progression (as assessed by investigator assessment) or death due to any cause, regardless of the use of subsequent anti-cancer therapy prior to documented PD or death. PFS for the patients without a documented PD or death was censored at the last disease assessment.
  • the HR for time to treatment failure and its 95% CI was estimated from a stratified Cox regression using the 4 randomization stratification factors (age [ ⁇ 65 years versus > 65 years], geographic region (China versus non-China), refractory status [yes or no], and del[17p]/TP53 status [present versus absent]).
  • the Kaplan-Meier method was used to estimate the distribution of time to treatment failure for each treatment group.
  • Time to treatment failure was calculated as the time from the date of randomization to the date of discontinuation of study treatment due to any cause. Time to treatment failure was censored at the data cutoff for the patients who did not discontinue study treatment.
  • Rate of PR-L or Higher by Independent Central Review Rate of response ratio for PR-L or higher by independent central review and its 95% Wald CI was estimated using the Cochran-Mantel-Haenszel method. Clopper-Pearson 95% CI for the rate of response was calculated for each treatment group.
  • OS was analyzed using the same methods employed for PFS by investigator assessment.
  • the EORTC QLQ-C30 questionnaire was summarized for each assessment timepoint for each treatment group.
  • the percentage of patients with a clinically meaningful change from baseline in “global health status/QOL” and functional domains was summarized as “improved,” “stable,” or “worsened” and compared between 2 treatment groups.
  • the data may also be analyzed using repeated measure mixed model to account for missing data under the Missing at Random assumption.
  • Cox and/or logistic regression models may be used to explore the association between the prognostic and predictive biomarkers and the clinical outcomes.
  • a population PK analysis may be performed to include plasma concentrations of zanubrutinib from this trial in an existing model. PK parameters such as apparent systemic clearance and AUC may be derived from the population PK analysis if supported by data.
  • An exposure-response (efficacy or safety endpoints) analysis may be performed if supported by data. The results from the population PK and exposure-response analyses may be reported separately from the Clinical Study Report.
  • the extent of exposure to the study drug was summarized descriptively as the number of cycles received (number and percentage of patients), duration of exposure (days), cumulative total dose received per patient (mg), dose intensity (mg/day), and relative dose intensity (%).
  • AE verbatim descriptions (as recorded by the investigator on the eCRF) was classified into standardized medical terminology using Medical Dictionary for Regulatory Activities (MedDRA). AEs was coded to MedDRA (Version 20.0 or higher) lower level term closest to the verbatim term. The linked MedDRA preferred term and primary system organ class will also be captured in the database.
  • MedDRA Medical Dictionary for Regulatory Activities
  • a treatment-emergent AE was defined as an AE that has an onset date on or after the first dose of study drug up to 30 days following the study drug discontinuation or the start of a new anticancer therapy, whichever comes first. After this period, only treatment-related SAEs were to be reported. Only the AEs that were treatment emergent was included in the summary tables. All AEs, treatment emergent or otherwise, was presented in patient data listings.
  • Treatment-related AEs include those events considered by the investigator to be related to the study drug or with a missing assessment of the causal relationship. SAEs, deaths, treatment-emergent AEs > Grade 3, study drug-related treatment-emergent AEs, and treatment- emergent AEs that led to treatment discontinuation, dose reduction, or dose interruption was summarized.
  • ECG assessments was performed as described. Descriptive statistics for absolute and change from baseline ECG parameters was presented.
  • zanubrutinib was compared head-to-head with ibrutinib as treatment for relap sed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma ( CLL/SLL).
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • zanubrutinib demonstrated superiority over ibrutinib in the primary endpoint, overall response rate.
  • PFS progression-free survival
  • Enrolled patients were randomized (1 : 1) to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity.
  • Study drugs were administered in an open-label fashion due to variations in dosing schedules and suggested dose modifications.
  • patients were randomized to treatment based on a computer-generated randomization schedule. Randomization was stratified by age, geographic region, refractory status, and del(17p)/7P53 mu/ status. Cross-over was not allowed.
  • the noninferiority of zanubrutinib to ibrutinib for PFS was tested under the noninferiority margin (hazard ratio) of 1.3319 using a stratified Wald test based on the four randomization stratification factors followed by superiority testing using a stratified log-rank test.
  • Hypothesis testing of PFS was at a 2-sided significance level of 0.04996 after minimal alpha was allocated to PFS at the overall response rate interim analysis and overall response rate final analysis.
  • the statistical analysis plan was developed prior to the predefined first analysis, the overall response rate interim analysis; this predefined plan has not been amended.
  • CI denotes confidence interval
  • CR complete response
  • CRi CR with incomplete bone marrow recovery
  • IA interim analysis
  • IRC independent review committee
  • ITT intent-to-treat
  • NA not assessed
  • NE not evaluable
  • nPR nodular partial response
  • ORR overall response rate
  • PD progressive disease
  • PR partial response
  • PR-L partial response with lymphocytosis
  • SD stable disease
  • Efficacy analyses were based on the intent-to-treat (ITT) population, defined as all patients randomized to treatment; safety profile was assessed in the safety population, defined as all patients who received any dose of the study drug. Categorical variables were summarized by the number (percentage) of participants; continuous variables were reported using descriptive statistics. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc).
  • zanubrutinib demonstrated longer PFS than ibrutinib (HR:0.52 [95%CI, 0.30-0.88]); PFS across other major subgroups consistently favored zanubrutinib.
  • Zanubrutinib also demonstrated a higher overall response rate than ibrutinib.
  • Zanubrutinib safety profile was improved over ibrutinib with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including lower rate of cardiac events leading to discontinuation or death.
  • CI denotes confidence interval
  • CR complete response
  • CRi CR with incomplete bone marrow recovery
  • IRC independent review committee
  • ITT intent-to-treat
  • NA not assessed
  • NE not evaluable
  • nPR nodular partial response
  • ORR overall response rate
  • PD progressive disease
  • PR partial response
  • PR-L partial response with lymphocytosis
  • SD stable disease
  • CI denotes confidence interval
  • IRC independent review committee
  • mo months
  • NE not estimable.
  • zanubrutinib demonstrated superiority for investigator-assessed PFS over ibrutinib with a hazard ratio (HR) of 0.65 (95% CI, 0.49-0.86) and 2-sided E- value of 0.0024 (FIG. 9).
  • HR hazard ratio
  • 87 patients with zanubrutinib and 118 patients with ibrutinib experienced disease progression or death.
  • the most common primary method of disease progression in both treatment arms was increase in lymph nodes (Table 19).
  • Zanubrutinib also met superiority for PFS as assessed by independent review committee with identical statistical results (FIG. 3 and FIG. 4).
  • Time-to-treatment failure is shown in FIG. 14; at 24 months, the treatment-failure event-free rate was 79.9% (95% CI 75.1-83.9) with zanubrutinib and 65.0% (95% CI 59.5-70.0) with ibrutinib.
  • COVID-19-related TEAE denotes any COVID-19 related preferred terms: COVID-19, COVID- 19 pneumonia, post-acute COVTD-19 syndrome, suspected COVTD-19.
  • SOC based on MedDRA version 24.0 denotes system organ class.
  • Rates of adverse events of special interest are presented in Table 23.
  • Colony-stimulating growth factor was used at a similar rate for patients treated with zanubrutinib versus ibrutinib (15.4% vs 15.7%). Hemorrhagic events, including major hemorrhagic events, occurred with similar frequency in patients on zanubrutinib and ibrutinib (Table 23). Any-grade hypertension was reported in 23.5% and 22.8% (FIG. 19), and grade 3 (no grade >4 was reported) in 15.1% and 13.6% of patients receiving zanubrutinib and ibrutinib, respectively.
  • zanubrutinib demonstrated superior PFS to ibrutinib; supporting the superior PFS by investigator assessment are the results by independent review committee assessment and sensitivity analyses including evaluation for the possible impact of disease progression due to study drug interruption. This PFS benefit was observed across all major subgroups, including the high-risk del(17p)/7P53 mu/ population. Zanubrutinib also demonstrated superior overall response rate by both investigator and independent review committee and higher rate of partial response with lymphocytosis or better. This is the first demonstration of improved PFS in a head-to-head study of BTKi monotherapy.
  • zanubrutinib demonstrated superior PFS over ibrutinib.
  • zanubrutinib was observed to have improved benefits over ibrutinib in the high-risk del(17p)/ZP55 muf subgroup, which was not observed in ELEVATE-RR.
  • Zanubrutinib has demonstrated high (>90%) steady-state BTKI occupancy in peripheral blood mononuclear cells and lymph nodes. In this study, treatment discontinuation, for any reason, was lower with zanubrutinib than ibrutinib, including discontinuation rates due to both AEs and progressive disease.
  • zanubrutinib had a more favorable safety profile compared with ibrutinib with a lower rate of treatment discontinuation and fewer cardiac disorder events, including fewer deaths.
  • Zanubrutinib, with its favorable risk-benefit profile has been demonstrated to be a potential new standard of care for BTKi-naive patients with relapsed/refractory CLL/SLL.
  • BCL2 B-cell lymphoma 2 BCL2 B-cell lymphoma 2, CD20 cluster of differentiation 20, ECOG PS Eastern Cooperative Oncology Group performance status, IGHV immunoglobulin heavy chain variable region, IMiD immunomodulatory drug, PI3K phosphatidylinositol 3 -kinase, SYK spleen associated tyrosine kinase.
  • zanubrutinib demonstrated the improved PFS probability compared to other major BTK inhibitors, e g., ibrutinib and acalabrutinib, based on the head-to- head studies of BTKi monotherapy. Furthermore, zanubrutinib (a BTK inhibitor) significantly improved PFS compared with another major BTK inhibitor, i.e., ibrutinib, and was associated with fewer cardiac adverse events in patients with relap sed/refractory CLL/SLL. This is the first demonstration of PFS superiority of zanubrutinib in a head-to-head comparison of BTK inhibitors for CLL.
  • 320 mg BID (a total daily dose of 640 mg) of zanubrutinib on a patient receiving a moderate CYP3A inducer leads to exposure (e.g., AUC or Cmax) similar to that on a patient receiving 160 mg BID of zanubrutinib (a total daily dose of 320 mg).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • WM Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • Cohort 2 Intolerant to acalabrutinib ⁇ ibrutinib treatment
  • the primary endpoints were the recurrence and the change in severity of ibrutinib and acalabrutinib intolerance events compared with corresponding treatment-emergent adverse events within each patient.
  • the term “adverse event” refers to a “treatment-emergent adverse event” unless otherwise stated.
  • the full “treatment-emergent adverse event” was not used.
  • Patients receive oral zanubrutinib at either 160 mg twice daily or 320 mg once daily on Days 1 to 28 of each 28-day cycle. Investigators in conjunction with patients select the dose regimen to employ; however, once a regimen was chosen, change was not allowed.
  • Study treatment commences on CID 1 and continues until disease progression, unacceptable toxicity, treatment consent withdrawal, or study termination, whichever occurs first. Approximately 30 days after the date of permanent study drug discontinuation, a safety follow-up visit was required. Patients who permanently discontinue treatment remain in the study and enter long-term follow-up where they were monitored for survival status and subsequent anticancer therapies. All subsequent study visits and assessments were scheduled based on the C1D1 date. Survival status and subsequent therapies for CLL/SLL, WM, MCL, or MZL were assessed approximately every 6 months by either telephone or in-person contact until patient’s end of study. [00662] No formal interim analyses were planned for this study. Summaries and analyses of subsets of the study data might be performed on a periodic basis for submission to professional meetings, manuscript preparations, and for internal decision-making, at BeiGene’s discretion.
  • the study was designed to evaluate the safety of zanubrutinib monotherapy with respect to the recurrence of adverse events that led to the intolerance of ibrutinib and/or acalabrutinib, and to evaluate the change in severity of recurrent intolerant events in patients with previously treated CLL/SLL, WM, MCL, or MZL.
  • the study enrolls 2 patient cohorts:
  • Cohort 1 patients who were intolerant only to prior ibrutinib
  • Zanubrutinib was also being investigated in other B-cell malignancies and in autoimmune disease.
  • Imaging studies computed tomography [CT] with/without contrast, positron emission tomography [PET], PET/CT, or magnetic resonance imaging [MRI])

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Abstract

L'invention concerne une méthode de traitement d'un patient présentant un trouble prolifératif des lymphocytes B, la méthode comprenant l'administration au patient du zanubrutinib, ou d'un sel pharmaceutiquement acceptable de celui-ci, le patient étant caractérisé en ce qu'il reçoit un inducteur CYP3A modéré. Dans un mode de réalisation, le zanubrutinib est administré à une dose d'environ 320 mg deux fois par jour, ou à une dose quotidienne totale d'environ 640 mg.
PCT/US2023/068121 2022-06-08 2023-06-08 Méthodes de traitement d'un trouble prolifératif des lymphocytes b WO2023240180A1 (fr)

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US202263366053P 2022-06-08 2022-06-08
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US202263383504P 2022-11-13 2022-11-13
US202263383503P 2022-11-13 2022-11-13
US63/383,503 2022-11-13
US63/383,504 2022-11-13
US202263384864P 2022-11-23 2022-11-23
US63/384,864 2022-11-23
US202263387796P 2022-12-16 2022-12-16
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WO2021173870A1 (fr) * 2020-02-27 2021-09-02 University Of Washington Composition et procédé pour préparer une suspension injectable à action prolongée contenant de multiples médicaments anticancéreux

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Publication number Priority date Publication date Assignee Title
WO2021173870A1 (fr) * 2020-02-27 2021-09-02 University Of Washington Composition et procédé pour préparer une suspension injectable à action prolongée contenant de multiples médicaments anticancéreux

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Title
WANG KUN, YAO XUETING, ZHANG MIAO, LIU DONGYANG, GAO YUYING, SAHASRANAMAN SRIKUMAR, OU YING C.: "Comprehensive PBPK model to predict drug interaction potential of Zanubrutinib as a victim or perpetrator", CPT: PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, WILEY BLACKWELL, vol. 10, no. 5, 1 May 2021 (2021-05-01), pages 441 - 454, XP093117408, ISSN: 2163-8306, DOI: 10.1002/psp4.12605 *

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