WO2020078894A1 - Associations oncothérapeutiques - Google Patents

Associations oncothérapeutiques Download PDF

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Publication number
WO2020078894A1
WO2020078894A1 PCT/EP2019/077764 EP2019077764W WO2020078894A1 WO 2020078894 A1 WO2020078894 A1 WO 2020078894A1 EP 2019077764 W EP2019077764 W EP 2019077764W WO 2020078894 A1 WO2020078894 A1 WO 2020078894A1
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Prior art keywords
dose
kit
crc
treatment
dmmr
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PCT/EP2019/077764
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English (en)
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Adriaan Dirk BINS
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Academisch Medisch Centrum
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • 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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism

Definitions

  • the oncotherapeutic product is a combination product comprising, the Programmed Death 1 (PD-1 ) antagonist agent pembrolizumab and the premature stop codon readthrough agent ataluren useful for the treatment of colorectal cancer (CRC).
  • the oncotherapeutic product is a kit comprising, the PD-1 antagonist agent pembrolizumab and the premature stop codon readthrough agent ataluren useful for the treatment of CRC.
  • the Programmed Death 1 (PD-1 ) receptor and PD-1 ligands 1 and 2 (PD-L1 and
  • PD-L2 PD-L2
  • PD-1 is activated by PD-L1 and PD-L2 expressed by stromal cells, tumor cells, or both, initiating T-cell death and localized immune suppression, potentially providing an immune-tolerant environment for tumor development and growth.
  • inhibition of this interaction can mediate local T-cell responses and enhance antitumor activity in nonclinical animal models.
  • An immune checkpoint inhibitor is a monoclonal antibody (MAb) specifically designed to trigger the immune system’s recognition of proliferating cells in a
  • Certain MAbs such as pembrolizumab bind to the cell PD1 receptor to inhibit binding of the PD-L1 ligand, thus increasing the population of cytotoxic T-cells available to recognize tumor cells for removal.
  • dMMR DNA mismatch repair
  • STR microsatellite Short Tandem Repeats
  • MSI microsatellite instability
  • FSMs frameshift mutations
  • PTC premature termination codons
  • the invention is based on the surprising insight that only 60% of neo-epitopes encoded downstream of insertion-deletion (INDEL) mutations found in coding DNA, as listed in The Cancer Genome Atlas for Colon Adenocarcinoma (TCGA-COAD), were longer than 10 amino acids (AA). Furthermore, only 40% of neo-epitopes were longer than 20AA, as shown in Figure 1 a and Figure 1 b herein. This represents an opportunity to improve the suboptimal response rate of CRC to ICI treatment, as many potentially immunogenic neo-epitopes may have an insufficient length for immune system recognition. Flence, short neo-epitopes cannot be targeted in the anti-tumor immune response. The minimal length required for such neo-epitopes is approximately 10AAs.
  • a combination of cancer immunotherapy with drugs that are capable of elongating short neo-epitopes to longer than 10AAs may potentiate the efficacy of immunotherapy in certain tumor environments.
  • MMR DNA mismatch repair
  • CRC having a deficient MMR (dMMR) process has been found to be moderately responsive to ICI monotherapy while CRC having a proficient MMR (pMMR) process has been found to be refractory to ICI monotherapy.
  • dMMR deficient MMR
  • pMMR proficient MMR
  • pMMR CRC is slightly INDEL enriched in coding DNA compared to other cancers, albeit to a lesser extent than dMMR CRC suggests that neo-epitopes of sufficient length in pMMR CRC are not abundant, resulting in a total amount of peptides insufficient for immune recognition.
  • the combination product or kit presented herein comprising, the ICI drug pembrolizumab and the read-trough-translatory drug ataluren enhances the therapeutic spectrum of ICI treatment for MMR cancers such as a dMMR CRC moderately responsive to ICI monotherapy or a refractory pMMR CRC.
  • one embodiment provided herein is a combination product comprising, a combination of the Programmed Death-1 (PD-1 ) receptor antagonist agent
  • the combination product comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren.
  • the combination product comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren.
  • combination product is for use in the treatment of a mammalian animal. In another preferred embodiment, the combination product is for use in the treatment of a human.
  • the combination product is a kit comprising, a combination of the Programmed Death-1 (PD-1 ) receptor antagonist agent
  • the kit comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren.
  • the kit described herein is prepared for use as a medicament.
  • the kit is for use in the treatment of a mammalian animal.
  • the kit is for use in the treatment of a human.
  • the combination product described herein is for use in the treatment of cancer.
  • the combination product is for use in the treatment of a colorectal cancer (CRC).
  • CRC colorectal cancer
  • the combination product is for use in the treatment of a CRC having a deficient MMR (dMMR) process (i.e., a dMMR CRC).
  • dMMR deficient MMR
  • pMMR proficient MMR
  • pMMR CRC pMMR CRC
  • pMMR CRC pMMR CRC
  • EC endometrial cancer
  • dMMR deficient MMR
  • dMMR EC
  • the combination product is for use in the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • the combination product is for use in the treatment of a dMMR CRC patient nafve to ICI immunotherapy.
  • a method for use of a combination product for the treatment of cancer in a patient in need thereof comprising, administering to the patient a combination product described herein.
  • the method for use of a combination product is for the treatment of colorectal cancer (CRC) in a patient in need thereof comprising, administering to the patient a combination product described herein.
  • the method for use of a combination product is for the treatment of endometrial cancer (EC).
  • the method for use of a combination product is for the treatment of a CRC having a deficient MMR (dMMR) process (i.e., a dMMR CRC).
  • dMMR deficient MMR
  • the method for use of a combination product is for the treatment of a CRC having a proficient MMR (pMMR) process (i.e., a pMMR CRC).
  • the method for use of a combination product is for the treatment of an endometrial cancer (EC) having a deficient MMR (dMMR) process (i.e., a dMMR EC).
  • the method for use of a combination product is for the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • the method for use of a combination product is for the treatment of a dMMR CRC patient nafve to ICI
  • the method for use of the combination product for the treatment of cancer in a patient in need thereof comprises, administering to a mammalian animal a combination product described herein. In another preferred embodiment, the method for use of the combination product for the treatment of cancer in a patient in need thereof comprises, administering to a human a combination product described herein.
  • the kit described herein is for use in the treatment of cancer.
  • the kit is for use in the treatment of a colorectal cancer (CRC).
  • CRC colorectal cancer
  • the kit is for use in the treatment of a dMMR CRC.
  • the kit is for use in the treatment of a pMMR CRC.
  • the kit is for use in the treatment of a dMMR EC.
  • the kit is for use in the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • the kit is for use in the treatment of a dMMR CRC patient na ' fve to ICI immunotherapy.
  • a method for use of a kit is described herein for the treatment of cancer in a patient in need thereof comprising, administering to the patient a kit described herein.
  • the method for use of a kit is for the treatment of colorectal cancer (CRC) in a patient in need thereof comprising, administering to the patient a kit described herein.
  • the method for use of a kit is for the treatment of colorectal cancer (CRC).
  • the method for use of a kit is for the treatment of a CRC having a deficient MMR (dMMR) process (i.e., a dMMR CRC).
  • dMMR deficient MMR
  • the method for use of a kit is for the treatment of a CRC having a proficient MMR (pMMR) process (i.e., a pMMR CRC).
  • pMMR proficient MMR
  • the method for use of a kit is for the treatment of an endometrial cancer (EC) having a deficient MMR (dMMR) process (i.e., a dMMR EC).
  • dMMR deficient MMR
  • the method for use of a kit is for the treatment of a dMMR CRC patient having
  • the method for use of a kit is for the treatment of a dMMR CRC patient na ' fve to ICI immunotherapy.
  • the method for use of the kit for the treatment of cancer in a patient in need thereof comprises, administering to a mammalian animal a kit described herein. In another preferred embodiment, the method for use of the kit for the treatment of cancer in a patient in need thereof comprises, administering to a human a kit described herein.
  • the combination product comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the method for use of a combination product for the treatment of cancer in a patient in need thereof comprises, administering to the patient an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the method for use of a kit for the treatment of cancer in a patient in need thereof comprises, administering to the patient an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the kit comprises, administering an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the effective amount of the PD-1 receptor antagonist agent pembrolizumab to be administered comprises, a single dose of 200 mg pembrolizumab every 3 weeks by injection, preferably by infusion.
  • the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose, wherein the second dose is administered about 6 hours after the first dose, the third dose is administered about 6 hours after the second dose, and a subsequent first dose is administered about 12 hours after the third dose of the preceding day,
  • the first daily dose is selected from the group consisting of 1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day and 10 mg/kg/day.
  • the second daily dose is selected from the group consisting of 1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day and 10 mg/kg/day.
  • the third daily dose is selected from the group consisting of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day and 20 mg/kg/day.
  • the regimen has a first, second and third daily dose selected from 1.25, 1 ,25 and 2.5 mg/kg/day, respectively.
  • the regimen has a first, second and third daily dose selected from 2.5, 2.5 and 5 mg/kg/day, respectively. In another preferred embodiment, the regimen has a first, second and third daily dose selected from 5, 5 and 10 mg/kg/day, respectively.
  • the regimen has a first, second and third daily dose selected from 10, 10 and 20 mg/kg/day, respectively.
  • the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose selected from 10, 10 and 20 mg/kg/day, respectively; wherein, the second dose of 10 mg/kg is administered about 6 hours after the first dose of 10 mg/kg, the third dose of 20 mg/kg is administered about 6 hours after the second dose of 10 mg/kg, and a subsequent first dose of 10 mg/kg is administered about 12 hours after the third dose of 20 mg/kg from the preceding day.
  • the combination product increases the length of one or more neo-epitopes produced during CRC tumorogenesis to enhance immune checkpoint inhibitor (ICI) therapy.
  • ICI immune checkpoint inhibitor
  • the combination product increases the length of one or more neo-epitopes in an amount sufficient to induce complexation with the Major Histocompatibility Complex (MHC).
  • MHC Major Histocompatibility Complex
  • the combination product results in a 50% increase in MHC-neo-epitope complexation rate.
  • the increased length of one or more neo-epitopes is sufficient to induce an immune response by one or more T-cells.
  • the combination product doubles neo-epitope length.
  • the combination product increases the immune response to reduce tumor size.
  • the combination product increases the immune response to induce CRC remission.
  • the combination product increases the immune response to induce remission of immunotherapy refractory CRC.
  • the combination product synergistically enhances ICI treatment than with either agent alone.
  • the kit increases the length of one or more neo-epitopes produced during CRC tumorogenesis to enhance immune checkpoint inhibitor (ICI) therapy.
  • ICI immune checkpoint inhibitor
  • the kit increases the length of one or more neo-epitopes in an amount sufficient to induce complexation with the Major Histocompatibility
  • the kit results in a 50% increase in MHC-neo-epitope complexation rate.
  • the increased length of one or more neo-epitopes is sufficient to induce an immune response by one or more T-cells.
  • the kit doubles neo-epitope length.
  • the kit increases the immune response to reduce tumor size.
  • the kit increases the immune response to induce CRC remission.
  • the kit increases the immune response to induce remission of immunotherapy refractory CRC.
  • kit synergistically enhances ICI treatment than with either agent alone.
  • Figure 1 a shows the frequency distribution of the distance (in number of amino acids [AAs]) between an insertion/deletion (INDEL) FSM and the first PTC on the x-axis, where the left y-axis represents the absolute number of INDEL mutated coding transcripts found in DNA as listed in The Cancer Genome Atlas for Colon
  • Adenocarcinoma (TCGA-COAD).
  • the right y-axis represents the same measurement as a percentage of the total number of INDEL mutated transcripts.
  • Figure 1 b shows the frequency distribution of the distance (in number of AAs) between the first PTC and the second PTC on the x-axis, downstream of INDEL mutations in the TCGA-COAD samples, where the left y-axis represents the absolute number of INDEL mutated coding transcripts in the samples and the right y-axis represents the same measurement as a percentage of the total number of INDEL mutated transcripts.
  • Figure 2 is a graph of mRNA levels of frameshift mutated genes identified by analysis of DNA sequencing data from 71 MSI-H colorectal patients from the TCGA- COAD database, ranked by mutation frequency. Each point represents one mutation in one patient.
  • Figure 3 is a graph of percent of reads of mRNA having frameshift mutations compared to DNA at particular genes of MSI-FI colorectal patients from the TCGA- COAD database identified in Figure 2 has having the highest mRNA levels, ranked by mutation frequency. Each point represents one mutation in one patient.
  • One embodiment provided herein is a combination product comprising, a combination of the Programmed Death-1 (PD-1 ) receptor antagonist agent
  • the combination product comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren.
  • the combination product is for use in the treatment of a mammalian animal. In another preferred embodiment, the combination product is for use in the treatment of a human.
  • kits comprising, a combination of the Programmed Death-1 (PD-1 ) receptor antagonist agent
  • the kit comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon
  • the kit described herein is prepared for use as a medicament.
  • the kit is for use in the treatment of a mammalian animal. In another preferred embodiment, the kit is for use in the treatment of a human.
  • the combination product described herein is for use in the treatment of cancer.
  • the combination product is for use in the treatment of a colorectal cancer (CRC).
  • CRC colorectal cancer
  • the combination product is for use in the treatment of a CRC having a deficient MMR (dMMR) process (i.e., a dMMR CRC).
  • dMMR deficient MMR
  • pMMR proficient MMR
  • the combination product described herein is for use in the treatment of a CRC having a proficient MMR (pMMR) process.
  • combination product is for use in the treatment of an endometrial cancer (EC) having a deficient MMR (dMMR) process (i.e., a dMMR EC).
  • dMMR deficient MMR
  • the combination product is for use in the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • the combination product is for use in the treatment of a dMMR CRC patient nafve to ICI immunotherapy.
  • a method for use of a combination product for the treatment of cancer in a patient in need thereof comprising, administering to the patient a combination product described herein.
  • the method for use of a combination product is for the treatment of colorectal cancer (CRC) in a patient in need thereof comprising, administering to the patient a combination product described herein.
  • the method for use of a combination product is for the treatment of endometrial cancer (EC).
  • the method for use of a combination product is for the treatment of a CRC having a deficient MMR (dMMR) process (i.e., a dMMR CRC).
  • dMMR deficient MMR
  • the method for use of a combination product is for the treatment of a CRC having a proficient MMR (pMMR) process (i.e., a pMMR CRC).
  • the method for use of a combination product is for the treatment of an endometrial cancer (EC) having a deficient MMR (dMMR) process (i.e., a dMMR EC).
  • the method for use of a combination product is for the treatment of a dMMR CRC patient having previously received ICI
  • the method for use of a combination product is for the treatment of a dMMR CRC patient nafve to ICI immunotherapy.
  • the method for use of the combination product for the treatment of cancer in a patient in need thereof comprises, administering to a mammalian animal a combination product described herein. In another preferred embodiment, the method for use of the combination product for the treatment of cancer in a patient in need thereof comprises, administering to a human a combination product described herein.
  • the kit described herein is for use in the treatment of cancer.
  • the kit is for use in the treatment of a colorectal cancer (CRC).
  • CRC colorectal cancer
  • the kit is for use in the treatment of a dMMR CRC.
  • the kit is for use in the treatment of a pMMR CRC.
  • the kit is for use in the treatment of a dMMR EC.
  • the kit is for use in the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • a colorectal cancer CRC
  • the kit is for use in the treatment of a dMMR CRC.
  • the kit is for use in the treatment of a pMMR CRC.
  • the kit is for use in the treatment of a dMMR EC.
  • the kit is for use in the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • the kit is for use in the treatment of a dMMR CRC patient na ' fve to ICI immunotherapy.
  • a method for use of a kit is described herein for the treatment of cancer in a patient in need thereof comprising, administering to the patient a kit described herein.
  • the method for use of a kit is for the treatment of colorectal cancer (CRC) in a patient in need thereof comprising, administering to the patient a kit described herein.
  • the method for use of a kit is for the treatment of colorectal cancer (CRC).
  • the method for use of a kit is for the treatment of a CRC having a deficient MMR (dMMR) process (i.e., a dMMR CRC).
  • dMMR deficient MMR
  • the method for use of a kit is for the treatment of a CRC having a proficient MMR (pMMR) process (i.e., a pMMR CRC).
  • pMMR proficient MMR
  • the method for use of a kit is for the treatment of an endometrial cancer (EC) having a deficient MMR (dMMR) process (i.e., a dMMR EC).
  • dMMR deficient MMR
  • the method for use of a kit is for the treatment of a dMMR CRC patient having
  • the method for use of a kit is for the treatment of a dMMR CRC patient na ' fve to ICI immunotherapy.
  • the method for use of the kit for the treatment of cancer in a patient in need thereof comprises, administering to a mammalian animal a kit described herein. In another preferred embodiment, the method for use of the kit for the treatment of cancer in a patient in need thereof comprises, administering to a human a kit described herein.
  • the combination product comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the method for use of a combination product for the treatment of cancer in a patient in need thereof comprises, administering to the patient an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the method for use of a kit for the treatment of cancer in a patient in need thereof comprises, administering to the patient an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the kit comprises, administering an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the effective amount of the PD-1 receptor antagonist agent pembrolizumab to be administered comprises, a single dose of 200 mg pembrolizumab every 3 weeks by injection, preferably by infusion.
  • the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose, wherein the second dose is administered about 6 hours after the first dose, the third dose is administered about 6 hours after the second dose, and a subsequent first dose is administered about 12 hours after the third dose of the preceding day,
  • the first daily dose is selected from the group consisting of 1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day and 10 mg/kg/day.
  • the second daily dose is selected from the group consisting of 1.25 mg/kg/day, 2.5 mg/kg/day, 5 mg/kg/day and 10 mg/kg/day.
  • the third daily dose is selected from the group consisting of 2.5 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day and 20 mg/kg/day.
  • the regimen has a first, second and third daily dose selected from 1.25, 1 ,25 and 2.5 mg/kg/day, respectively.
  • the regimen has a first, second and third daily dose selected from 2.5, 2.5 and 5 mg/kg/day, respectively.
  • the regimen has a first, second and third daily dose selected from 5, 5 and 10 mg/kg/day, respectively.
  • the regimen has a first, second and third daily dose selected from 10, 10 and 20 mg/kg/day, respectively.
  • the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose selected from 10, 10 and 20 mg/kg/day, respectively; wherein, the second dose of 10 mg/kg is administered about 6 hours after the first dose of 10 mg/kg, the third dose of 20 mg/kg is administered about 6 hours after the second dose of 10 mg/kg, and a subsequent first dose of 10 mg/kg is administered about 12 hours after the third dose of 20 mg/kg from the preceding day.
  • the combination product increases the length of one or more neo-epitopes produced during CRC tumorogenesis to enhance immune checkpoint inhibitor (ICI) therapy.
  • ICI immune checkpoint inhibitor
  • the combination product increases the length of one or more neo-epitopes in an amount sufficient to induce complexation with the Major Histocompatibility Complex (MHC).
  • MHC Major Histocompatibility Complex
  • the combination product results in a 50% increase in MHC-neo-epitope complexation rate.
  • the increased length of one or more neo-epitopes is sufficient to induce an immune response by one or more T-cells.
  • the combination product doubles neo-epitope length.
  • the combination product increases the immune response to reduce tumor size. In another embodiment, the combination product increases the immune response to induce CRC remission.
  • the combination product increases the immune response to induce remission of immunotherapy refractory CRC.
  • the combination product synergistically enhances ICI treatment than with either agent alone.
  • the kit increases the length of one or more neo-epitopes produced during CRC tumorogenesis to enhance immune checkpoint inhibitor (ICI) therapy.
  • ICI immune checkpoint inhibitor
  • the kit increases the length of one or more neo-epitopes in an amount sufficient to induce complexation with the Major Histocompatibility
  • the kit results in a 50% increase in MHC-neo-epitope complexation rate.
  • the increased length of one or more neo-epitopes is sufficient to induce an immune response by one or more T-cells.
  • the kit doubles neo-epitope length.
  • the kit increases the immune response to reduce tumor size.
  • the kit increases the immune response to induce CRC remission.
  • the kit increases the immune response to induce remission of immunotherapy refractory CRC.
  • kit synergistically enhances ICI treatment than with either agent alone.
  • out-of-frame mRNA may have one or more PTCs that result in termination of protein translation and the induction of nonsense mediated decay.
  • PTC protein translation
  • the peptide For the truncated neo-epitope gene product resulting from such translation to be recognized by the immune system, the peptide must be of sufficient length to be bound to Major Histocompatibility Complex (MHC) proteins expressed by antigen presenting cells (APC).
  • MHC Major Histocompatibility Complex
  • MHC has a protein binding groove with restrictive sequence specificity
  • short neo-epitopes having a random sequence produced by an aberrant mRNA in a tumor environment are more unlikely to be complexed with MHC; those having a peptide length of more than about 10AAs are more likely to be complexed with MHC and, thus, may be targeted by T-cells having a receptor specific for the MHC-neo- epitope complex.
  • T-cells having a receptor specific for the MHC-neo- epitope complex.
  • dMMR mCRC is a highly immunogenic tumor 2 .
  • the average response rate for ICIs in solid tumors has been shown to be around 20%. In pMMR mCRC this response rate is below 10%.
  • MAb monoclonal antibody
  • cytotoxic T-cells must be able to distinguish between normal AA sequences (i.e., ’epitopes’) and aberrant AA sequences (i.e.,’neo-epitopes’) in the tumor proteome. T-cells distinguish between epitopes and neo-epitopes since, in contrast to
  • TCGA-COAD data shown in Figure 1 a and Figure 1 b suggest that many potentially immunogenic neo-epitopes may be of insufficient length for complexation with MHC.
  • the minimal length required for any peptide to bind an MHC isomer is approximately 10 AAs. Since MHC has considerable sequence specificity, a random sequence of 10 AAs or less is very unlikely to bind MHC. Further, since MHC binding is proportional to neo-epitope length, longer neo-epitopes may increase the amount of MHC-neo-epitope complexes with the consequence of a greater immune response in the presence of an ICI.
  • Figure 1 a shows that only 60% of the neo-epitopes encoded downstream of INDEL mutations (in coding DNA) were longer than 10 AAs. Only 40% were longer than 20 AAs.
  • Figure 1 b shows that the potential elongation of neo-epitopes up to the second PTC results in a median increase of just under 20 AA. Hence this should roughly double the size of such neo-epitopes and make them capable of immune recognition.
  • pMMR mismatch repair proficient
  • an increase in neo- epitope length is expected to increase MHC-neo-epitope complexation and thereby increase immune recognition, thus enabling treatment of CRC currently refractory to immunotherapy.
  • the combination of the ICI pembrolizumab with the readthrough agent ataluren may elongate neo-epitopes, increase the amount of MHC-neo-epitope complexes and may engage an increased cytotoxic T-cell population in an anti-cancer response to potentiate the benefit of cancer immunotherapy.
  • Pembrolizumab (Keytruda ® ) is a potent and highly selective humanized
  • mAb monoclonal antibody of the lgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
  • mAb monoclonal antibody
  • Keytruda as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults, as monotherapy for the treatment of locally advanced or metastatic NSCLC in adults whose tumors express PD-L1 with a >1 % TPS and who have received at least one prior chemotherapy regimen.
  • Ataluren TranslarnaTM is an orally administered, non-aminoglycoside, ribosomal readthrough translation enhancing small molecule designed to allow the protein making apparatus (the ribosome) in cells to skip over (i.e., readthrough) a premature stop codon (PTC), allowing translation of the sequence downstream of a PTC in mRNA transcripts.
  • PTC premature stop codon
  • the presence of a readthrough agent may enable the translation of additional out-of-frame code.
  • Ataluren has received conditional marketing authorization from the European Commission to treat Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older.
  • combination product and kit embodiments described herein include:
  • a combination product comprising, a combination of the Programmed Death-1 (PD-1 ) receptor antagonist agent pembrolizumab and the premature stop codon readthrough agent ataluren.
  • PD-1 Programmed Death-1
  • a method for use of the combination product for the treatment of cancer in a patient in need thereof comprising, administering the combination product to the patient, wherein the cancer is selected from the group consisting of colorectal cancer (CRC) and endometrial cancer (EC).
  • CRC colorectal cancer
  • EC endometrial cancer
  • the CRC is selected from the group consisting of a CRC having a deficient MMR (dMMR) process (dMMR CRC), a CRC having a proficient MMR (pMMR) process (pMMR CRC); and, wherein the EC is selected from an EC having a deficient MMR (dMMR) process (dMMR EC).
  • dMMR deficient MMR
  • pMMR proficient MMR
  • EC is selected from an EC having a deficient MMR (dMMR) process (dMMR EC).
  • the method for use wherein the patient is selected from the group consisting of a mammalian animal and a human.
  • the method for use, wherein the combination product comprises an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of cancer in a patient in need thereof comprising, administering the combination product to the patient.
  • the method for use, wherein the effective amount of the PD-1 receptor antagonist agent pembrolizumab to be administered comprises, a single dose of 200 mg pembrolizumab every 3 weeks by infusion.
  • the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose, wherein the second dose is administered about 6 hours after the first dose, the third dose is administered about 6 hours after the second dose, and a subsequent first dose is administered about 12 hours after the third dose of the preceding day,
  • the method for use wherein the regimen has a first, second and third daily dose selected from 1.25, 1 ,25 and 2.5 mg/kg/day, respectively.
  • the method for use wherein the regimen has a first, second and third daily dose selected from 2.5, 2.5 and 5 mg/kg/day, respectively.
  • the method for use, wherein the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose selected from 10, 10 and 20 mg/kg/day, respectively; wherein, the second dose of 10 mg/kg is administered about 6 hours after the first dose of 10 mg/kg, the third dose of 20 mg/kg is administered about 6 hours after the second dose of 10 mg/kg, and a subsequent first dose of 10 mg/kg is administered about 12 hours after the third dose of 20 mg/kg from the preceding day.
  • a kit comprising, a combination of the Programmed Death-1 (PD-1 ) receptor antagonist agent pembrolizumab and the premature stop codon readthrough agent ataluren.
  • PD-1 Programmed Death-1
  • kits wherein the kit is prepared for use as a medicament.
  • kits for the treatment of cancer in a patient in need thereof
  • kits comprising, administering the kit to the patient, wherein the cancer is selected from the group consisting of colorectal cancer (CRC) and endometrial cancer (EC).
  • CRC colorectal cancer
  • EC endometrial cancer
  • the CRC is selected from the group consisting of a CRC having a deficient MMR (dMMR) process (dMMR CRC), a CRC having a proficient MMR (pMMR) process (pMMR CRC); and, wherein the EC is selected from an EC having a deficient MMR (dMMR) process (dMMR EC).
  • dMMR deficient MMR
  • pMMR proficient MMR
  • EC is selected from an EC having a deficient MMR (dMMR) process (dMMR EC).
  • kit wherein the patient is selected from the group consisting of a mammalian animal and a human.
  • kit wherein the kit comprises an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for the treatment of cancer in a patient in need thereof comprising, administering the kit to the patient.
  • kits wherein the effective amount of the PD-1 receptor antagonist agent pembrolizumab to be administered comprises, a single dose of 200 mg
  • the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose, wherein the second dose is administered about 6 hours after the first dose, the third dose is administered about 6 hours after the second dose, and a subsequent first dose is administered about 12 hours after the third dose of the preceding day,
  • kits wherein the regimen has a first, second and third daily dose selected from 1.25, 1 ,25 and 2.5 mg/kg/day, respectively
  • kits wherein the regimen has a first, second and third daily dose selected from 2.5, 2.5 and 5 mg/kg/day, respectively.
  • kits wherein the regimen has a first, second and third daily dose selected from 5, 5 and 10 mg/kg/day, respectively.
  • kits wherein the regimen has a first, second and third daily dose selected from 10, 10 and 20 mg/kg/day, respectively.
  • the effective amount of the premature stop codon readthrough agent ataluren comprises, a regimen having a first, second and third daily dose selected from 10, 10 and 20 mg/kg/day, respectively; wherein, the second dose of 10 mg/kg is administered about 6 hours after the first dose of 10 mg/kg, the third dose of 20 mg/kg is administered about 6 hours after the second dose of 10 mg/kg, and a subsequent first dose of 10 mg/kg is administered about 12 hours after the third dose of 20 mg/kg from the preceding day.
  • the term“about” means a range around a given value wherein the resulting value is substantially the same as the expressly recited value. In one embodiment,“about” means within 25% of a given value or range. For example, the phrase“about 70% by weight” comprises at least all values from 52% to 88% by weight. In another embodiment, the term“about” means within 10% of a given value or range. For example, the phrase“about 70% by weight” comprises at least all values from 63% to 77% by weight. In another embodiment, the term“about” means within 7% of a given value or range. For example, the phrase“about 70% by weight” comprises at least all values from 65% to 75% by weight.
  • the terms“therapies” and“therapy” can refer to any protocol(s), method(s), compositions, formulations, and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a condition or disorder or one or more symptoms thereof ⁇ e.g., one or more symptoms or one or more conditions associated therewith).
  • the terms“therapies” and“therapy” refer to drug therapy such as chemotherapy, adjuvant therapy, radiation, surgery, biological therapy, supportive therapy, antiviral therapy and/or other therapies useful in treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof ⁇ e.g., one or more symptoms or one or more conditions associated therewith).
  • the term“therapy” refers to a therapy other than the combination product or kit described herein.
  • a therapy refers to a therapy other than a treatment using the combination product or kit described herein.
  • a therapy includes the use of the combination product or kit described herein as an adjuvant therapy.
  • a drug therapy such as chemotherapy, biological therapy, surgery, supportive therapy, antiviral therapy and/or other therapies useful in treatment, management, prevention, or amelioration of a condition or disorder or one or more symptoms thereof ⁇ e.g., one or more symptoms or one or more conditions associated therewith).
  • human infant refers to a newborn to 1 year old year human.
  • the term“human toddler” refers to a human that is 1 year to 3 years old.
  • human child refers to a human that is 1 year to 18 years old.
  • human adult refers to a human that is 18 years or older.
  • the term“middle-aged human” refers to a human between the ages of 30 and 64.
  • yielderly human refers to a human 65 years or older.
  • the term“subject” may be used interchangeably with the term “patient” where both terms refer to an individual being administered a therapy as described herein.
  • the individual is a human.
  • the term“effective amount” in the context of administering the combination product or kit described herein to a subject having a dMMR mCRC, dMMR mEC, or pMMR mCRC refers to that amount of the combination product or kit described herein
  • an “effective amount” of the combination product or kit described herein refers to an amount of the combination product or kit which is sufficient to achieve at least one, two, three, four or more of the beneficial or therapeutic effects described herein.
  • premature stop codon readthrough agent refers to the small molecule compound ataluren having demonstrated translational readthrough of PTCs, enabling the synthesis and expression of full-length functional proteins at sufficient levels to achieve therapeutic benefit.
  • W02004/091502 discloses ataluren and its use for translational readthrough of PTCs.
  • PD-1 receptor antagonist refers to a compound capable of blocking or reducing the interaction of PD-L1 on tumor cells while enhancing T-cell interaction with the PD-1 receptor
  • TILs tumor-infiltrating lymphocytes
  • PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control.
  • the normal function of PD-1 expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions.
  • PD-1 (encoded by the gene Pdcdl ) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).
  • PD-L1 Binding of PD-L1 to PD-1 inhibits T-cell activation triggered through the T-cell receptor.
  • PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory
  • PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.
  • healthy organs express little (if any) PD-L1 , a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.
  • PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (Mel). This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention.
  • dMMR microsatellite stable
  • dMMR CRC patients can be included whether they are treatment na ' fve or have had one or more prior chemotherapy regimens. For medical reasons, certain pMMR CRC patients can be included if they have received two or more prior chemotherapy regimens. For medical reasons, dMMR EC patients can be included if they have received one prior chemotherapy regimen.
  • the effective ataluren dose is determined in 2-4 dose escalation cohorts of 3 patients each, who will then receive pembrolizumab at a fixed dose of 200 mg i.v. every 21 days in combination with 3 days oral ataluren continuously. In all cohorts the ataluren dose will be based on body weight according to a standard regimen.
  • Ataluren will be dosed at 25% of body weight (2.5 mg/kg morning dose; 2.5 mg/kg midday dose; 5 mg/kg evening dose); the second cohort will be dosed at 50% of body weight (5 mg/kg morning dose; 5 mg/kg midday dose; 10 mg/kg evening dose) and the third cohort will be dosed at 100% body weight (10 mg/kg morning dose; 10 mg/kg midday dose; 20 mg/kg evening dose).
  • Pembrolizumab will be administered at a fixed dose of 200 mg i.v. every 21 days.
  • Cohort A may include up to 20 dMMR CRC or EC patients and Cohort B may include up to 15 pMMR CRC patients; each Cohort will be treated with the combination product or kit (pembrolizumab combined with ataluren) in an open label Phase 2 pilot design.
  • CTLA-4 anti-cytotoxic T lymphocyte antigen-4
  • anti-PD1 monoclonal antibodies will be excluded.
  • the study is designed to evaluate the toxicity and the treatment benefit of pembrolizumab combined with ataluren.
  • the added benefit of ataluren will be assessed by case-matched comparison of the results of this trial with those of the pembrolizumab metastatic melanoma (mMel) trial (ClinicalTrials.gov Identifier NCT01876511 ).
  • NCT01876511 patients with comparable characteristics were treated with pembrolizumab only.
  • the study protocol described herein is analogous to the
  • the primary endpoints for Cohorts A and B are the immune-related progression- free survival (irPFS) rate at 21 weeks and the immune-related objective response rate (irORR) assessed using immune-related response criteria (irRC); the irPFS is defined as the proportion of subjects alive and free of disease progression at 21 weeks as determined by irRC; the irORR is defined as the proportion of subjects whose best overall response is a Complete Response (CR) or Partial Response (PR). The results within each cohort will be assessed separately.
  • irPFS immune-related progression- free survival
  • irORR immune-related objective response rate assessed using immune-related response criteria
  • dMMR tumors will be defined using standard clinical criteria and require at least two loci to be evaluable 1 .
  • Patient immune and clinical responses will be evaluated through the following methods at baseline and during treatment using: i). tumor biopsies; ii). peripheral blood lymphocytes; iii). serum and plasma; and. iv). CT scan.
  • Patients who have a confirmed CR by two scans > 6 weeks apart and who have been on combined pembrolizumab/ataluren treatment for at least 6 months may discontinue the treatment after completing at least two cycles beyond the initial determination of CR.
  • the pembrolizumab/ataluren treatment may be resumed upon disease recurrence in these patients.
  • the study will determine immune-related progression free survival (irPFS) rate at 21 weeks and objective response rate (irORR) at 30 weeks in patients with dMMR mCRC, pMMR mCRC and dMMR mEC treated with pembrolizumab combined with ataluren using immune related Response Criteria (irRC).
  • the use of ataluren is intended to synergistically augment the efficacy of pembrolizumab without additional toxicity in dMMR mCRC, pMMR mCRC and dMMR mEC, wherein use of ataluren may enhance the therapeutic spectrum of pembrolizumab to include pMMR mCRC.
  • the study will also be used to: i). Determine the overall survival of patients with dMMR mCRC, pMMR mCRC and dMMR mEC treated with pembrolizumab combined with ataluren; ii). Estimate irPFS and PFS in patients with dMMR mCRC, pMMR mCRC and dMMR mEC treated with pembrolizumab combined with ataluren at 30 weeks using irRC and RECIST 1.1 iii). Estimate best overall response rate and disease control rate in patients with dMMR mCRC, pMMR mCRC and dMMR mEC treated with
  • pembrolizumab combined with ataluren iv. Assess safety and characterize toxicities of pembrolizumab combined with ataluren in patients with dMMR mCRC, pMMR mCRC and dMMR mEC; v). Compare the outcomes of the present primary and secondary study objectives with a series of case-matched controls treated within the
  • the study will also be used to: i). Compare mRNA levels in the tumor before and after start of ataluren; ii). Assess tumor tissue for disease stability over the course of treatment using next generation sequencing technology; iii). Compare archived tumor and polyp tissue (when available) obtained at baseline and after treatment failure;
  • NCT01295827 evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities were observed.
  • NCT01295827 showed evidence of pembrolizumab target engagement and objective evidence of tumor size reduction at all Q2W dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg). No MTD has been identified to date. The highest NCT01295827 dose tested 10.0 mg/kg will be the dose and schedule utilized in Cohorts A, B, C and D of the protocol herein to test for initial tumor activity. Recent data from other pembrolizumab clinical studies have shown that a lower dose and a less frequent schedule may be sufficient for target engagement and clinical activity.
  • NCT01295827 PK data analysis of pembrolizumab administered Q2W and Q3W showed a slower systemic clearance, limited volume of distribution, and a long half-life (refer to pembrolizumab IB).
  • Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement was durable (>21 days). This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing schedule.
  • a population PK analysis has been performed using serum concentration time data from 476 patients.
  • clearance and volume parameters of pembrolizumab were found to be dependent on body weight.
  • the relationship between clearance and body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and would support both body weight normalized dosing or a fixed dose across all body weights.
  • Pembrolizumab has been found to have a wide therapeutic range based on NCT01295827. The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established exposure margins of 0.5 - 5.0 for pembrolizumab in the melanoma indication.
  • the exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure).
  • the population PK evaluation revealed that there was no significant impact of tumor burden on exposure.
  • exposure was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between different indication settings.
  • pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients; ii). the flat exposure-response relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W; iii). the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as assessed by the population PK model); and, iv). the assumption that the dynamic of pembrolizumab target engagement will not vary meaningfully with tumor type.
  • pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide exposures that i). are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks; ii). will maintain individual patient exposures in the exposure range established in melanoma as associated with maximal efficacy response; and, iii). will maintain individual patient’s exposure in a range established in NCT01295827 that are well tolerated and safe.
  • a fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to reduce potential for dosing errors.
  • a fixed dosing scheme will also reduce complexity in the logistical chain at treatment facilities and reduce wastage.
  • nmDMD Duchenne muscular dystrophy
  • the nephrosis primarily involved the distal nephron and was characterized by degenerative changes and epithelial cell proliferation in association with renal tubular dilatation and proteinaceous material in the tubules.
  • the renal finding was reversible and no drug-related effects on the kidney were observed in rats dosed for 24 months or in dogs dosed for 52 weeks despite achievement of exposures in rats and dogs that were comparable to or greater than those observed in mice.
  • dogs dosed for > 20 weeks lymphohistiocytic infiltrates with adjacent foci of parenchymal degeneration in sites of corticosteroid production were observed; sites of mineralocorticoid production were unaffected.
  • the histologic findings in the adrenal gland were not reversible up to 8 weeks following chronic administration. Functional findings included an increase in serum basal
  • Ataluren had no effect on male and female fertility in rats. Ataluren was not teratogenic in rats and rabbits; fetal toxicity and postnatal development effects were observed only at doses which resulted in maternal toxicity. Maternal administration of ataluren in rats had no effect on reproduction of offspring and on embryo/fetal development in the next generation. Ataluren is not genotoxic. No ataluren-related tumors were observed in a 26-week carcinogenicity study conducted in a transgenic mouse model (Tg.rasH2 mice). Tumors observed in rats occurred at exposures that exceeded clinical exposure and were not considered relevant to humans. The completed toxicology program supports dosing in patients >2 years old.
  • a juvenile toxicology program in dogs is ongoing, and when completed, will bridge to the completed toxicology program and will support dosing in neonates and older patients.
  • Findings vacuum of the ganglion cell, optic fiber and inner nuclear layers of the retina
  • Findings not present in the completed toxicology program which supports dosing in patients > 2 years of age were observed in the 28-day dose range finding study in neonatal dogs.
  • the endpoints are similar to the endpoints in the pembrolizumab NCT01876511 trial, with minor adaptations to accommodate the new Q3W treatment regimen.
  • dMMR EC patients can be included after one metastatic treatment (instead of two metastatic or non-metastatic chemotherapy treatments required in the NCT01876511 trial).
  • NCT01876511 study facilitates case-matched cross-trial comparisons of the results of both studies.
  • Phase-1 / Dose Escalation 6-12 patients with histologically proven metastatic or locally advanced deficient mismatch repair (dMMR) colorectal adenocarcinoma (CRC), dMMR endometrial carcinoma (EC) or mismatch repair proficient (pMMR) CRC.
  • dMMR metastatic or locally advanced deficient mismatch repair
  • CRC colorectal adenocarcinoma
  • EC dMMR endometrial carcinoma
  • pMMR mismatch repair proficient
  • Cohort A 20 patients with histologically proven metastatic or locally advanced deficient mismatch repair (dMMR) colorectal adenocarcinoma (CRC) or dMMR
  • dMMR histologically proven metastatic or locally advanced deficient mismatch repair
  • CRC colorectal adenocarcinoma
  • dMMR histologically proven metastatic or locally advanced deficient mismatch repair
  • Cohort B 15 patients with histologically proven metastatic or locally advanced pMMR CRC.
  • a subject must have at least one lesion with measurable disease as defined by 10 mm in longest diameter for a soft tissue lesion or 15mm in short axis for a lymph node by RECIST 1.1 and irRC criteria for response assessment.
  • a subject must have received at least 1 prior cancer therapy regimen for metastatic EC.
  • a subject must have: i). Received at least 2 prior cancer therapy regimens for metastatic or non-metastatic CRC; ii). A life expectancy of greater than 3 months; and, ii). Normal organ and marrow function.
  • QD OD once daily oral dose
  • Q3W three doses/week
  • PBZ pembrolizumab
  • Phase 1 the dose of ataluren will be escalated according to the dose scheme outlined in Table 2, wherein the subgroup minimally requires three patients, each dosed based on body weight at the indicated percentage of the approved 10,10,20 regimen.
  • Phase 1 patients will start treatment in a staged approach.
  • the start dates of the study treatment for the included patients will be spaced minimally 3 weeks apart.
  • Dose limiting toxicity (DLT) will be evaluated after 28 days (Cycle 0 and Cycle 1 ).
  • Pembrolizumab treatment (200 mg) should be administered on Day 1 of each cycle (except Cycle 0) as a 30 minute IV infusion every 3 weeks.
  • Discontinuation of study treatment may be considered for subjects who have attained a confirmed CR after having been treated for at least 24 weeks with the ataluren/pembrolizumab combination product or kit and had at least two treatment cycles beyond the date when the initial CR was declared.
  • Subjects who then experience radiographic disease progression may be eligible for up to one year of additional treatment with the combination product or kit if: i). no cancer treatment was
  • Treatment with the combination product or kit is expected to trigger immune- mediated responses, which require activation of the immune system prior to the observation of clinical responses.
  • immune activation may take weeks to months to be evident.
  • Some patients may have objective volume increase of tumor lesions or other disease parameters within weeks following the start of the treatment. Such patients may not have had sufficient time to develop the required immune activation or, in some patients, tumor volume or other disease parameter increases may represent infiltration of lymphocytes into the original tumor.
  • tumor volume or relevant laboratory parameter increases during the first 2-4 months of the study would constitute PD and lead to discontinuation of imaging to detect response, thus disregarding the potential for subsequent immune-mediated clinical response.
  • tumor assessments will be made using RECIST 1.1 and immune-related RECIST criteria (irRC). Subjects that meet the above criteria and continue on study therapy must discontinue the treatment if there are no signs of disease stabilization by 7 months using irRC.
  • Cohort A will enroll 20 patients; Cohort B will enroll 15 patients. For Cohort A and Cohort B, there will be 1 final analysis for irPFS and 1 final analysis for irORR.
  • irORR immune-related Response Criteria
  • irORR will be estimated as the proportion of subjects whose best overall response is either a CR or PR with corresponding 95% Cl.
  • a non-responder to therapy are those patients who drop out of the study due to toxicity and do not have a follow-up scan.
  • the formal statistical testing for irORR will take place only if 21 -week irPFS is determined to be statistically significant. Therefore, an adjusted alpha for two co-primary endpoints will not be used.
  • the case-matching will be performed on the following variables at the time of last infusion (or first day of last cycle for oral treatment) of the previous study: i). Toxicity; ii). Progression as reason for discontinuation; iii). Number of previous treatment groups administered; iv). Age; ii). ECOG performance status; v). RAS status for colon patients (mutant / wildtype); vi). LDH levels (normal / above upper limit of normal); and, vii). Synchronous/metachronous (>6 months) metastatic disease.
  • Data will be compared between groups for primary and secondary outcomes using chi-squared tests for categorical variables.
  • the irORR results will be case-matched and compared with the irORR results from the NCT01876511 study.
  • a pilot study has determined that a 50% power is sufficient to detect a 20% irORR rate in the pMMR patients at an alpha of 5%.
  • the irPFS results will be case-matched and compared with the irPFS results from the NCT01876511 study.
  • a pilot study has determined that a 50% power is sufficient to detect a 25% % increase in the irPFS rate at 21 weeks at an alpha of 5%.
  • OS Overall survival
  • PFS Progression Free Survival
  • ORR Objective Response Rate
  • BOR Best Overall Response
  • DCR is the proportion of patients with CR, PR, or SD.
  • the Date of Objective Response Rate is defined as the time between the date of initial complete or partial response to the date of the first documented tumor progression or death due to any cause. Subjects who neither progress nor die will be censored on the date of their last assessment.
  • the Time to Objective Response is defined as the time from the first day of study treatment to the date of the first documented CR or PR. DOOR and TTOR will be evaluated for responsive patients (CR or PR) only.
  • RECIST version 1.1 (As published in the European Journal of Cancer 3 ) will be used for assessment of tumor response in this study. While either CT or MRI may be utilized, as per RECIST 1.1 , CT is the preferred imaging technique in this study. In addition, volumetric analysis will be explored by central review for response
  • Neoplastic masses that can be precisely measured in 2 in-plane perpendicular diameters. Both its longest diameter and its longest perpendicular must be greater than or equal to 10 mm. Lymph nodes must have a short-axis line-length of > 15 mm.
  • Malignant lymph nodes must be measurable in 2 perpendicular diameters. Both its longest diameter and its longest perpendicular must be greater than or equal to 15 mm. The quantitative endpoint will be defined as the product of the longest diameter with its longest perpendicular.
  • Non-measurable lesions are those that are not suitable for quantitative
  • the SPD of the index lesions and of new, measurable lesions are added together to provide the total time-point tumor burden.
  • irSD Stable Disease
  • irPD Progressive Disease
  • use of the combination product or kit described herein for preventing, treating or ameliorating a dMMR mCRC, dMMR mEC, or pMMR mCRC inhibits proliferation or reduces an in vitro or in vivo proliferating cell or cell line population by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 80%, 85%, 90%, 95 %, or 100% relative to proliferation or in vitro or in vivo proliferating cell or cell line population prior to use of the combination product or kit described herein, as assessed by methods well known in the art.
  • use of the combination product or kit described herein for preventing, treating or ameliorating a dMMR mCRC, dMMR mEC, or pMMR mCRC inhibits proliferation or reduces an in vitro or in vivo proliferating cell or cell line population in a range of from about 5% to about 20%, 10% to 30%, 15% to 40%, 15% to 50%, 20% to 30%, 20% to 40%, 20% to 50%, 30% to 60%, 30% to 70%, 30% to 80%, 30% to 90%, 30% to 95%, 30% to 99%, or from about 40% to about 100%, or any range in between, relative to proliferation or in vitro or in vivo proliferating cell or cell line population prior to use of the combination product or kit described herein, as assessed by methods well known in the art.
  • the combination product is a kit comprising, a combination of a Programmed Death-1 (PD-1 ) receptor antagonist agent
  • the kit comprises, an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon
  • the kit described herein is prepared for use as a medicament.
  • the kit is for use in the treatment of a mammalian animal.
  • the kit is for use in the treatment of a human.
  • the kit described herein is for use in the treatment of cancer.
  • the kit is for use in the treatment of a colorectal cancer (CRC).
  • CRC colorectal cancer
  • the kit is for use in the treatment of a dMMR CRC.
  • the kit is for use in the treatment of a pMMR CRC.
  • the kit is for use in the treatment of a dMMR EC.
  • the kit is for use in the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • a colorectal cancer CRC
  • the kit is for use in the treatment of a dMMR CRC.
  • the kit is for use in the treatment of a pMMR CRC.
  • the kit is for use in the treatment of a dMMR EC.
  • the kit is for use in the treatment of a dMMR CRC patient having previously received ICI immunotherapy.
  • the kit is for use in the treatment of a dMMR CRC patient na ' fve to ICI immunotherapy.
  • a method for use of a kit is described herein for the treatment of cancer in a patient in need thereof comprising, administering to the patient a kit described herein.
  • the method for use of a kit is for the treatment of colorectal cancer (CRC) in a patient in need thereof comprising, administering to the patient a kit described herein.
  • the method for use of a kit is for the treatment of colorectal cancer (CRC).
  • the method for use of a kit is for the treatment of a CRC having a deficient MMR (dMMR) process (i.e., a dMMR CRC).
  • dMMR deficient MMR
  • the method for use of a kit is for the treatment of a CRC having a proficient MMR (pMMR) process (i.e., a pMMR CRC).
  • pMMR proficient MMR
  • the method for use of a kit is for the treatment of an endometrial cancer (EC) having a deficient MMR (dMMR) process (i.e., a dMMR EC).
  • dMMR deficient MMR
  • the method for use of a kit is for the treatment of a dMMR CRC patient having
  • the method for use of a kit is for the treatment of a dMMR CRC patient na ' fve to ICI immunotherapy.
  • the kit comprises, administering an effective amount of the PD-1 receptor antagonist agent pembrolizumab and an effective amount of the premature stop codon readthrough agent ataluren for use in the treatment of a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • a cancer selected from the group consisting of a colorectal cancer (CRC) and an endometrial cancer (EC).
  • the kit increases the length of one or more neo-epitopes produced during CRC tumorogenesis to enhance immune checkpoint inhibitor (ICI) therapy.
  • ICI immune checkpoint inhibitor
  • the kit increases the length of one or more neo-epitopes in an amount sufficient to induce complexation with the Major Histocompatibility
  • the kit results in a 50% increase in MHC-neo-epitope complexation rate.
  • the increased length of one or more neo-epitopes is sufficient to induce an immune response by one or more T-cells.
  • the kit doubles neo-epitope length. In another embodiment, the kit increases the immune response to reduce tumor size.
  • the kit increases the immune response to induce CRC remission.
  • the kit increases the immune response to induce remission of immunotherapy refractory CRC.
  • kit synergistically enhances ICI treatment than with either agent alone.
  • the kit may contain each agent in one or more containers. Additionally, one or more other therapies useful for the treatment of a dMMR mCRC, dMMR mEC, or pMMR mCRC, or other relevant agents can also be included in the kit.
  • the kit may contain instructions printed with information to aid the patient in taking the combination product doses including, but not limited to, the product name for each agent and approved uses, the relative order of use for each agent, instructions for when and how to administer the agents and the dose required for therapeutic benefit.
  • the kit may contain a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency for manufacture, use or sale for human administration.
  • FSM frameshift mutation
  • a dataset of mutations is required for the analysis, having a sample id, a mutated gene id, the location of the mutation on the chromosome (start, stop) and the mutation subtype.
  • the pPS defines the exact position of the mutation within the cDNA of the corresponding transcript, the position of the mutation in the normal reading frame of the transcript and the strand where the mutation is located, calculating the shift in reading frame resulting from the mutational length and subtype, which is either an insertion or a deletion.
  • the Script checks every codon in the adjusted reading frame one by one, starting from the mutation locus, to determine the presence of a PTC. Upon finding a first PTC (PTC1 ), the Script continues to run until the presence of a second PTC (PTC2) is localized. The data obtained was formatted as a tab delimited file.
  • the raw data was imported into a Microsoft Excel file used to calculate absolute and percent counts of transcripts containing specific PTCs, distances from PTC1 to PTC2 and their corresponding means, as shown in Figures 1 a and 1 b, the cumulative number of mutated transcripts are referenced on the x-axis with distances between FSMs and PTCs ( Figure 1 a) and distances between PTC1 -PTC2 greater than a specific number of AAs shown on the y-axis ( Figure 1 b).
  • microsatellites in MSI colorectal carcinoma was identified as follows. This was done in order to identify loci where ataluren is likely to affect frame shifting in such populations. Frameshifted mutated loci were identified in coding DNA in DNA sequencing data from 71 MSI-H colorectal cancer patients from the TCGA-COAD database.
  • the frameshifted loci that were found to appear the most frequently in that database were in the following genes: BRAF, AC004687-2-RNF 43, ACVR2A, DOCK3, BMPR2, ZBTB20, LARP4B, QKI, USP35, MVK, RAB28, SETD18, SVIL, AL031847-2-RPL22, CCR5, PLEKHA6, HNRNPL, MECOM, and NFASC.
  • Loci with the highest RNA levels identified in Figure 2 with levels above the dotted line shown in that figure (specifically, AC004687-2-RNF-43, ACVR2A, BMR2, LAP4B, QKI, USP35, MVK, RAB28, SETD1 B, SVIL, AL031847-2-RPL22, CCR5, PLEKHA6, HNRNPL, and MECOM), were studied further.
  • a phase 1 dose escalation study is conducted as follows to determine the MTD of ataluren. 6 to 12 subjects with histologically proven metastatic or locally advanced deficient mismatch repair (dMMR) colorectal adenocarcinoma (CRC), dMMR
  • dMMR histologically proven metastatic or locally advanced deficient mismatch repair
  • CRC colorectal adenocarcinoma
  • EC endometrial carcinoma
  • pMMR mismatch repair proficient
  • Each subject has received at least 1 prior cancer therapy regimen for metastatic EC.
  • the effective ataluren dose is determined in 2-4 dose escalation cohorts of at least 3 subjects each, who then receive pembrolizumab at a fixed dose of 200 mg i.v. every 21 days in combination with 3 days oral ataluren continuously. In all cohorts the ataluren dose is based on body weight according to a standard regimen.
  • Ataluren is dosed at 25% of body weight (2.5 mg/kg morning dose; 2.5 mg/kg midday dose; 5 mg/kg evening dose); the second cohort is dosed at 50% of body weight (5 mg/kg morning dose; 5 mg/kg midday dose; 10 mg/kg evening dose) and the third cohort is dosed at 100% body weight (10 mg/kg morning dose; 10 mg/kg midday dose; 20 mg/kg evening dose).
  • DLT Dose limiting toxicity
  • a phase 2 part two study is conducted on two cohorts of patients in which each patient receives pembrolizumab combined with ataluren dosed at the MTD of ataluren determined from the study described in Example 2.
  • Pembrolizumab is administered at a fixed dose of 200 mg i.v. every 21 days.
  • the two cohorts of patients are as follows:
  • Cohort A 20 patients with histologically proven metastatic or locally advanced deficient mismatch repair (dMMR) colorectal adenocarcinoma (CRC) or dMMR endometrial carcinoma (EC)
  • dMMR histologically proven metastatic or locally advanced deficient mismatch repair
  • CRC colorectal adenocarcinoma
  • EC dMMR endometrial carcinoma
  • Cohort B 15 patients with histologically proven metastatic or locally advanced pMMR CRC.

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Abstract

L'invention concerne un produit oncothérapeutique utile pour le traitement du cancer. Dans un mode de réalisation préféré, le produit oncothérapeutique est un produit d'association ou un kit comprenant du pembrolizumab, l'agent antagoniste du récepteur de mort programmée 1 (PD-1), et de l'ataluren, l'agent de translecture de codon d'arrêt prématuré, utiles pour le traitement du cancer colorectal.
PCT/EP2019/077764 2018-10-15 2019-10-14 Associations oncothérapeutiques WO2020078894A1 (fr)

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