WO2022147150A1 - Treatment of malignant solid tumors - Google Patents
Treatment of malignant solid tumors Download PDFInfo
- Publication number
- WO2022147150A1 WO2022147150A1 PCT/US2021/065545 US2021065545W WO2022147150A1 WO 2022147150 A1 WO2022147150 A1 WO 2022147150A1 US 2021065545 W US2021065545 W US 2021065545W WO 2022147150 A1 WO2022147150 A1 WO 2022147150A1
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- WO
- WIPO (PCT)
- Prior art keywords
- cancer
- poziotinib
- subject
- her2
- patient
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Definitions
- This patent document relates to treatment of cancer with poziotinib or a pharmaceutically acceptable salt thereof.
- EGFR and HER2 mutations including exon 20 insertion mutations, have been identified in a variety of cancer types. Treatments that specifically target HER2 overexpression have been shown to be clinically beneficial to patients with breast cancer and several targeted therapies have been approved by the FDA for treatment of patients with NSCLC and breast cancer. Similarly, there are investigations of FDA-approved EGFR targeting agents in HER2 overexpressed and mutant colorectal, head and neck, and pancreatic cancers.
- An aspect of the document provides a method for treating malignant solid tumors in a subject, wherein the subject has been determined to have one or more EGFR or HER2 activating mutations.
- the method generally includes administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof to the subject, which has been determined to have one or more EGFR or HER2 activating mutations.
- the cancer is selected from breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
- the cancer is metastatic.
- the cancer is advanced. In some embodiments, the subject has been determined to be HER2 negative with HER2 activating mutations. In some embodiments, the subject has been determined to be HER2 positive with HER2 activating mutations. In some embodiments, the cancer is breast cancer, colorectal cancer, or high-grade glioma, including Grade 3 and 4 glioblastoma multiforme. In some embodiments, the cancer is grade 4 glioblastoma multiforme.
- the subject’s tumor has been determined to be HER2 -positive with HER2 activating mutation, and the subject has been treated with an anti-cancer agent, and the cancer has progressed during the treatment.
- the subject has been treated with one or more anti-cancer agents selected from HER2 targeted agent, alkylating agent, anthracycline, anti-metabolite, microtubule inhibitor, motor inhibitor, immunotherapy, hormonal (anti-estrogen) agent, aromatase inhibitor, PIK3CA inhibitor, anti -bone metastasis agent, immune checkpoint inhibitor, and any combination thereof.
- the cancer has developed resistance to the one or more anti-cancer agents.
- the anticancer agents are selected from the group consisting of trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents, including but not limited to cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); pemetrexed; ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan or any combination thereof.
- the cancer is breast cancer.
- the cancer is non-small cell lung cancer.
- the subject has been determined to be HER2 negative with HER2 activating mutations.
- the subject has been determined to be HER2 -positive and has been treated with one or more anti-cancer agents, and the cancer has progressed during the treatment. In some embodiments, the cancer has developed resistance to the one or more anti-cancer agents.
- the anti-cancer agent is selected from the group consisting of pembrolizumab, nivolumab, nivolumab, ipilimumab, trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents including but not limited to cisplatin, 5-flouriuricil oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan or any combination thereof, or any combination thereof.
- the cancer is colorectal cancer.
- the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain.
- the subject has been determined to have one or more HER2 activating mutations selected from S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R.
- HER2 activating mutations include HER2 exon 20 insertions in kinase domain.
- the subj ect has been determined to have high-grade glioma with
- the subject has been determined to have solid tumors with EGFR activating mutations, wherein the subject may or may not have NSCLC or highgrade glioma).
- the EGFR activating mutations are located in extracellular and / or transmembrane, including for example, EGFRvIII, R108K, R222C, A289T, P596L, G598V.
- the EGFR activating mutations are located in kinase domain, including for example, EGFRvIII, R108K, R222C, A289T, P596L, G598V, Exon 20 insertions, E709K, G719X, V742I, E746_A750del, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V.
- kinase domain including for example, EGFRvIII, R108K, R222C, A289T, P596L, G598V, Exon 20 insertions, E709K, G719X, V742I, E746_A750del, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V.
- the subject has not received chemotherapy, biologies, immunotherapy, HER2 targeted therapy, curative-intent radiotherapy for the treatment of the cancer.
- Poziotinib or the pharmaceutically acceptable salt thereof is administered as a first line of therapy.
- the poziotinib or the pharmaceutically acceptable salt thereof is administered orally.
- the subject is administered the hydrochloride salt of the poziotinib.
- the poziotinib or the pharmaceutically acceptable salt thereof is administered at a daily dose of 5-25 mg.
- the subject is administered the hydrochloride salt of the poziotinib at a daily dose of about 8 mg, about 12 mg, about 16 mg, about 18 mg, about 20 mg, or about 24 mg.
- the poziotinib or the pharmaceutically acceptable salt thereof is administered daily.
- the poziotinib or the pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered twice a day (e.g. 6 mg BID, 7 mg BID, 8 mg BID, etc). In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered on a continuous basis. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered on 28 day cycles.
- the method further includes administering an additional anti- cancer therapy.
- the additional anti-cancer therapy is chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy or immunotherapy.
- the poziotinib or the pharmaceutically acceptable salt thereof and / or anti-cancer therapy are administered intravenously, subcutaneously, intraosseously, orally, transdermally, in sustained release, in controlled release, in delayed release, as a suppository, or sublingually.
- Another aspect of the patent document provides a method of reducing adverse events in treating a subject with cancer.
- the method includes administering twice a day or administering intermittently a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 25 mg.
- the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 14 mg to about 26 mg.
- a hydrochloride salt of the poziotinib is administered.
- the poziotinib or a pharmaceutically acceptable salt is administered at a selected dose and frequency so that at least 15 continuous days of administration is achieved before a first drug interruption. In some embodiments, the poziotinib or a pharmaceutically acceptable salt is administered at a selected dose and frequency so that drug interruption is reduced by at least 15% in comparison with same daily dosage of QD (once a day) administration.
- Figure 1 shows an example study design diagram.
- Figure 2 shows the schedule of study assessments and procedures.
- Figure 3 shows the treatment cycle in a clinical study on treatment of breast cancer.
- Figure 4 shows key baseline characteristics of the patients with breast cancer.
- Figure 5 summarizes prior therapy for the patients with breast cancer.
- Figure 6 shows Poziotinib drug exposure in two cohorts of clinical study.
- Figure 7 summarizes the efficacy of clinical study of breast cancer treatment with poziotinib.
- ORR Overal Response Rate
- DCR Disease Control Rate
- PFS Progression-free Survival
- DoR Duration of Response.
- the Evaluable Population consists of all patients who are enrolled, complete at least one cycle of poziotinib treatment, and have at least one evaluable postbaseline tumor response evaluation using RECIST, vl. l Results are derived by Sponsor based on RECIST, vl. l, and include criteria: CR/PR requires confirmation scan that is >4 weeks from previous scan; and Patient needs to be on-treatment for >6 weeks when SD is evaluated.
- Figure 8 shows progression-free survival in the clinical study.
- Figure 9 shows swimmers plot in the clinical study.
- Figure 10 shows adverse events in two cohorts of clinical study.
- poziotinib exhibits improved efficacies in patients with certain EGFR or HER2 activating mutations.
- the term “about” as used herein generally refers to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 20” may mean from 18 to 22. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.
- the term “and/or” includes any and all combinations of one or more of the associated listed items. Expressions such as "at least one of,” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list. When referring to a dosing protocol, the term “day”, “per day” and the like, refer to a time within one calendar day which begins at midnight and ends at the following midnight.
- the term “daily dosage” as used herein generally refers to the total amount of poziotinib or a pharmaceutically acceptable salt thereof administered during the same day. When the poziotinib or a pharmaceutically acceptable salt thereof is administered more than once during the same day, the daily dosage is generally splitted equally among the multiple administrations.
- high grade glioma include grades III or IV. In high grade glioma, the tumors are fast-growing, and they spread quickly through brain tissue, which makes them hard to treat.
- treating means: (1) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
- treating or treatment and rate of success for a treatment can be evaluated by such measurements as (a) Progression-free Survival (PFS) defined herein as the time from first dose administration of therapeutic intervention in a clinical trial to disease progression or death from any cause; (b) Objective Response Rate (ORR ) defined herein as proportion of patients with a tumor size reduction of a predefined amount and for a minimum period of time using RECIST vl.l criteria; Disease Control Rate (DCR) defined herein as the percentage of patients with advanced or metastatic cancer who have achieved either a complete response, partial response or stable disease to a therapeutic intervention in clinical trials of anticancer agents; Overall Survival (OS) Rate defined herein as the percentage of people in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease; Time to Progression (TTP) define herein as the length of time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the
- advanced cancer refers to a cancer where definitive treatment such as surgical resection or radiation therapy of the solid tumor cannot provide a cure, and other therapies are unlikely to control or cure the disease
- metalastatic refers to the spread of cancer cells from the place where they first formed to another part or parts of the body.
- the term "effective amount” as used herein means that amount of a drug or pharmaceutical agent that will elicit the biological or clinical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
- therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
- the term also includes within its scope amounts effective to enhance normal physiological function. Specific doses can be readily determined by one having ordinary skill in the art, using routine procedures
- pharmaceutically acceptable carrier and/or excipient refers to a carrier and/or excipient pharmacologically and/or physiologically compatible to a subject and an active component.
- a pharmaceutically acceptable carrier includes, without limitation, pH regulators, surfactants, adjuvants, and ionic strength enhancers.
- pH regulators include, without limitation, phosphate buffer solutions; surfactants include, without limitation, cationic, anionic or nonionic surfactants, for example, Tween-80;
- ionic strength enhancers include, without limitation, sodium chloride.
- resistant in the context of cancer treatment refers to a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents (e.g., any agent described herein).
- salts means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
- Non-limiting examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as acetic acid, embonic acid, aspartic acid, besylic acid, camsylic acid, edisylic acid, 1,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, 2-naphthalenesulfonic acid,
- Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
- Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide.
- Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-m ethylglucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
- subject used interchangeable with “patient” refers to a mammal with a condition or disease that is associated with overexpression of EGFR (HER1) or HER2 or any mutant thereof, who would benefit from the administration of poziotinib or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof comprising additionally a pharmaceutically acceptable carrier and/or excipient.
- EGFR activating mutations or “HER2 mutation” refers to kinase domain mutations in EGFR or HER2. These mutations lead to a ligand-independent activation of tyrosine kinase activity.
- HER2 -positive refers to the overexpression of the human epidermal growth factor receptor-2 (HER2) gene.
- wild-type refers to a polypeptide or polynucleotide sequence that occurs in a native population without genetic modification.
- a mutant includes a polypeptide or polynucleotide sequence having at least one modification to an amino acid or nucleic acid compared to the corresponding amino acid or nucleic acid found in a wild-type polypeptide or polynucleotide, respectively. Included in the term mutant is Single Nucleotide Polymorphism (SNP) where a single base pair distinction exists in the sequence of a nucleic acid strand compared to the most prevalently found (wild-type) nucleic acid strand.
- SNP Single Nucleotide Polymorphism
- An aspect of this patent document provides a method of cancer of solid tumor in a subject who has been determined to be HER2 positive or have one or more EGFR or HER2 activating mutations.
- the method includes administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject.
- Poziotinib is an oral, quinazoline-based pan-HER inhibitor that irreversibly blocks signaling through the EGFR family of tyrosine-kinase receptors, including human epidermal growth factor receptor (HERl/ErbBl/EGFR), HER2 (ErbB2), and HER4 (ErbB4), as well as HER receptor mutations. This, in turn, leads to inhibition of the proliferation of tumor cells that overexpress these receptors. It is well established that several malignancies, including lung, breast, gastric, colorectal, head, and neck, and pancreatic carcinomas, are associated with a mutation in or overexpression of members of the EGFR receptor family.
- poziotinib or a pharmaceutically acceptable salt thereof can lead to the inhibition of the proliferation of tumor cells that overexpress these receptors.
- the chemical formula of poziotinib is l-[4-[4-(3,4-dichloro-2-fluorophenylamino)- 7-methoxyquinazolin-6-yloxy]-piperidin-l-yl]prop-2-en-l-one shown below.
- the pharmaceutically acceptable salt may be an inorganic acid salt, an organic acid salt, or a metal salt.
- the inorganic acid salt may be a salt of hydrochloric acid, hydrobromic acid phosphoric acid, sulfuric acid, or disulfuric acid.
- the organic acid salt may be a salt of malic acid, maleic acid, citric acid, fumaric acid, besylic acid, camsylic acid, or edisylic acid.
- the metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt.
- Poziotinib may be a hydrochloride in the form of a tablet.
- Poziotinib or a pharmaceutically acceptable salt thereof may be in a crystalline form or amorphous form and can be administered in a daily dose of 0.1 mg to 50 mg.
- Non-limiting examples of the cancer of solid tumor include breast cancer, colorectal cancer, gastric cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), head and neck cancer, bladder cancer, pancreatic cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, gastric cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer and skin cancer.
- the cancer is metastatic.
- the cancer is breast cancer.
- the patient has HER2-positive or HER2 -negative breast cancer with HER2 activating mutations.
- the cancer is breast cancer or lung cancer, and the subject has been determined to be HER2-positive and has been treated with an anti-cancer agent and the cancer has progressed during the treatment, wherein the anti-cancer agent can be trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents including but not limited to cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan or any combination thereof.
- the anti-cancer agent can be trastuzumab, pertuzumab,
- the cancer is colorectal cancer or lung cancer.
- the cancer is colorectal cancer
- the subject has been determined to be HER2-positive and has been treated with an anti-cancer agent, and the cancer has progressed during the treatment, wherein the anti-cancer agent can pembrolizumab, nivolumab, nivolumab, ipilimumab, trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents including but not limited to cisplatin, 5-flouriuricil oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; ten
- poziotinib may exhibit improved efficacy in comparison with conventional anti-cancer agents.
- the activating mutation may be located at Furin-like extracellular region, transmembrane, and / or kinase domain.
- Non-limiting examples of EGFR activating mutations include EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, V742I, E746_A750del, L747X, A750P, S768VV769L, S768VV774M, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V and exon 20 insertions.
- the cancer patient has been determined to have one, two, three, four, five, or more of the EGFR activating mutations selected from EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, V742I, E746_A750del, L747X, A750P, S768I/V769L, S768VV774M, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V.
- the EGFR activating mutations selected from EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD,
- the cancer patient has been determined to have one, two, three, four, five, or more of the EGFR activating mutations selected from EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, G719X, V742I, E746_A750del, , S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V.
- the EGFR activating mutations selected from EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, G719X, V742I, E746_A750del, , S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V.
- Non-limiting examples of EGFR exon mutations as activating mutations include M766_A767insASV, A767insASV, A767insTLA, A767_V769dupASV, V769_D770insASV, V769_D770insGSV, V769_D770insGVV, V769_D770insSAVS, V769_D770insSLRD, V769_H773>LDNPNPH, V769_D770insE, V769_D770insGTV, V769_D770insGVM, V769_N771dupVDN, D770_N771insSVD, D770>GY, D770_N771insG, D770_N771insY, D770_N771insNPG, N771_P772insT, D770_N771insGL, D770_N771insSVG, D
- the cancer patient has been determined to have one, two, three, four, five, or more of the EGFR activating mutations.
- Non-limiting examples of HER2 activating mutations include S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, L869R, and exon 20 insertions.
- Non-limiting examples of HER2 mutations as activating mutations include A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, A775_G776insYVMS, A775_G776insAVMA, A775_G776insSVMA, A775_G776insC, Y772_V773insM, Y772dupYVMA, Y772_A775dup, A775_G776insI, G776delinsVC,
- the cancer patient has been determined to have one, two, three, four, five, or more of the HER2 activating mutations.
- the cancer patient has been determined to have one, two, three, four, five, or more activating mutations selected from S310F, 1655 V, L755X, I767M, D769X, V777X, L786V, V842I, and L869R.
- the cancer patient has been determined to have one, two, three, four, five, or more activating mutations selected from S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R.
- the cancer patient has been determined to have at least one, two, three, or more activating mutations selected from T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R. In some embodiments of any method disclosed herein, the cancer patient has been determined to have at least one, two, three, or more activating mutations selected from I655V, V659E, R678Q, and V697L.
- the cancer patient has been determined to have at least one, two, three, or more activating mutations selected from I655V, V659E, R678Q, and V697L. In some embodiments of any method disclosed herein, the cancer patient has been determined to have at least S310F and/or S310Y. In some embodiments of any method disclosed herein, the patent has been determined to be free from T798M or T798I in HER2 or T790M in EGFR. In some embodiments of any method disclosed herein, the patient has been determined to be free from any of T798M and T798I in HER2 and T790M in EGFR.
- the patient sample can be any bodily tissue or fluid that includes nucleic acids from the cancer in the subject.
- the sample will be a blood sample comprising circulating tumor cells or cell free DNA.
- the sample can be a tissue, such as a breast or colorectal tissue.
- the breast or colorectal tissue can be from a tumor tissue and may be fresh frozen or formalin-fixed, paraffin- embedded (FFPE).
- Wild-type or mutant EGFR and HER2 can be identified by DNA amplification and sequencing techniques, DNA and RNA detection techniques, including, without limitation, Northern and Southern blot, respectively, and/or various biochip and array technologies or in-situ hybridization.
- DNA and RNA detection techniques including, without limitation, Northern and Southern blot, respectively, and/or various biochip and array technologies or in-situ hybridization.
- a variety of techniques can be used in the analysis including, without limitation, immunodiagnostic techniques such as ELISA, Western blot or immunocytochemistry.
- the determination may use a next generation sequencing diagnostic test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay, or by an FDA approved test (e.g., cobas® EGFR mutation test v2 or therascreen EGFR RGQ PCR kit) performed by a US CLIA certified and locally licensed clinical laboratory or similarly accredited lab for ex-US sites using tissue samples.
- OCA OncoMine Comprehensive Assay
- FDA approved test e.g., cobas® EGFR mutation test v2 or therascreen EGFR RGQ PCR kit
- tissue samples mutations can be determined from a patient’s biological sample, such as plasma.
- sequence analysis can be performed using techniques known in the art including, without limitation, sequence analysis, and electrophoretic analysis.
- sequence analysis include Maxam-Gilbert sequencing, Sanger sequencing, capillary array DNA sequencing, thermal cycle sequencing (Sears etal., 1992), solid-phase sequencing (Zimmerman etal., 1992), sequencing with mass spectrometry such as matrix-assisted laser desorption/ionization time- of-flight mass spectrometry (MALDI-TOF/MS; Fu et al., 1998), and sequencing by hybridization (Chee et al., 1996; Drmanac et al., 1993; Drmanac et al., 1998).
- MALDI-TOF/MS matrix-assisted laser desorption/ionization time- of-flight mass spectrometry
- Non-limiting examples of electrophoretic analysis include slab gel electrophoresis such as agarose or polyacrylamide gel electrophoresis, capillary electrophoresis, and denaturing gradient gel electrophoresis. Additionally, next generation sequencing methods can be performed using commercially available kits and instruments from companies such as the Life Technologies/Ion Torrent PGM or Proton, the Illumina HiSEQ or MiSEQ, and the Roche/454 next generation sequencing system.
- nucleic acid analysis can include direct manual sequencing (Church and Gilbert, 1988; Sanger etal., 1977; U.S. Patent No. 5,288,644); automated fluorescent sequencing; single-stranded conformation polymorphism assays (SSCP) (Schafer etal., 1995); clamped denaturing gel electrophoresis (CDGE); two-dimensional gel electrophoresis (2DGE or TDGE); conformational sensitive gel electrophoresis (CSGE); denaturing gradient gel electrophoresis (DGGE) (Sheffield et al., 1989); denaturing high performance liquid chromatography (DHPLC, Underhill et al., 1997); infrared matrix-assisted laser desorption/ionization (IR-MALDI) mass spectrometry (WO 99/57318); mobility shift analysis (Orita et al., 1989); restriction enzyme analysis (Flavell et al., 1978; Geever et al., 1981); quantitative real
- Another aspect provides a method of treating a cancer of solid tumor in a subject comprising administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has been determined to be HER2 positive.
- Non-limiting examples of cancers include the cancer is selected from the group consisting of breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer, bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
- the cancer is metastatic.
- the cancer is breast cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is stage IV breast cancer, which has spread beyond the breast and nearby lymph nodes to other parts of the body. The subject may or may not have CNS (e.g., brain) metastases.
- CNS e.g., brain
- the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. In some embodiments, the subject has been determined to have one or more EGFR activating mutations.
- HER2 and EGFR activating mutations are as described above.
- the subject has previously received at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or more lines of therapy.
- therapy include chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti- angiogenic therapy, or immunotherapy.
- the subject has previously received at least two HER2 therapies.
- the subject has previously received at least trastuzumab and optionally one or more additional therapies.
- the subject has previously received at least trastuzumab and TDM1.
- the subject has previously received at least trastuzumab, TDM1, pertuzumab, and optionally one or more additional therapies.
- Nonlimiting examples of additional lines of therapies of anticancer agents include lapatinib and neratinib.
- the method includes administering the poziotinib or a pharmaceutically acceptable salt thereof once, twice, or three times a day.
- a daily dosage of 10, 12, 14, 16 mg of poziotinib or a pharmaceutically acceptable salt thereof can be administered once or twice a day.
- a daily dosage of 24 mg of poziotinib or a pharmaceutically acceptable salt thereof can be administered once, twice or three times a day for two weeks followed by a drug holiday or rest of one week when no poziotinib or a pharmaceutically acceptable salt thereof is administered.
- poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (10 mg BID) at a daily dosage of 20 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (9 mg BID) at a daily dosage of 18 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (8 mg BID) at a daily dosage of 16 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (7 mg BID) at a daily dosage of 14 mg.
- poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (6 mg BID) at a daily dosage of 12 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (5 mg BID) at a daily dosage of 10 mg.
- the methods of this patent document can also be applied to treating or preventing CNS metastases in a subject, wherein the subject has been diagnosed to have a cancer.
- the method includes administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof.
- the CNS metastases is brain metastases.
- the scope and range of EGFR and HER2 mutations, the cancers, the prior therapies, the additional/auxiliary therapies, the administration schedule and the suitable patient populations are as described above.
- Another aspect provides a method of reducing adverse events in treating a subject with cancer, comprising administering twice or three times a day a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 15 mg to about 25 mg.
- the method includes administering the poziotinib or a pharmaceutically acceptable salt twice a day with a daily dosage of about 16 mg or about 24 mg.
- the method includes administering the poziotinib or a pharmaceutically acceptable salt once or twice a day with a daily dosage of about 24 mg for two weeks followed by a week of no administration.
- adverse events include diarrhea, rash, stomatitis, and pneumonitis.
- the adverse event is grade 3 or higher level.
- the method also effectively reduces drug interruptions.
- Drug interruption is one or more days of a drug-free period after continuous daily administration of the drug.
- a medical professional is able to determine whether a drug interruption is necessary based on factors such as side effect, toxicity and other factors.
- the method reduces drug interruption by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 55% in comparison with same daily dosage of QD (once a day) administration. .
- the method prolongs the length to first drug interruption with median days to first interruption ranging from 10 to 50 days including for example at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29 and at least 30 days.
- the method provides delayed first interruption by 1-20 days including at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, and at least 12 days in comparison with same daily dosage of QD (once a day) administration. .
- the method provides median days to first dose reduction of at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, or at least 60 days.
- the scope and range of EGFR and HER2 mutations, the cancers, the prior therapies, the additional/auxiliary therapies, the administration schedule and the suitable patient populations are as described above.
- Non-limiting examples of cancers are as described above.
- the cancer is metastatic.
- the cancer is breast cancer.
- the cancer is metastatic breast cancer.
- the cancer is stage IV breast cancer.
- the cancer is non-small cell lung cancer.
- the subject has been diagnosed to have one or more HER2 and EGFR activating mutations, non-limiting examples of which are as described above.
- the subject has previously received one, two, three or more lines of therapy for the cancer.
- the subject may have previously received at least trastuzumab and optionally one or more additional therapies.
- the subject has previously received at least trastuzumab and TDM1.
- the subject has previously received at least trastuzumab, TDM1, pertuzumab, and optionally one or more additional therapies.
- the subject in the methods described herein is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein).
- the subject is in need of enhancing an immune response.
- the subject is, or is at risk of being, immunocompromised.
- the subject is undergoing or has undergone a chemotherapeutic treatment and/or radiation therapy.
- the subject is, or is at risk of being, immunocompromised as a result of an infection.
- the subject is human.
- the methods disclosed herein are applicable to patent with or without prior cancer treatment.
- the subject has not received chemotherapy, biologies, immunotherapy, HER2 targeted therapy, curative-intent radiotherapy for the treatment of the cancer.
- the patient has not received a systemic treatment.
- the patient has not received treatment with a different anti-cancer agent.
- the patient has not been administered a tyrosine kinase inhibitor (TKI) for cancer treatment.
- TKI tyrosine kinase inhibitor
- the patient has not been administered poziotinib or EGFR or HER2 exon 20 insertion mutation-selective TKIs.
- the patient has received a systemic treatment, which has developed resistance to the treatment.
- the patient has received treatment with a different anti-cancer agent, which has developed resistance to the anti-cancer agent.
- the patient has been administered a tyrosine kinase inhibitor (TKI) for the treatment, which has developed resistance to the treatment with the TKI.
- the patient has been administered poziotinib or EGFR or HER2 exon 20 insertion mutation-selective TKIs for the treatment, which has developed resistance to the treatment with the TKI.
- the cancer is breast cancer or colorectal cancer.
- the poziotinib of a pharmaceutically acceptable salt thereof such as poziotinib hydrochloride salt, may be administered orally, such as in a tablet.
- the poziotinib may be administered in a dose of 4-25 mg, such as at a dose of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 mg.
- the dosing may be daily, every other day, every 3 days, or weekly.
- the dosing may be on a continuous schedule, such as on 28 days cycles.
- the poziotinib of a pharmaceutically acceptable salt thereof can be used in combination with at least one additional therapy.
- the additional therapy may be radiation therapy, surgery (e.g., lumpectomy and a mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing.
- the additional therapy may be in the form of adjuvant or neoadjuvant therapy.
- the additional therapy is the administration of a small molecule enzymatic inhibitor or anti-metastatic agent.
- the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence and/or severity of side effects of treatment, such as anti -nausea agents, etc.).
- the additional therapy is radiation therapy.
- the additional therapy is surgery.
- the additional therapy is a combination of radiation therapy and surgery.
- the additional therapy is gamma irradiation.
- the additional therapy is therapy targeting PBK/AKT/mTOR pathway, HSP90 inhibitor, tubulin inhibitor, apoptosis inhibitor, and/or chemopreventative agent.
- the additional therapy may be one or more of the chemotherapeutic agents known in the art.
- Non-limiting examples of anti-cancer agent or therapy include alkylating agents: Busulfan, dacarbazine, ifosfamide, hexamethylmelamine, thiotepa, dacarbazine, lomustine, chlorambucil, procarbazine, altretamine, estramustine phosphate, mechlorethamine, streptozocin, temozolomide, Semustine cyclophosphamide; platinum agents: spiroplatin, tetraplatin, ormaplatin, iproplatin, ZD-0473 (AnorMED), oxaliplatin carboplatin, lobaplatin (Aeterna), satraplatin (Johnson Matthey), BBR-3464 (Hoffmann-La Roche), SM-11355 (Sumitomo), AP-5280 (Access), cisplatin, arboplatin, cisplatin, satraplatin, oxaliplatin, oxa
- Non-limiting examples of the anti-cancer agents include bevacizurnab, bortezomib, capecitabine, cetuximab, fluorouracil, imatinib, irinotecan, leucovorin, oxaliplatin, panitumumab, pemetrexed, temozolomide, cisplatin, paclitaxel, erlotinib, sunitinib, lapatinib, sorafenib, carboplatin, doxorubicin, docetaxel, gemcitabine, etoposide, gefitinib, PD153035, cetuximab, bevacizurnab, panitumumab, trastuzumab, anti-c-Met antibodies, gefitinib, ZD6474, EMD-72000, pariitumab, ICR- 62, CI-1033, lapatinib, AEE788, E
- anticancer agents include alkylating agents, such as thiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophy cins (particularly cryptophycin 1 and cryptophycin 8);
- the anti-cancer agents are selected from HER2 targeted agent, alkylating agent (e.g. Cyclophosphamide), anthracyclines (e.g., Doxorubicin, Doxil (liposomal doxy), Epirubicin), anti-metabolite (e.g. Capecitabine (Xeloda), Fluorouracil, Gemcitabine, Methotrexate) microtubule inhibitor (Docetaxel, Paclitaxel, Eribulin, Ixabepilone, Vinorelbine), mTOR inhibitor (e.g. Afinitor), immunotherapy (e.g.
- Atezolizumal hormonal (anti-estrogen) agent
- hormonal (anti-estrogen) agent e.g. Tamoxifen (SERMS - blockers), Toremifene, Fulvestrant (degrader or SERDs), Ethinylestradiol, Flucxymesterone, Megestrol lacetate), aromatase inhibitor (e.g. Anastrozole, Letrozole, Exemestane), PIK3CA inhibitor (e.g. Alpelisib), anti-bone metastasis agent (Zoledronic acid, Pamidronate, denosumab), and immune checkpoint inhibitor.
- these agents are used for the treatment of breast cancer.
- Non-limiting examples of Her2-targeted agents include trastuzumab, pertuzumab, lapatinib, neratinib, Fam-traz deruxtecan-nki, T-DM1 and Trastuzumab and substitutes (Kanjinti, Ogivri, Herzuma, Ontruzant, Trazimera), and antibody-drug conjugate thereof (e.g. Trastuzumab duocarm azine).
- Non-limiting examples of checkpoint inhibitors include inhibitors of PD-1, PD-L1, CTLA4 and TIGIT (T cell immunoglobulin and ITIM domain).
- Ipilimumab (Yervoy®; blocking a checkpoint protein called CTLA-4); pembrolizumab (Keytruda®), Cemiplimab (Libtayo) and nivolumab (Opdivo®) (targeting another checkpoint protein called PD- 1); atezolizumab (Tecentriq®), Avelumab (Bavencio), and Durvalumab (Imfinzi) (targeting PD-L1); MK-7684, Etigilimab /OMP-313 M32, Tiragolumab/MTIG7192A/RG-6058, BMS-986207, AB-154 and ASP-8374 (targeting TIGIT).
- Further examples include Irinotecan, Nivolumab, Ipilimumab, Oxaliplatin, Cetuximab, Panitumumab, Dabrafenib, Trametinib, Encorafenib, Bevacizumab, 5-FU, Capecitabine, Pembrolizumab, Ramucirumab, and Ziv-aflibercept.
- these agents are used for the treatment of colorectal cancer.
- agent for chemotherapy examples include SHP2 inhibitors (e.g. RMC-4550 and RMC-4630), phosphatase inhibitors (e.g. Tautomycin), CDK 4/6 inhibitors (abemaciclib (Lilly), palbociclib (Pfizer)) and protein-protein interaction disruptors (BI 1701963).
- SHP2 inhibitors e.g. RMC-4550 and RMC-4630
- phosphatase inhibitors e.g. Tautomycin
- CDK 4/6 inhibitors abemaciclib (Lilly), palbociclib (Pfizer)
- protein-protein interaction disruptors BI 1701963
- the methods disclosed herein include administering to the subject one or more anti-cancer agents described above. Additional immunotherapies may be used in combination or in conjunction with methods of the embodiments.
- immunotherapeutics generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells.
- Rituximab (RITUXAN®) is such an example.
- the immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell.
- the antibody alone may serve as an effector of therapy or it may recruit other cells to actually affect cell killing.
- the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve as a targeting agent.
- the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target.
- Various effector cells include cytotoxic T cells and NK cells.
- Antibody-drug conjugates have emerged as a breakthrough approach to the development of cancer therapeutics. Cancer is one of the leading causes of deaths in the world.
- Antibody-drug conjugates comprise monoclonal antibodies (MAbs) that are covalently linked to cell-killing drugs. This approach combines the high specificity of MAbs against their antigen targets with highly potent cytotoxic drugs, resulting in “armed” MAbs that deliver the payload (drug) to tumor cells with enriched levels of the antigen. Targeted delivery of the drug also minimizes its exposure in normal tissues, resulting in decreased toxicity and improved therapeutic index.
- ADCETRIS® currentuximab vedotin
- KADCYLA® tacuzumab emtansine or T-DM1
- T-DM1 trastuzumab duocarmazine
- immunotherapies include immune adjuvants, e.g., Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene, and aromatic compounds (U.S. Patents 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides etal., 1998); cytokine therapy, e.g., interferons , > > and ⁇ , IL-1, GM-CSF, and TNF (Bukowski et al., 1998; Davidson et al., 1998; Hellstrand et al., 1998); gene therapy, e.g., TNF, IL-1, IL-2, and p53 (Qin et al., 1998; Austin-Ward and Villaseca, 1998; U.S.
- immune adjuvants e.g., Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene, and aromatic compounds
- cytokine therapy e.g
- Patents 5,830,880 and 5,846,945) ; and monoclonal antibodies, e.g., anti-CD20, antiganglioside GM2, and anti-pl85 (Hollander, 2012; Hanibuchi et al., 1998; U.S. Patent 5,824,311). It is contemplated that one or more anti-cancer therapies may be employed with the antibody therapies described herein.
- agents may be used in combination with certain aspects of embodiments of the methods described herein to improve the therapeutic efficacy of treatment.
- additional agents include agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents. Increases in intercellular signaling by elevating the number of GAP junctions would increase the anti- hyperproliferative effects on the neighboring hyperproliferative cell population.
- cytostatic or differentiation agents can be used in combination with certain aspects of the present embodiments to improve the anti-hyperproliferative efficacy of the treatments.
- Inhibitors of cell adhesion are contemplated to improve the efficacy of the present embodiments.
- Examples of cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with certain aspects of the present embodiments to improve the treatment efficacy.
- the subject has received one, two, three, four, five, six, seven, eight or more lines of therapy, including for example, one or more anti-cancer agents described above.
- the subject has received one, two, three, four, five, six, seven, eight or more lines of therapies selected from Her2 -targeted agent, non-exon 20 insertion-selective tyrosine kinase inhibitor, immune checkpoint inhibitor, radiation therapy, hormone therapy, targeted therapy, stem cell transplant, precision medicine, and other chemotherapy.
- the subject has received chemotherapy only (e.g. one, two, three, four, five, six, seven, eight or more anti-cancer agents).
- the subject has received a therapy of HER2- targeted agent. In some embodiments, the subject has received therapy of an immune checkpoint inhibitor. In some embodiments, the subject has received therapy of an immune checkpoint inhibitor but without a HER2 -targeted agent. In some embodiments, the subject has not received therapy of other EGFR or HER2 Exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI). In some embodiments, the cancer has developed resistance to one, two, three or more anti-cancer agents or therapies, including for example, one or more anti-cancer agents described above.
- the poziotinib or a pharmaceutically acceptable salt thereof may be administered before, during, after, or in various combinations relative to an additional cancer therapy, such as immune checkpoint therapy.
- the administrations may be in intervals ranging from concurrently to minutes to days to weeks.
- the poziotinib or a pharmaceutically acceptable salt thereof is provided to a patient separately from an additional therapeutic agent, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the two compounds would still be able to exert an advantageously combined effect on the patient.
- poziotinib or the pharmaceutically acceptable salt thereof is administered at a dose of 5-25 mg.
- the subject is administered the hydrochloride salt of the poziotinib at a dose of 8 mg, 12 mg, or 16 mg.
- poziotinib or the pharmaceutically acceptable salt thereof is administered daily. In some embodiments, poziotinib or the pharmaceutically acceptable salt thereof is administered on a continuous basis. In some embodiments, poziotinib or the pharmaceutically acceptable salt thereof is administered on 5, 7, 10, 14 or 28 day cycles.
- a related aspect discloses a kit for treating cancer of solid tumor, such as those disclosed herein.
- An example of such a kit may include poziotinib or a pharmaceutically acceptable salt thereof.
- the kit may further comprise instructions for use of the kit.
- the kit may further comprise instructions for use of the primers to detect the presence or absence of the specific EFGR and/or HER2 activating mutations described herein.
- the kit may further comprise instructions for diagnostic purposes, indicating that a positive identification of EGFR and/or HER2 activating mutations described herein in a sample from a cancer patient indicates sensitivity to the poziotinib or a pharmaceutically acceptable salt thereof.
- the kit may further comprise instructions that indicate that a positive identification of EGFR and/or HER2 activating mutations described herein in a sample from a cancer patient indicates that a patient should be treated with poziotinib or a pharmaceutically acceptable salt thereof.
- the kit may further include an additional agent described herein for use in combination with poziotinib or a pharmaceutically acceptable salt thereof.
- poziotinib or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for use as a medicament for treating cancer of solid tumor in a subject, wherein the subject has been determined to have one or more EGFR or HER2 activating mutations.
- the cancer is selected from breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
- the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. In some embodiments, the subject has been determined to have one or more HER2 activating mutations selected from the group consisting of S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R.
- the subject has been determined to have one or more EGFR activating mutations selected from the group consisting of EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, V742I, E746_A750del, L747X, A750P, S768VV769L, S768I/V774M, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V.
- EGFR activating mutations selected from the group consisting of EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718
- the subject is free from T798M or T798I in HER2 or T790M in EGFR.
- the subject has previously received one, two, three or more lines of therapy for the cancer.
- the subject has been determined to be HER2-positive with HER2 activating mutations and the cancer has developed resistance to an anti-cancer agent selected from the group consisting of HER2 targeted agent, alkylating agent, anthracycline, anti-metabolite, microtubule inhibitor, motor inhibitor, immunotherapy, hormonal (anti -estrogen) agent, aromatase inhibitor, PIK3CA inhibitor, anti-bone metastasis agent, immune checkpoint inhibitor, and any combination thereof.
- the cancer is breast cancer.
- the subject the subject has been determined to be HER2-positive with HER2 activating mutations and has been treated with an anti-cancer agent and the cancer has progressed during the treatment, wherein the anti-cancer agent is selected from the group consisting of Irinotecan, Nivolumab, Ipilimumab, Oxaliplatin, Cetuximab, Panitumumab, Dabrafenib, Trametinib, Encorafenib, Bevacizumab, 5-FU, Capecitabine, Pembrolizumab, Ramucirumab, Ziv-aflibercept, and any combination thereof.
- the cancer is colorectal cancer.
- the cancer is a high-grade glioma.
- the subject has not received chemotherapy, biologies, immunotherapy, HER2 targeted therapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy, or curative-intent radiotherapy for the treatment of the cancer.
- the cancer is metastatic.
- the cancer is advanced.
- the subject has been determined to have HER2 activating mutations.
- the poziotinib or the pharmaceutically acceptable saltthereof is administered orally.
- the subject is administered the hydrochloride salt of the poziotinib.
- the poziotinib or the pharmaceutically acceptable salt thereof is administered at a dose of about 5 to about 25 mg. In some embodiments, the subject is administered the hydrochloride salt of the poziotinib at a daily dose of about 8 mg, about 10 mg, about 12 mg, about 14 mg, or about 16 mg. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered at a daily dosage of about 14 mg or about 16 mg. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered on 28 day cycles.
- the use further includes administering an additional anti-cancer therapy.
- the additional anti-cancer therapy is chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy or immunotherapy.
- the additional anti-cancer therapy is selected from the group consisting of HER2 targeted agent, alkylating agent, anthracycline, anti-metabolite, microtubule inhibitor, motor inhibitor, immunotherapy, hormonal (anti -estrogen) agent, aromatase inhibitor, PIK3CA inhibitor, anti-bone metastasis agent, immune checkpoint inhibitor, and any combination thereof.
- the poziotinib or the pharmaceutically acceptable salt thereof and / or anti-cancer therapy are administered intravenously, subcutaneously, intraosseously, orally, transdermally, in sustained release, in controlled release, in delayed release, as a suppository, or sublingually.
- poziotinib or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for use as a medicament for treating a cancer of solid tumor in a subject, wherein the subject has been determined to be HER2 positive.
- the cancer is selected from the group consisting of breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer, bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
- the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. In some embodiments, the subject has been determined to have one or more EGFR activating mutations. In some embodiments, the subject has previously received one, two, three or more lines of therapy for the cancer. In some embodiments, the subject has previously received at least trastuzumab and optionally TDM1. In some embodiments, the subject has previously received at least trastuzumab, TDM1 and pertuzumab. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic.
- the use includes administering the poziotinib or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the use includes administering the poziotinib or a pharmaceutically acceptable salt twice a day with a daily dosage of about 16 mg. In some embodiments, the use includes administering a daily dosage of about 24 mg of the poziotinib or a pharmaceutically acceptable salt for two weeks followed by a week of no administration.
- poziotinib or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for use as a medicament for reducing adverse events in treating a subject with cancer, wherein the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 15 mg to about 25 mg.
- the subject has previously received one, two, three or more lines of therapy for the cancer.
- the subject has previously received at least trastuzumab and optionally TDM1.
- the subject has previously received at least trastuzumab, TDM1 and pertuzumab.
- the cancer is breast cancer.
- the cancer is metastatic.
- the use includes administering administering the poziotinib or a pharmaceutically acceptable salt twice a day with a daily dosage of about 14 mg or about 16 mg.
- the use includes administering administering a daily dosage of about 24 mg of the poziotinib or a pharmaceutically acceptable salt for two weeks followed by a week of no administration.
- the use includes administering administering a daily dosage of about 24 mg of the poziotinib or a pharmaceutically acceptable salt twice a day.
- the use includes administering a hydrochloride salt of the poziotinib.
- the use includes administering the poziotinib or a pharmaceutically acceptable salt at a selected dose and frequency in order to achieve at least 5, at least 10, at least 15, least 20 or at least 25 continuous days of administration before a first drug interruption. In some embodiments, the use includes administering the poziotinib or a pharmaceutically acceptable salt at a selected dose and frequency in order to reduce drug interruption by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% in comparison with same daily dosage of QD (once a day) administration.
- Example 1 Use of Poziotinib in Patients with Solid Tumors, with EGFR or HER2 Activating Mutations.
- a study protocol including three (3) patient cohorts has been designed. Each treatment cycle is 28 calendar days in duration.
- Figure 1 shows a diagram of study design. The five patient cohorts are:
- the First-Stage of each cohort enrolled 9 patients.
- a cohort would enroll patients into Second-Stage if the required responses were observed in 9 patients in the First-Stage in each cohort.
- the Screening period (Day -30 to Day 1) lasts up to 30 days prior to Cycle 1, Day 1. Patients must provide written Informed Consent prior to undergoing any study procedure. Patients must meet all Inclusion/Exclusion Criteria in order to participate in the study. Each treatment cycle is 28 calendar days in duration. Tumor assessments were scheduled at Baseline/pre-dose, Week 4, Week 8 and every 8 weeks thereafter. Baseline tumor assessments could be within 30 days prior to Cycle 1, Day 1.
- the primary treatment period for all patients were from the time of the first dose of poziotinib to the first occurrence of disease progression, intolerable adverse events, the start of a new anticancer treatment, death or reaching a maximum of 24 months on therapy.
- the primary, secondary, and exploratory efficacy endpoints were evaluated from the primary treatment period data.
- the patient continued to receive poziotinib only if the following criteria were met: absence of symptoms and signs indicating clinically significant progression of disease, no decline in ECOG or Karnofsky performance status, and the absence of symptomatic rapid disease progression requiring urgent medical intervention. If the investigator and medical monitor agreed that the patient continued to derive clinical benefits in spite of progression, the patient could continue to receive poziotinib. In addition, the patient was made aware of therapeutic options and reconsented.
- the total duration of the study was approximately 3 years although patients were treated until meeting a discontinuation criterion.
- Primary Treatment Period 28 days per cycle for up to 24 months of treatment or until death, intolerable adverse events, progressive disease or other protocol-specified reasons for patient withdrawal or a maximum of 24 months
- Patient has a metastatic solid tumor that has no available standard therapy
- IHC HER2-positive (based on ASCO/CAP guidelines) are included only when they have progressed on trastuzumab, pertuzumab, and T-DM1 • IHC HER2-negative (based on ASCO /CAP guidelines), prior treatment with trastuzumab, pertuzumab, and T-DM1 is not required
- ER-positive are permitted to continue endocrine therapy concurrently with the study Patients with colorectal cancer who are MSI-H should have progressed on pembrolizumab or nivolumab or nivolumab/ipilimumab. Patient is positive for EGFR or HER2 mutations based on DNA genetic testing of either tumor tissue or plasma samples, but tissue is preferred.
- NGS next generation sequencing
- OCA OncoMine Comprehensive Assay
- Guardant360 Assay or FoundationOne Assay that detects specific mutations, performed by a US CLIA certified and CAP accredited clinical laboratory or similarly accredited lab for ex-US sites using tissue or plasma samples.
- NGS next generation sequencing
- OCA OncoMine Comprehensive Assay
- CAP Guardant360 Assay
- FoundationOne Assay that detects specific mutations, performed by a US CLIA certified and CAP accredited clinical laboratory or similarly accredited lab for ex-US sites using tissue or plasma samples.
- RECIST Response Evaluation Criteria in Solid Tumors
- RANO Criteria a target lesion(s) must be radiographically measurable.
- CNS metastatic lesion cannot be considered target lesions in Cohorts 1-3.
- Brain metastases may be allowed if patient’s condition is stable. Stable brain metastases are defined as stable symptoms, no requirement for high dose or increasing doses of systemic corticosteroid, nor progression on imaging studies for at least 4 weeks prior to enrolment. If applicable, patients must complete brain radiation therapy and return to suitable condition prior to eligibility assessment of the study. For the patient who has had radiation therapy, post-treatment MRI tests should show no increases in brain lesion size/volume and there should be no new lesions compared to pre-treatment MRI for at least 4 weeks. A new lesion is defined as lesion size greater than 5 mm and not previously present and/or not requiring radiation therapy. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 10. Patient has recovered from prior systemic therapy for metastatic disease to Grade ⁇ 1 for non-hematologic toxicities (except for Grade ⁇ 2 peripheral neuropathy) and has adequate hematologic, hepatic, and renal function at Baseline, as defined by:
- Absolute neutrophil count must be > 1 .0/ 10 9 /L
- AST/SGOT Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase
- ALT/SGPT alanine aminotransferase/serum glutamic-pyruvic transaminase
- UPN xupper limit of normal
- Postmenopausal is defined as any of: age > 60 years, age ⁇ 60 years and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range, prior bilateral oophorectomy, or if taking tamoxifen or toremifene, and age ⁇ 60 years then FSH and plasma estradiol in postmenopausal ranges).
- FSH follicle-stimulating hormone
- Patient has primary tumors in central nervous system (CNS) or in brain, including glioblastoma multiforme (GBM), meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or unstable brain metastasis except if qualified under inclusion criteria for Cohort 4.
- CNS central nervous system
- GBM glioblastoma multiforme
- meningeal carcinomatosis meningeal carcinomatosis
- leptomeningeal carcinomatosis spinal cord compression
- unstable brain metastasis except if qualified under inclusion criteria for Cohort 4.
- Patient has received anticancer chemotherapy, biologies, immunotherapy, targeted therapy (including HER2 targeted therapy), curative-intent radiotherapy, or other investigational treatment within 15 days.
- Local radiation therapy for bone pain may be allowed.
- Standard and approved hormonal therapies for hormonal i. receptor positive tumors are allowed.
- Patient has not recovered (i.e, still at > Grade 1) from drug-induced pancreatitis or has a history of drug-induced pancreatitis.
- Patient has not recovered (i.e, still at > Grade 1) from interstitial lung disease or has a history of interstitial lung disease or radiation pneumonitis.
- Patient has Grade 2 or higher skin disorders (rash), mucositis, or stomatitis within 15 days.
- CHF congestive heart failure
- NYHA New York Heart Association
- Patient has a high risk of cardiac disease, as determined by the Investigator, may undergo either echocardiogram (ECHO) or multi-gated acquisition (MUGA) during Screening and has a cardiac ejection fraction ⁇ 50%.
- ECHO echocardiogram
- MUGA multi-gated acquisition
- Patient has a QTcF > 470 ms.
- Patient has a history of other malignancies within the last 3 years, except for non-melanoma skin cancer, carcinoma in situ of the cervix, or PSA-stable, asymptomatic, early stage of prostate cancer or superficial bladder cancer without active treatment.
- Patient has clinically significant or recent acute gastrointestinal disease presenting as diarrhea and/or coloenteritis as the main symptom (i.e. acute enteritis, malabsorption, or Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) Grade 2 or higher diarrhea due to other drug-related reasons within 15 days, except fully recovered food poisoning related diarrhea.
- CTCAE Common Terminology Criteria for Adverse Events
- Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function or malabsorption syndrome.
- Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, asymptomatic biliary stones, liver metastasis, or stabilized chronic liver diseases).
- Patient has a medical condition that in the opinion of the investigator or medical monitor would put her/him at an unreasonable risk including drug toxicity during the trial
- Patient has known hypersensitivity to poziotinib or history of allergic reactions attributed to compounds of similar chemical composition to poziotinib.
- Patient has an active or uncontrolled infection, active bleeding disorder, any underlying medical condition, or other serious illness that would impair the ability of the patient to receive protocol treatment.
- Patient is pregnant or breast-feeding.
- CRF case report form
- Informed Consent was obtained prior to the start of any protocol-specified assessments or procedures. The procedures and evaluations required for enrollment into the study are summarized below. All potential study patients will be screened, and eligibility determined prior to enrollment. The results of any procedures or laboratory assessments performed prior to the signing of Informed Consent as part of the site’s routine standard of practice was allowed for use as a Screening Assessment at the discretion of the Sponsor. This information was to be discussed with the Medical Monitor before the patient is enrolled in the study.
- the Patient ID will include two parts: the site number assigned by Spectrum will be comprised of 5 digits with a 2-digit alphabetic country code followed by a 3 -digit site specific numeric code and a hyphenated 3-digit patient sequential number, unique to a site, separated by a hyphen (i.e., US001-001).
- a CRF was only completed for patients who were enrolled and received a Patient ID.
- Pregnancy test blood beta-human chorionic gonadotropin [
- Tumor assessment Screening tumor assessment for patient eligibility will be based on scans performed locally within 30 days before the patient signed the ICF; Baseline tumor assessment (either CT, PET/CT, or MRI for non-brain organs and brain MRI) will be performed within 2 weeks prior to, or on Cycle 1, Day 1
- Serum biochemistry prior to poziotinib administration may be obtained up to 7 days prior to Cycle 1, Day 1)
- Tumor assessment either CT, PET/CT, or MRI for non-brain organs and brain MRI (unless the patient has documented disease progression; the same imaging acquisition method as the baseline should be used)
- Tumor assessment either CT, PET/CT, or MRI for non-brain organs and brain MRI (unless the patient has documented disease progression or has undergone a tumor assessment with the previous 8 weeks; the same imaging acquisition method as the baseline should be used)
- the End-of-Treatment Visit is required 35 ( ⁇ 5) days after the last dose of poziotinib is administered.
- the following assessments are to be performed at this visit:
- ECOG Performance Status assessment • Tumor assessment (either CT, PET/CT, or MRI for non-brain organs and brain MRI (unless the patient has documented disease progression or has undergone a tumor assessment within the previous 8 weeks; same imaging acquisition method as the baseline should be used)
- a complete physical examination including a description of external signs of the neoplastic disease and co-morbidities, was performed at Screening Visit and Day 1 of each cycle, and at the End-of-Study Visit. Symptom-directed examinations were required at other visits. Physical examinations are to be completed by a physician or other health professional licensed to perform such examinations. Findings will be documented in the patient’s medical record and on the appropriate CRF pages. Any abnormalities are to be recorded on the AE CRF.
- CBC Complete Blood Count
- Pregnancy Test A blood (at Screening) or urine (on Day 1 of each cycle starting Cycle 2) P-hCG test will be performed for all women of childbearing potential.
- cardiac ejection fraction may be assessed by either echocardiogram or multi -gated acquisition (MUGA) scan at Screening, and the investigator can order subsequent tests based on patient standard of care as determined by the Investigator.
- MUGA multi -gated acquisition
- Tumor assessment for study patient’s eligibility must be performed by Investigators using computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI) for non-brain organs and MRI for brain at Screening up to 30 days prior to Cycle 1, Day 1. Imaging studies performed prior to the signing of Informed Consent as part of the site’s routine standard of practice are allowed at the discretion of the Sponsor as the Screening assessment. Brain MRI must be performed to assess the brain metastasis status at the screening per eligibility criteria. This information is to be discussed with the Sponsor’s Medical Monitor before the patient is enrolled in the study. Baseline tumor assessment will be performed within 2 weeks prior to, or on Cycle 1, Day 1. PostBaseline tumor assessments must be performed at Cycle 2 Day 1, at Cycle 3 Day 1, and every 8 weeks thereafter until patient discontinuation or up to 24 months.
- CT computed tomography
- PET positron emission tomography
- MRI magnetic resonance imaging
- Each subsequent tumor assessment must use the same radiologic technique as in Baseline, either CT, PET/CT, or MRI.
- Tumor assessments will be made according to RECIST, version 1.1 [14] using appropriate radiologic imaging or other techniques. For radiographic assessment, CT, PET/CT, or MRI must be performed at every assessment.
- Tumor assessment is based on the study investigator’s assessment with local radiology review and report according to the RECIST 1.1 and/or RANO (for Cohort 4) criteria for response evaluation.
- Tissue samples at Screening are acquired prior to Cycle 1, Day 1 during the screening period. If possible, tumor tissue samples from a biopsy when progression occurs during the study should be collected. This is not mandatory but is highly encouraged. The tumor tissue will be used for genetic analysis (DNA and or RNA sequencing) to understand poziotinib response and resistance mechanisms.
- Plasma samples are required at baseline (prior to start of study treatment), and optional on the day of each on-study imaging session, beginning at the 8-week imaging session, once every 8 weeks with imaging scan.
- the plasma samples will be used for genetic analysis (DNA sequencing) to understand poziotinib response mechanism and progression of disease.
- Guardant’s 360 or FoundationACT assays will be used, Plasma sample collection and storage will follow vendors’ standard procedures as described in the vendors’ Laboratory Manual.
- Premedications (such as anti emetics) used for supportive care are allowed as per institutional standards or guidelines and Investigator discretion.
- Poziotinib is a substrate for cytochrome P450 (CYP) 3A4 and 2D6 enzymes. Patients may be taking medications that are strong inhibitors or inducers of these two enzymes (Table 1). The plasma concentration of poziotinib could be different in these patients. The Investigator should try to substitute a medication that is not a strong inhibitor/inducer of these enzymes, if possible. If there is not an available substitute for a medication that a patient is taking or the patient is not willing to change medications, the Investigator must monitor the patient closely for possible AEs or changes in response.
- Poziotinib is also a moderate inhibitor of CYP2C8 and CYP2D6, so patients who take medications that are sensitive substrates for these two enzymes (Table 1) should be followed closely for possible changes in the patient’ s response to these medications. Patients should be advised that grapefruit juice and St. John’s Wort should be avoided during the study treatment.
- Pre-medications should be administered before poziotinib on Day 1. All supportive medications for potential diarrhea and rash management should be distributed to the patient on Day 1 with instructions on their use.
- Mucositis/stomatitis can be treated in a supportive manner aiming to control symptoms.
- Prophylactic methods to reduce or prevent mucositis/stomatitis include:
- Rash may be managed according to the algorithm and/or per standard of care as determined by the Investigator or Institutional Guidelines.
- Paronychia may be managed according to the algorithm and/or per standard of care as determined by the Investigator or Institutional Guidelines
- Warfarin or other coumadin-derived anticoagulants should be used cautiously during treatment with poziotinib. When it cannot be avoided, regular monitoring of INR is required, and prior authorization from the Sponsor’s Medical Monitor is required.
- Plasma or tumor samples are collected for EGFR or HER2 activating mutations.
- Plasma hepatocyte growth factor (HGF) concentration can be determined using quantitative sandwich enzyme immunoassay technique (Seoul Clinical Laboratories Co., Ltd., Yongin, Korea).
- the poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.
- Poziotinib tablets are supplied in 2.0-mg and 8.0-mg dose strengths and contain 2.0 mg and 8.0 mg of poziotinib hydrochloride salt, respectively.
- Poziotinib is supplied as 8-mg and 2-mg tablets and will be administered on an outpatient basis orally once daily at approximately the same time each day with food and a glass of water.
- geometric mean plasma concentration (Cmax) of poziotinib in the fed state was about 27% lower than the fasted state.
- the rationale for administering poziotinib with food is to reduce any potential toxicity that is associated with the Cmax.
- this dose may be administered any time during the day, but at least 8 hours prior to the next scheduled dose.
- Dosing modification recommendations are described in the table below. Dose reductions are in 2 mg increments, regardless of starting dose and will be at the Investigator’s discretion. The Sponsor should be notified. Dose reductions other than by 2 mg increments require the Sponsor’s Medical Monitor approval.
- the patient may stay on therapy at their current dose or can be increased up to the starting dose of 16 mg/day at the discretion of the Investigator based on the patient’s tolerability to the drug, investigator’s opinion that the patient is still deriving clinical benefits and consideration of other available treatments but must be approved by the Sponsor’s Medical Monitor prior to implementation.
- Safety data was reviewed on a regular basis by the monitoring team from the Spectrum Pharmaceuticals, Inc. or its designee.
- Adverse events were characterized by intensity (severity), causality, and seriousness by the Investigator based on the regulatory definitions included below.
- NCI National Cancer Institute
- CCAE Common Terminology Criteria for Adverse Events
- An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.
- a treatment-emergent AE (TEAE) is any AE that occurs from the first dose of study treatment until 35 ( ⁇ 5) days after the last dose of study treatment. [0201] The study recorded all AEs according to the information in Section 7.3. Examples of AEs include:
- AEs may include pre-treatment or post-treatment events that occur as a result of protocol- mandated procedures (e.g., invasive procedures).
- the abnormal laboratory value is predefined as an AE in the protocol or in another document communicated to the Investigator by Spectrum or designee.
- Examples of events that do not constitute AEs include:
- the adverse events of special interest identified with poziotinib treatment include diarrhea, skin rash, oral cavity mucositis/stomatitis, fatigue, and vomiting/nausea.
- the date of death should be the date of AE stop for all ongoing AEs at the time of death.
- an AE is judged “expected” if its description agrees in nature and severity with the description of AEs previously noted with the study drug as detailed in the current Investigator’s Brochure.
- An “unexpected” AE is one for which the specificity or severity is neither consistent with the current Investigator’s Brochure nor the risk information described in the general investigational plan.
- the Sponsor will be responsible for assessing the expectedness of AEs.
- the most common AEs associated with poziotinib treatment include:
- Is life-threatening i.e., any event that, in the opinion of the Investigator, poses an immediate risk of death to the patient from that event.
- At least 2 prior HER2-directed therapy regimen(s) for MBC including trastuzumab and T- DM1
- Multi-cohort study to establish the dose regimen was as follows. The treatment cycle is illustrated in Figure 3. ORR was assessed by response evaluation criterion in solid tumors (RECIST, vl. l)
- Cohort 1 24 mg (three 8 mg tablets once daily) for 2 weeks, rest 1 week
- Cohort 2 16 mg (two 8 mg tablets once daily) continuously dosing
- Poziotinib demonstrated clinical activity in both dose groups with confirmed ORR of 23% and 22% respectively in these heavily pre-treated metastatic breast cancer patients.
- the efficacy results were summarized in Figure 7.
- Progression-free survival and swimmers plot are shown in Figure 8 and Figure 9 respectively.
- Patients with intermittent 24 mg were able to stay loner on therapy with higher dose intensity.
- Adverse events for both groups are summarized in Figure 10.
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Abstract
A method of treating solid tumors in a subject is disclosed herein. The method generally includes administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to a subject in need thereof.
Description
Treatment of Malignant Solid Tumors
TECHNICAL FIELD
[0001] This patent document relates to treatment of cancer with poziotinib or a pharmaceutically acceptable salt thereof.
BACKGROUND
[0002] Many solid tumors, including lung, breast, bladder, head and neck, and gastrointestinal cancers, are associated with either an activating mutation in or an overexpression of members of the ErbB receptor family, especially EGFR and HER2. EGFR and HER2 mutations, including exon 20 insertion mutations, have been identified in a variety of cancer types. Treatments that specifically target HER2 overexpression have been shown to be clinically beneficial to patients with breast cancer and several targeted therapies have been approved by the FDA for treatment of patients with NSCLC and breast cancer. Similarly, there are investigations of FDA-approved EGFR targeting agents in HER2 overexpressed and mutant colorectal, head and neck, and pancreatic cancers. In a recent basket trial of patients with lung, breast, bladder, colorectal, and several other solid tumors, HER2 mutations were shown to be clinically targetable with neratinib; although, outcomes were modest. However, to date, excluding NSCLC, there has been limited FDA-approved targeted therapies for EGFR or HER2 mutant solid tumors. Therefore, there is a significant clinical need to identify targeted novel therapies.
SUMMARY OF THE INVENTION
[0003] An aspect of the document provides a method for treating malignant solid tumors in a subject, wherein the subject has been determined to have one or more EGFR or HER2 activating mutations. The method generally includes administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof to the subject, which has been determined to have one or more EGFR or HER2 activating mutations. In some embodiments, the cancer is selected from breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer,
testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is advanced. In some embodiments, the subject has been determined to be HER2 negative with HER2 activating mutations. In some embodiments, the subject has been determined to be HER2 positive with HER2 activating mutations. In some embodiments, the cancer is breast cancer, colorectal cancer, or high-grade glioma, including Grade 3 and 4 glioblastoma multiforme. In some embodiments, the cancer is grade 4 glioblastoma multiforme.
[0004] In some embodiments, the subject’s tumor has been determined to be HER2 -positive with HER2 activating mutation, and the subject has been treated with an anti-cancer agent, and the cancer has progressed during the treatment. In some embodiments, the subject has been treated with one or more anti-cancer agents selected from HER2 targeted agent, alkylating agent, anthracycline, anti-metabolite, microtubule inhibitor, motor inhibitor, immunotherapy, hormonal (anti-estrogen) agent, aromatase inhibitor, PIK3CA inhibitor, anti -bone metastasis agent, immune checkpoint inhibitor, and any combination thereof. In some embodiments, the cancer has developed resistance to the one or more anti-cancer agents. In some embodiments, the anticancer agents are selected from the group consisting of trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents, including but not limited to cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); pemetrexed; ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan or any combination thereof. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the subject has been determined to be HER2 negative with HER2 activating mutations.
[0005] In some embodiments, the subject has been determined to be HER2 -positive and has been treated with one or more anti-cancer agents, and the cancer has progressed during the treatment. In some embodiments, the cancer has developed resistance to the one or more anti-cancer agents. In some embodiments, the anti-cancer agent is selected from the group consisting of pembrolizumab, nivolumab, nivolumab, ipilimumab, trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents including but not limited to cisplatin, 5-flouriuricil oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate;
daunomycin; aminopterin; xeloda; ibandronate; irinotecan or any combination thereof, or any combination thereof. In some embodiments, the cancer is colorectal cancer.
[0006] In some embodiments, the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. In some embodiments, the subject has been determined to have one or more HER2 activating mutations selected from S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R. In some embodiments, HER2 activating mutations include HER2 exon 20 insertions in kinase domain.
[0007] In some embodiments, the subj ect has been determined to have high-grade glioma with
EGFR activating mutations. In some embodiments, the subject has been determined to have solid tumors with EGFR activating mutations, wherein the subject may or may not have NSCLC or highgrade glioma). In some embodiments, the EGFR activating mutations are located in extracellular and / or transmembrane, including for example, EGFRvIII, R108K, R222C, A289T, P596L, G598V. In some embodiments, the EGFR activating mutations are located in kinase domain, including for example, EGFRvIII, R108K, R222C, A289T, P596L, G598V, Exon 20 insertions, E709K, G719X, V742I, E746_A750del, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V.
[0008] In some embodiments, the subject has not received chemotherapy, biologies, immunotherapy, HER2 targeted therapy, curative-intent radiotherapy for the treatment of the cancer. In some embodiments, Poziotinib or the pharmaceutically acceptable salt thereof is administered as a first line of therapy.
[0009] In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the subject is administered the hydrochloride salt of the poziotinib. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered at a daily dose of 5-25 mg. In some embodiments, the subject is administered the hydrochloride salt of the poziotinib at a daily dose of about 8 mg, about 12 mg, about 16 mg, about 18 mg, about 20 mg, or about 24 mg. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered daily. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered twice a day (e.g. 6 mg BID, 7 mg BID, 8 mg BID, etc). In some embodiments, the poziotinib or the pharmaceutically acceptable
salt thereof is administered on a continuous basis. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered on 28 day cycles.
[0010] In some embodiments, the method further includes administering an additional anti- cancer therapy. The additional anti-cancer therapy is chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy or immunotherapy. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof and / or anti-cancer therapy are administered intravenously, subcutaneously, intraosseously, orally, transdermally, in sustained release, in controlled release, in delayed release, as a suppository, or sublingually.
[0011] Another aspect of the patent document provides a method of reducing adverse events in treating a subject with cancer. The method includes administering twice a day or administering intermittently a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 10 mg to about 25 mg. In some embodiments, the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 14 mg to about 26 mg. In some embodiments, a hydrochloride salt of the poziotinib is administered.
[0012] In some embodiments, the poziotinib or a pharmaceutically acceptable salt is administered at a selected dose and frequency so that at least 15 continuous days of administration is achieved before a first drug interruption. In some embodiments, the poziotinib or a pharmaceutically acceptable salt is administered at a selected dose and frequency so that drug interruption is reduced by at least 15% in comparison with same daily dosage of QD (once a day) administration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Figure 1 shows an example study design diagram.
[0014] Figure 2 shows the schedule of study assessments and procedures.
[0015] Figure 3 shows the treatment cycle in a clinical study on treatment of breast cancer.
[0016] Figure 4 shows key baseline characteristics of the patients with breast cancer.
[0017] Figure 5 summarizes prior therapy for the patients with breast cancer.
[0018] Figure 6 shows Poziotinib drug exposure in two cohorts of clinical study.
[0019] Figure 7 summarizes the efficacy of clinical study of breast cancer treatment with poziotinib. ORR=Overal Response Rate; DCR=Disease Control Rate; PFS=Progression-free Survival; DoR= Duration of Response. The Evaluable Population consists of all patients who are enrolled, complete at least one cycle of poziotinib treatment, and have at least one evaluable postbaseline tumor response evaluation using RECIST, vl. l Results are derived by Sponsor based on RECIST, vl. l, and include criteria: CR/PR requires confirmation scan that is >4 weeks from previous scan; and Patient needs to be on-treatment for >6 weeks when SD is evaluated.
[0020] Figure 8 shows progression-free survival in the clinical study.
[0021] Figure 9 shows swimmers plot in the clinical study.
[0022] Figure 10 shows adverse events in two cohorts of clinical study.
DETAILED DESCRIPTION
[0023] Various embodiments of this patent document disclose methods of treating cancers of solid tumors with poziotinib or a pharmaceutically acceptable salt thereof. In particular, it has been discovered that poziotinib exhibits improved efficacies in patients with certain EGFR or HER2 activating mutations.
[0024] While the following text may reference or exemplify specific embodiments of a method of treating a cancer, it is not intended to limit the scope of the method to such particular reference or examples. Various modifications may be made by those skilled in the art, in view of practical and economic considerations, such as the dosage and administration of poziotinib or a pharmaceutically acceptable salt thereof and the determination of EGFR or HER2 activating mutations.
[0025] The articles "a" and "an" as used herein refers to "one or more" or "at least one," unless otherwise indicated. That is, reference to any element or component of an embodiment by the indefinite article "a" or "an" does not exclude the possibility that more than one element or component is present.
[0026] The term “about” as used herein generally refers to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 20” may mean from 18 to 22. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4. As used herein, the term "and/or" includes
any and all combinations of one or more of the associated listed items. Expressions such as "at least one of," when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list. When referring to a dosing protocol, the term "day", "per day" and the like, refer to a time within one calendar day which begins at midnight and ends at the following midnight.
[0027] The term “daily dosage” as used herein generally refers to the total amount of poziotinib or a pharmaceutically acceptable salt thereof administered during the same day. When the poziotinib or a pharmaceutically acceptable salt thereof is administered more than once during the same day, the daily dosage is generally splitted equally among the multiple administrations.
[0028] The term "high grade glioma" include grades III or IV. In high grade glioma, the tumors are fast-growing, and they spread quickly through brain tissue, which makes them hard to treat.
[0029] By the term "treating" or “treatment” and any derivatives thereof as used herein, is meant therapeutic therapy. In reference to a particular condition, treating means: (1) to ameliorate or prevent the condition of one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or treatment thereof, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
[0030] In addition, as used herein treating or treatment and rate of success for a treatment can be evaluated by such measurements as (a) Progression-free Survival (PFS) defined herein as the time from first dose administration of therapeutic intervention in a clinical trial to disease progression or death from any cause; (b) Objective Response Rate (ORR ) defined herein as proportion of patients with a tumor size reduction of a predefined amount and for a minimum period of time using RECIST vl.l criteria; Disease Control Rate (DCR) defined herein as the percentage of patients with advanced or metastatic cancer who have achieved either a complete response, partial response or stable disease to a therapeutic intervention in clinical trials of anticancer agents; Overall Survival (OS) Rate defined herein as the percentage of people in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease; Time to Progression (TTP) define herein as the length of time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body; or other
clinical endpoint or indexes, measurable or ascertainable directly or indirectly through serogate laboratory markers generally known to one of ordinary skill in the art.
[0031] The term “advanced cancer” refers to a cancer where definitive treatment such as surgical resection or radiation therapy of the solid tumor cannot provide a cure, and other therapies are unlikely to control or cure the disease
[0032] The term “metastatic” refers to the spread of cancer cells from the place where they first formed to another part or parts of the body.
[0033] The term "effective amount" as used herein means that amount of a drug or pharmaceutical agent that will elicit the biological or clinical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. Specific doses can be readily determined by one having ordinary skill in the art, using routine procedures
[0034] The term "pharmaceutically acceptable carrier and/or excipient" as used herein refers to a carrier and/or excipient pharmacologically and/or physiologically compatible to a subject and an active component. A pharmaceutically acceptable carrier includes, without limitation, pH regulators, surfactants, adjuvants, and ionic strength enhancers. For example, pH regulators include, without limitation, phosphate buffer solutions; surfactants include, without limitation, cationic, anionic or nonionic surfactants, for example, Tween-80; ionic strength enhancers include, without limitation, sodium chloride.
[0035] The term “resistant” in the context of cancer treatment refers to a cancer that does not respond, or exhibits a decreased response to, one or more chemotherapeutic agents (e.g., any agent described herein).
[0036] The term “pharmaceutically acceptable salts” means salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Non-limiting examples of such salts include acid addition salts formed with
inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as acetic acid, embonic acid, aspartic acid, besylic acid, camsylic acid, edisylic acid, 1,2-ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, 2-naphthalenesulfonic acid,
3 -phenylpropionic acid, 4,4'-methylenebis(3-hydroxy- 2-ene- 1 -carboxylic acid),
4-methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, formic acid, fumaric acid, gestysic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lactobionic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, /?-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, phthalic acid, propionic acid, -toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutyl acetic acid, and trimethylacetic acid.
[0037] Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-m ethylglucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
[0038] The term “subject” used interchangeable with “patient” refers to a mammal with a condition or disease that is associated with overexpression of EGFR (HER1) or HER2 or any mutant thereof, who would benefit from the administration of poziotinib or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof comprising additionally a pharmaceutically acceptable carrier and/or excipient. Such subjects particularly include those patients having certain EGFR or HER2 activating mutations.
[0039] The term “EGFR activating mutations” or “HER2 mutation” refers to kinase domain mutations in EGFR or HER2. These mutations lead to a ligand-independent activation of tyrosine kinase activity.
[0040] The term “HER2 -positive” refers to the overexpression of the human epidermal growth factor receptor-2 (HER2) gene.
[0041] The term "wild-type" as used herein is understood in the art and refers to a polypeptide or polynucleotide sequence that occurs in a native population without genetic modification. As is also understood in the art, a "mutant" includes a polypeptide or polynucleotide sequence having at least one modification to an amino acid or nucleic acid compared to the corresponding amino acid or nucleic acid found in a wild-type polypeptide or polynucleotide, respectively. Included in the term mutant is Single Nucleotide Polymorphism (SNP) where a single base pair distinction exists in the sequence of a nucleic acid strand compared to the most prevalently found (wild-type) nucleic acid strand. Cancers that are either wild-type or mutant for EGFR or HER2 or have amplification of EGFR or HER2 genes or have over expression of EGFR or HER2 protein are identified by known methods.
[0042] An aspect of this patent document provides a method of cancer of solid tumor in a subject who has been determined to be HER2 positive or have one or more EGFR or HER2 activating mutations. The method includes administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject.
[0043] Poziotinib is an oral, quinazoline-based pan-HER inhibitor that irreversibly blocks signaling through the EGFR family of tyrosine-kinase receptors, including human epidermal growth factor receptor (HERl/ErbBl/EGFR), HER2 (ErbB2), and HER4 (ErbB4), as well as HER receptor mutations. This, in turn, leads to inhibition of the proliferation of tumor cells that overexpress these receptors. It is well established that several malignancies, including lung, breast, gastric, colorectal, head, and neck, and pancreatic carcinomas, are associated with a mutation in or overexpression of members of the EGFR receptor family. The administration of poziotinib or a pharmaceutically acceptable salt thereof can lead to the inhibition of the proliferation of tumor cells that overexpress these receptors. The chemical formula of poziotinib is l-[4-[4-(3,4-dichloro-2-fluorophenylamino)- 7-methoxyquinazolin-6-yloxy]-piperidin-l-yl]prop-2-en-l-one shown below.
[0044] The pharmaceutically acceptable salt may be an inorganic acid salt, an organic acid salt, or a metal salt. The inorganic acid salt may be a salt of hydrochloric acid, hydrobromic acid phosphoric acid, sulfuric acid, or disulfuric acid. The organic acid salt may be a salt of malic acid, maleic acid, citric acid, fumaric acid, besylic acid, camsylic acid, or edisylic acid. The metal salt may be a calcium salt, sodium salt, magnesium salt, strontium salt, or potassium salt. In one embodiment, Poziotinib may be a hydrochloride in the form of a tablet. Poziotinib or a pharmaceutically acceptable salt thereof may be in a crystalline form or amorphous form and can be administered in a daily dose of 0.1 mg to 50 mg.
[0045] Non-limiting examples of the cancer of solid tumor include breast cancer, colorectal cancer, gastric cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), head and neck cancer, bladder cancer, pancreatic cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, gastric cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer and skin cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is breast cancer. In some embodiments, the patient has HER2-positive or HER2 -negative breast cancer with HER2 activating mutations.
[0046] In some embodiments of any method disclosed herein, the cancer is breast cancer or lung cancer, and the subject has been determined to be HER2-positive and has been treated with an anti-cancer agent and the cancer has progressed during the treatment, wherein the anti-cancer agent can be trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents including but not limited to cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan or any combination thereof.
[0047] In some embodiments of any method disclosed herein, the cancer is colorectal cancer or lung cancer. In some embodiments, the cancer is colorectal cancer, and the subject has been determined to be HER2-positive and has been treated with an anti-cancer agent, and the cancer has progressed during the treatment, wherein the anti-cancer agent can pembrolizumab, nivolumab, nivolumab, ipilimumab, trastuzumab, pertuzumab, T-DM1, neratinib, dacomitinib, Osimertinib, platinum based and non-platinum based chemotherapeutic agents including but not limited to cisplatin, 5-flouriuricil oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan or any combination thereof.
[0048] For cancer patients with certain EGFR or HER2 activating mutations, poziotinib may exhibit improved efficacy in comparison with conventional anti-cancer agents. In some embodiments of any method disclosed herein, the activating mutation may be located at Furin-like extracellular region, transmembrane, and / or kinase domain. Non-limiting examples of EGFR activating mutations include EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, V742I, E746_A750del, L747X, A750P, S768VV769L, S768VV774M, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V and exon 20 insertions.
[0049] In some embodiments of any method disclosed herein, the cancer patient has been determined to have one, two, three, four, five, or more of the EGFR activating mutations selected from EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, V742I, E746_A750del, L747X, A750P, S768I/V769L, S768VV774M, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V. In some embodiments of any method disclosed herein, the cancer patient has been determined to have one, two, three, four, five, or more of the EGFR activating mutations selected from EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, G719X, V742I, E746_A750del, , S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V.
[0050] Non-limiting examples of EGFR exon mutations as activating mutations include M766_A767insASV, A767insASV, A767insTLA, A767_V769dupASV, V769_D770insASV, V769_D770insGSV, V769_D770insGVV, V769_D770insSAVS, V769_D770insSLRD, V769_H773>LDNPNPH, V769_D770insE, V769_D770insGTV, V769_D770insGVM,
V769_N771dupVDN, D770_N771insSVD, D770>GY, D770_N771insG, D770_N771insY, D770_N771insNPG, N771_P772insT, D770_N771insGL, D770_N771insSVG, D770delinsGY, D770delinsVG, D770_N771insH, D770_P772dup, D770insEF, D770_N771>GYN,
D770_N771>GSVDN, D770_N771>GVVDN, D770_N771insH, D770_P772dupDNP,
D770_N771>QVH, D770_N771insAVD, D770_N771insGT, D770_N771insGV, D770insNPG, D770_N771>EGN, M766_D770dup, M766_S768dup, N771>GF, N771>PH, N771_P772insG, N771_P772insH, N771_P772insV, N771delinsGY, N771delinsTH, N771_H773dupNPH,
N771_P772insHH, N771_P772insNN, N771_P772>GYP, N771_P772insGTDN, N771_P772insY, N771_P772>SVDSP, N771_P772>SPHP, N771_P772>SHP, N771_P772>SEDNS,
N771_P772>RDP, N771_P772>KGP, N771_P772>KFP, N771>GY, N771_P772insSQGN, N771dup, N771dupN, P772>HR, P772_H773insPNP, P772_H773insDNP, S768_V769>IL, S768dupSVD, S768_D779dupSVD, S768_V769>PL, S768_V769>TLASV, V769_D770insCV, A763_Y764insFQEA, A763_Y764insLQEA, H773dup, H773dupH, H773_V774dupH , H773_V774insNPH, H773_V774insNPY, H773_V774insHPH, H773_V774insH, H773_V774insTH, H773_V774insSH, H773_V774insH, H773_V774insAH, H773_V774insY, H773_V774insPY, H773_V774>NPNPYV, H773_V774>PNPYV, H773>YNPY,
V774_C775insHV, V774_C775>AHVC, V774_C775>GNPHVC, V774_C775>GTNPHVC, V774_C775insHNPHV, H773_V774>LM, H773_V774>QW, H773_V774insGH,
H773_V774insPH, P772_C775dup, Y764_V765insHH and P772_H773insYNP. In some embodiments of any method disclosed herein, the cancer patient has been determined to have one, two, three, four, five, or more of the EGFR activating mutations.
[0051] Non-limiting examples of HER2 activating mutations include S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, L869R, and exon 20 insertions. Non-limiting examples of HER2 mutations as activating mutations include A775_G776insYVMA, A775_G776insSVMA, A775_G776insVVMA, A775_G776insYVMS, A775_G776insAVMA, A775_G776insSVMA, A775_G776insC, Y772_V773insM, Y772dupYVMA, Y772_A775dup, A775_G776insI, G776delinsVC,
G776delinsVV, G776delinsLC, G776delinsIC, G776_V777delinsCVC, G776delinsAVG, M774delinsWLV, G776delinsLC, G778_S779InsCPG, G778_P780dup, G778dupGSP, G776V/S, 776 > VC, G776 > IC, G776 > LC, V777L/M, G778insLPS, P780insGSP, L786V, G778insGCP,
G778_S779insCPG, G780_P781dupGSP, V777_G778insCG, G776_V777insVC, and
P780_Y781insGSP. In some embodiments of any method disclosed herein, the cancer patient has been determined to have one, two, three, four, five, or more of the HER2 activating mutations.
[0052] In some embodiments of any method disclosed herein, the cancer patient has been determined to have one, two, three, four, five, or more activating mutations selected from S310F, 1655 V, L755X, I767M, D769X, V777X, L786V, V842I, and L869R. In some embodiments, the cancer patient has been determined to have one, two, three, four, five, or more activating mutations selected from S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R. In some embodiments of any method disclosed herein, the cancer patient has been determined to have at least one, two, three, or more activating mutations selected from T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R. In some embodiments of any method disclosed herein, the cancer patient has been determined to have at least one, two, three, or more activating mutations selected from I655V, V659E, R678Q, and V697L. In some embodiments of any method disclosed herein, the cancer patient has been determined to have at least one, two, three, or more activating mutations selected from I655V, V659E, R678Q, and V697L. In some embodiments of any method disclosed herein, the cancer patient has been determined to have at least S310F and/or S310Y. In some embodiments of any method disclosed herein, the patent has been determined to be free from T798M or T798I in HER2 or T790M in EGFR. In some embodiments of any method disclosed herein, the patient has been determined to be free from any of T798M and T798I in HER2 and T790M in EGFR.
[0053] For purpose of determining EGFR or HER2 activating mutations, the patient sample can be any bodily tissue or fluid that includes nucleic acids from the cancer in the subject. In certain embodiments, the sample will be a blood sample comprising circulating tumor cells or cell free DNA. In other embodiments, the sample can be a tissue, such as a breast or colorectal tissue. The breast or colorectal tissue can be from a tumor tissue and may be fresh frozen or formalin-fixed, paraffin- embedded (FFPE).
[0054] Wild-type or mutant EGFR and HER2 can be identified by DNA amplification and sequencing techniques, DNA and RNA detection techniques, including, without limitation, Northern and Southern blot, respectively, and/or various biochip and array technologies or in-situ hybridization. A variety of techniques can be used in the analysis including, without limitation, immunodiagnostic
techniques such as ELISA, Western blot or immunocytochemistry. For instance, the determination may use a next generation sequencing diagnostic test, such as OncoMine Comprehensive Assay (OCA) or FoundationOne Assay, or by an FDA approved test (e.g., cobas® EGFR mutation test v2 or therascreen EGFR RGQ PCR kit) performed by a US CLIA certified and locally licensed clinical laboratory or similarly accredited lab for ex-US sites using tissue samples. Besides tissue samples, mutations can be determined from a patient’s biological sample, such as plasma.
[0055] Analysis of nucleic acid markers can be performed using techniques known in the art including, without limitation, sequence analysis, and electrophoretic analysis. Non-limiting examples of sequence analysis include Maxam-Gilbert sequencing, Sanger sequencing, capillary array DNA sequencing, thermal cycle sequencing (Sears etal., 1992), solid-phase sequencing (Zimmerman etal., 1992), sequencing with mass spectrometry such as matrix-assisted laser desorption/ionization time- of-flight mass spectrometry (MALDI-TOF/MS; Fu et al., 1998), and sequencing by hybridization (Chee et al., 1996; Drmanac et al., 1993; Drmanac et al., 1998). Non-limiting examples of electrophoretic analysis include slab gel electrophoresis such as agarose or polyacrylamide gel electrophoresis, capillary electrophoresis, and denaturing gradient gel electrophoresis. Additionally, next generation sequencing methods can be performed using commercially available kits and instruments from companies such as the Life Technologies/Ion Torrent PGM or Proton, the Illumina HiSEQ or MiSEQ, and the Roche/454 next generation sequencing system.
[0056] Other methods of nucleic acid analysis can include direct manual sequencing (Church and Gilbert, 1988; Sanger etal., 1977; U.S. Patent No. 5,288,644); automated fluorescent sequencing; single-stranded conformation polymorphism assays (SSCP) (Schafer etal., 1995); clamped denaturing gel electrophoresis (CDGE); two-dimensional gel electrophoresis (2DGE or TDGE); conformational sensitive gel electrophoresis (CSGE); denaturing gradient gel electrophoresis (DGGE) (Sheffield et al., 1989); denaturing high performance liquid chromatography (DHPLC, Underhill et al., 1997); infrared matrix-assisted laser desorption/ionization (IR-MALDI) mass spectrometry (WO 99/57318); mobility shift analysis (Orita et al., 1989); restriction enzyme analysis (Flavell et al., 1978; Geever et al., 1981); quantitative real-time PCR (Raca et al., 2004); heteroduplex analysis; chemical mismatch cleavage (CMC) (Cotton et al., 1985); RNase protection assays (Myers et al., 1985); use of polypeptides that recognize nucleotide mismatches, e.g., E. coli mutS protein; allele-specific PCR, and combinations of such methods. See, e.g., U.S. Patent.
[0057] Another aspect provides a method of treating a cancer of solid tumor in a subject comprising administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has been determined to be HER2 positive.
[0058] Non-limiting examples of cancers include the cancer is selected from the group consisting of breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer, bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is stage IV breast cancer, which has spread beyond the breast and nearby lymph nodes to other parts of the body. The subject may or may not have CNS (e.g., brain) metastases.
[0059] In some embodiments, the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. In some embodiments, the subject has been determined to have one or more EGFR activating mutations. Non-limiting examples of HER2 and EGFR activating mutations are as described above.
[0060] In some embodiments, the subject has previously received at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or more lines of therapy. Examples of therapy include chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti- angiogenic therapy, or immunotherapy. In some embodiments, the subject has previously received at least two HER2 therapies. In some embodiments, the subject has previously received at least trastuzumab and optionally one or more additional therapies. In some embodiments, the subject has previously received at least trastuzumab and TDM1. In some embodiments, the subject has previously received at least trastuzumab, TDM1, pertuzumab, and optionally one or more additional therapies. Nonlimiting examples of additional lines of therapies of anticancer agents include lapatinib and neratinib.
[0061] In some embodiments of any method disclosed herein, the method includes administering the poziotinib or a pharmaceutically acceptable salt thereof once, twice, or three times a day. For instance, a daily dosage of 10, 12, 14, 16 mg of poziotinib or a pharmaceutically acceptable salt thereof can be administered once or twice a day. A daily dosage of 24 mg of poziotinib or a pharmaceutically acceptable salt thereof can be administered once, twice or three times a day for two weeks followed by a drug holiday or rest of one week when no poziotinib or a pharmaceutically acceptable salt thereof is administered. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (10 mg BID) at a daily dosage of 20 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (9 mg BID) at a daily dosage of 18 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (8 mg BID) at a daily dosage of 16 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (7 mg BID) at a daily dosage of 14 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (6 mg BID) at a daily dosage of 12 mg. In some embodiments of any method disclosed herein, poziotinib or a pharmaceutically acceptable salt thereof is administered twice a day (5 mg BID) at a daily dosage of 10 mg.
[0062] The methods of this patent document can also be applied to treating or preventing CNS metastases in a subject, wherein the subject has been diagnosed to have a cancer. The method includes administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof. In some embodiments, the CNS metastases is brain metastases. The scope and range of EGFR and HER2 mutations, the cancers, the prior therapies, the additional/auxiliary therapies, the administration schedule and the suitable patient populations are as described above.
[0063] Another aspect provides a method of reducing adverse events in treating a subject with cancer, comprising administering twice or three times a day a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 15 mg to about 25 mg. In some embodiments, the method includes administering the poziotinib or a
pharmaceutically acceptable salt twice a day with a daily dosage of about 16 mg or about 24 mg. In some embodiments, the method includes administering the poziotinib or a pharmaceutically acceptable salt once or twice a day with a daily dosage of about 24 mg for two weeks followed by a week of no administration. Nonlimiting examples of adverse events include diarrhea, rash, stomatitis, and pneumonitis. In some embodiments, the adverse event is grade 3 or higher level. The scope and range of EGFR and HER2 mutations, the cancers, the prior therapies, the additional/auxiliary therapies, the administration schedule and the suitable patient populations are as described above.
[0064] The method also effectively reduces drug interruptions. Drug interruption is one or more days of a drug-free period after continuous daily administration of the drug. A medical professional is able to determine whether a drug interruption is necessary based on factors such as side effect, toxicity and other factors. . In some embodiments of any method disclosed herein, the method reduces drug interruption by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 55% in comparison with same daily dosage of QD (once a day) administration. . In some embodiments of any method disclosed herein, the method prolongs the length to first drug interruption with median days to first interruption ranging from 10 to 50 days including for example at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29 and at least 30 days. In some embodiments of any method disclosed herein, the method provides delayed first interruption by 1-20 days including at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, and at least 12 days in comparison with same daily dosage of QD (once a day) administration. . In some embodiments of any method disclosed herein, the method provides median days to first dose reduction of at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, or at least 60 days. The scope and range of EGFR and HER2 mutations, the cancers, the prior therapies, the additional/auxiliary therapies, the administration schedule and the suitable patient populations are as described above.
[0065] Non-limiting examples of cancers are as described above. In some embodiments of any method disclosed herein, the cancer is metastatic. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic breast cancer. In some embodiments, the cancer is stage IV breast cancer. In some embodiments, the cancer is non-small cell lung cancer. In
some embodiments, the subject has been diagnosed to have one or more HER2 and EGFR activating mutations, non-limiting examples of which are as described above.
[0066] In some embodiments of any method disclosed herein, the subject has previously received one, two, three or more lines of therapy for the cancer. For example, the subject may have previously received at least trastuzumab and optionally one or more additional therapies. In some embodiments, the subject has previously received at least trastuzumab and TDM1. In some embodiments, the subject has previously received at least trastuzumab, TDM1, pertuzumab, and optionally one or more additional therapies.
[0067] The subject in the methods described herein is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein). In one embodiment, the subject is in need of enhancing an immune response. In certain embodiments, the subject is, or is at risk of being, immunocompromised. For example, the subject is undergoing or has undergone a chemotherapeutic treatment and/or radiation therapy. Alternatively, or in combination, the subject is, or is at risk of being, immunocompromised as a result of an infection. In some embodiments, the subject is human.
[0068] The methods disclosed herein are applicable to patent with or without prior cancer treatment. In some embodiments, the subject has not received chemotherapy, biologies, immunotherapy, HER2 targeted therapy, curative-intent radiotherapy for the treatment of the cancer. In some embodiments, the patient has not received a systemic treatment. In some embodiments, the patient has not received treatment with a different anti-cancer agent. In some embodiments, the patient has not been administered a tyrosine kinase inhibitor (TKI) for cancer treatment. In some embodiments, the patient has not been administered poziotinib or EGFR or HER2 exon 20 insertion mutation-selective TKIs. In some embodiments, the patient has received a systemic treatment, which has developed resistance to the treatment. In some embodiments, the patient has received treatment with a different anti-cancer agent, which has developed resistance to the anti-cancer agent. In some embodiments, the patient has been administered a tyrosine kinase inhibitor (TKI) for the treatment, which has developed resistance to the treatment with the TKI. In some embodiments, the patient has been administered poziotinib or EGFR or HER2 exon 20 insertion mutation-selective TKIs for the treatment, which has developed resistance to the treatment with the TKI. In some embodiments, the cancer is breast cancer or colorectal cancer.
[0069] The poziotinib of a pharmaceutically acceptable salt thereof, such as poziotinib hydrochloride salt, may be administered orally, such as in a tablet. The poziotinib may be administered in a dose of 4-25 mg, such as at a dose of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 mg. The dosing may be daily, every other day, every 3 days, or weekly. The dosing may be on a continuous schedule, such as on 28 days cycles.
[0070] The poziotinib of a pharmaceutically acceptable salt thereof can be used in combination with at least one additional therapy. The additional therapy may be radiation therapy, surgery (e.g., lumpectomy and a mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional therapy may be in the form of adjuvant or neoadjuvant therapy.
[0071] In some embodiments of the methods described herein, the additional therapy is the administration of a small molecule enzymatic inhibitor or anti-metastatic agent. In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence and/or severity of side effects of treatment, such as anti -nausea agents, etc.). In some embodiments, the additional therapy is radiation therapy. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is a combination of radiation therapy and surgery. In some embodiments, the additional therapy is gamma irradiation. In some embodiments, the additional therapy is therapy targeting PBK/AKT/mTOR pathway, HSP90 inhibitor, tubulin inhibitor, apoptosis inhibitor, and/or chemopreventative agent. The additional therapy may be one or more of the chemotherapeutic agents known in the art.
[0072] Non-limiting examples of anti-cancer agent or therapy include alkylating agents: Busulfan, dacarbazine, ifosfamide, hexamethylmelamine, thiotepa, dacarbazine, lomustine, chlorambucil, procarbazine, altretamine, estramustine phosphate, mechlorethamine, streptozocin, temozolomide, Semustine cyclophosphamide; platinum agents: spiroplatin, tetraplatin, ormaplatin, iproplatin, ZD-0473 (AnorMED), oxaliplatin carboplatin, lobaplatin (Aeterna), satraplatin (Johnson Matthey), BBR-3464 (Hoffmann-La Roche), SM-11355 (Sumitomo), AP-5280 (Access), cisplatin, arboplatin, cisplatin, satraplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, temozolomide, procarbazin;
antimetabolites: azacytidine, Floxuridine, 2-chlorodeoxyadenosine, 6-mercaptopurine, 6-thioguanine, cytarabine, 2-fluorodeoxy cytidine, methotrexate, tomudex, fludarabine, raltitrexed, trimetrexate, deoxycoformycin, pentostatin, hydroxyurea, decitabine (SuperGen), clofarabine (Bioenvision), irofulven (MGI Pharma), DMDC (Hoffmann-La Roche), ethynyl cytidine (Taiho) gemcitabine, capecitabine; topoisomerase inhibitors: amsacrine, epirubicin, etoposide, teniposide or mitoxantrone, 7-ethyl-10- hydroxy-camptothecin, dexrazoxanet (TopoTarget), pixantrone (Novuspharma), rebeccamycin analogue (Exelixis), BBR-3576 (Novuspharma), rubitecan (SuperGen), irinotecan (CPT-11), topotecan; antitumor antibiotics: valrubicin, therarubicin, idarubicin, rubidazone, plicamycin, porfiromycin mitoxantrone (novantrone), amonafide, azonafide, anthrapyrazole, oxantrazole, losoxantrone, MEN- 10755 (Menarini), GPX-100 (Gem Pharmaceuticals), Epirubicin, mitoxantrone, doxorubicin; antimitotic agents: colchicine, vinblastine, vindesine, dolastatin 10 (NCI), rhizoxin (Fujisawa), mivobulin (Warner-Lambert), cemadotin (BASF), RPR 109881A (Aventis), TXD 258 (Aventis), epothilone B (Novartis), T 900607 (Tularik), T 138067 (Tularik), cryptophy cin 52 (Eli Lilly), vinflunine (Fabre), auristatin PE (Teikoku Hormone), BMS 247550 (BMS), BMS 184476 (BMS), BMS 188797 (BMS), taxoprexin (Protarga), SB 408075 (GlaxoSmithKline), Vinorelbine, Trichostatin A, E7010 (Abbott), PG-TXL (Cell Therapeutics), IDN 5109 (Bayer), A 105972 (Abbott), A 204197 (Abbott), LU 223651 (BASF), D 24851 (ASTAMedica), ER-86526 (Eisai), combretastatin A4 (BMS), isohomohalichondrin-B (PharmaMar), ZD 6126 (AstraZeneca), AZ10992 (Asahi), IDN-5109 (Indena), AVLB (Prescient NeuroPharma), azaepothilone B (BMS), BNP-7787 (BioNumerik), CA-4 prodrug (OXiGENE), dolastatin- 10 (NIH), CA-4 (OXiGENE), docetaxel, vincristine, paclitaxel; aromatase inhibitors: aminoglutethimide, atamestane (BioMedicines), letrozole, anastrazole, YM-511 (Yamanouchi), formestane, exemestane; thymidylate synthase inhibitors: pemetrexed (Eli Lilly), ZD-9331 (BTG), nolatrexed (Eximias), CoFactor™ (BioKeys); dna antagonists: trabectedin (PharmaMar) ; glufosfamide (Baxter International), albumin + 32P (Isotope Solutions), thymectacin (NewBiotics), edotreotide (Novartis), mafosfamide (Baxter International), apaziquone (Spectrum Pharmaceuticals), 06 benzyl guanine (Paligent); farnesyltransferase inhibitors: arglabin (NuOncology Labs), lonafarnib (Schering-Plough), BAY-43- 9006 (Bayer), tipifarnib (Johnson & Johnson), perillyl alcohol (DOR BioPharma);
pump inhibitors: CBT-1 (CBA Pharma), tariquidar (Xenova), MS-209 (Schering AG), zosuquidar trihydrochloride (Eli Lilly), biricodar dicitrate (Vertex); histone acetyltransferase inhibitors: tacedinaline (Pfizer), SAHA (Aton Pharma), MS-275 (Schering AG), pivaloyloxymethyl butyrate (Titan), depsipeptide (Fujisawa); metalloproteinase inhibitors: Neovastat (Aeterna Laboratories), marimastat (British Biotech), CMT-3 (CollaGenex), BMS-275291 (Celltech); ribonucleoside reductase inhibitors: gallium maltolate (Titan), triapine (Vion), tezacitabine (Aventis), didox (Molecules for Health); tnf alpha agonists/antagonists: virulizin (Lorus Therapeutics), CDC-394 (Celgene), revimid (Celgene); endothelin a receptor antagonist: atrasentan (Abbott), ZD-4054 (AstraZeneca), YM-598 (Yamanouchi); retinoic acid receptor agonists: fenretinide (Johnson & Johnson), LGD-1550 (Ligand), alitretinoin (Ligand); immuno-modulators: Pembrolizumab (formerly lambrolizumab, brand name Keytruda); interferon, oncophage (Antigenics), GMK (Progenies), adenocarcinoma, vaccine (Biomira), CTP-37 (AVI BioPharma), IRX-2 (Immuno-Rx), PEP-005 (Peplin Biotech), synchrovax vaccines (CTL Immuno), melanoma vaccine (CTL Immuno), p21 RAS vaccine (GemVax) , MAGE-A3 (GSK), nivolumab (BMS), abatacept (BMS), dexosome therapy (Anosys), pentrix (Australian Cancer Technology), ISF-154 (Tragen), cancer vaccine (Intercell), norelin (Biostar), BLP-25 (Biomira), MGV (Progenies), B-alethine (Dovetail), CLL therapy (Vasogen), Ipilimumab (BMS), CM- 10 (cCam Biotherapeutics), MPDL3280A (Genentech); hormonal and antihormonal agents: estrogens, conjugated estrogens, ethinyl estradiol, chlortrianisen, idenestrol, hydroxyprogesterone caproate, medroxyprogesterone, testosterone, testosterone propionate, fluoxymesterone, methyltestosterone, diethylstilbestrol, megestrol, bicalutamide, flutamide, nilutamide, dexamethasone, prednisone, methylprednisolone, prednisolone, aminoglutethimide, leuprolide, octreotide, mitotane, P-04 (Novogen), 2-methoxyestradiol (EntreMed), arzoxifene (Eli Lilly), tamoxifen, toremofine, goserelin, Leuporelin, bicalutamide; photodynamic agents: talaporfin (Light Sciences), Theralux (Theratechnologies), motexafin gadolinium (Pharmacyclics), Pd-bacteriopheophorbide (Yeda), lutetium texaphyrin (Pharmacy dies), hyperidn; and kinase inhibitors: afatinib, osimertinib, imatinib (Novartis), leflunomide (Sugen/Pharmada), ZD 1839 (AstraZeneca), erlotinib (Oncogene Sdence), canertinib (Pfizer), squalamine (Genaera), SU5416 (Pharmacia), SU6668 (Pharmada), ZD4190 (AstraZeneca), ZD6474 (AstraZeneca), vatalanib (Novartis), PKI166 (Novartis), GW2016 (GlaxoSmithKline), EKB-509 (Wyeth), trastuzumab (Genentech), OSL774 (Tarceva™), CI-1033 (Pfizer), SU11248 (Pharmada), RH3 (York Medical),
Genistein, Radicinol, Met-MAb (Roche), EKB-569 (Wyeth), kahalide F (PharmaMar), CEP-701 (Cephalon), CEP-751 (Cephalon), MLN518 (Millenium), PKC412 (Novartis), Phenoxodiol (Novogen), C225 (ImClone), rhu-Mab (Genentech), MDX-H210 (Medarex), 2C4 (Genentech), MDX- 447 (Medarex), ABX-EGF (Abgenix), IMC-1C11 (ImClone), Tyrphostins, Gefitinib (Iressa), PTK787 (Novartis), EMD 72000 (Merck), Emodin, Radicinol, Vemurafenib (B-Raf enzyme inhibitor, Daiichi Sankyo), SR-27897 (CCK A inhibitor, Sanofi- Sy nthelabo), tocladesine (cyclic AMP agonist, Ribapharm), alvocidib (CDK inhibitor, Aventis), CV-247 (COX-2 inhibitor, Ivy Medical), P54 (COX- 2 inhibitor, Phytopharm), CapCell™ (CYP450 stimulant, Bavarian Nordic), GCS-100 (gal3 antagonist, GlycoGenesys), G17DT immunogen (gastrin inhibitor, Aphton), efaproxiral (oxygenator, Alios Therapeutics), PI-88 (heparanase inhibitor, Progen), tesmilifene (histamine antagonist, YM BioSciences), histamine (histamine H2 receptor agonist, Maxim), tiazofurin (IMPDH inhibitor, Ribapharm), cilengitide (integrin antagonist, Merck KGaA), SR-31747 (IL-1 antagonist, Sanofi- Synthelabo), CCI-779 (mTOR kinase inhibitor, Wyeth), exisulind (PDE V inhibitor, Cell Pathways), CP-461 (PDE V inhibitor, Cell Pathways), AG-2037 (GART inhibitor, Pfizer), WX-UK1 (plasminogen activator inhibitor, Wilex), PBI-1402 (PMN stimulant, ProMetic LifeSciences), bortezomib (proteasome inhibitor, Millennium), SRL-172 (T cell stimulant, SR Pharma), TLK-286 (glutathione S transferase inhibitor, Telik), PT- 100 (growth factor agonist, Point Therapeutics), midostaurin (PKC inhibitor, Novartis), bryostatin-1 (PKC stimulant, GPC Biotech), CDA-II (apoptosis promotor, Everlife), SDX-101 (apoptosis promotor, Salmedix), rituximab (CD20 antibody, Genentech, carmustine, Mitoxantrone, Bleomycin, Absinthin, Chrysophanic acid, Cesium oxides, BRAF inhibitors, PDL1 inhibitors, MEK inhibitors, bevacizumab, angiogenesis inhibitors, dabrafenib, ceflatonin (apoptosis promotor, ChemGenex); BCX-1777 (PNP inhibitor, BioCryst), ranpimase (ribonuclease stimulant, Alfacell), galarubicin (RNA synthesis inhibitor, Dong-A), tirapazamine (reducing agent, SRI International), N, acetylcysteine (reducing agent, Zambon), R-flurbiprofen (NF- kappaB inhibitor, Encore), 3 CPA (NF-kappaB inhibitor, Active Biotech), seocalcitol (vitamin D receptor agonist, Leo), 13 l-LTM-601 (DNA antagonist, TransMolecular), efl ornithine (ODC inhibitor , ILEX Oncology), minodronic acid (osteoclast inhibitor, Yamanouchi), indisulam (p53 stimulant, Eisai), aplidine (PPT inhibitor, PharmaMar), gemtuzumab (CD33 antibody, Wyeth Ay erst), PG2 (hematopoiesis enhancer, Pharmagenesis), Immunol™ (triclosan oral rinse, Endo), triacetyluridine (uridine prodrug , Wellstat), SN-4071 (sarcoma agent, Signature BioScience), TransMID-107™ (immunotoxin, KS Biomedix), PCK-3145 (apoptosis promotor, Procyon), doranidazole (apoptosis
promotor, Pola), CHS-828 (cytotoxic agent, Leo), trans-retinoic acid (differentiator, NIH), MX6 (apoptosis promotor, MAXIA), apomine (apoptosis promotor, ILEX Oncology), urocidin (apoptosis promotor, Bioniche), Ro-31-7453 (apoptosis promotor, La Roche), brostallicin (apoptosis promotor, Pharmacia), P-lapachone, gelonin, cafestol, kahweol, caffeic acid, Tyrphostin AG , PD-1 inhibitors, CTLA-4 inhibitors, sorafenib, BRAF inhibitors.
[0073] Non-limiting examples of the anti-cancer agents include bevacizurnab, bortezomib, capecitabine, cetuximab, fluorouracil, imatinib, irinotecan, leucovorin, oxaliplatin, panitumumab, pemetrexed, temozolomide, cisplatin, paclitaxel, erlotinib, sunitinib, lapatinib, sorafenib, carboplatin, doxorubicin, docetaxel, gemcitabine, etoposide, gefitinib, PD153035, cetuximab, bevacizurnab, panitumumab, trastuzumab, anti-c-Met antibodies, gefitinib, ZD6474, EMD-72000, pariitumab, ICR- 62, CI-1033, lapatinib, AEE788, EKB-569, EXEL 7647/EXEL 0999, erlotinib, imatinib, sorafinib, sunitinib, dasatinib, vandetinib, temsirolimus, PTK787, pazopanib, AZD2171, everolimus, seliciclib, AMG 706, axitinib, PD0325901, PKC-412, CEP701, XL880, bosutinib, BIBF1120, BIBF1120, nilotinib, AZD6244, HKL272, MS-275, BI2536, GX15-070, AZD0530, enzastaurin, MLN-518, ARQ197, CM101, IFN-. alpha., IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonists, angiostatic steroids plus heparin, Cartilage-Derived Angiogenesis Inhibitory Factor, matrix metalloproteinase inhibitors, batimastat, marimastat, angiostatin, endostatin, 2- methoxyestradiol, tecogalan, thrombospondin, .alpha.V.beta.3 inhibitors, linomide, and ADH-1, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, carboplatin, cisplatin, satraplatin, oxaliplatin, altretamine, ET-743, XL119, dacarbazine, chlormethine, bendamustine, trofosfamide, uramustine, fotemustine, nimustine, prednimustine, ranimustine, semustine, nedaplatin, triplatin tetranitrate, mannosulfan, treosulfan, temozolomide, carboquone, triaziquone, triethylenemelamine, procarbazin, doxorubicin, daunorubicin, epirubicin, idarubicin, anthracenedione, mitoxantrone, mitomycin C, bleomycin, dactinomycin, plicatomycin, irinotecan, camptothecin, rubitecan, belotecan, etoposide, teniposide, topotecan, paclitaxel, taxol, docetaxel, BMS-275183, xyotax, tocosal, vinorlebine, vincristine, vinblastine, vindesine, vinzolidine, etoposide, teniposide, ixabepilone, larotaxel, ortataxel, tesetaxel, ispinesib, fluorouracil, floxuridine, methotrexate, xeloda, arranon, leucovorin, hydroxyurea, thioguanine, mercaptopurine, cytarabine, pentostatin, fludarabine phosphate, cladribine, asparaginase,
gemcitabine, pemetrexed, bortezomib, aminopterin, raltitrexed, clofarabine, enocitabine, sapacitabine, azacitidine.
[0074] Additional examples of the anticancer agents include alkylating agents, such as thiotepa and cyclosphosphamide; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophy cins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5- oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; anti-metabolites, such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogues, such as denopterin, pteropterin, and trimetrexate; purine analogs, such as fludarabine, 6- mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenals, such as mitotane and trilostane; folic acid replenisher, such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKpolysaccharide complex; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2”-tri chlorotri ethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; taxoids, e.g., paclitaxel and docetaxel gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluorometlhylomithine (DMFO); retinoids, such as retinoic acid; capecitabine; carboplatin, procarbazine, plicomycin, gemcitabien, navelbine, famesyl-protein transferase inhibitors, transplatinum, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.
[0075] In some embodiments of the methods described herein, the anti-cancer agents are selected from HER2 targeted agent, alkylating agent (e.g. Cyclophosphamide), anthracyclines (e.g., Doxorubicin, Doxil (liposomal doxy), Epirubicin), anti-metabolite (e.g. Capecitabine (Xeloda), Fluorouracil, Gemcitabine, Methotrexate) microtubule inhibitor (Docetaxel, Paclitaxel, Eribulin, Ixabepilone, Vinorelbine), mTOR inhibitor (e.g. Afinitor), immunotherapy (e.g. Atezolizumal), hormonal (anti-estrogen) agent (e.g. Tamoxifen (SERMS - blockers), Toremifene, Fulvestrant (degrader or SERDs), Ethinylestradiol, Flucxymesterone, Megestrol lacetate), aromatase inhibitor (e.g. Anastrozole, Letrozole, Exemestane), PIK3CA inhibitor (e.g. Alpelisib), anti-bone metastasis agent (Zoledronic acid, Pamidronate, denosumab), and immune checkpoint inhibitor. In some embodiments, these agents are used for the treatment of breast cancer.
[0076] Non-limiting examples of Her2-targeted agents include trastuzumab, pertuzumab, lapatinib, neratinib, Fam-traz deruxtecan-nki, T-DM1 and Trastuzumab and substitutes (Kanjinti, Ogivri, Herzuma, Ontruzant, Trazimera), and antibody-drug conjugate thereof (e.g. Trastuzumab duocarm azine).
[0077] Non-limiting examples of checkpoint inhibitors include inhibitors of PD-1, PD-L1, CTLA4 and TIGIT (T cell immunoglobulin and ITIM domain). Further examples include Ipilimumab (Yervoy®; blocking a checkpoint protein called CTLA-4); pembrolizumab (Keytruda®), Cemiplimab (Libtayo) and nivolumab (Opdivo®) (targeting another checkpoint protein called PD- 1); atezolizumab (Tecentriq®), Avelumab (Bavencio), and Durvalumab (Imfinzi) (targeting PD-L1); MK-7684, Etigilimab /OMP-313 M32, Tiragolumab/MTIG7192A/RG-6058, BMS-986207, AB-154 and ASP-8374 (targeting TIGIT).
[0078] Further examples include Irinotecan, Nivolumab, Ipilimumab, Oxaliplatin, Cetuximab, Panitumumab, Dabrafenib, Trametinib, Encorafenib, Bevacizumab, 5-FU, Capecitabine, Pembrolizumab, Ramucirumab, and Ziv-aflibercept. In some embodiments, these agents are used for the treatment of colorectal cancer.
[0079] Further examples of agent for chemotherapy include SHP2 inhibitors (e.g. RMC-4550 and RMC-4630), phosphatase inhibitors (e.g. Tautomycin), CDK 4/6 inhibitors (abemaciclib (Lilly), palbociclib (Pfizer)) and protein-protein interaction disruptors (BI 1701963).
[0080] In some embodiments, the methods disclosed herein include administering to the subject one or more anti-cancer agents described above. Additional immunotherapies may be used in combination or in conjunction with methods of the embodiments. In the context of cancer treatment, immunotherapeutics, generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells. Rituximab (RITUXAN®) is such an example. The immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell. The antibody alone may serve as an effector of therapy or it may recruit other cells to actually affect cell killing. The antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve as a targeting agent. Alternatively, the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target. Various effector cells include cytotoxic T cells and NK cells.
[0081] Antibody-drug conjugates have emerged as a breakthrough approach to the development of cancer therapeutics. Cancer is one of the leading causes of deaths in the world. Antibody-drug conjugates (ADCs) comprise monoclonal antibodies (MAbs) that are covalently linked to cell-killing drugs. This approach combines the high specificity of MAbs against their antigen targets with highly potent cytotoxic drugs, resulting in “armed” MAbs that deliver the payload (drug) to tumor
cells with enriched levels of the antigen. Targeted delivery of the drug also minimizes its exposure in normal tissues, resulting in decreased toxicity and improved therapeutic index. The approval of two ADC drugs, ADCETRIS® (brentuximab vedotin) in 2011 and KADCYLA® (trastuzumab emtansine or T-DM1) in 2013 by FDA validated the approach. Another example is Trastuzumab duocarmazine. There are currently more than 30 ADC drug candidates in various stages of clinical trials for cancer treatment. As antibody engineering and linker-payload optimization are becoming more and more mature, the discovery and development of new ADCs are increasingly dependent on the identification and validation of new targets that are suitable to this approach and the generation of targeting MAbs. Two criteria for ADC targets are upregulated/high levels of expression in tumor cells and robust internalization.
[0082] Examples of immunotherapies include immune adjuvants, e.g., Mycobacterium bovis, Plasmodium falciparum, dinitrochlorobenzene, and aromatic compounds (U.S. Patents 5,801,005 and 5,739,169; Hui and Hashimoto, 1998; Christodoulides etal., 1998); cytokine therapy, e.g., interferons , > > and □, IL-1, GM-CSF, and TNF (Bukowski et al., 1998; Davidson et al., 1998; Hellstrand et al., 1998); gene therapy, e.g., TNF, IL-1, IL-2, and p53 (Qin et al., 1998; Austin-Ward and Villaseca, 1998; U.S. Patents 5,830,880 and 5,846,945); and monoclonal antibodies, e.g., anti-CD20, antiganglioside GM2, and anti-pl85 (Hollander, 2012; Hanibuchi et al., 1998; U.S. Patent 5,824,311). It is contemplated that one or more anti-cancer therapies may be employed with the antibody therapies described herein.
[0083] It is contemplated that other agents may be used in combination with certain aspects of embodiments of the methods described herein to improve the therapeutic efficacy of treatment. These additional agents include agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents. Increases in intercellular signaling by elevating the number of GAP junctions would increase the anti- hyperproliferative effects on the neighboring hyperproliferative cell population. In other embodiments, cytostatic or differentiation agents can be used in combination with certain aspects of the present embodiments to improve the anti-hyperproliferative efficacy of the treatments. Inhibitors of cell adhesion are contemplated to improve the efficacy of the present embodiments. Examples of cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further
contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with certain aspects of the present embodiments to improve the treatment efficacy.
[0084] In some embodiments of the methods described herein, the subject has received one, two, three, four, five, six, seven, eight or more lines of therapy, including for example, one or more anti-cancer agents described above. In some embodiments, the subject has received one, two, three, four, five, six, seven, eight or more lines of therapies selected from Her2 -targeted agent, non-exon 20 insertion-selective tyrosine kinase inhibitor, immune checkpoint inhibitor, radiation therapy, hormone therapy, targeted therapy, stem cell transplant, precision medicine, and other chemotherapy. In some embodiments, the subject has received chemotherapy only (e.g. one, two, three, four, five, six, seven, eight or more anti-cancer agents). In some embodiments, the subject has received a therapy of HER2- targeted agent. In some embodiments, the subject has received therapy of an immune checkpoint inhibitor. In some embodiments, the subject has received therapy of an immune checkpoint inhibitor but without a HER2 -targeted agent. In some embodiments, the subject has not received therapy of other EGFR or HER2 Exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI). In some embodiments, the cancer has developed resistance to one, two, three or more anti-cancer agents or therapies, including for example, one or more anti-cancer agents described above.
[0085] The poziotinib or a pharmaceutically acceptable salt thereof may be administered before, during, after, or in various combinations relative to an additional cancer therapy, such as immune checkpoint therapy. The administrations may be in intervals ranging from concurrently to minutes to days to weeks. In embodiments where the poziotinib or a pharmaceutically acceptable salt thereof is provided to a patient separately from an additional therapeutic agent, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the two compounds would still be able to exert an advantageously combined effect on the patient. In such instances, it is contemplated that one may provide a patient with the antibody therapy and the anticancer therapy within about 12 to 24 or 72 h of each other and, more particularly, within about 6-12 h of each other. In some situations it may be desirable to extend the time period for treatment significantly where several days (2, 3, 4, 5, 6, or 7) to several weeks (1, 2, 3, 4, 5, 6, 7, or 8) lapse between respective administrations. In some embodiments, poziotinib or the pharmaceutically acceptable salt thereof is administered at a dose of 5-25 mg. In some embodiments, the subject is
administered the hydrochloride salt of the poziotinib at a dose of 8 mg, 12 mg, or 16 mg. In some embodiments, poziotinib or the pharmaceutically acceptable salt thereof is administered daily. In some embodiments, poziotinib or the pharmaceutically acceptable salt thereof is administered on a continuous basis. In some embodiments, poziotinib or the pharmaceutically acceptable salt thereof is administered on 5, 7, 10, 14 or 28 day cycles.
[0086] A related aspect discloses a kit for treating cancer of solid tumor, such as those disclosed herein. An example of such a kit may include poziotinib or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions for use of the kit. The kit may further comprise instructions for use of the primers to detect the presence or absence of the specific EFGR and/or HER2 activating mutations described herein. The kit may further comprise instructions for diagnostic purposes, indicating that a positive identification of EGFR and/or HER2 activating mutations described herein in a sample from a cancer patient indicates sensitivity to the poziotinib or a pharmaceutically acceptable salt thereof. The kit may further comprise instructions that indicate that a positive identification of EGFR and/or HER2 activating mutations described herein in a sample from a cancer patient indicates that a patient should be treated with poziotinib or a pharmaceutically acceptable salt thereof. The kit may further include an additional agent described herein for use in combination with poziotinib or a pharmaceutically acceptable salt thereof.
[0087] The following embodiments further illustrate the methods disclosed herein.
[0088] In some emodiments of this patent document, there is disclosed poziotinib or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for use as a medicament for treating cancer of solid tumor in a subject, wherein the subject has been determined to have one or more EGFR or HER2 activating mutations. In some embodiments, the cancer is selected from breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer (i.e., cholangiocarcinoma), bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some embodiments, the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. In some
embodiments, the subject has been determined to have one or more HER2 activating mutations selected from the group consisting of S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R. In some embodiments, the subject has been determined to have one or more EGFR activating mutations selected from the group consisting of EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, V742I, E746_A750del, L747X, A750P, S768VV769L, S768I/V774M, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V. In some embodiments, the subject is free from T798M or T798I in HER2 or T790M in EGFR. In some embodiments, the subject has previously received one, two, three or more lines of therapy for the cancer. In some embodiments, the subject has been determined to be HER2-positive with HER2 activating mutations and the cancer has developed resistance to an anti-cancer agent selected from the group consisting of HER2 targeted agent, alkylating agent, anthracycline, anti-metabolite, microtubule inhibitor, motor inhibitor, immunotherapy, hormonal (anti -estrogen) agent, aromatase inhibitor, PIK3CA inhibitor, anti-bone metastasis agent, immune checkpoint inhibitor, and any combination thereof. In some embodiments, the cancer is breast cancer. In some embodiments, the subject the subject has been determined to be HER2-positive with HER2 activating mutations and has been treated with an anti-cancer agent and the cancer has progressed during the treatment, wherein the anti-cancer agent is selected from the group consisting of Irinotecan, Nivolumab, Ipilimumab, Oxaliplatin, Cetuximab, Panitumumab, Dabrafenib, Trametinib, Encorafenib, Bevacizumab, 5-FU, Capecitabine, Pembrolizumab, Ramucirumab, Ziv-aflibercept, and any combination thereof. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is a high-grade glioma. In some embodiments, the subject has not received chemotherapy, biologies, immunotherapy, HER2 targeted therapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy, or curative-intent radiotherapy for the treatment of the cancer. In some embodiments, the cancer is metastatic. In some embodiments, the cancer is advanced. In some embodiments, the subject has been determined to have HER2 activating mutations. In some embodiments, the poziotinib or the pharmaceutically acceptable saltthereof is administered orally. In some embodiments, the subject is administered the hydrochloride salt of the poziotinib. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered at a dose of about 5 to about 25 mg. In some embodiments, the subject is administered the hydrochloride salt of the poziotinib at a daily dose of about 8 mg, about 10 mg, about 12 mg, about 14 mg, or about 16 mg. In some embodiments, the poziotinib or the pharmaceutically
acceptable salt thereof is administered at a daily dosage of about 14 mg or about 16 mg. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof is administered on 28 day cycles. In some embodiments, the use further includes administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is chemotherapy, radiotherapy, gene therapy, surgery, hormonal therapy, anti-angiogenic therapy or immunotherapy. In some embodiments, the additional anti-cancer therapy is selected from the group consisting of HER2 targeted agent, alkylating agent, anthracycline, anti-metabolite, microtubule inhibitor, motor inhibitor, immunotherapy, hormonal (anti -estrogen) agent, aromatase inhibitor, PIK3CA inhibitor, anti-bone metastasis agent, immune checkpoint inhibitor, and any combination thereof. In some embodiments, the poziotinib or the pharmaceutically acceptable salt thereof and / or anti-cancer therapy are administered intravenously, subcutaneously, intraosseously, orally, transdermally, in sustained release, in controlled release, in delayed release, as a suppository, or sublingually.
[0089] In some emodiments of this patent document, there is disclosed poziotinib or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for use as a medicament for treating a cancer of solid tumor in a subject, wherein the subject has been determined to be HER2 positive. In some embodiments, the cancer is selected from the group consisting of breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer, bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer. In some embodiments, the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain. In some embodiments, the subject has been determined to have one or more EGFR activating mutations. In some embodiments, the subject has previously received one, two, three or more lines of therapy for the cancer. In some embodiments, the subject has previously received at least trastuzumab and optionally TDM1. In some embodiments, the subject has previously received at least trastuzumab, TDM1 and pertuzumab. In some embodiments,
the cancer is breast cancer. In some embodiments, the cancer is metastatic. In some embodiments, the use includes administering the poziotinib or a pharmaceutically acceptable salt thereof twice a day. In some embodiments, the use includes administering the poziotinib or a pharmaceutically acceptable salt twice a day with a daily dosage of about 16 mg. In some embodiments, the use includes administering a daily dosage of about 24 mg of the poziotinib or a pharmaceutically acceptable salt for two weeks followed by a week of no administration.
[0090] In some emodiments of this patent document, there is disclosed poziotinib or a pharmaceutically acceptable salt thereof in a therapeutically effective amount for use as a medicament for reducing adverse events in treating a subject with cancer, wherein the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 15 mg to about 25 mg. In some embodiments, the subject has previously received one, two, three or more lines of therapy for the cancer. In some embodiments, the subject has previously received at least trastuzumab and optionally TDM1. In some embodiments, the subject has previously received at least trastuzumab, TDM1 and pertuzumab. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is metastatic. In some embodiments, the use includes administering administering the poziotinib or a pharmaceutically acceptable salt twice a day with a daily dosage of about 14 mg or about 16 mg. In some embodiments, the use includes administering administering a daily dosage of about 24 mg of the poziotinib or a pharmaceutically acceptable salt for two weeks followed by a week of no administration. In some embodiments, the use includes administering administering a daily dosage of about 24 mg of the poziotinib or a pharmaceutically acceptable salt twice a day. In some embodiments, the use includes administering a hydrochloride salt of the poziotinib. In some embodiments, the use includes administering the poziotinib or a pharmaceutically acceptable salt at a selected dose and frequency in order to achieve at least 5, at least 10, at least 15, least 20 or at least 25 continuous days of administration before a first drug interruption. In some embodiments, the use includes administering the poziotinib or a pharmaceutically acceptable salt at a selected dose and frequency in order to reduce drug interruption by at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% in comparison with same daily dosage of QD (once a day) administration.
[0091] Examples
[0092] Example 1. Use of Poziotinib in Patients with Solid Tumors, with EGFR or HER2 Activating Mutations.
[0093] To evaluate the efficacy and the safety/tolerability of poziotinib in patients having solid tumors, a study protocol including three (3) patient cohorts has been designed. Each treatment cycle is 28 calendar days in duration. Figure 1 shows a diagram of study design. The five patient cohorts are:
• Cohort 1: Patients that have HER2 -positive or HER2-negative breast cancer with HER2 activating mutations (see Table A) (N=30)
• Cohort 2: Patients that have colorectal cancer with HER2 activating mutations (see Table A) (N=30)
• Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal cancer) with HER2 activating mutations (see Table A) (N=30)
[0094] This study included a two-stage design in each cohort separately. The First-Stage of each cohort enrolled 9 patients. A cohort would enroll patients into Second-Stage if the required responses were observed in 9 patients in the First-Stage in each cohort.
[0095] Patients in all cohorts orally self-administered poziotinib within 30 minutes after consumption of a meal at approximately the same time each day. Poziotinib were administered with approximately 240 mL (8 fluid ounces) of water. All patients were given loperamide, for daily use, starting from the first day of the study (4 mg two to three times a day or according to treating physician’s instruction).
[0096] The Screening period (Day -30 to Day 1) lasts up to 30 days prior to Cycle 1, Day 1. Patients must provide written Informed Consent prior to undergoing any study procedure. Patients must meet all Inclusion/Exclusion Criteria in order to participate in the study. Each treatment cycle is 28 calendar days in duration. Tumor assessments were scheduled at Baseline/pre-dose, Week 4, Week 8 and every 8 weeks thereafter. Baseline tumor assessments could be within 30 days prior to Cycle 1, Day 1.
[0097] The primary treatment period for all patients were from the time of the first dose of poziotinib to the first occurrence of disease progression, intolerable adverse events, the start of a new anticancer treatment, death or reaching a maximum of 24 months on therapy. The primary, secondary, and exploratory efficacy endpoints were evaluated from the primary treatment period data.
[0098] At the time of disease progression, the patient continued to receive poziotinib only if the following criteria were met: absence of symptoms and signs indicating clinically significant progression of disease, no decline in ECOG or Karnofsky performance status, and the absence of symptomatic rapid disease progression requiring urgent medical intervention. If the investigator and medical monitor agreed that the patient continued to derive clinical benefits in spite of progression, the patient could continue to receive poziotinib. In addition, the patient was made aware of therapeutic options and reconsented.
[0099] Study and Treatment Duration
[0100] The total duration of the study was approximately 3 years although patients were treated until meeting a discontinuation criterion. The duration of study participation for each patient included the following:
• Screening Period: Up to 30 days
• Primary Treatment Period: 28 days per cycle for up to 24 months of treatment or until death, intolerable adverse events, progressive disease or other protocol-specified reasons for patient withdrawal or a maximum of 24 months
• End-of-Treatment Visit: 35 (±5) days after the last dose of poziotinib
[0101] Patient Enrollment and Participation
[0102] Prior to enrollment, the following inclusion and exclusion criteria were to be met in order to participate in the study.
[0103] Inclusion Criteria:
1. Patient is 18 years of age or older
2. Patient must be willing and capable of giving written Informed Consent, adhering to dosing and visit schedules, and meeting all study requirements
3. Patient has a metastatic solid tumor that has no available standard therapy
4. Breast cancer patients must have an NGS HER2 activating mutation:
• IHC HER2-positive (based on ASCO/CAP guidelines) are included only when they have progressed on trastuzumab, pertuzumab, and T-DM1
• IHC HER2-negative (based on ASCO /CAP guidelines), prior treatment with trastuzumab, pertuzumab, and T-DM1 is not required
• ER-positive (based on ASCO/CAP guidelines) are permitted to continue endocrine therapy concurrently with the study Patients with colorectal cancer who are MSI-H should have progressed on pembrolizumab or nivolumab or nivolumab/ipilimumab. Patient is positive for EGFR or HER2 mutations based on DNA genetic testing of either tumor tissue or plasma samples, but tissue is preferred. Patients with documented EGFR or HER2 mutations are identified by local testing from participating sites using next generation sequencing (NGS) test such as OncoMine Comprehensive Assay (OCA), Guardant360 Assay, or FoundationOne Assay that detects specific mutations, performed by a US CLIA certified and CAP accredited clinical laboratory or similarly accredited lab for ex-US sites using tissue or plasma samples. Patient with a solid tumor with at least one of the listed activating mutations (see Table A below). Patient has measurable disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and/or RANO Criteria. These target lesion(s) must be radiographically measurable. CNS metastatic lesion cannot be considered target lesions in Cohorts 1-3. Brain metastases may be allowed if patient’s condition is stable. Stable brain metastases are defined as stable symptoms, no requirement for high dose or increasing doses of systemic corticosteroid, nor progression on imaging studies for at least 4 weeks prior to enrolment. If applicable, patients must complete brain radiation therapy and return to suitable condition prior to eligibility assessment of the study. For the patient who has had radiation therapy, post-treatment MRI tests should show no increases in brain lesion size/volume and there should be no new lesions compared to pre-treatment MRI for at least 4 weeks. A new lesion is defined as lesion size greater than 5 mm and not previously present and/or not requiring radiation therapy. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
10. Patient has recovered from prior systemic therapy for metastatic disease to Grade <1 for non-hematologic toxicities (except for Grade <2 peripheral neuropathy) and has adequate hematologic, hepatic, and renal function at Baseline, as defined by:
• Absolute neutrophil count (ANC) must be > 1 .0/ 109/L
• Platelet count >75 x 109/L
• Hemoglobin >9.0 g/dL
• Total bilirubin < 1.5 x ULN; if hepatic metastases are present, < 2.0 xULN
• Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) <2.5 xupper limit of normal (ULN); if hepatic metastases are present, <5.0xULN
• Creatinine clearance >50 mL/min (calculated according to Cockcroft and Gault formula: CCr = {((1 40-age) x weight)/(72xSCr)}) x 0.85 (if female), Scr in mg/dL)
• Patient is willing to practice 2 forms of contraception, one of which must be a barrier method, from study entry until at least 30 days after the last dose of poziotinib.
• Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to study treatment. Females who are postmenopausal do not require this test. (Postmenopausal is defined as any of: age > 60 years, age < 60 years and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range, prior bilateral oophorectomy, or if taking tamoxifen or toremifene, and age < 60 years then FSH and plasma estradiol in postmenopausal ranges).
[0105] Exclusion Criteria:
1. Patient has primary tumors in central nervous system (CNS) or in brain, including glioblastoma multiforme (GBM), meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or unstable brain metastasis except if qualified under inclusion criteria for Cohort 4.
2. Patient with T798M or T798I mutations in HER2, or patients with the T790M mutation in EGFR.
3. Patients with breast or gastric cancers with no HER2 mutations (see Table A).
4. Patient has received anticancer chemotherapy, biologies, immunotherapy, targeted therapy (including HER2 targeted therapy), curative-intent radiotherapy, or other investigational treatment within 15 days. Local radiation therapy for bone pain may be allowed. Standard and approved hormonal therapies for hormonal i. receptor positive tumors are allowed.
5. Patient has used strong inhibitors/inducers of CYP3A4 and CYP2D6 within 2 weeks prior to the study.
6. Patient has not recovered (i.e, still at > Grade 1) from drug-induced pancreatitis or has a history of drug-induced pancreatitis.
7. Patient has not recovered (i.e, still at > Grade 1) from interstitial lung disease or has a history of interstitial lung disease or radiation pneumonitis.
8. Patient has Grade 2 or higher skin disorders (rash), mucositis, or stomatitis within 15 days.
9. Patient has a history of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment.
10. Patient has a high risk of cardiac disease, as determined by the Investigator, may undergo either echocardiogram (ECHO) or multi-gated acquisition (MUGA) during Screening and has a cardiac ejection fraction <50%.
11. Patient has a QTcF > 470 ms.
12. Patient has a history of other malignancies within the last 3 years, except for non-melanoma skin cancer, carcinoma in situ of the cervix, or PSA-stable, asymptomatic, early stage of prostate cancer or superficial bladder cancer without active treatment.
13. Patient has clinically significant or recent acute gastrointestinal disease presenting as diarrhea and/or coloenteritis as the main symptom (i.e. acute enteritis, malabsorption, or Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) Grade 2 or higher diarrhea due to other drug-related reasons within 15 days, except fully recovered food poisoning related diarrhea.
14. Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function or malabsorption syndrome.
15. Patient has an active liver disease or biliary tract disease (except for Gilbert’s disease, asymptomatic biliary stones, liver metastasis, or stabilized chronic liver diseases).
16. Patient has a medical condition that in the opinion of the investigator or medical monitor would put her/him at an unreasonable risk including drug toxicity during the trial
17. Patient has known hypersensitivity to poziotinib or history of allergic reactions attributed to compounds of similar chemical composition to poziotinib.
18. Patient has an active or uncontrolled infection, active bleeding disorder, any underlying medical condition, or other serious illness that would impair the ability of the patient to receive protocol treatment.
19. Patient has had recent major surgery or invasive procedure within 15 days prior to starting study treatment.
20. Patient is pregnant or breast-feeding.
[0106] Patient Discontinuation/Withdrawal Criteria
[0107] Patients can withdraw from participation in this study at any time, for any reason, specified or unspecified, and without prejudice.
[0108] All treated patients must be withdrawn from the study at 24 months or earlier due to the following reasons: a. Development of an adverse event (AE) that interferes with the patient’s participation b. Initiation of non-protocol therapy c. Development of progressive disease (PD) d. Patient withdrawal of informed consent e. Delay of poziotinib administration for >28 days since last study drug administration f. Investigator decision g. Sponsor decision h. Lost to follow-up i. Pregnancy j . Death
[0109] The reason for the patient discontinuing study treatment or terminating from the study must be recorded on the case report form (CRF). Patients who discontinue treatment or who were withdrawn from treatment returned for an End-of-Treatment Visit 35 (±5) days after the last dose of poziotinib or prior to beginning a new treatment, whichever was first. If death was recorded as the reason for study discontinuation, the cause of death should be recorded on the CRF.
[0110] Screening
[0111] Informed Consent was obtained prior to the start of any protocol-specified assessments or procedures. The procedures and evaluations required for enrollment into the study are summarized below. All potential study patients will be screened, and eligibility determined prior to enrollment. The results of any procedures or laboratory assessments performed prior to the signing of Informed Consent as part of the site’s routine standard of practice was allowed for use as a Screening Assessment at the discretion of the Sponsor. This information was to be discussed with the Medical Monitor before the patient is enrolled in the study.
[0112] Patients must have disease that was resistant to or relapsed following available standard systemic therapy (according to NCCN or ASCO guidelines), or for which there was no standard systemic therapy or reasonable therapy in the physician’s judgment likely to result in clinical benefit or
if such therapy has been refused by the patient. Documentation of the reason must be provided for patients who have not received a standard therapy likely to result in clinical benefit.
[0113] All procedures are to be performed as outlined in Figure 2 prior to the start of study treatment, unless otherwise noted.
[0114] Patient Assignment
[0115] Each patient who signs an Informed Consent Form for participation in this study was assigned a unique screening number according to the instructions in the study binder.
[0116] Confirmation of eligibility was received by the investigational site from Spectrum prior to enrollment of a patient. After a patient has signed the ICF, the Investigator or site staff should assign a Patient ID. The Patient ID will include two parts: the site number assigned by Spectrum will be comprised of 5 digits with a 2-digit alphabetic country code followed by a 3 -digit site specific numeric code and a hyphenated 3-digit patient sequential number, unique to a site, separated by a hyphen (i.e., US001-001).
[0117] A CRF was only completed for patients who were enrolled and received a Patient ID.
[0118] Screening Visit (Within 30 Days of Cycle 1, Day 1)
[0119] Upon enrollment into the study, the following screening assessments will be performed within 30 days prior to Cycle 1, Day 1.
• Informed Consent
• Relevant medical history
• Demographic data
• Height and weight
• Complete physical examination
• Vital signs
• Eastern Cooperative Oncology Group (ECOG) Performance Status assessment
• Pregnancy test (blood beta-human chorionic gonadotropin [|3-HCG]) in women of childbearing potential
• Tumor assessment: Screening tumor assessment for patient eligibility will be based on scans performed locally within 30 days before the patient signed the ICF; Baseline tumor assessment (either CT, PET/CT, or MRI for non-brain organs and brain MRI) will be performed within 2 weeks prior to, or on Cycle 1, Day 1
• Tumor histopathology report (from local pathologist) and molecular test report for mutation diagnosis
• Complete blood count (CBC) with 5-part differential and platelets prior to poziotinib administration (may be obtained up to 7 days prior to Cycle 1, Day 1)
• Serum biochemistry prior to poziotinib administration (may be obtained up to 7 days prior to Cycle 1, Day 1)
• Electrocardiogram (ECG)
• Echocardiogram or MUGA scan to evaluate cardiac ejection fraction (only for patients who have a high risk of cardiac disease, as determined by the Investigator)
• Tissue sample (from archival or fresh biopsy) for tumor genotyping if it is available
• Plasma sample for biomarker analysis
• Whole blood sample for pharmacogenomic analysis
• Adverse event assessment using NCI CTCAE, version 5.0. Only study-related SAEs to be recorded during Screening
• Concomitant medication review
[0120] Treatment Period -Cycle 1, Day 1
Upon enrollment into the study, the following assessments will be performed for Cycle 1, Day 1.
• Eligibility confirmation
• Patient ID
Height and Weight
Physical examination
• Vital signs
• ECOG Performance Status assessment
• CBC with 5-part differential and platelets
• Serum Chemistry
• Sparse pharmacokinetic sampling
• Dispense poziotinib and loperamide
• Adverse event assessment using NCI CTCAE, version 5.0
• Dispense Patient Diary
• Concomitant medications review
• Contact patient by telephone calls between Day 3- 8 for any AE, such as skin rash and diarrhea, and take action properly
[0121] Treatment Period - Cycle 1, Day 8 (±1 Day)
The following tests and assessments will be performed for Cycle 1, Day 8:
• Complete blood count with 5-part differential and platelets
• Adverse events using NCI CTCAE, Version 5.0
• Patient Diary Review
• Concomitant medications review
[0122] Treatment Period - Cycle 1, Day 14 (±3 Days)
The following tests and assessments will be performed for Cycle 1, Day 14.
• Adverse event assessment using NCI CTCAE, Version 5.0
• Concomitant medications
[0123] Treatment Period - Cycle 2, Day 1
The following tests and assessments will be performed for Cycle 2, Day 1.
Height and Weight
• Physical examination
• Vital Signs
• ECOG Performance Status assessment
• Pregnancy test (urine beta-human chorionic gonadotropin [P-HCG]) in women of childbearing potential
• Tumor assessment: either CT, PET/CT, or MRI for non-brain organs and brain MRI (unless the patient has documented disease progression; the same imaging acquisition method as the baseline should be used)
• Complete blood count with 5-part differential
• Serum biochemistry
• Plasma sample for biomarker analysis
• Sparse pharmacokinetic sampling
• Dispense poziotinib and loperamide
• Adverse event assessment using NCI CTCAE, Version 5.0
• Dispense and Collect Patient Diary
• Concomitant medications review
[0124] Treatment Period - Cycle 2, Day 8 (±1 Day)
The following tests and assessments will be performed for Cycle 2, Day 8:
• Complete blood count with 5-part differential and platelets
• Adverse event assessment using NCI CTCAE, Version 5.0; a telephone call to patient for the follow up of AEs between Days 3 to 8
• Patient Diary review
• Concomitant medications review
[0125] Treatment Period - Cycle 3+, Day 1 (up to 24 months)
The following tests and assessments will be performed for Cycle 3, Day 1 :
• Weight
• Physical examination
• Vital Signs
• ECOG Assessment
• Pregnancy test (urine beta-human chorionic gonadotropin [P-HCG]) in women of childbearing potential
• Tumor assessment: either CT, PET/CT, or MRI for non-brain organs and brain MRI (unless the patient has documented disease progression or has undergone a tumor assessment with the previous 8 weeks; the same imaging acquisition method as the baseline should be used)
• Complete blood count with 5-part differential
• Serum biochemistry
• Plasma sample for biomarker analysis
• Dispense poziotinib and loperamide
• Adverse event assessment using NCI CTCAE, Version 5.0
• Dispense and Collect Patient Diary
• Concomitant medications review
[0126] End-of-Study Visit (35 [±5] Days After Last Dose of Study Treatment)
The End-of-Treatment Visit is required 35 (±5) days after the last dose of poziotinib is administered. The following assessments are to be performed at this visit:
• Height and Weight
• Physical examination
• Vital signs
ECOG Performance Status assessment
• Tumor assessment (either CT, PET/CT, or MRI for non-brain organs and brain MRI (unless the patient has documented disease progression or has undergone a tumor assessment within the previous 8 weeks; same imaging acquisition method as the baseline should be used)
• CBC with 5-part differential and platelets
• Serum biochemistry
• Newly biopsied tumor tissue taken from patients who progress for biomarker analysis (optional, but highly encouraged)
• Plasma sample for biomarker analysis if the patient progresses (optional)
• Adverse event assessment using NCI CTCAE, Version 5.0
• Patient Diary Collection
• Concomitant medications review
[0127] Relevant Medical History
[0128] At Screening Visit, the patient’s relevant medical history was collected, to include previous therapy, as well as significant and relevant past diseases and current medications.
[0129] Physical Examination
[0130] A complete physical examination, including a description of external signs of the neoplastic disease and co-morbidities, was performed at Screening Visit and Day 1 of each cycle, and at the End-of-Study Visit. Symptom-directed examinations were required at other visits. Physical examinations are to be completed by a physician or other health professional licensed to perform such examinations. Findings will be documented in the patient’s medical record and on the appropriate CRF pages. Any abnormalities are to be recorded on the AE CRF.
[0131] Vital Signs
[0132] Vital signs, to include temperature, blood pressure, heart rate, and respiratory rate, are to be recorded at Screening and Day 1 of each cycle and at the End-of-Study Visit. Heart rate and blood pressure will be recorded before poziotinib administration.
[0133] ECOG Performance Status
[0134] Patients’ Performance Status was evaluated using criteria as developed by the Eastern Cooperative Oncology Group at Screening and Day 1 of each cycle and at the End-of-Study Visit.
[0135] Clinical Laboratory Tests
[0136] A local laboratory was used to process all clinical specimens. The following clinical laboratory parameters was evaluated in this study:
[0137] Complete Blood Count (CBC): A CBC, including white blood cells (WBC), with 5-part differential, hemoglobin, and platelets will be performed at Screening, Day 1 and Day 8 of Cycle 1 and Cycle 2, Day 1 of each cycle, and at the End-of-Study Visit. The results of the laboratory assessments should be evaluated and medically accepted by the responsible physician before the start of each cycle.
[0138] Chemistry Panel: A comprehensive chemistry and electrolytes, including blood urea nitrogen (BUN), AST/SGOT, ALT/SGPT, alkaline phosphatase (ALP), total bilirubin, albumin, calcium, lactate dehydrogenase, sodium, potassium, chloride, phosphate, magnesium, creatinine, uric acid, and glucose, will be performed at Screening Visit, Day 1 of each cycle, and at the End-of-Study Visit.
[0139] Special note for the Day 1 sampling of each cycle: If possible, blood samples should be drawn on Day 1 of each cycle (prior to treatment); however, for logistical reasons, it is also acceptable to draw samples for assessment up to 7 days prior to the start of a cycle. The results of the laboratory assessments should be evaluated and medically accepted by the responsible physician before the start of each cycle.
[0140] Pregnancy Test: A blood (at Screening) or urine (on Day 1 of each cycle starting Cycle 2) P-hCG test will be performed for all women of childbearing potential.
[0141] PK Sample
[0142] All patients had blood samples drawn pre-dose and at 1 hour and 3 hours (±15 min) postdose for sparse PK sampling on Day 1 of Cycle 1 and pre-dose on Day 1 of Cycle 2.
[0143] Electrocardiogram (ECG)
[0144] A 12-1 ead ECG was performed at Screening and repeated as needed during the study.
[0145] Cardiac Ejection Fraction
[0146] For patients who are at high risk of cardiac disease, as determined by the Investigator, cardiac ejection fraction may be assessed by either echocardiogram or multi -gated acquisition (MUGA) scan at Screening, and the investigator can order subsequent tests based on patient standard of care as determined by the Investigator.
[0147] Tumor Assessment
[0148] Tumor assessment for study patient’s eligibility must be performed by Investigators using computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI) for non-brain organs and MRI for brain at Screening up to 30 days prior to Cycle 1, Day 1. Imaging studies performed prior to the signing of Informed Consent as part of the site’s routine standard of practice are allowed at the discretion of the Sponsor as the Screening assessment. Brain MRI must be performed to assess the brain metastasis status at the screening per eligibility criteria. This information is to be discussed with the Sponsor’s Medical Monitor before the patient is enrolled in the study. Baseline tumor assessment will be performed within 2 weeks prior to, or on Cycle 1, Day 1. PostBaseline tumor assessments must be performed at Cycle 2 Day 1, at Cycle 3 Day 1, and every 8 weeks thereafter until patient discontinuation or up to 24 months.
[0149] Each subsequent tumor assessment must use the same radiologic technique as in Baseline, either CT, PET/CT, or MRI. Tumor assessments will be made according to RECIST, version 1.1 [14] using appropriate radiologic imaging or other techniques. For radiographic assessment, CT, PET/CT, or MRI must be performed at every assessment.
[0150] Measurable and non-measurable lesions should be documented appropriately.
[0151] Tumor assessment is based on the study investigator’s assessment with local radiology review and report according to the RECIST 1.1 and/or RANO (for Cohort 4) criteria for response evaluation.
[0152] Tissue, Plasma, and Whole Blood Samples Retained
[0153] Tissue samples at Screening, if available, are acquired prior to Cycle 1, Day 1 during the screening period. If possible, tumor tissue samples from a biopsy when progression occurs during the study should be collected. This is not mandatory but is highly encouraged. The tumor tissue will be used
for genetic analysis (DNA and or RNA sequencing) to understand poziotinib response and resistance mechanisms.
[0154] Plasma Samples
[0155] Plasma samples are required at baseline (prior to start of study treatment), and optional on the day of each on-study imaging session, beginning at the 8-week imaging session, once every 8 weeks with imaging scan. The plasma samples will be used for genetic analysis (DNA sequencing) to understand poziotinib response mechanism and progression of disease. Guardant’s 360 or FoundationACT assays will be used, Plasma sample collection and storage will follow vendors’ standard procedures as described in the vendors’ Laboratory Manual.
[0156] Whole Blood Samples
[0157] Whole blood samples were collected once at Screening or during the study for pharmacogenomic analysis.
[0158] All medications administered from Screening to the Safety Follow-up Visit were recorded on the CRF. A concomitant medication is any medication a patient is using from Day 1 of Cycle 1 to the Safety Follow-up Visit. Poziotinib is not considered a concomitant medication.
[0159] All concomitant medications recorded at study entry must have a related, ongoing concomitant illness listed under the medical history at the time of patient entry into the trial. Patients may continue to use any ongoing medications not prohibited by the protocol.
[0160] All prescription and over-the-counter medications at trial entry as well as any new medications started during the trial must be documented on the CRF and in the source documents. The documentation should continue until 35 (±5) days after the last dose of poziotinib.
[0161] Premedications (such as anti emetics) used for supportive care are allowed as per institutional standards or guidelines and Investigator discretion.
[0162] Other supportive and palliative therapies may be allowed during the study upon prior authorization from Sponsor’s Medical Monitor.
[0163] Possible Drug Interactions
[0164] Poziotinib is a substrate for cytochrome P450 (CYP) 3A4 and 2D6 enzymes. Patients may be taking medications that are strong inhibitors or inducers of these two enzymes (Table 1). The
plasma concentration of poziotinib could be different in these patients. The Investigator should try to substitute a medication that is not a strong inhibitor/inducer of these enzymes, if possible. If there is not an available substitute for a medication that a patient is taking or the patient is not willing to change medications, the Investigator must monitor the patient closely for possible AEs or changes in response.
[0165] Poziotinib is also a moderate inhibitor of CYP2C8 and CYP2D6, so patients who take medications that are sensitive substrates for these two enzymes (Table 1) should be followed closely for possible changes in the patient’ s response to these medications. Patients should be advised that grapefruit juice and St. John’s Wort should be avoided during the study treatment.
[0166] Table 1 Examples of Important Clinical Inhibitors/Inducers/Substrates for P450 Enzymes Involved in the Metabolism of Poziotinib
Source: htps://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm
[0167] Premedication and Supportive Treatment
[0168] Pre-medications, as per Institutional standard of care as determined by the Investigator, should be administered before poziotinib on Day 1. All supportive medications for potential diarrhea and rash management should be distributed to the patient on Day 1 with instructions on their use.
[0169] Diarrhea Management
[0170] Spectrum will supply loperamide for diarrhea management. Diarrhea should be monitored very closely. Diarrhea can be managed per standard of care as determined by the Investigator, Institutional Guidelines, or considering the algorithm.
[0171] Mucositis Management
[0172] Mucositis/stomatitis can be treated in a supportive manner aiming to control symptoms. Prophylactic methods to reduce or prevent mucositis/stomatitis include:
• Avoidance of spicy, acidic, or irritating foods and alcoholic drinks
• Use of solutions such as saline (diluted solution with salt water and baking soda by dissolving a 2 teaspoon of salt and 1 teaspoon of baking soda in approximately 1 liter of water) and using this solution every 4 hours
• Use of Nystatin solution
• Use of Magic Mouthwash (for instance, a combination of viscous lidocaine 2% + Mylanta + diphenhydramine elixir + prednisolone solution
[0173] Rash Management
[0174] Rash may be managed according to the algorithm and/or per standard of care as determined by the Investigator or Institutional Guidelines.
[0175] Paronychia management
[0176] Paronychia may be managed according to the algorithm and/or per standard of care as determined by the Investigator or Institutional Guidelines
[0177] Uses of Warfarin or Other Coumadin-Derived Anticoagulants
[0178] Warfarin or other coumadin-derived anticoagulants should be used cautiously during treatment with poziotinib. When it cannot be avoided, regular monitoring of INR is required, and prior authorization from the Sponsor’s Medical Monitor is required.
[0179] No additional cytotoxic agents, biologic therapy, or immune response modifiers for cureintent purpose are to be administered to patients until study treatment has been discontinued.
[0180] Prohibited Therapies or Medications
[0181] No other anti-cancer therapy, including chemotherapy, radiation therapy, immunotherapy, target therapy (including HER2 targeted therapy), biologies, or experimental medications, are permitted during the trial. Any disease progression that requires anti-tumor therapy will be a cause for discontinuation from the study.
[0182] Biomarker and molecular analyses
[0183] Plasma or tumor samples are collected for EGFR or HER2 activating mutations. Plasma hepatocyte growth factor (HGF) concentration can be determined using quantitative sandwich enzyme immunoassay technique (Seoul Clinical Laboratories Co., Ltd., Yongin, Korea).
[0184] STUDY DRUG AND PHARMACEUTICAL INFORMATION
[0185] Study treatment was handled and administered according to the study sites’ regulations for the handling and administration of cytotoxic anticancer agents.
[0186] Poziotinib Composition and Formulations
[0187] The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration. Poziotinib tablets are supplied in 2.0-mg and 8.0-mg dose strengths and contain 2.0 mg and 8.0 mg of poziotinib hydrochloride salt, respectively.
[0188] Poziotinib is supplied as 8-mg and 2-mg tablets and will be administered on an outpatient basis orally once daily at approximately the same time each day with food and a glass of water. In the food effect study, it was shown that geometric mean plasma concentration (Cmax) of poziotinib in the fed state was about 27% lower than the fasted state. The rationale for administering poziotinib with food is to reduce any potential toxicity that is associated with the Cmax.
[0189] If the poziotinib dose is missed, this dose may be administered any time during the day, but at least 8 hours prior to the next scheduled dose.
[0190] Poziotinib Storage and Handling
[0191] Dosing modification recommendations are described in the table below. Dose reductions are in 2 mg increments, regardless of starting dose and will be at the Investigator’s discretion. The Sponsor should be notified. Dose reductions other than by 2 mg increments require the Sponsor’s Medical Monitor approval.
[0192] No dose reductions below 8 mg/day are allowed.
[0194] If the patient has a first documented confirmed progression, the patient may stay on therapy at their current dose or can be increased up to the starting dose of 16 mg/day at the discretion of the Investigator based on the patient’s tolerability to the drug, investigator’s opinion that the patient is still deriving clinical benefits and consideration of other available treatments but must be approved by the Sponsor’s Medical Monitor prior to implementation.
[0195] Safety Measures
[0196] Safety data was reviewed on a regular basis by the monitoring team from the Spectrum Pharmaceuticals, Inc. or its designee.
[0197] Adverse events were characterized by intensity (severity), causality, and seriousness by the Investigator based on the regulatory definitions included below.
[0198] This study utilized the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Scale Version 5.0 for AE grading.
[0199] Adverse Events
[0200] An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. A treatment-emergent AE (TEAE) is any AE that occurs from the first dose of study treatment until 35 (±5) days after the last dose of study treatment.
[0201] The study recorded all AEs according to the information in Section 7.3. Examples of AEs include:
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.
• New conditions detected or diagnosed after investigational product administration.
• Signs, symptoms, or the clinical sequelae of a suspected drug interaction.
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational drug or a concurrent medication.
• AEs may include pre-treatment or post-treatment events that occur as a result of protocol- mandated procedures (e.g., invasive procedures).
[0202] Abnormal laboratory results are to be recorded as AEs, if any of the following conditions are met:
• The abnormal laboratory value leads to a therapeutic intervention.
• The abnormal laboratory value is considered to be clinically significant by the Investigator.
• The abnormal laboratory value is predefined as an AE in the protocol or in another document communicated to the Investigator by Spectrum or designee.
[0203] Examples of events that do not constitute AEs include:
• Medical or surgical procedures (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.
• Situations where an untoward medical occurrence does not occur (e.g., social and/or convenience admission to a hospital).
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that does not worsen.
• Planned and prescheduled hospitalizations and procedures.
• Progressive disease and death due to disease progression.
[0204] The adverse events of special interest identified with poziotinib treatment include diarrhea, skin rash, oral cavity mucositis/stomatitis, fatigue, and vomiting/nausea.
[0205] Guidelines for Recording and Attribution Scoring of Adverse Events
[0206] Timely and complete reporting of all AEs is required for all patients. Monitoring and documentation of all AEs allows for identification of potential study-drug or dose-related AEs, and for adherence to regulatory requirements. Please refer to the CRF Completion Guidelines located in the study binder for detailed instructions for AE reporting.
[0207] Recording of Adverse Events
[0208] All AEs that occur from the first dose of study treatment through 35 (±5) days after the last dose of study treatment is administered are to be recorded on the AE CRF. From the time the study Informed Consent is signed through the first dose of study drug administration, only SAEs that are related to study procedures are to be recorded.
[0209] The resolution of all AEs must be routinely recorded and be reconciled at the end of the study. The following conventions will be followed when patient completes or discontinues from the study:
• If a patient dies, the date of death should be the date of AE stop for all ongoing AEs at the time of death.
• If a patient discontinues due to an AE(s), the outcome of the AE is to be followed for 35 (±5) days from the date of discontinuation or until the AE has returned to Grade <1. The status of the AE and the date of last contact with the patient will be captured. If the AE has not returned to Grade <1 by the end of the study, the AE stop date should be left as ongoing.
[0210] All AEs will be classified by intensity/severity (Section 7.3.2), relationship to study drug (Section 7.5), and as serious or non-serious (Section 7.7) by the Investigator.
[0211 ] Grading of Adverse Events
[0212] This study will utilize the NCI CTCAE Scale, Version 5.0 for AE grading.
[0213] Follow-up of Adverse Events
[0214] All AEs and significant abnormal laboratory values are to be followed up in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and other applicable regulatory requirements (e.g., United States [US] Code of Federal Regulations [CFR]). All AEs that are ongoing during the treatment period will be followed up for 35 (±5) days from the date of the last dose of poziotinib.
[0215] The Investigator must make a causality assessment and document their opinion as to the relationship of all AEs and SAEs to study treatment (Table 3).
[0217] In addition, the event either occurs immediately following study treatment administration, improves on stopping study treatment, reappears on repeat exposure, or there is a positive reaction at the application site.
[0218] Expectedness
[0219] For investigational drugs, an AE is judged “expected” if its description agrees in nature and severity with the description of AEs previously noted with the study drug as detailed in the current Investigator’s Brochure. An “unexpected” AE is one for which the specificity or severity is neither
consistent with the current Investigator’s Brochure nor the risk information described in the general investigational plan. The Sponsor will be responsible for assessing the expectedness of AEs.
[0220] The most common AEs associated with poziotinib treatment include:
• Diarrhea
Rash/Dermatitis acneiform
• Stomatitis/Mucosal inflammation
• Paronychia
• Nausea
• Decreased Appetite
• Dry Skin
• Fatigue
• Vomiting
• Pruritus
[0221 ] Serious Adverse Events
[0222] In the interest of patient care and to allow Spectrum to fulfill all regulatory requirements, any SAE, regardless of causal relationship to study treatment, is to be reported to the Sponsor within 24 hours of knowledge of the event. SAEs are defined (21 CFR 312.32, ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use E2A Guideline) as those AEs that meet any of the following criteria:
• Results in death.
• Is life-threatening: i.e., any event that, in the opinion of the Investigator, poses an immediate risk of death to the patient from that event.
• Requires inpatient hospitalization or prolongation of existing hospitalization (excluding hospitalizations for study therapy, disease-related procedures, or placement of an indwelling catheter, unless associated with other SAEs).
• Results in a persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions.
• Results in a congenital anomaly/birth defect.
• Includes important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in this definition.
[0223] Adverse events that do not meet any of the above criteria for serious should be regarded as non-serious.
[0224] Serious Adverse Event Reporting
[0225] From the time the study Informed Consent was signed through the first dose of study drug administration, only SAEs that were related to study procedures were recorded. All SAEs that occurred from the first dose of study drug administration through 35 (±5) days after the last dose of study treatment were reported to the sponsor within 24 hours of knowledge of the event.
[0226] Example 2
[0227] Clinical activity of poziotinib in adult patients with HER2 positive metastatic breast cancer who received at least two HER2 therapies was evaluated. Key inclusion and exclusion criteria were as follows:
[0228] Key Inclusion Criteria
* Histopathologically confirmed primary breast cancer with metastatic lesions s Confirmed HER2 overexpression or gene-amplified tumor via immunohistochemistry [IHC] with IHC 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+
« At least 2 prior HER2-directed therapy regimen(s) for MBC, including trastuzumab and T- DM1
« Adequate hematologic, hepatic and renal function defined by
- ANC >1.0X109/L
• Platelet count >100x109/L
• Hemoglobin >9 g/dL
- Total bilirubin <1.5 mg/dL; if hepatic metastases present, <2.5 mg/dL
- AST/SGOT, ALT/SGPT, GGT <2.5xULN; if hepatic metastases present, <5.0xULN
- Creatinine <2.2 mg/dL or calculated creatinine clearance >40 mL/min
& Measurable disease as per RECIST, vl .1 at Screening
[0229] Key Exclusion Criteria
« Previous treatment with poziotinib
Brain metastases that are symptomatic or require therapy to control symptoms; history of radiation, surgery, or other therapy including steroids to control symptoms from brain metastases within 15 days of enrollment o' Received anticancer chemotherapy, biologies, immunotherapy, cure-intent radiotherapy or investigational treatment within 15 days, except for hormone, palliative or supportive therapy o History of congestive heart failure (CHF) Class III/I V as per NYHA functional classification or serious cardiac arrhythmias requiring treatment o Has left ventricular ejection fraction (LVEF) <50% by either echo or MUGA
« Confirmed clinically significant or recent acute gastrointestinal disease presenting with diarrhea and/or enteritis as a main symptom
[0230] Multi-cohort study to establish the dose regimen was as follows. The treatment cycle is illustrated in Figure 3. ORR was assessed by response evaluation criterion in solid tumors (RECIST, vl. l)
Cohort 1 : 24 mg (three 8 mg tablets once daily) for 2 weeks, rest 1 week
Cohort 2: 16 mg (two 8 mg tablets once daily) continuously dosing
[0231] A total of 33 patients were enrolled in cohort 1. Most had stage IV breast cancer and median number of previous HER2 therapy was 3 with a range from 2 to 5 therapies. All 33 patients received trastuzumab, 32 received T-DM1, and 25 received pertuzumab.
[0232] A total of 34 patients were enrolled in cohort 2. Most had stage IV breast cancer and median number of previous HER2 therapy was 3 with a range from 2 to 5 therapies. All 34 patients received trastuzumab, 33 received T-DM1, and 26 received pertuzumab. Figure 4 shows key baseline characteristics of the patients. Figure 5 summarizes prior therapy for the patients.
[0233] In cohort 1, the median number of cycles was 3.0 with one patient who completed up to 34 cycles. Median duration of treatment was 56.0 days with one patient who completed 707 days. The median relative dose intensity was 61.7%. In cohort 2, the median number of cycles was 2.0 with one patient who completed up to 31 cycles. Median duration of treatment was 45.5 days with one patient who completed 660 days. The median relative dose intensity was 55.2%. Poziotinib drug exposure for both cohorts is shown in Figure 6.
[0234] Poziotinib demonstrated clinical activity in both dose groups with confirmed ORR of 23% and 22% respectively in these heavily pre-treated metastatic breast cancer patients. The efficacy results were summarized in Figure 7. Progression-free survival and swimmers plot are shown in Figure 8 and Figure 9 respectively. There was similar treatment related adverse events in both dose groups including diarrhea and rash. Patients with intermittent 24 mg were able to stay loner on therapy with higher dose intensity. Adverse events for both groups are summarized in Figure 10.
[0235] It will be appreciated by persons skilled in the art that fibers described herein are not limited to what has been particularly shown and described. Rather, the scope of the method of treatment is defined by the claims which follow. It should further be understood that the above description is only representative of illustrative examples of embodiments. The description has not attempted to exhaustively enumerate all possible variations. The alternate embodiments may not have been presented for a specific step or component of the method, and may result from a different combination of described steps or components, or that other un-described alternate embodiments may be available for a step or component, is not to be considered a disclaimer of those alternate embodiments. It will be appreciated that many of those un-described embodiments are within the literal scope of the following claims, and others are equivalent.
Claims
1. A method of treating cancer of solid tumor in a subject comprising administering a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has been determined to have one or more EGFR or HER2 activating mutations.
2. The method of claim 1, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, gastric cancer, glioma, anal cancer, appendix cancer, bile duct cancer, bladder cancer, brain tumor, cervical cancer, esophageal cancer, eye cancer, fallopian tube cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, melanoma, oral cancer, ovarian cancer, pancreatic cancer, parathyroid disease, penile cancer, pituitary tumor, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, and vulvar cancer.
3. The method of any one of claims 1-2, wherein the subject has been determined to have one or more HER2 activating mutations at one or more locations selected from the group consisting of Furin-like extracellular region, transmembrane, and kinase domain.
4. The method of any one of claims 1-3, wherein the subject has been determined to have one or more HER2 activating mutations selected from the group consisting of S310F/Y, I655V, V659E, R678Q, V697L, T733I, L755X, I767M, D769H/N/Y, V773M, V777L/M, L786V, V842I, and L869R.
5. The method of any one of claims 1-4, wherein the subject has been determined to have one or more EGFR activating mutations selected from the group consisting of EGFRvIII, R108K, R222C, A289T, P596L, G598V, E709K, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, V742I, E746_A750del, L747X, A750P, S768I/V769L, S768I/V774M, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, and A864V.
6. The method of any one of claims 1-5, wherein the subject is free from T798M or T798I in HER2 or T790M in EGFR.
7. The method of any one of claims 1-6, wherein the subject has previously received one, two, three or more lines of therapy for the cancer.
8. The method of any one of claims 1-7, wherein the subject has been determined to be HER2 -positive with HER2 activating mutations and the cancer has developed resistance to an anti-cancer agent selected from the group consisting of HER2 targeted agent, alkylating agent, anthracycline, antimetabolite, microtubule inhibitor, motor inhibitor, immunotherapy, hormonal (anti-estrogen) agent,
aromatase inhibitor, PIK3CA inhibitor, anti -bone metastasis agent, immune checkpoint inhibitor, and any combination thereof. The method of any one of claims 1-8, wherein the cancer is breast cancer. The method of any one of claims 1-9, wherein the subject has previously received at least trastuzumab and optionally TDM1 or pertuzumab. The method of any one of claims 1-7, wherein the subject the subject has been determined to be HER2 -positive with HER2 activating mutations and has been treated with an anti -cancer agent and the cancer has progressed during the treatment, wherein the anti-cancer agent is selected from the group consisting of Irinotecan, Nivolumab, Ipilimumab, Oxaliplatin, Cetuximab, Panitumumab, Dabrafenib, Trametinib, Encorafenib, Bevacizumab, 5-FU, Capecitabine, Pembrolizumab, Ramucirumab, Ziv-aflibercept, and any combination thereof. The method of any one of claims 1-8 and 11, wherein the cancer is colorectal cancer. The method of any one of claims 1-8 and 11, wherein the cancer is a high-grade glioma. The method of any one of claims 1-13, wherein the cancer is metastatic. The method of any one of claims 1-13, wherein the cancer is advanced. The method of any one of claims 1-15, comprising administering a hydrochloride salt of poziotinib twice a day with a daily dosage of about 14 mg or about 16 mg. The method of any one of claims 1-16, further comprising administering an additional anti -cancer therapy. A method of reducing adverse events in treating a subject with cancer, comprising administering twice a day or administering intermittently and daily a therapeutically effective amount of poziotinib or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the daily dosage of poziotinib or a pharmaceutically acceptable salt thereof ranges from about 14 mg to about 25 mg. The method of claim 18, comprising administering the poziotinib or a pharmaceutically acceptable salt twice a day with a daily dosage of about 14 mg or about 16 mg. The method claim 18, comprising administering a daily dosage of about 24 mg of the poziotinib or a pharmaceutically acceptable salt for two weeks followed by a week of no administration. The method of any one of claims 18-20, wherein a hydrochloride salt of the poziotinib is administered.
The method of any one of claims 18-21, wherein the poziotinib or a pharmaceutically acceptable salt is administered at a selected dose and frequency so that at least 15 continuous days of administration is achieved before a first drug interruption. The method of any one of claims 18-22, wherein the poziotinib or a pharmaceutically acceptable salt is administered at a selected dose and frequency so that drug interruption is reduced by at least 15% in comparison with same daily dosage of QD (once a day) administration.
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WO2020205632A1 (en) * | 2019-03-29 | 2020-10-08 | Board Of Regents, The University Oftexas System | Compounds with anti-tumor activity against cancer cells bearing her2 exon 21 insertions |
WO2022026442A1 (en) * | 2020-07-27 | 2022-02-03 | Spectrum Pharmaceuticals, Inc. | Treatment of non-small cell lung cancer with poziotinib |
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WO2020205632A1 (en) * | 2019-03-29 | 2020-10-08 | Board Of Regents, The University Oftexas System | Compounds with anti-tumor activity against cancer cells bearing her2 exon 21 insertions |
WO2022026442A1 (en) * | 2020-07-27 | 2022-02-03 | Spectrum Pharmaceuticals, Inc. | Treatment of non-small cell lung cancer with poziotinib |
Non-Patent Citations (1)
Title |
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BARAIBAR ET AL.: "Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC", CRIT REV ONCOL HEMATOL, vol. 148, no. 102906, April 2020 (2020-04-01), pages 1 - 13, XP086094303 * |
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32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 20/10/2023) |