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WO2018136961A1 - Méthodes de traitement de patients à l'aide d'un agoniste du récepteur alpha de l'acide rétinoïque et d'un anticorps anti-cd38 - Google Patents

Méthodes de traitement de patients à l'aide d'un agoniste du récepteur alpha de l'acide rétinoïque et d'un anticorps anti-cd38 Download PDF

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Publication number
WO2018136961A1
WO2018136961A1 PCT/US2018/014904 US2018014904W WO2018136961A1 WO 2018136961 A1 WO2018136961 A1 WO 2018136961A1 US 2018014904 W US2018014904 W US 2018014904W WO 2018136961 A1 WO2018136961 A1 WO 2018136961A1
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Prior art keywords
tamibarotene
subject
antibody
cell
treatment
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PCT/US2018/014904
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English (en)
Inventor
Michael R. MCKEOWN
Nan KE
Kathryn AUSTGEN
Christopher FIORE
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Syros Pharmaceuticals Inc.
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Priority claimed from PCT/US2017/055562 external-priority patent/WO2018067946A1/fr
Application filed by Syros Pharmaceuticals Inc. filed Critical Syros Pharmaceuticals Inc.
Publication of WO2018136961A1 publication Critical patent/WO2018136961A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]

Definitions

  • Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds.
  • retinoids Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases.
  • Retinoic acid and its other naturally occurring retinoid analogs (9-cis retinoic acid, all-trans 3,4-didehydro retinoic acid, 4-oxo retinoic acid and retinol) are pleiotropic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lungs.
  • Retinoids exert their biological effects through a series of hormone nuclear receptors that are ligand inducible transcription factors belonging to the
  • the retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes ( ⁇ , ⁇ , and ⁇ ). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. All-trans retinoic acid is the physiological hormone for the retinoic acid receptors and binds with
  • Retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical and systemic retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis.
  • retinoids A limitation in the therapeutic use of retinoids has stemmed from the relative toxicity observed with the naturally occurring retinoids, all-trans retinoic acid and 9-cis retinoic acid. These natural ligands are non-selective in terms of RAR subtype and therefore have pleiotropic effects throughout the body, which are often toxic.
  • RARA specific agonists have held high promise for the treatment of cancers and many have entered human clinical trials.
  • RARA specific agonist only one RARA specific agonist, tamibarotene, has ever been approved for the treatment of cancer.
  • tamibarotene is only approved in Japan and only for the treatment of acute promyelocytic leukemia, despite trials in the US and Europe.
  • the disconnect between the theoretical efficacy of RARA agonists in cancer and the dearth of regulatory approvals for such agents raises the question of why such agonists are not effective and safe in humans. Therefore, there is a need to better understand why RARA agonists have not met their therapeutic potential.
  • Cluster of differentiation 38 is a protein expressed on the surface, primarily on white blood cells, and considered a cell surface marker indicative of differentiation initiation. It functions as a cyclic ADP-ribose hydrolase which plays a role in cell signaling (Mehta, K. & Cheema, S., Leuk. Lymphoma, 32, 441-449 (1999)). It is generally found to be highly expressed in cells of the B-cell and plasma cell lineage. In multiple myeloma a subset of patients have high CD38 expression, which has led to the development of anti-CD38 therapeutic antibodies, such as daratumumab (Lokhorst, H. M. et al., N. Engl. J.
  • cancer cells which express CD38 can be selectively targeted for elimination by the immune system using these therapeutic antibodies.
  • CD38 hl high CD38-expressing tumor cells
  • lower levels of CD38 expression cause the therapeutic antibody to have less to no effect (Nijhof, I. S. et al., Blood, 128, 959-970 (2016)). This is why normal white blood cells or multiple myeloma cells that are initially low in CD38 expression (or becomes low as a mechanism of resistance) do not get efficiently cleared by anti-CD38 treatment.
  • CD38 expression in AML is considered to be generally low (CD38 lD ), but moderate in expression in a subset of patients (CD38 dim ).
  • Naturally-occurring CD38 hi AML cells are not typical and the percent positivity in AML is generally low.
  • AML is believed unlikely to respond to anti-CD38 treatment, a finding that has been demonstrated with daratumumab monotherapy (Dos Santos, C. et al., Blood, 124, 2312-2312 (2014).
  • the present disclosure provides methods for treating a subject suffering from a hematological cancer (e.g., multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
  • MM multiple myeloma
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALCL anaplastic large cell lymphoma
  • BALL B-cell acute lymphoblastic leukemia
  • BNHL B-cell non-Hodgkin lymphoma
  • CML chronic myelogenous lymphoma
  • DLBCL Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or T-cell acute lymphoblastic leukemia (TALL)
  • a retinoid e.g., a retinoic acid receptor alpha- specific agonist, e.g., tamibarotene
  • an anti-CD38 antibody e.g., daratumumab
  • the method is employed when the hematological cancer is: a) unresponsive to a CD38 inhibitor as a monotherapy; and/or b) characterized as CD38 " , CD38 lD , or CD38 dim .
  • the invention provides a method for treating a subject having a hematological cancer that is unresponsive to a treatment with an anti-CD38 antibody in the absence of a retinoid, wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody.
  • the subject is only selected for treatment if their hematological cancer has been unresponsive to a prior treatment with an anti-CD38 antibody as a monotherapy (i.e., in the absence of coadministration of a retinoid).
  • the subject is suffering from a hematological cancer selected from multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), or T-cell acute lymphoblastic leukemia (TALL).
  • MM multiple myeloma
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALCL anaplastic large cell lymphoma
  • BALL B-cell acute lymphoblastic leukemia
  • BALL B-cell non-Hodgkin lymphoma
  • CML chronic myelogen
  • the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
  • ACL anaplastic large cell lymphoma
  • BALL B-cell acute lymphoblastic leukemia
  • BNHL B-cell non-Hodgkin lymphoma
  • CML chronic myelogenous lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • Hodgkin lymphoma or T-cell acute lymphoblastic leukemia (TALL).
  • the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
  • MM multiple myeloma
  • non-APL AML non-acute promyelocytic myeloid leukemia
  • MDS myelodysplastic syndrome
  • CLL chronic lymphocytic leukemia
  • the retinoid is a RARA-specific agonist. In more specific aspects of the first embodiment, the retinoid is tamibarotene. In other aspects of the first embodiment, the anti-CD38 antibody is daratumumab.
  • the subject is administered a retinoid (e.g., a RARA agonist, e.g., tamibarotene) for a period of time prior to administration of an anti-CD38 antibody (e.g., daratumumab); and is co-administered the anti-CD38 antibody only when the CD38 level in the subject (e.g., in the subject's hematological cancer cells) is determined to be CD38 hl following initial administration of the retinoid (e.g., tamibarotene).
  • a retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the CD38 level in the subject is determined at one or more different times following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more times between 6 hours and two weeks following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 120 hours following the initial administration of the retinoid (e.g., tamibarotene).
  • the CD38 level in the subject is determined at one or more of the following time period following initial administration of the retinoid (e.g., tamibarotene): 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days. In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 72 hours following the initial administration of the retinoid (e.g., tamibarotene).
  • the retinoid e.g., tamibarotene
  • a sample of a subject's diseased cells is tested for CD38 induction prior to any treatment.
  • this would involve obtaining a sample of the subject's diseased cells; growing such cells ex vivo; optionally measuring a baseline level of CD38 induction in those cells; treating the ex vivo cells with a retinoid (e.g., tamibarotene); and determining the level of CD38 induction following such treatment.
  • a retinoid e.g., tamibarotene
  • the subject is determined to be a candidate for the retinoid (e.g., tamibarotene)/anti-CD38 antibody (e.g., daratumumab) combination treatment.
  • retinoid e.g., tamibarotene
  • anti-CD38 antibody e.g., daratumumab
  • the anti-CD38 antibody e.g., daratumumab
  • the retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the treatment regimen does not require any specific order of administering the retinoid and the anti-CD38 antibody.
  • it may be advantageous to administer the anti-CD38 antibody prior to the retinoid so as to limit or eliminate any side effects of the antibody and/or to optimize the pharmacokinetics of each agent.
  • the anti-CD38 antibody e.g., daratumumab
  • the retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the invention provides a method for treating a subject having a hematological cancer that is characterized as CD38 " , CD38 lD or CD38 dim , wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody.
  • the subject is only selected for treatment if they have a hematological cancer that is characterized as CD38 " , CD38 lD or CD38 dim .
  • the subject is suffering from a hematological cancer selected from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALCL anaplastic large cell lymphoma
  • BALL B-cell acute lymphoblastic leukemia
  • BALL B-cell non-Hodgkin lymphoma
  • CML chronic myelogenous lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • Hodgkin lymphoma or T-cell
  • the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
  • ACL anaplastic large cell lymphoma
  • BALL B-cell acute lymphoblastic leukemia
  • BNHL B-cell non-Hodgkin lymphoma
  • CML chronic myelogenous lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • Hodgkin lymphoma or T-cell acute lymphoblastic leukemia (TALL).
  • the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
  • MM multiple myeloma
  • non-APL AML non-acute promyelocytic myeloid leukemia
  • MDS myelodysplastic syndrome
  • CLL chronic lymphocytic leukemia
  • the retinoid is a RARA-specific agonist.
  • the retinoid is tamibarotene, ATRA, or a derivative thereof (e.g., fenretinide).
  • the anti-CD38 antibody is daratumumab.
  • the CD38 level in the subject is determined prior to administration of the therapy.
  • a sample of a subject's diseased cells is tested for CD38 induction prior to any treatment as described for the fourth embodiment. If the CD38 level in this sample of the subject's diseased cells is determined to be CD38 hl after treatment with the retinoid, then the subject is determined to be a candidate for the retinoid (e.g., tamibarotene)/anti-CD38 antibody (e.g., daratumumab) combination treatment.
  • the retinoid e.g., tamibarotene
  • anti-CD38 antibody e.g., daratumumab
  • the subject is administered a retinoid (e.g., a RARA agonist, e.g., tamibarotene) for a period of time prior to administration of the anti-CD38 antibody (e.g., daratumumab); and is co-administered the anti-CD38 antibody only when the CD38 level in the subject (e.g., in the subject's hematological cancer cells) is determined to be CD38 hl following initial administration of the retinoid (e.g., tamibarotene).
  • a retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the CD38 level in the subject is determined at one or more different times following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined at one or more times between 6 hours and two weeks following the initial administration of the retinoid (e.g., tamibarotene). In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 120 hours following the initial administration of the retinoid (e.g., tamibarotene).
  • the CD38 level in the subject is determined at one or more of the following time period following initial administration of the retinoid (e.g., tamibarotene): 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, and 14 days. In some aspects of the first embodiment, the CD38 level in the subject is determined between 6 and 72 hours following the initial administration of the retinoid (e.g., tamibarotene).
  • the retinoid e.g., tamibarotene
  • the anti-CD38 antibody e.g., daratumumab
  • the retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the treatment regimen does not require any specific order of administering the retinoid and the anti-CD38 antibody.
  • it may be advantageous to administer the anti-CD38 antibody prior to the retinoid so as to limit or eliminate any side effects of the antibody and/or to optimize the pharmacokinetics of each agent.
  • the anti-CD38 antibody e.g., daratumumab
  • the retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the determination of whether a subject's hematological cancer is CD38 " , CD38 10 , CD38 dim or CD38 hi is made by analyzing the subject's blood cells (e.g., bone marrow, PBMCs and/or enriched PBMCs) using an anti-human CD38 antibody in conjunction with a fluorescence-activated cell sorter (FACS).
  • FACS fluorescence-activated cell sorter
  • the invention provides a method for treating a subject having a hematological cancer, wherein the method comprises co-administering to the subject a retinoid and an anti-CD38 antibody.
  • the subject is suffering from a hematological cancer selected from multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, or T-cell acute lymphoblastic leukemia (TALL).
  • MM multiple myeloma
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • ALCL anaplastic large cell lymphoma
  • BALL
  • the subject is suffering from a hematological cancer selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
  • ACL anaplastic large cell lymphoma
  • BALL B-cell acute lymphoblastic leukemia
  • BNHL B-cell non-Hodgkin lymphoma
  • CML chronic myelogenous lymphoma
  • diffuse large B-cell lymphoma selected from anaplastic large cell lymphoma (ALCL), B-cell acute lymphoblastic leukemia (BALL), B-cell non-Hodgkin lymphoma (BNHL), Burkitt's lymphoma, chronic myelogenous lymphoma (CML), diffuse large B-cell lymphoma
  • the subject is suffering from a hematological cancer selected from multiple myeloma (MM), non-acute promyelocytic myeloid leukemia (non-APL AML), myelodysplastic syndrome (MDS), or chronic lymphocytic leukemia (CLL).
  • MM multiple myeloma
  • non-APL AML non-acute promyelocytic myeloid leukemia
  • MDS myelodysplastic syndrome
  • CLL chronic lymphocytic leukemia
  • the retinoid is a RARA-specific agonist.
  • the retinoid is tamibarotene.
  • the anti-CD38 antibody is daratumumab.
  • the anti-CD38 antibody e.g., daratumumab
  • the retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the anti-CD38 antibody e.g., daratumumab
  • the retinoid e.g., a RARA agonist, e.g., tamibarotene
  • the present invention features a method for treating a subject having a hematological cancer (e.g., non-APL AML, MDS or MM), wherein the composition comprises an agonist of RARA (e.g., tamibarotene) co- administered with an antibody specific for CD38 (e.g., daratumumab).
  • RARA e.g., tamibarotene
  • tamibarotene is administered orally.
  • the subject is administered
  • the anti-CD38 antibody is administered no more than once a week at a dose of between 10-20 mg/kg body weight of the subject.
  • Figs. 1 A- IF depict the effect of tamibarotene ("SY1425") on CD38 levels in various AML cell lines.
  • Figs. 11A-11D demonstrate the effect of tamibarotene on different cell lines as measured by FITC cell sorting.
  • Fig. HE is a graphical representation of the CD38 mRNA levels in various cell lines before and after treatment with tamibarotene.
  • Fig. 1 IF is a graphical representation of the % of cells that are positive for CD38 as determined by FITC cell sorting.
  • Figs. 2A-2D depict the effect of tamibarotene and daratumumab ("Dara"), alone or in combination, on NK cell proliferation and tumor cell death in various NK cell/ AML cell line co-cultures, as observed by phase contrast microscopy.
  • Dara daratumumab
  • Figs. 3A-3C depict the effect of a control antibody or Dara alone or in combination with tamibarotene on the number of apoptotic cells in NK cell/ AML co-culture for various AML cell lines.
  • Fig. 4 depicts the effect of a control antibody or Dara alone or in
  • Figs. 5A-5B depict the effect of a control antibody or Dara alone or in combination with tamibarotene on CD38 levels in two different multiple myeloma cell line (MM1S; Fig. 5A) (HUNS1; Fig. 5B) as measured by FITC cell sorting.
  • Fig. 6 depicts the effect of a control antibody or Dara alone or in
  • Fig. 7 depicts the effect of a control antibody or Dara alone or in combination with tamibarotene on interferon-gamma secretion in a NK cell/multiple myeloma co-culture for the various multiple cell lines depicted in Figs. 5A-5B and 6.
  • Fig. 8A depicts the effect of tamibarotene treatment on the expression of
  • FIG. 8B depicts the effect of tamibarotene treatment on the expression of CD38 in various AML and MDS patient samples after 24 or 48 hours as measured by FACS, as well as the expression of RARA and IRF8 mRNA as measured by qPCR.
  • Figs. 9A-9D compares the effect of tamibarotene treatment on CD38 levels in an AML cell line, an AML patient sample, and a multiple myeloma cell line, as well as the baseline CD38 level in a CD38 hl multiple myeloma patient sample.
  • Figs 10A-10D compare the effect of tamibarotene and all-trans retinoic acid
  • Fig. 11 compares the effect of tamibarotene and all-trans retinoic acid
  • Fig. 12 compares the effect of tamibarotene and all- trans retinoic acid (ATRA) on CD38 levels in a mouse Kasumi-1 xenograft model after one week as measured by FACS.
  • ATRA all- trans retinoic acid
  • Fig. 13 compares the effect of tamibarotene and all- trans retinoic acid
  • ATRA on CD38 levels in mouse THP-1, Kasumi-1 and MV4-11 xenograft models after one week as measured by IHC.
  • Fig. 14 depicts the effect of various treatments on the size of a xenograft
  • FIG. 15A-15E depict sections of xenograft MV-411 tumors removed from mice following various treatments and stained with anti-human CD38 antibody.
  • Fig. 16 depicts the effect of various treatments on the size of a xenograft MM1S tumor over time in a mouse.
  • Fig. 17 depicts the effect of various treatments on the size of a xenograft
  • administer As used herein, the terms “administer,” “administering,” or
  • administration refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.
  • an agonist may be used to refer to an agent, condition, or event whose presence, level, degree, type, or form correlates with increased level or activity of another agent (i.e. , the agonized agent).
  • an agonist may be or include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and/or any other entity that shows the relevant activating activity.
  • an agonist may be direct (in which case it exerts its influence directly upon its target); in some embodiments, an agonist may be indirect (in which case it exerts its influence by other than binding to its target; e.g. , by interacting with a regulator of the target, so that level or activity of the target is altered).
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g.
  • Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.
  • a biological sample from a subject suffering from a hematological cancer is a bone marrow aspirate.
  • a biological sample from a subject suffering from a hematological cancer is a fractionated whole blood sample.
  • a biological sample from a subject suffering from a hematological cancer is a PBMC fraction from the subject's whole blood (a "PBMC sample").
  • a PBMC sample from a subject suffering from a hematological cancer is further enriched for specific blasts using various enrichment techniques such as antibody-linked bead enrichment protocols, fluorescent label cell sorting, or other techniques known in the art (an "enriched PBMC sample").
  • biomarker refers to an entity whose presence, level, or form, correlates with a particular biological event or state of interest, so that it is considered to be a "marker” of that event or state.
  • a biomarker may be or comprises a marker for a particular disease state or stage, or for likelihood that a particular disease, disorder or condition may develop.
  • a biomarker may be or comprise a marker for a particular disease or therapeutic outcome, or likelihood thereof.
  • a biomarker is predictive, in some embodiments, a biomarker is prognostic, in some embodiments, a biomarker is diagnostic, of the relevant biological event or state of interest.
  • a biomarker may be an entity of any chemical class.
  • a biomarker may be or comprise a nucleic acid, a polypeptide, a lipid, a carbohydrate, a small molecule, an inorganic agent (e.g. , a metal or ion), or a combination thereof.
  • a biomarker is a cell surface marker.
  • a biomarker is intracellular.
  • a biomarker is found outside of cells (e.g.
  • a presence or level of a particular marker correlates with activity (or activity level) of a particular signaling pathway, for example that may be characteristic of a particular class of tumors.
  • the statistical significance of the presence or absence of a biomarker may vary depending upon the particular biomarker.
  • detection of a biomarker is highly specific in that it reflects a high probability that the tumor is of a particular subclass. Such specificity may come at the cost of sensitivity (e.g. , a negative result may occur even if the tumor is a tumor that would be expected to express the biomarker).
  • co-administer or “co- administering” as used herein in the context of the administration of therapies (e.g., a RARA agonist and an antibody specific for CD38), indicates that one therapy may be used in combination with another therapy or therapies during the course of the subject's affliction with the disorder.
  • therapies e.g., a RARA agonist and an antibody specific for CD38
  • the administration of therapies is simultaneous or concurrent, meaning that the delivery of one treatment is still occurring when the delivery of the second begins.
  • the delivery of one treatment ends before the delivery of the other treatment begins.
  • the treatment is more effective because of combined administration.
  • the second treatment is more effective, e.g., an equivalent effect is seen with less of the second treatment, or the second treatment reduces symptoms to a greater extent, than would be seen if the second treatment were administered in the absence of the first treatment, or the analogous situation is seen with the first treatment.
  • delivery is such that the reduction in a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other.
  • the effect of the two treatments can be partially additive, wholly additive, or greater than additive.
  • the delivery can be such that an effect of the first treatment delivered is still detectable when the second is delivered.
  • a RARA agonist and an antibody specific to CD38 can be administered simultaneously, in the same or in separate compositions, or sequentially.
  • the RARA agonist can be administered first, and the antibody specific to CD38 can be administered second, or the order of administration can be reversed.
  • condition As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.
  • an "effective amount" of a compound described herein, such a RARA agonist and/or an antibody specific for CD38 refers to an amount sufficient to elicit the desired biological response, i.e. , treating the condition.
  • the effective amount of a compound described herein, such a RARA agonist and/or an antibody specific for CD38 may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount encompasses therapeutic and prophylactic treatment.
  • an effective amount encompasses only therapeutic treatment.
  • an effective amount of an inventive compound or composition may reduce the tumor burden or stop the growth or spread of a tumor.
  • a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e. , a male or female of any age group, e.g. , a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g. , primates (e.g. , cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g.
  • humans i.e. , a male or female of any age group, e.g. , a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g. , young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals
  • the animal is a mammal.
  • the animal may be a male or female and at any stage of development.
  • a non-human animal may be a transgenic animal.
  • the subject is a human.
  • a "therapeutically effective amount" of a compound described herein, such a RARA agonist and/or an antibody specific for CD38 is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition” (e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • pathological condition e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof
  • “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • the present invention features methods of treating a subject having cancer
  • RARA e.g., non-APL AML, MDS or MM
  • RARA agonist in combination with an antibody specific for CD38, for example, when a biomarker for RARA or IRF8 is identified
  • RARA agonist with which to treat a patient identified as having a super enhancer associated with a RARA gene may be made from any RARA agonist known in the art. It is preferable that the RARA agonist utilized in the methods of the invention be specific for RARA and have significantly less (at least 10X less, at least 100X less, at least 1,000X less, at least 10,000X less, at least 100,000X less) agonistic activity against other forms of RaR, e.g., RaR- ⁇ and RaR- ⁇ .
  • the RARA agonist is selected from a compound disclosed in or any compound falling within the genera set forth in any one of the following United States patents: US 4,703,110, US 5,081,271, US 5,089,509, US 5,455,265, US 5,759,785, US 5,856,490, US 5,965,606, US 6,063,797, US 6,071,924, US 6,075,032, US 6,187,950, US 6,355,669, US 6,358,995, and US 6,387,950, each of which is incorporated by reference.
  • the RARA agonist is selected from any of the following known RARA agonists set forth in Table 1, or a pharmaceutically acceptable salt thereof, or a solvate or hydrate of the foregoing: Table 1.
  • the RARA agonist is (AGN-195183).
  • Antibodies Specific for CD38 is (AGN-195183).
  • CD38 is a transmembrane glycoprotein involved in a number of metabolic functions including the catabolism of extracellular nucleotides, receptor-mediated adhesion, regulation of migration, and a variety of signaling events.
  • Antibodies targeting CD38 may modulate any one of these functions, thus contributing to the efficacy of a RARA agonist in the treatment of a cancer.
  • the antibody specific for CD38 may recognize and/or bind to any portion of fragment of CD38.
  • the antibody specific for CD38 may comprise a monoclonal antibody, a humanized antibody, or a human antibody.
  • Exemplary antibodies that are specific for CD38 include isatuximab, daratumumab,
  • the antibody specific for CD38 is daratumumab.
  • the subject to be treated with a RARA agonist (e.g. , tamibarotene) and an antibody specific for CD38 is suffering from relapsed or refractory non- APL AML.
  • a subject is classified as having relapsed or refractory non-APL AML if they: a) do not demonstrate a partial response after a first cycle of induction chemotherapy; or b) do not demonstrate a complete response after a second cycle of induction chemotherapy; or c) relapse after conventional chemotherapy; or d) relapse are undergoing a single stem cell transplantation.
  • the subject to be treated with a RARA agonist (e.g. , tamibarotene) and an antibody specific for CD38 is suffering from refractory MM.
  • the subject to be treated with a RARA agonist is an elderly unfit subject.
  • a RARA agonist e.g. , tamibarotene
  • the term "elderly unfit" as used herein means the subject is a human at least 60 years of age and who is determined by a physician to not be a candidate for standard induction therapy.
  • the subject is co-administered a RARA agonist (e.g., tamibarotene) and an antibody specific to CD38 (e.g., daratumumab).
  • a RARA agonist e.g., tamibarotene
  • the RARA agonist is administered simultaneously with the antibody specific to CD38 (e.g., daratumumab).
  • the RARA agonist e.g., tamibarotene
  • the antibody specific to CD38 e.g., daratumumab
  • the subject is co-administered a RARA agonist (e.g., tamibarotene) and an antibody specific to CD38 (e.g., daratumumab).
  • the RARA agonist e.g., tamibarotene
  • an antibody specific to CD38 e.g., daratumumab
  • the RARA agonist and an antibody specific to CD38 are administered within about 1 minute, about 2 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 36 hours, or about 48 hours of one another.
  • a patient population includes one or more subjects
  • a patient population includes one or more subjects (e.g. , comprises or consists of subjects) who have not received previous therapy for treatment of cancer (e.g. , non-APL AML, MDS or MM).
  • a patient population comprises or consists of patients who have not received previous therapy for treatment of non-APL AML, MDS or MM.
  • a patient who received previous therapy may have received previous therapy selected from the group consisting of chemotherapy,
  • a patient has received a transplant.
  • a patient has received standard cytotoxic chemotherapy.
  • standard cytotoxic chemotherapy includes cytarabine and/or an anthracycline.
  • standard cytotoxic chemotherapy may include additional chemotherapy and/or hematopoietic stem cell transplantation (HSTC).
  • HSTC hematopoietic stem cell transplantation
  • a patient has received hypomethylating agents.
  • a patient has received lenalidomide.
  • a patient population includes one or more subjects
  • a RARA agonist therapy e.g., tamibarotene
  • a composition is administered in combination with the other therapy (e.g. chemotherapy agents), in addition to an antibody specific for CD38.
  • the other therapy e.g. chemotherapy agents
  • such other therapy may comprise or consist of therapy for cancer (e.g., as described herein), pain, nausea, constipation, for treatment of one or more side effects (e.g., pruritus, hair loss, sleeplessness, etc.) associated with cancer therapy, etc., or any combination thereof.
  • the present invention provides a method of treating non-APL AML, MDS or MM, which comprises treating a patient identified as having non- APL AML, MDS or MM, with a therapeutically effective amount of RARA agonist therapy (e.g., tamibarotene) or a pharmaceutically acceptable salt thereof and an antibody specific for CD38.
  • RARA agonist therapy e.g., tamibarotene
  • the invention provides a method for treating a patient for non-APL AML, MDS or MM previously treated with a treatment regimen comprising chemotherapy by administering to such a patient a therapeutically effective amount of a RARA agonist (e.g., tamibarotene) and an antibody specific CD38.
  • a RARA agonist e.g., tamibarotene
  • the present disclosure provides a method for treating a patient for non-APL AML, MDS or MM where no standard therapies exist.
  • the present disclosure provides a method for treating a patient that is not suited for standard therapy.
  • a patient or patient population may not be (e.g. , may exclude) a patient who has a previous history of hypersensitivity to an ingredient of tamibarotene.
  • a patient or patient population may not be (e.g. , may exclude) a patient who is receiving vitamin A formulations.
  • a patient or patient population may not be (e.g. , may exclude) a patient who has hypervitaminosis A.
  • a patient or patient population may not be (e.g. , may exclude) an elderly patient.
  • a patient or patient population may be or include one or more elderly patients.
  • an elderly patient may be monitored more frequently to detect potential adverse events (including for example, low levels of serum albumin and/or elevated concentrations of free drug in plasma, etc.) as compared with one or more younger patients.
  • the administration of the RARA agonist and/or the antibody specific CD38 may be reduced, suspended, and/or terminated for an elderly patient determined to display one or more signs of such an adverse event.
  • each active agent e.g., a RARA agonist or an antibody specific for CD38
  • a RARA agonist for use in accordance with the present invention is formulated, dosed, and administered in a therapeutically effective amount using pharmaceutical compositions and dosing regimens that are consistently with good medical practice and appropriate for the relevant agent(s) and subject.
  • therapeutic compositions can be administered by any appropriate method known in the art, including, without limitation, oral, mucosal, by- inhalation, topical, buccal, nasal, rectal, or parenteral (e.g., intravenous, infusion, intratumoral, intranodal, subcutaneous, intraperitoneal, intramuscular, intradermal, transdermal, or other kinds of administration).
  • a RARA agonist e.g., tamibarotene
  • an antibody specific for CD38 will be administered intravenously.
  • a dosing regimen for a particular active agent may involve intermittent or continuous administration, for example to achieve a particular desired pharmacokinetic profile or other pattern of exposure in one or more tissues or fluids of interest in the subject receiving therapy.
  • different agents administered in combination may be administered via different routes of delivery and/or according to different schedules.
  • one or more doses of a first active agent is administered substantially simultaneously with, and in some embodiments via a common route and/or as part of a single composition with, one or more other active agents.
  • Factors to be considered when optimizing routes and/or dosing schedule for a given therapeutic regimen may include, for example, the particular indication being treated, the clinical condition of a subject (e.g., age, overall health, prior therapy received and/or response thereto, etc.) the site of delivery of the agent, the nature of the agent, the mode and/or route of administration of the agent, the presence or absence of combination therapy, and other factors known to medical practitioners.
  • relevant features of the indication being treated may include, among other things, one or more of cancer type, stage, location, etc.
  • one or more features of a particular pharmaceutical composition and/or of a utilized dosing regimen may be modified over time (e.g., increasing or decreasing amount of active in any individual dose, increasing or decreasing time intervals between doses, etc.), for example in order to optimize a desired therapeutic effect or response.
  • type, amount, and frequency of dosing of active agents in accordance with the present invention are governed by safety and efficacy requirements that apply when relevant agent(s) is/are administered to a mammal, preferably a human.
  • such features of dosing are selected to provide a particular, and typically detectable, therapeutic response as compared with what is observed absent therapy.
  • an exemplary desirable therapeutic response may involve, but is not limited to, inhibition of and/or decreased tumor growth, tumor size, metastasis, one or more of the symptoms and side effects that are associated with a tumor, as well as increased apoptosis of tumor cells, therapeutically relevant decrease or increase of one or more cell marker or circulating markers and the like.
  • Such criteria can be readily assessed by any of a variety of immunological, cytological, and other methods that are disclosed in the literature.
  • therapeutic dosing regimens may be combined with or adjusted in light of detection methods that assess expression of one or more inducible markers prior to and/or during therapy.
  • a RARA agonist (e.g. , tamibarotene) therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 1 mg/m 2 , 2 mg/m 2 , 3 mg/m 2 , 4 mg/m 2 , 5 mg/m 2 , 6 mg/m 2 , 7 mg/m 2 , 8 mg/m 2 , 9 mg/m 2 , 10 mg/m 2 , 11 mg/m 2 , 12 mg/m 2 , 13 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , or a dose between any two of these values of a RARA agonist (e.g.
  • a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 1 mg/m 2 and 50 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 5 mg/m 2 and 25 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of between 5 mg/m 2 and 15 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of 12 mg/m 2 . In some embodiments, a RARA agonist (e.g. , tamibarotene) therapy regimen comprises a dose of 6 mg/m 2 .
  • a RARA agonist (e.g., tamibarotene) therapy regimen comprises a plurality of doses of a tamibarotene composition.
  • a tamibarotene therapy regimen comprises, for example 2, 5, 10, 20, 30, 60, 90, 180, 365 doses or a number of doses between any two of these values and/or comprises a repeated pattern of doses (e.g. , at least one cycle of two daily doses, which cycle may be repeated, optionally with a period of alternative administration, or optionally no administration, separating different cycles).
  • a tamibarotene therapy regimen is administered twice a day.
  • a tamibarotene therapy regimen is administered once a day. In some embodiments, a tamibarotene therapy regimen comprises a total dose of 6 mg/m 2 to 12 mg/m 2 , divided as twice daily oral dosing.
  • an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, or a dose between any two of these values of a an antibody specific for CD38 (e.g.
  • an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 1 mg/kg and 100 mg/kg. In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 5 mg/kg and 50 mg/kg. In some embodiments, an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a dose of between 10 mg/kg and 20 mg/kg.
  • an antibody specific for CD38 (e.g. , daratumumab) therapy regimen comprises a plurality of doses of a daratumumab composition.
  • a daratumumab therapy regimen comprises, for example 2, 5, 10, 20, 30, 60, 90, 180, 365 doses or a number of doses between any two of these values and/or comprises a repeated pattern of doses (e.g. , at least one cycle of two daily doses, which cycle may be repeated, optionally with a period of alternative administration, or optionally no
  • a daratumumab therapy regimen is administered once a week. In some embodiments, a daratumumab therapy regimen is administered no more than once a week. In some embodiments, a daratumumab therapy regimen is administered once every two weeks. In some embodiments, a daratumumab therapy regimen comprises a total dose of 10 mg/kg to 20 mg/kg no more than once a week.
  • a pharmaceutical composition refers to a mixture of a compound, such as tamibarotene or an antibody specific for CD38, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • a compound such as tamibarotene or an antibody specific for CD38
  • other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates
  • compositions containing a compound may be administered in therapeutically effective amounts by any conventional form and route known in the art including, but not limited to: intravenous, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.
  • a compound can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers or excipients well known in the art.
  • Such carriers permit the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • excipients such as fillers, disintegrants, glidants, surfactants, recrystallization inhibitors, lubricants, pigments, binders, flavoring agents, and so forth can be used for customary purposes and in typical amounts without affecting the properties of the compositions.
  • the excipient is one or more of lactose hydrate, corn starch, hydroxypropyl cellulose and/or magnesium stearate.
  • tamibarotene may be formulated with one or more of lactose hydrate, corn starch, hydroxypropyl cellulose and/or magnesium stearate.
  • the packaged pharmaceutical compositions of the present invention comprise a written insert or label comprising instructions to use the RARA agonist and the antibody targeting CD38 in a subject suffering from a cancer.
  • the instructions may be adhered or otherwise attached to a vessel comprising the RARA agonist and the antibody targeting CD38.
  • the instructions and the vessel comprising the RARA agonist will be separate from one another, but present together in a single package, box or other type of container.
  • the instructions in the packaged pharmaceutical composition will typically be mandated or recommended by a governmental agency approving the therapeutic use of the RARA agonist and the antibody targeting CD38.
  • the instructions may optionally comprise dosing information, the types of cancer for which treatment with the RARA agonist and/or and the antibody targeting CD38 were approved, physicochemical information about the RARA agonist and/or and the antibody targeting CD38; pharmacokinetic information about the RARA agonist and/or and the antibody targeting CD38; or drug-drug interaction information.
  • the instructions direct that the composition be administered to a subject diagnosed as suffering from non-APL AML.
  • the instructions direct that the composition be administered to a subject diagnosed as suffering from non-APL MM.
  • the pharmaceutical composition comprises tamibarotene. In some aspects, the pharmaceutical composition comprises AGN-195183. In some aspects, the pharmaceutical composition comprises daratumumab. In some embodiments, the pharmaceutical composition comprises both tamibarotene and daratumumab.
  • FIG. 1A shows that 72h tamibarotene treatment at a concentration of 50 nmol/L does not induce CD38 expression in a RARA mRNA low cell line, Kasumi (CD38 ).
  • Fig. IB demonstrates that following 72h tamibarotene treatment of RARA mRNA high cell line, MV411, the entire cell population expresses high levels of CD38 (CD38 hl ).
  • OCI-AML3 RARA mRNA high
  • has low CD38 MFI CD38 DIM
  • Fig. ID shows 72h tamibarotene treatment does not induce CD38 expression in another RARA mRNA low cell line, OCI-M1 (CD38 ).
  • CD38 hl induction by tamibarotene can be predicted by RARA mRNA level.
  • Fig. IE shows the level of CD38 mRNA expression detected in each cell line before and after treatment.
  • Fig. IF shows the percentage of CD38 hi cells based on FACS are shown before and after tamibarotene treatment.
  • the APL cell line, NB4 is also shown.
  • Example 2 RARA mRNA predicts NK cell mediated cytotoxicity of AML cell line, MV411, following tamibarotene and daratumumab combination therapy
  • FIGS. 2A-2D are representative images of phase contrast images of RARA mRNA high MV411 cell line in co-culture assay with the following treatment conditions: Fig. 2A) 72h DMSO MV411 cell line pretreatment and 38h co-culture control antibody treatment. Fig.
  • FIG. 2B 72h SY1425 (50nM) MV411 cell line pretreatment and 38h co-culture control antibody treatment.
  • Fig. 2C 72h DMSO MV411 cell line pretreatment and 38h co-culture daratumumab treatment.
  • Fig. 2D 72h SY1425 (50nM) MV411 cell line pretreatment and 38h co-culture daratumumab treatment.
  • Example 3 RARA mRNA level predicts NK cell mediated cytotoxicity of AML cell lines following tamibarotene and daratumumab combination therapy
  • Example 4 NK cell activation in co-culture assay only occurs post tamibarotene and daratumumab combination treatment as determined by NK cell IFN gamma secretion.
  • Interferon gamma (IFNy) secretion is an indication of NK cell activation.
  • IFNy secretion was quantitated 38h post AML cell line and NK cell co-culture following the indicated treatment conditions (Fig. 4).
  • Significantly increased levels of IFNy are observed following combination treatment with tamibarotene and daratumumab only in the RARA mRNA high AML cell lines (MV411 and OCI-AML3) and NK cell co-culture assay in comparison to single agent treatment conditions.
  • MV411 and OCI-AML3 the RARA mRNA high AML cell lines
  • NK cell co-culture assay in comparison to single agent treatment conditions.
  • these are the only cell lines that demonstrate the CD38 hl phenotype following tamibarotene treatment.
  • Example 5 Tamibarotene increases the intensity of CD38 expression in multiple myeloma cells.
  • MM multiple myeloma cell line
  • Fig. 5 A multiple myeloma cell line
  • Fig. 5B dim state
  • Example 6 Tamibarotene increase in CD38 ffl phenotype further sensitizes MM cell line to daratumumab dependent NK cell-mediated cytotoxicity.
  • MM cell lines with tamibarotene will increase sensitivity to CD38 antibody treatment.
  • Fig. 6 demonstrates that following tamibarotene and daratumumab combination treatment, MM IS tumor cell death is increased in comparison to single agent anti-CD38 antibody treatment as quantitated by Annexin V staining.
  • Fig. 7 The multiple myeloma cell line that achieved high CD38 intensity, MM1S, showed strong cell killing in response to combination treatment.
  • Example 7 Tamibarotene induces CD38 ffl phenotype in primary non-APL AML and MPS patient samples.
  • the CD38 induction levels observed for AML patient samples correlated well with results obtained from high RARA RNA AML cell lines (e.g., compare tamibarotene-induced CD38 MFI in patient sample AML_1 with AML cell line MV411 in Fig. 9C-9D).
  • tamibarotene caused an increase in the CD38 hl phenotype similar to that observed in daratumumab-sensitive multiple myeloma cell lines and multiple myeloma patients (e.g., compare patient sample MM_1 with multiple myeloma cell line MM1S in Fig. 9A-9B).
  • the inventors believe that high RARA mRNA AML patients will benefit from a combination treatment of a RARA-specific agonist, such as tamibarotene, and an anti-CD38 antibody, such as daratumumab.
  • Example 8 Tamibarotene Causes a Greater Increase in CD38 Induction than ATRA in AML cell line xenografts having high RARA or IRF8 Levels.
  • ATRA causes a greater induction in CD38 levels than tamibarotene in HL-60 cells, an AML cell lines typically characterized as APL (A Uruno et al., 2011, J Leuk Biol, 90, pp 235-247).
  • APL A Uruno et al., 2011, J Leuk Biol, 90, pp 235-247.
  • MV411 has a high level of RARA mRNA and IRF8 mRNA (i.e., above a threshold), while THP-1 has a high level of IRF-8 mRNA. Kasumi-1 cells are considered to have levels of IRF8 and RARA that are below the threshold.
  • THP-1 cells RPMI1640 medium supplemented with 10% heat inactivated fetal bovine serum and 0.05mM ⁇ -mercaptoethanol
  • MV4-11 cells IMDM medium supplemented with 10% heat inactivated fetal bovine serum
  • Kasumi-1 cells
  • RPMI1640 medium supplemented with 20% heat inactivated fetal bovine serum
  • 37°C in an atmosphere of 5% CO 2 in air.
  • the cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • mice were ⁇ -irradiated (200 rads) 24 h before tumor cell inoculation.
  • Each mouse was inoculated subcutaneously at the right flank region with the appropriate tumor cell line (THP-1 cells: lx 10 7 cells in 0.1 ml of PBS (1:1 Matrigel); MV4-11 cells: 5 x 10 6 cells in 0.1 ml of PBS (1:1 Matrigel); Kasumi-1 cells: 1 x 10 7 cells in 0.1 ml of PBS (1:1 Matrigel)) for tumor development.
  • THP-1 cells lx 10 7 cells in 0.1 ml of PBS (1:1 Matrigel
  • MV4-11 cells 5 x 10 6 cells in 0.1 ml of PBS (1:1 Matrigel
  • Kasumi-1 cells 1 x 10 7 cells in 0.1 ml of PBS (1:1 Matrigel)
  • Treatment with tamibarotene, ATRA or vehicle was started when the mean tumor size reached approximately 100-200 mm 3 .
  • the mice were divided into 3 groups of nine and each was orally administered drug (ATRA 4 mg/kg;
  • tamibarotene 3 mg/kg or vehicle alone BID for up to 28 days.
  • the date of tumor cell inoculation was denoted as day 0.
  • Three mice per group were sacrificed on day 7, 14, and 21 after grouping (4-week study total).
  • Half of the tumor was collected for embedding into a FFPE block for immunohistochemistry staining (IHC), and the other half of tumor was collected for CD38 FACS analysis of the tumor cells.
  • IHC immunohistochemistry staining
  • FFPE blocks were sectioned (3 ⁇ ) on a manual rotary microtome and prepared for IHC staining utilizing a BOND RX autostainer (Leica) following manufacturer's directions and using an anti-CD38 antibody directed against the C-terminus of CD38 (clone SP149; Abeam; Cat. No. abl83326).
  • Antibody was diluted 1:100 in pH 9.0 EDTA buffer and then incubated with tumor slices for 20 minutes. Signal was developed using DAB and the manufacturer's (Leica) Bond Polymer Refine Detection kit.
  • tamibarotene-treated MV4-11 xenograft mice showed a mean fluorescence intensity (MFI) of over 200 with over 80% of the tumor cells being CD38 hi by FACS analysis.
  • MFI mean fluorescence intensity
  • ATRA-treated MV4-11 xenograft mice showed a MFI of slightly over 100 with approximately 70% of the tumor cells being CD38 hl .
  • FIG. 10B Immunohistochemical staining of tumor sections with an anti-CD38 antibody confirmed the surprising and unexpected superiority of tamibarotene over ATRA in this xenograft model (FIG. 10B). This trend became even more pronounced at 3 weeks.
  • FIG. IOC at three weeks, in tamibarotene-treated MV4-11 xenografts, over 60% of the tumor cells remained CD38 hl , with a MFI of around 110, while in ATRA-treated xenografts less than 20% of the tumor cells remained CD38 hi with a MFI of around 50.
  • FIG. 10D shows immunohistochemical staining of tumor cells after three weeks, which confirms the superiority of tamibarotene over ATRA.
  • Example 9 A combination of Tamibarotene and Daratumumab is superior to a combination of ATRA and Daratumumab in inhibiting the growth of an AML cell line xenograft.
  • Subcutaneous MV4-11 xenografts were established in NOD.SCID mice at
  • Example 8 Crown Bioscience (Beijing, China), essentially as described in Example 8.
  • Each mouse was inoculated subcutaneously at the right flank region with MV4-11 tumor cells (5 x 10 6 ) in 0.1 ml of PBS (1 : 1 matrigel) for tumor development.
  • the treatments were started when the mean tumor size reached approximately 50-150 mm 3 .
  • the date of tumor cell inoculation was denoted as day 0.
  • the animals were checked for any effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss (body weights measured twice per week), eye/hair matting and any other abnormal effect.
  • the entire procedures of dosing as well as tumor and body weight measurement was conducted in a Laminar Flow Cabinet.
  • Tamibarotene was formulated by using a DMSO stock solution (30 mg/ml), diluted 1/100 into PBS to make a final solution at 0.3 mg/ml adjusted to pH 8. Tamibarotene was administered at 3 mg/kg in a 10 ml/kg volume PO twice a day for 28 days.
  • ATRA Tretinoin
  • ATRA was formulated by using a DMSO stock solution (40mg/ml), diluted 1/100 into PBS to make a final solution at 0.4 mg/ml adjusted to pH 8.
  • ATRA was administered at 4 mg/kg in a 10 ml/kg volume PO twice a day for 28 days.
  • mice in the combination arm were given the same dosing schedules, volumes, and formulations for each agent.
  • Mice in the vehicle arm were given the same dosing schedules, volumes, and formulations, but lacking SY-1425 or ATRA and daratumumab. Tumor volumes were measured twice weekly over the course of the study.
  • Daratumumab was administered i.v at 1 mg/kg once a week on week 1 and week 3.
  • mice per arm were sacrificed prior to dosing to collect tumor. Each tumor was embedded into FFPE block for H.E. staining, and IHC staining with Human CD38. The remaining tumors were harvested at termination of the study and, each half tumor was embedded into FFPE block as described in the previous example, with the 2 nd half being snap frozen.
  • tumor tissue from different treatment regimens is IHC stained for human CD38.
  • Treatment with SY-1425 alone or in combination with daratumumab shows greater CD38 staining than ATRA alone, ATRA in combination with daratumumab, or vehicle control.
  • Example 10 A combination of Tamibarotene and Daratumumab is superior to a combination of ATRA and Daratumumab in inhibiting the growth of a multiple myeloma cell line xenograft.
  • mice were ⁇ -irradiated (200 rads) 24 h before tumor cell inoculation.
  • Each mouse was inoculated subcutaneously at the right flank region with MM.1S tumor cells (1 x 10 7 ) in 0.1 ml of PBS for tumor development. The treatments were started when the mean tumor size reaches approximately 150 (100-200) mm 3 . The date of tumor cell inoculation was denoted as day 0.
  • Tumor volumes were measured twice per week in two dimensions using a caliper, as described in the previous Example. Dosages and dosing of tamibarotene, ATRA and daratumumab and preparation of tumors for analysis were as described in the previous example. The results of these studies are shown in FIG. 16, where treatment with SY-1425 alone or in combination with daratumumab were the only treatment to demonstrate significant inhibition of MM IS xenograft growth over the vehicle control.
  • Example 11 A combination of Tamibarotene and an anti-mouse CD38 antibody is superior to a combination of ATRA and the anti-mouse CD38 antibody in inhibiting the growth of a lymphocytic leukemia cell line xenograft.
  • L1210 tumor cells were maintained in vitro as suspension culture in DMEM medium supplemented with 10% heat inactivated fetal bovine serum at 37°C in an atmosphere of 5% CO 2 in air. The tumor cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation.
  • Each mouse was inoculated subcutaneously at the right lower flank region with L1210 tumor cells (2xl0 5 ) in 0.1 ml of PBS for tumor development. The treatments were started when the mean tumor size reaches approximately 50-100 mm 3 . The date of tumor cell inoculation is denoted as day 0.
  • Tumor volumes were measured twice per week in two dimensions using a caliper, as described in the previous Example. Dosages and dosing of tamibarotene and ATRA and preparation of tumors for analysis were as described in the previous example.
  • Anti-CD38 (Rat mAb CD38, NIMR-5) was formulated in PBS to a solution of 1 mg/ml. It was administered i.v at 10 mg/kg BIW for 4 weeks.
  • CD38 antibody acting synergistic ally with SY-1425 as compared to with ATRA This can be seen by comparing the difference in effect between SY1425 alone and SY-1425 + anti-CD38 antibody versus the difference between ATRA alone and ATRA + anti-CD38 antibody.
  • the differential decrease in tumor growth caused by adding the anti-CD38 antibody to SY-1425 was greater than the differential decrease caused by adding that antibody to ATRA.
  • Embodiments or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed embodiments is introduced into another embodiment.
  • any embodiment that is dependent on another embodiment can be modified to include one or more limitations found in any other embodiment that is dependent on the same base embodiment.
  • elements are presented as lists, e.g. , in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

L'invention concerne des méthodes qui définissent des populations cellulaires sensibles aux agonistes RARA et identifient des sous-groupes de patients qui bénéficieront d'un traitement avec des agonistes RARA en combinaison avec une autre thérapie, plus spécifiquement une thérapie anti-CD38. L'invention concerne également des compositions pharmaceutiques conditionnées qui comprennent un agoniste RARA et des instructions pour déterminer si cette polythérapie est appropriée pour être utilisée dans un traitement.
PCT/US2018/014904 2017-01-23 2018-01-23 Méthodes de traitement de patients à l'aide d'un agoniste du récepteur alpha de l'acide rétinoïque et d'un anticorps anti-cd38 WO2018136961A1 (fr)

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US11053552B2 (en) 2016-04-08 2021-07-06 Syros Pharmaceuticals, Inc. Methods of stratifying patients for treatment with retinoic acid receptor-α agonists
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10697025B2 (en) 2015-03-31 2020-06-30 Syros Pharmaceuticals, Inc. Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists
US11447831B2 (en) 2015-03-31 2022-09-20 Syros Pharmaceuticals, Inc. Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists
US11053552B2 (en) 2016-04-08 2021-07-06 Syros Pharmaceuticals, Inc. Methods of stratifying patients for treatment with retinoic acid receptor-α agonists
RU2826217C1 (ru) * 2019-11-13 2024-09-05 Тайхо Фармасьютикал Ко., Лтд. Способы лечения заболеваний и нарушений, связанных с lsd1, ингибиторами lsd1

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