WO2022197290A1 - Methods of administering tesetaxel with cyp3a4 inhibitors - Google Patents
Methods of administering tesetaxel with cyp3a4 inhibitors Download PDFInfo
- Publication number
- WO2022197290A1 WO2022197290A1 PCT/US2021/022724 US2021022724W WO2022197290A1 WO 2022197290 A1 WO2022197290 A1 WO 2022197290A1 US 2021022724 W US2021022724 W US 2021022724W WO 2022197290 A1 WO2022197290 A1 WO 2022197290A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tesetaxel
- dose
- patient
- cyp3a inhibitor
- administering
- Prior art date
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Classifications
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Definitions
- Breast cancer is a heterogeneous disease comprised of several molecular subtypes, which are commonly grouped into clinical subtypes based on receptor status.
- Receptors that are assessed in standard clinical practice include the estrogen receptor (ER) and the progesterone receptor (PR), which are collectively referred to as the hormone receptors (HR), and human epidermal growth factor receptor 2 (HER2).
- ER estrogen receptor
- PR progesterone receptor
- HR hormone receptor
- HER2 human epidermal growth factor receptor 2
- Breast cancers generally are categorized by the presence or absence of these receptors. The most common form of breast cancer is HR-positive and HER2-negative, accounting for approximately 64% of newly diagnosed cases.
- HER2- positive breast cancer and triple negative breast cancer (TNBC) which lacks all 3 receptors, are less common, accounting for approximately 13% and 11% of breast cancers, respectively.
- Breast cancer typically is staged (Stage 0-IV) based on the size of the tumor, whether or not the tumor is invasive, whether or not the cancer is in the lymph nodes and whether or not the cancer has spread (metastasized) to other parts of the body beyond the breast, most often the bones, lungs, liver or brain.
- the prognosis for women with locally advanced or metastatic breast cancer (LA/MBC) remains poor; the 5-year survival rate for metastatic disease is about 22%, making this an area of continued, high unmet medical need.
- Tesetaxel is a novel, orally administered taxane.
- Taxanes are an established class of anticancer agents that are broadly used in various cancers, including breast cancer.
- the primary pharmacologic mechanism of tesetaxel is to stabilize cellular microtubule formation (inhibit tubulin depolymerization) in rapidly dividing cells, leading to arrest of unscheduled cell division at the G2/M phase of the cell cycle and cell death.
- Tesetaxel has several pharmacologic properties that make it unique among taxanes: • Tesetaxel is a capsule for oral administration with a low pill burden;
- Tesetaxel has a long ( ⁇ 8-day) terminal plasma half-life (ti/2) in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing;
- Tesetaxel’ s formulation does not contain poly oxy ethylated castor oil or polysorbate 80, solubilizing agents contained in other taxane formulations known to cause hypersensitivity reactions;
- Tesetaxel has been shown to retain activity against taxane-resistant tumors in nonclinical studies.
- tesetaxel includes the addition of two nitrogen- containing functional groups. Tesetaxel is chemically designed to: (1) not be substantially effluxed by the P-gly coprotein (P-gp) pump, with the intent of retaining activity against chemotherapy-resistant tumor cells; (2) have high oral bioavailability, which requires that a drug substantially survive first-pass metabolism in the liver; (3) have high solubility; and (4) have a long ti/2 in humans.
- P-gp P-gly coprotein
- the high oral bioavailability of tesetaxel has been attributed to various causes, including the fact that tesetaxel is a poor substrate for P-gp and CYP3A and thus is absorbed orally and survives first-pass liver metabolism.
- tesetaxel was designed to be a poor substrate for CYP3A relative to other taxanes and thus it could not have been predicted whether tesetaxel could be safely administered to patients with disrupted CYP3A metabolism and, if so, whether any dosage modification would be required.
- the present disclosure relates generally to the discovery of methods for safely administering tesetaxel to patients receiving CYP3A inhibitors.
- the present disclosure provides a method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising administering a first dose to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-
- the present disclosure provides a method for safely treating cancer in a patient receiving treatment with a CYP3A inhibitor, comprising administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- treatment with the CYP3A inhibitor comprises administering a dose of the CYP3A inhibitor on one or more days of the first 21 -day cycle.
- the patient has been diagnosed with a cancer, such as breast cancer.
- the present disclosure provides in various aspects methods of administering tesetaxel to patients receiving treatment with CYP3A inhibitors.
- Those of ordinary skill in the art will appreciate that the tesetaxel dosing methods discussed herein apply to any patient with a CYP3 A inhibitor present in their body at an amount sufficient to substantially alter the pharmacokinetics of tesetaxel when tesetaxel is administered (e.g., patients who are within 3, 4, or 5 half-lives of when the CYP3A inhibitor was administered).
- the population of affected patients thus includes, e.g., those who receive a CYP3A inhibitor during a tesetaxel treatment cycle, as well as those who received a CYP3A inhibitor before beginning tesetaxel therapy.
- the dose adjustments continue until the CYP3A inhibitor in the patient is no longer effective to substantially alter the pharmacokinetics of tesetaxel (e.g., until 3, 4, or 5 half-lives of the CYP3A inhibitor have elapsed).
- the present disclosure provides a method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- the method further comprises administering a second dose of tesetaxel to the patient on day 1 of a second 21 -day cycle, wherein the second dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% of the indicated tesetaxel dose for a patient not receiving treating with a CYP3A inhibitor.
- the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 13.5, 12, 10.5, or 9 mg/m 2 tesetaxel.
- the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 6-24 mg/m 2 tesetaxel, such as 6, 9, 12, 15, 18, or 21 mg/m 2 tesetaxel.
- the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% of the indicated tesetaxel dose for a patient not receiving treating with a CYP3A inhibitor.
- the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- the second dose of tesetaxel for a patient receiving a CYP3A inhibitor comprises 13.5, 12, 10.5, or 9 mg/m 2 tesetaxel.
- the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 6-24 mg/m 2 tesetaxel, such as 6,
- the present disclosure provides a method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising: administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose is an indicated dose of tesetaxel for a patient not receiving treatment with a CYP3A inhibitor; and administering a second dose of tesetaxel to the patient on day 1 of a second 21 -day cycle, wherein the second dose of tesetaxel is 20-80% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- This treatment protocol is useful, for example, when a patient receives a CYP3A inhibitor after administration of the first dose of tesetaxel but before the second dose of tesetaxel.
- the indicated tesetaxel dose for a patient not receiving treatment with a CYP3 A inhibitor is 6-27 mg/m 2 tesetaxel, preferably 18-27 mg/m 2 tesetaxel. In certain embodiments, the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 18, 21, 24, or 27 mg/m 2 tesetaxel, preferably 27 mg/m 2 tesetaxel.
- the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. In certain embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 13.5, 12, 10.5, or 9 mg/m 2 tesetaxel. In certain embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 6-24 mg/m 2 tesetaxel, such as 6, 9, 12, 15, 18, or 21 mg/m 2 tesetaxel.
- first 21 -day cycle and/or a second 21 -day cycle does not necessarily reflect the absolute first 21 -day cycle and the absolute second 21 -day cycle, respectively, but may instead refer to any two consecutive 21 -day cycles.
- a first 21 -day cycle may correspond to a patient’s third absolute 21 -day cycle
- a second 21 -day cycle may correspond to the patient’s fourth absolute 21 -day cycle.
- a first 21 -day cycle may correspond to a patient’s third absolute 21 -day cycle of tesetaxel administration but which is the first 21 -day cycle that is characterized by a reduced dose of tesetaxel (e.g., the first 21 -day cycle that is characterized by a dose of tesetaxel that is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor).
- a second 21 -day cycle may correspond to a patient’s fifth absolute 21 -day cycle of tesetaxel administration but the first 21 -day cycle that is characterized by a reduced dose of tesetaxel (e.g., the first 21 -day cycle that is characterized by a dose of tesetaxel that is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor).
- a reduced dose of tesetaxel e.g., the first 21 -day cycle that is characterized by a dose of tesetaxel that is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
- the present disclosure provides dosing methods that may be flexibly implemented as the patient begins or stops receiving treatment with a CYP3A inhibitor, and contemplates as many cycles of indicated (e.g., 27 mg/m 2 ) or reduced (e.g., 9-24 mg/m 2 ) doses of tesetaxel as required by the individual patient’s CYP3A administration schedule.
- the first dose and the second dose may be equal or different. In certain embodiments, the first dose and the second dose are equal.
- Treatment with the CYP3A inhibitor may comprise administering a dose of the CYP3A inhibitor on one or more days of the first 21-day cycle (e.g., one or more of days 1-21 of the first 21 -day cycle). In certain embodiments, treatment with the CYP3A inhibitor may commence after day 1 of the 21 -day cycle, such as one or more of days 2-21 of the first 21 -day cycle. In certain embodiments, the method comprises administering a dose of the CYP3A inhibitor on one or more days of the second 21 -day cycle.
- CYP3A inhibitors relevant to the methods of the present disclosure include any suitable CYP3A inhibitor.
- CYP3A inhibitors may be classified as strong, moderate, or weak.
- the CYP3A inhibitor is a strong CYP3A inhibitor.
- the CYP3A inhibitor is a moderate CYP3A inhibitor.
- the CYP3A inhibitor is a weak CYP3A inhibitor.
- the Food and Drug Administration defines strong, moderate, and weak inhibitors as drugs that increase the AUC of sensitive index substrates of a given metabolic pathway (such as oral midazolam or other CYP3A substrates) >5-fold, >2- to ⁇ 5-fold, and >1.25- to ⁇ 2-fold, respectively.
- a given metabolic pathway such as oral midazolam or other CYP3A substrates
- United States Food and Drug Administration Guidance for Industry, Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions. January 2020. Clinical Pharmacology.
- Exemplary strong CYP3A inhibitors include boceprevir, ceritinib, clarithromycin, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit, grapefruit juice, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, nefazodone, nelfinavir, lopinavir and ritonavir, paritaprevir and ritonavir (and ombitasvir and/or dasabuvir), pomegranate, pomegranate juice, posaconazole, ribociclib, ritonavir, saquinavir and ritonavir, tipranavir and ritonavirtroleandomycin, tucatinib, and voriconazole.
- Exemplary moderate CYP3A inhibitors include aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, netupitant, palonosetron, tofisopam, verapamil, and voriconazole.
- the effect of grapefruit juice may vary among brands and may be strong or moderate depending on the preparation.
- Exemplary weak CYP3A inhibitors include amiodarone, atomoxetine, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, entrectinib, esomeprazole, fluvoxamine, fosaprepitant, imatinib, istradefylline, ivacaftor, lesinurad, lomitapide, norfluoxetine, omeprazole, pantoprazole, quercetin, ranitidine, ranolazine, simeprevir, and ticagrelor.
- the CYP3A inhibitor is itraconazole.
- CYP3A metabolism in the patient is inhibited.
- the method further comprises administering an antiemetic agent, such as dexamethasone, ondansetron, dolasetron, palonosetron, aprepitant, or rolapitant, or a combination of any of the foregoing.
- an antiemetic agent such as dexamethasone, ondansetron, dolasetron, palonosetron, aprepitant, or rolapitant, or a combination of any of the foregoing.
- the patient has been diagnosed with a cancer.
- the cancer is breast cancer.
- the cancer is locally advanced breast cancer.
- the cancer is metastatic breast cancer.
- the breast cancer is hormone receptor (HR)-positive.
- the patient has previously received endocrine therapy.
- the breast cancer is estrogen receptor (ER)-positive.
- the breast cancer is ER-negative.
- the breast cancer is progesterone receptor (PR)-positive.
- the breast cancer is PR-negative.
- the breast cancer is HER2-negative.
- the breast cancer is HER2-positive.
- the breast cancer is HR-positive and HER2-negative.
- the breast cancer is HR-negative and HER2-negative.
- the method comprises repeating the 21-day cycle at least once (e.g., a first 21-day cycle and a second 21 -day cycle). In some embodiments, the method comprises repeating the 21- day cycle until the cancer progresses or until unacceptable toxicity is observed.
- the tesetaxel may also be conjointly administered with other suitable therapeutic agents.
- tesetaxel and capecitabine may be effectively used in conjoint therapy, as described in International Patent Application PCT/US18/35653, published as WO 2018/223029, which is hereby incorporated by reference herein in its entirety.
- the combination can provide greater efficacy than capecitabine alone.
- the methods disclosed herein may result in longer progression-free survival (PFS), longer survival, a greater treatment response, a longer duration of response and/or better disease control.
- PFS progression-free survival
- the combination is more efficacious as administration of capecitabine alone (e.g ., at a dose of 2,500 mg/m 2 or 2,000 mg/m 2 daily for 14 consecutive days of a 21 -day cycle), and in some embodiments, the combination is more efficacious and has a more tolerable safety profile. More tolerable treatment regimens, such as those disclosed herein, are more likely to be continued by patients, and thus may be more likely to be effective.
- the method comprises administering a therapeutically effective amount of tesetaxel and a therapeutically effective amount of capecitabine conjointly.
- the therapeutically effective amount of tesetaxel is the dose of tesetaxel described herein (e.g., 40-60% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor).
- the therapeutically effective amount of tesetaxel is an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 27 mg/m 2 of tesetaxel.
- the method further comprises administering capecitabine daily starting on day 1 of the 21 -day cycle for 14 consecutive 24-hour periods.
- any suitable dose of capecitabine may be used.
- the daily dosage may be divided into a number of smaller, divided doses, such as 2, 3, 4, 5, 6 or more divided doses.
- the daily dosage of capecitabine is divided into two divided doses.
- a daily dosage regimen may begin with a partial dose on the first day and end with a partial dose on the last day, such that the daily dosage is delivered in a number of 24-hour periods, which may or may not correspond to calendar days.
- dosing of capecitabine is alternately discussed herein in terms of the total daily dosage (i.e., the total amount administered in a day or in a 24-hour period) or in terms of divided doses (i.e., the individual doses administered over the course of a day or a 24- hour period that combine to meet the total daily dosage).
- capecitabine is administered at twice-daily intervals (i.e., 2 times per 24-hour period) for a period of time, such as for 14 consecutive 24-hour periods.
- a first dose of capecitabine is administered on day 1
- subsequent doses are administered at twice-daily intervals with a final dose administered on day 15.
- capecitabine is administered twice daily for 14 consecutive calendar days (i.e., 2 doses of capecitabine are administered on each of days 1-14).
- reference to a number of “daily dosages” of capecitabine herein refers to administering capecitabine for that number of 24-hour periods and encompasses administering capecitabine for that number of calendar days.
- administering a therapeutically effective amount of capecitabine comprises administering capecitabine twice daily on days 1-14 of the 21 -day cycle. In some embodiments, the method comprises administering a therapeutically effective amount of capecitabine in 28 doses at twice-daily intervals beginning on day 1 of the 21 -day cycle. In some embodiments, the method comprises administering a first dose of capecitabine on day 1 of the 21 -day cycle and administering a final 28 th dose on day 15 of the 21 -day cycle.
- administering a therapeutically effective amount of capecitabine comprises administering a first dose of capecitabine after noon (e.g ., in the evening) of day 1 of the 21 -day cycle and administering a final 28 th dose before noon (e.g., in the morning) on day 15 of the 21- day cycle.
- administering a therapeutically effective amount of capecitabine comprises administering 14 daily dosages of 300-2,000 mg/m 2 (such as 1,000-1,800 mg/m 2 ) of capecitabine beginning on day 1 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 14 daily dosages of 1,650 mg/m 2 of capecitabine beginning on day 1 of the 21 -day cycle.
- administering a therapeutically effective amount of capecitabine comprises administering 825 mg/m 2 of capecitabine at twice-daily intervals for 14 consecutive 24-hour periods beginning on day 1 of the 21 -day cycle. In some such embodiments, administering a therapeutically effective amount of capecitabine comprises administering 825 mg/m 2 of capecitabine twice daily on days 1-14 of the 21-day cycle. In other such embodiments, administering capecitabine comprises administering a first dose of 825 mg/m 2 of capecitabine on day 1, administering subsequent doses of 825 mg/m 2 of capecitabine at twice-daily intervals, and administering a final dose of 825 mg/m 2 of capecitabine on day 15.
- administering a therapeutically effective amount of capecitabine comprises administering 14 daily dosages of 1,750 mg/m 2 of capecitabine beginning on day 1 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 875 mg/m 2 of capecitabine at twice-daily intervals for 14 consecutive 24-hour periods beginning on day 1 of the 21 -day cycle. In some such embodiments, administering a therapeutically effective amount of capecitabine comprises administering 875 mg/m 2 twice daily on days 1-14 of the 21 -day cycle.
- administering a therapeutically effective amount of capecitabine comprises administering a first dose of 875 mg/m 2 on day 1, administering subsequent doses of 875 mg/m 2 of capecitabine at twice-daily intervals, and administering a final dose of 875 mg/m 2 of capecitabine on day 15.
- administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 150-1,000 mg/m 2 of capecitabine at twice-daily intervals. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 150-1,000 mg/m 2 of capecitabine at twice-daily intervals for 14 consecutive 24- hour periods. In some such embodiments, administering a therapeutically effective amount of capecitabine comprises administering 150-1,000 mg/m 2 twice daily on days 1-14 of the 21-day cycle.
- administering a therapeutically effective amount of capecitabine comprises administering a first dose of 150-1,000 mg/m 2 of capecitabine on day 1, and administering subsequent doses of 150-1,000 mg/m 2 of capecitabine at twice-daily intervals and concluding by administering a final dose of 150-1,000 mg/m 2 of capecitabine on day 15.
- administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 150-1,000 mg/m 2 of capecitabine at twice-daily intervals beginning with the first dose on day 1 of the 21 -day cycle and ending with the 28 th dose on day 15 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 825 mg/m 2 of capecitabine at twice-daily intervals.
- administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 825 mg/m 2 of capecitabine at twice-daily intervals beginning with the first dose on day 1 of the 21 -day cycle and ending with the 28 th dose on day 15 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 875 mg/m 2 of capecitabine at twice-daily intervals.
- administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 875 mg/m 2 of capecitabine at twice-daily intervals beginning with the first dose on day 1 of the 21 -day cycle and ending with the 28 th dose on day 15 of the 21 -day cycle.
- the patient has previously been treated with a taxane.
- the patient has previously been treated with a taxane in the neoadjuvant or adjuvant setting.
- the taxane is paclitaxel, docetaxel or albumin-bound (nab) paclitaxel.
- the patient has not previously been treated with a taxane.
- the primary cancer is breast cancer, such as MBC or LA/MBC.
- the breast cancer is locally advanced breast cancer.
- the breast cancer is metastatic breast cancer.
- Metastatic breast cancer may include, but is not limited to, breast cancer that has spread to the central nervous system (CNS). Treatment of CNS cancers, including CNS cancers that are metastases of breast cancer, is described in PCT/US2019/049642, filed September 5, 2019 and published as WO 2020/081165, which is hereby incorporated by reference herein in its entirety. Tesetaxel is brain-penetrant; that is, it crosses the blood-brain barrier.
- tesetaxel unlike docetaxel and paclitaxel, may be conveniently utilized in the treatment of tumors of the CNS, such as brain tumors.
- the structures of tesetaxel, docetaxel and paclitaxel are shown below:
- the breast cancer is HR-positive, such as ER-positive or PR- positive. In some embodiments, the patient has previously received endocrine therapy. In some embodiments, the breast cancer is HER2-negative. In some embodiments, the breast cancer is HR-positive and HER2-negative. In some embodiments, the breast cancer is HR-negative (i.e., ER-negative and PR-negative) and HER2-negative. In some embodiments, the breast cancer is HER2-positive. Definitions
- a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
- prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population ( e.g ., by a statistically and/or clinically significant amount).
- treating includes prophylactic and/or therapeutic treatments.
- prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal), then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition); whereas, if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
- the unwanted condition e.g., disease or other unwanted state of the host animal
- terapéuticaally effective amount means the concentration of a compound that is sufficient to elicit the desired therapeutic effect.
- the phrases “conjoint administration,” “administered conjointly,” “receiving conjoint treatment,” and grammatical variations refer to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still therapeutically effective in the body (e.g., the two compounds are simultaneously therapeutically effective in the patient, which may include synergistic effects of the two compounds).
- the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly (i.e., at substantially the same time) or sequentially (i.e., with one compound administered first and the other compound administered at a later time).
- the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 7 days, 14 days or 15 days of one another, or wherein the different therapeutic compounds are administered within the same treatment cycle as one another.
- an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
- prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention.
- a common method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiologic conditions to reveal the desired molecule.
- the prodrug is converted by an enzymatic activity of the host animal.
- esters or carbonates e.g ., esters or carbonates of alcohols or carboxylic acids
- some or all of the compounds of the invention in a formulation represented above can be replaced with the corresponding suitable prodrug (e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester).
- Tesetaxel is a taxane having the following structure:
- Tesetaxel and its preparation are described in U.S. Patent No. 6,677,456, which is incorporated by reference in its entirety.
- Various crystal forms of tesetaxel are described in U.S. Patent No. 7,410,980, which is hereby incorporated by reference in its entirety.
- an “indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor” is the recommended tesetaxel dose on a prescribing information label, which may either be the recommended starting dose or a dose that has been modified as described on the label (exclusive of any modifications for concomitant administration with a CYP3A inhibitor).
- the indicated dose may be reduced from the starting dose following the occurrence of neutropenia or other adverse reaction.
- the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 6-27 mg/m 2 tesetaxel, preferably 18- 27 mg/m 2 tesetaxel.
- the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 18, 21, 24, or 27 mg/m 2 tesetaxel, preferably 27 mg/m 2 tesetaxel.
- compositions and methods of the present invention may be utilized to treat an individual in need thereof.
- the individual is a human.
- the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters.
- the aqueous solution is pyrogen-free, or substantially pyrogen-free.
- the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
- the pharmaceutical composition can be in dosage unit form such as a tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
- the composition can also be present in a transdermal delivery system (e.g ., a skin patch).
- the composition can also be present in a solution suitable for topical administration, such as an eye drop.
- a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, to increase solubility or to increase the absorption of a compound such as a compound of the invention.
- physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
- the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
- the preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self- microemulsifying drug delivery system.
- the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
- Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
- phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit-risk ratio.
- pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
- a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (e.g ., as drenches in aqueous or non-aqueous solutions or suspensions, tablets, capsules [including sprinkle capsules and gelatin capsules], boluses, powders, granules or pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (e.g., as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment or spray applied to the skin, or as an eye drop).
- routes of administration including, for example, orally (e.g
- the compound may also be formulated for inhalation.
- a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
- the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration.
- the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
- Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
- an active compound such as a compound of the invention
- the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
- Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water- in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
- capsules including sprinkle capsules and gelatin capsules
- cachets pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth)
- lyophile powders, gran
- compositions or compounds may also be administered as a bolus, electuary or paste.
- solid dosage forms for oral administration capsules [including sprinkle capsules and gelatin capsules], tablets, pills, dragees, powders, granules and the like)
- the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption
- absorbents such as kaolin and bentonite clay
- lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof
- complexing agents such as, modified and unmodified cyclodextrins
- coloring agents such as, modified and unmodified cyclodextrins
- capsules including sprinkle capsules and gelatin capsules
- the pharmaceutical compositions may also comprise buffering agents.
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high-molecular-weight polyethylene glycols and the like.
- a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared using a binder (e.g ., gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose) or surface-active or dispersing agent.
- Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
- compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
- These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
- embedding compositions that can be used include polymeric substances and waxes.
- the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
- Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art, such
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
- Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
- Formulations of the pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
- Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, oral spray or oral ointment.
- compositions can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum or intestine.
- Formulations that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
- Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
- the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that may be required.
- the ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
- Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
- dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
- Ophthalmic formulations eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention.
- Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference.
- liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids.
- a preferred route of administration is local administration (e.g ., topical administration, such as eye drops, or administration via an implant).
- parenteral administration and “administered parenterally” as used herein mean modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
- compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
- aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
- polyols such as glycerol, propylene glycol, polyethylene glycol and the like
- vegetable oils such as olive oil
- injectable organic esters such as ethyl oleate.
- Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
- compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
- the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
- Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
- active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5%, more preferably, 0.5 to 90%, of active ingredient in combination with a pharmaceutically acceptable carrier.
- Methods of introduction may also be provided by rechargeable or biodegradable devices.
- Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
- a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
- Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
- the selected dosage level will depend upon a variety of factors, including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
- a suitable daily dosage of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
- the effective daily dosage of the active compound may be administered as 1 , 2, 3, 4, 5, 6 or more sub-doses (or divided doses) administered separately at appropriate intervals throughout a day, optionally, in unit dosage forms.
- an active compound may be administered one or two times daily on the days on which it is administered.
- the methods of the invention may be used alone or the compounds administered may be used conjointly with another type of therapeutic agent.
- contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra- alkyl ammonium salts.
- contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl (morpholine, piperazine, potassium, 1 -(2-hydroxy ethyl)pyrrolidine, sodium, triethanolamine, tromethamine and zinc salts.
- contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxyl- naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, e
- the pharmaceutically acceptable acid-addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
- the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
- wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
- antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal- chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
- water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
- oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
- the primary endpoint of the study was the ratio of the geometric mean Cmax for tesetaxel in the presence and absence of itraconazole and the ratio of the geometric mean AUCo-336h for tesetaxel in the presence and absence of itraconazole.
Abstract
The present disclosure provides methods of administering tesetaxel to a patient with a cancer, such as breast cancer, comprising administering tesetaxel with a CYP3A inhibitor.
Description
METHODS OF ADMINISTERING TESETAXEL WITH CYP3A4 TNHTBTTORS
BACKGROUND OF THE INVENTION
Breast cancer is the most common cancer in women worldwide, with an estimated 2.1 million new cases diagnosed per year. In Europe, an estimated 523,000 new cases are diagnosed and approximately 138,000 women will die of the disease each year, making it the leading cause of cancer death in women. In the United States (U.S.), an estimated 271,000 new cases are diagnosed and approximately 42,000 women will die of the disease each year, making it the second-leading cause of cancer death in women.
Breast cancer is a heterogeneous disease comprised of several molecular subtypes, which are commonly grouped into clinical subtypes based on receptor status. Receptors that are assessed in standard clinical practice include the estrogen receptor (ER) and the progesterone receptor (PR), which are collectively referred to as the hormone receptors (HR), and human epidermal growth factor receptor 2 (HER2). Breast cancers generally are categorized by the presence or absence of these receptors. The most common form of breast cancer is HR-positive and HER2-negative, accounting for approximately 64% of newly diagnosed cases. HER2- positive breast cancer and triple negative breast cancer (TNBC), which lacks all 3 receptors, are less common, accounting for approximately 13% and 11% of breast cancers, respectively.
Breast cancer typically is staged (Stage 0-IV) based on the size of the tumor, whether or not the tumor is invasive, whether or not the cancer is in the lymph nodes and whether or not the cancer has spread (metastasized) to other parts of the body beyond the breast, most often the bones, lungs, liver or brain. The prognosis for women with locally advanced or metastatic breast cancer (LA/MBC) remains poor; the 5-year survival rate for metastatic disease is about 22%, making this an area of continued, high unmet medical need.
SUMMARY OF THE INVENTION
Tesetaxel is a novel, orally administered taxane. Taxanes are an established class of anticancer agents that are broadly used in various cancers, including breast cancer. The primary pharmacologic mechanism of tesetaxel, like other taxanes, is to stabilize cellular microtubule formation (inhibit tubulin depolymerization) in rapidly dividing cells, leading to arrest of unscheduled cell division at the G2/M phase of the cell cycle and cell death. Tesetaxel has several pharmacologic properties that make it unique among taxanes:
• Tesetaxel is a capsule for oral administration with a low pill burden;
• Tesetaxel has a long (~8-day) terminal plasma half-life (ti/2) in humans, enabling the maintenance of adequate drug levels with relatively infrequent dosing;
• Tesetaxel’ s formulation does not contain poly oxy ethylated castor oil or polysorbate 80, solubilizing agents contained in other taxane formulations known to cause hypersensitivity reactions; and
• Tesetaxel has been shown to retain activity against taxane-resistant tumors in nonclinical studies.
Relative to other approved taxanes, tesetaxel includes the addition of two nitrogen- containing functional groups. Tesetaxel is chemically designed to: (1) not be substantially effluxed by the P-gly coprotein (P-gp) pump, with the intent of retaining activity against chemotherapy-resistant tumor cells; (2) have high oral bioavailability, which requires that a drug substantially survive first-pass metabolism in the liver; (3) have high solubility; and (4) have a long ti/2 in humans. The high oral bioavailability of tesetaxel has been attributed to various causes, including the fact that tesetaxel is a poor substrate for P-gp and CYP3A and thus is absorbed orally and survives first-pass liver metabolism. This results in therapeutically effective amounts of tesetaxel in the body following oral administration, which cannot be achieved with other taxanes such as paclitaxel and docetaxel (Ono et al, Biol. Pharm. Bull. (2004) 27(3):345- 351).
It has been discovered that patients receiving treatment with CYP3A inhibitors may exhibit altered tesetaxel pharmacokinetics. This is surprising in light of the fact that tesetaxel was designed to be a poor substrate for CYP3A relative to other taxanes and thus it could not have been predicted whether tesetaxel could be safely administered to patients with disrupted CYP3A metabolism and, if so, whether any dosage modification would be required. The present disclosure relates generally to the discovery of methods for safely administering tesetaxel to patients receiving CYP3A inhibitors.
Thus, in some aspects, the present disclosure provides a method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising administering a first dose to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-
80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
In other aspects, the present disclosure provides a method for safely treating cancer in a patient receiving treatment with a CYP3A inhibitor, comprising administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. In certain embodiments, treatment with the CYP3A inhibitor comprises administering a dose of the CYP3A inhibitor on one or more days of the first 21 -day cycle. In certain embodiments, the patient has been diagnosed with a cancer, such as breast cancer.
DETAILED DESCRIPTION OF THE INVENTION
As further detailed below, the present disclosure provides in various aspects methods of administering tesetaxel to patients receiving treatment with CYP3A inhibitors. Those of ordinary skill in the art will appreciate that the tesetaxel dosing methods discussed herein apply to any patient with a CYP3 A inhibitor present in their body at an amount sufficient to substantially alter the pharmacokinetics of tesetaxel when tesetaxel is administered (e.g., patients who are within 3, 4, or 5 half-lives of when the CYP3A inhibitor was administered). The population of affected patients thus includes, e.g., those who receive a CYP3A inhibitor during a tesetaxel treatment cycle, as well as those who received a CYP3A inhibitor before beginning tesetaxel therapy. In certain embodiments of the methods disclosed herein, the dose adjustments continue until the CYP3A inhibitor in the patient is no longer effective to substantially alter the pharmacokinetics of tesetaxel (e.g., until 3, 4, or 5 half-lives of the CYP3A inhibitor have elapsed).
In some aspects, the present disclosure provides a method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. In certain embodiments, the method further comprises administering a second dose of tesetaxel to the patient on day 1 of a second 21 -day cycle, wherein the second dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
In certain preferred embodiments, the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,
52, 53, 54, 55, 56, 57, 58, 59, or 60% of the indicated tesetaxel dose for a patient not receiving treating with a CYP3A inhibitor. In certain especially preferred embodiments, the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. In certain embodiments, the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 13.5, 12, 10.5, or 9 mg/m2 tesetaxel. In certain embodiments, the first dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 6-24 mg/m2 tesetaxel, such as 6, 9, 12, 15, 18, or 21 mg/m2 tesetaxel.
In certain preferred embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% of the indicated tesetaxel dose for a patient not receiving treating with a CYP3A inhibitor. In certain especially preferred embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor is 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. In certain embodiments, the second dose of tesetaxel for a patient receiving a CYP3A inhibitor comprises 13.5, 12, 10.5, or 9 mg/m2 tesetaxel. In certain embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 6-24 mg/m2 tesetaxel, such as 6,
9, 12, 15, 18, or 21 mg/m2 tesetaxel.
In certain aspects, the present disclosure provides a method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising: administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose is an indicated dose of tesetaxel for a patient not receiving treatment with a CYP3A inhibitor; and administering a second dose of tesetaxel to the patient on day 1 of a second 21 -day cycle, wherein the second dose of tesetaxel is 20-80% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. This treatment protocol is useful, for example, when a patient receives a CYP3A inhibitor after administration of the first dose of tesetaxel but before the second dose of tesetaxel.
In certain embodiments, the indicated tesetaxel dose for a patient not receiving treatment with a CYP3 A inhibitor is 6-27 mg/m2 tesetaxel, preferably 18-27 mg/m2 tesetaxel. In certain
embodiments, the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 18, 21, 24, or 27 mg/m2 tesetaxel, preferably 27 mg/m2 tesetaxel.
In certain embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. In certain especially preferred embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor. In certain embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 13.5, 12, 10.5, or 9 mg/m2 tesetaxel. In certain embodiments, the second dose of tesetaxel for a patient receiving treatment with a CYP3A inhibitor comprises 6-24 mg/m2 tesetaxel, such as 6, 9, 12, 15, 18, or 21 mg/m2 tesetaxel.
As used herein, reference to a first 21 -day cycle and/or a second 21 -day cycle does not necessarily reflect the absolute first 21 -day cycle and the absolute second 21 -day cycle, respectively, but may instead refer to any two consecutive 21 -day cycles. In some non-limiting examples, a first 21 -day cycle may correspond to a patient’s third absolute 21 -day cycle, and a second 21 -day cycle may correspond to the patient’s fourth absolute 21 -day cycle. In other non limiting examples, a first 21 -day cycle may correspond to a patient’s third absolute 21 -day cycle of tesetaxel administration but which is the first 21 -day cycle that is characterized by a reduced dose of tesetaxel (e.g., the first 21 -day cycle that is characterized by a dose of tesetaxel that is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor). In still other non-limiting examples, a second 21 -day cycle may correspond to a patient’s fifth absolute 21 -day cycle of tesetaxel administration but the first 21 -day cycle that is characterized by a reduced dose of tesetaxel (e.g., the first 21 -day cycle that is characterized by a dose of tesetaxel that is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor). This is because, as will be appreciated by those of ordinary skill in the art, patient management concerns may require the patient to receive treatment with a CYP3A inhibitor, or to cease such treatment, for reasons that may be independent of decisions regarding tesetaxel dosing. The present disclosure provides dosing methods that may be flexibly implemented as the patient begins or stops receiving treatment with a CYP3A inhibitor, and
contemplates as many cycles of indicated (e.g., 27 mg/m2) or reduced (e.g., 9-24 mg/m2) doses of tesetaxel as required by the individual patient’s CYP3A administration schedule.
The first dose and the second dose may be equal or different. In certain embodiments, the first dose and the second dose are equal.
Treatment with the CYP3A inhibitor may comprise administering a dose of the CYP3A inhibitor on one or more days of the first 21-day cycle (e.g., one or more of days 1-21 of the first 21 -day cycle). In certain embodiments, treatment with the CYP3A inhibitor may commence after day 1 of the 21 -day cycle, such as one or more of days 2-21 of the first 21 -day cycle. In certain embodiments, the method comprises administering a dose of the CYP3A inhibitor on one or more days of the second 21 -day cycle.
CYP3A inhibitors relevant to the methods of the present disclosure include any suitable CYP3A inhibitor. CYP3A inhibitors may be classified as strong, moderate, or weak. In certain embodiments, the CYP3A inhibitor is a strong CYP3A inhibitor. In other embodiments, the CYP3A inhibitor is a moderate CYP3A inhibitor. In other embodiments, the CYP3A inhibitor is a weak CYP3A inhibitor.
Classification of CYP3A inhibitors as strong, moderate, or weak is based on clinical knowledge, and delineating between these terms is within the level of ordinary skill in the art.
For example, the Food and Drug Administration defines strong, moderate, and weak inhibitors as drugs that increase the AUC of sensitive index substrates of a given metabolic pathway (such as oral midazolam or other CYP3A substrates) >5-fold, >2- to <5-fold, and >1.25- to <2-fold, respectively. United States Food and Drug Administration, Guidance for Industry, Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions. January 2020. Clinical Pharmacology.
Exemplary strong CYP3A inhibitors include boceprevir, ceritinib, clarithromycin, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit, grapefruit juice, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, nefazodone, nelfinavir, lopinavir and ritonavir, paritaprevir and ritonavir (and ombitasvir and/or dasabuvir), pomegranate, pomegranate juice, posaconazole, ribociclib, ritonavir, saquinavir and ritonavir, tipranavir and ritonavirtroleandomycin, tucatinib, and voriconazole.
Exemplary moderate CYP3A inhibitors include aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine,
grapefruit juice, imatinib, netupitant, palonosetron, tofisopam, verapamil, and voriconazole. As will be appreciated by those of skill in the art, the effect of grapefruit juice may vary among brands and may be strong or moderate depending on the preparation.
Exemplary weak CYP3A inhibitors include amiodarone, atomoxetine, chlorzoxazone, cilostazol, cimetidine, ciprofloxacin, clotrimazole, entrectinib, esomeprazole, fluvoxamine, fosaprepitant, imatinib, istradefylline, ivacaftor, lesinurad, lomitapide, norfluoxetine, omeprazole, pantoprazole, quercetin, ranitidine, ranolazine, simeprevir, and ticagrelor.
In certain embodiments, the CYP3A inhibitor is itraconazole.
In certain embodiments, CYP3A metabolism in the patient is inhibited.
In certain embodiments, the method further comprises administering an antiemetic agent, such as dexamethasone, ondansetron, dolasetron, palonosetron, aprepitant, or rolapitant, or a combination of any of the foregoing.
In some embodiments, the patient has been diagnosed with a cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is locally advanced breast cancer. In other embodiments, the cancer is metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor (HR)-positive. In some embodiments, the patient has previously received endocrine therapy. In some embodiments, the breast cancer is estrogen receptor (ER)-positive. In other embodiments, the breast cancer is ER-negative. In some embodiments, the breast cancer is progesterone receptor (PR)-positive. In other embodiments, the breast cancer is PR-negative. In some embodiments, the breast cancer is HER2-negative. In other embodiments, the breast cancer is HER2-positive. In some embodiments, the breast cancer is HR-positive and HER2-negative. In some embodiments, the breast cancer is HR-negative and HER2-negative.
The treatment cycles described herein may be repeated as necessary. In some embodiments, the method comprises repeating the 21-day cycle at least once (e.g., a first 21-day cycle and a second 21 -day cycle). In some embodiments, the method comprises repeating the 21- day cycle until the cancer progresses or until unacceptable toxicity is observed.
The tesetaxel may also be conjointly administered with other suitable therapeutic agents. For example, tesetaxel and capecitabine may be effectively used in conjoint therapy, as described in International Patent Application PCT/US18/35653, published as WO 2018/223029, which is hereby incorporated by reference herein in its entirety. When so used, the combination can
provide greater efficacy than capecitabine alone. For instance, the methods disclosed herein may result in longer progression-free survival (PFS), longer survival, a greater treatment response, a longer duration of response and/or better disease control. In some embodiments, the combination is more efficacious as administration of capecitabine alone ( e.g ., at a dose of 2,500 mg/m2 or 2,000 mg/m2 daily for 14 consecutive days of a 21 -day cycle), and in some embodiments, the combination is more efficacious and has a more tolerable safety profile. More tolerable treatment regimens, such as those disclosed herein, are more likely to be continued by patients, and thus may be more likely to be effective.
In some embodiments, the method comprises administering a therapeutically effective amount of tesetaxel and a therapeutically effective amount of capecitabine conjointly. In some such embodiments, the therapeutically effective amount of tesetaxel is the dose of tesetaxel described herein (e.g., 40-60% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor). In other such embodiments, the therapeutically effective amount of tesetaxel is an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor, such as 27 mg/m2 of tesetaxel. In some embodiments, when the tesetaxel is administered on day 1 of a 21 -day cycle, the method further comprises administering capecitabine daily starting on day 1 of the 21 -day cycle for 14 consecutive 24-hour periods.
Any suitable dose of capecitabine may be used. When a daily dosage of capecitabine is specified, the daily dosage may be divided into a number of smaller, divided doses, such as 2, 3, 4, 5, 6 or more divided doses. In some preferred embodiments, the daily dosage of capecitabine is divided into two divided doses. When administering divided doses, a daily dosage regimen may begin with a partial dose on the first day and end with a partial dose on the last day, such that the daily dosage is delivered in a number of 24-hour periods, which may or may not correspond to calendar days. Thus, dosing of capecitabine is alternately discussed herein in terms of the total daily dosage (i.e., the total amount administered in a day or in a 24-hour period) or in terms of divided doses (i.e., the individual doses administered over the course of a day or a 24- hour period that combine to meet the total daily dosage).
In some embodiments, capecitabine is administered at twice-daily intervals (i.e., 2 times per 24-hour period) for a period of time, such as for 14 consecutive 24-hour periods. In some such embodiments, which are further described below, a first dose of capecitabine is administered on day 1 , and subsequent doses are administered at twice-daily intervals with a
final dose administered on day 15. In other such embodiments, which are further described below, capecitabine is administered twice daily for 14 consecutive calendar days (i.e., 2 doses of capecitabine are administered on each of days 1-14). Thus, reference to a number of “daily dosages” of capecitabine herein refers to administering capecitabine for that number of 24-hour periods and encompasses administering capecitabine for that number of calendar days.
In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering capecitabine twice daily on days 1-14 of the 21 -day cycle. In some embodiments, the method comprises administering a therapeutically effective amount of capecitabine in 28 doses at twice-daily intervals beginning on day 1 of the 21 -day cycle. In some embodiments, the method comprises administering a first dose of capecitabine on day 1 of the 21 -day cycle and administering a final 28th dose on day 15 of the 21 -day cycle. In some such embodiments, administering a therapeutically effective amount of capecitabine comprises administering a first dose of capecitabine after noon ( e.g ., in the evening) of day 1 of the 21 -day cycle and administering a final 28th dose before noon (e.g., in the morning) on day 15 of the 21- day cycle.
In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 14 daily dosages of 300-2,000 mg/m2 (such as 1,000-1,800 mg/m2) of capecitabine beginning on day 1 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 14 daily dosages of 1,650 mg/m2 of capecitabine beginning on day 1 of the 21 -day cycle.
In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 825 mg/m2 of capecitabine at twice-daily intervals for 14 consecutive 24-hour periods beginning on day 1 of the 21 -day cycle. In some such embodiments, administering a therapeutically effective amount of capecitabine comprises administering 825 mg/m2 of capecitabine twice daily on days 1-14 of the 21-day cycle. In other such embodiments, administering capecitabine comprises administering a first dose of 825 mg/m2 of capecitabine on day 1, administering subsequent doses of 825 mg/m2 of capecitabine at twice-daily intervals, and administering a final dose of 825 mg/m2 of capecitabine on day 15.
In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 14 daily dosages of 1,750 mg/m2 of capecitabine beginning on day 1 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of
capecitabine comprises administering 875 mg/m2 of capecitabine at twice-daily intervals for 14 consecutive 24-hour periods beginning on day 1 of the 21 -day cycle. In some such embodiments, administering a therapeutically effective amount of capecitabine comprises administering 875 mg/m2 twice daily on days 1-14 of the 21 -day cycle. In other such embodiments, administering a therapeutically effective amount of capecitabine comprises administering a first dose of 875 mg/m2 on day 1, administering subsequent doses of 875 mg/m2 of capecitabine at twice-daily intervals, and administering a final dose of 875 mg/m2 of capecitabine on day 15.
In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 150-1,000 mg/m2 of capecitabine at twice-daily intervals. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 150-1,000 mg/m2 of capecitabine at twice-daily intervals for 14 consecutive 24- hour periods. In some such embodiments, administering a therapeutically effective amount of capecitabine comprises administering 150-1,000 mg/m2 twice daily on days 1-14 of the 21-day cycle. In other such embodiments, administering a therapeutically effective amount of capecitabine comprises administering a first dose of 150-1,000 mg/m2 of capecitabine on day 1, and administering subsequent doses of 150-1,000 mg/m2 of capecitabine at twice-daily intervals and concluding by administering a final dose of 150-1,000 mg/m2 of capecitabine on day 15.
In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 150-1,000 mg/m2 of capecitabine at twice-daily intervals beginning with the first dose on day 1 of the 21 -day cycle and ending with the 28th dose on day 15 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 825 mg/m2 of capecitabine at twice-daily intervals. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 825 mg/m2 of capecitabine at twice-daily intervals beginning with the first dose on day 1 of the 21 -day cycle and ending with the 28th dose on day 15 of the 21 -day cycle. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 875 mg/m2 of capecitabine at twice-daily intervals. In some embodiments, administering a therapeutically effective amount of capecitabine comprises administering 28 doses of 875 mg/m2 of capecitabine at twice-daily intervals beginning with the first dose on day 1 of the 21 -day cycle and ending with the 28th dose on day 15 of the 21 -day cycle.
In some embodiments, the patient has previously been treated with a taxane. In some embodiments, the patient has previously been treated with a taxane in the neoadjuvant or adjuvant setting. In some embodiments, the taxane is paclitaxel, docetaxel or albumin-bound (nab) paclitaxel. In some embodiments, the patient has not previously been treated with a taxane. In some embodiments, the primary cancer is breast cancer, such as MBC or LA/MBC. In some embodiments, the breast cancer is locally advanced breast cancer. In some embodiments, the breast cancer is metastatic breast cancer. Metastatic breast cancer may include, but is not limited to, breast cancer that has spread to the central nervous system (CNS). Treatment of CNS cancers, including CNS cancers that are metastases of breast cancer, is described in PCT/US2019/049642, filed September 5, 2019 and published as WO 2020/081165, which is hereby incorporated by reference herein in its entirety. Tesetaxel is brain-penetrant; that is, it crosses the blood-brain barrier. This is unexpected because other taxanes, such as docetaxel and paclitaxel, have not been found to be effective against CNS metastases. Accordingly, tesetaxel, unlike docetaxel and paclitaxel, may be conveniently utilized in the treatment of tumors of the CNS, such as brain tumors. The structures of tesetaxel, docetaxel and paclitaxel are shown below:
In some embodiments, the breast cancer is HR-positive, such as ER-positive or PR- positive. In some embodiments, the patient has previously received endocrine therapy. In some embodiments, the breast cancer is HER2-negative. In some embodiments, the breast cancer is HR-positive and HER2-negative. In some embodiments, the breast cancer is HR-negative (i.e., ER-negative and PR-negative) and HER2-negative. In some embodiments, the breast cancer is HER2-positive.
Definitions
As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population ( e.g ., by a statistically and/or clinically significant amount).
The term “treating” includes prophylactic and/or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal), then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition); whereas, if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
The phrase “therapeutically effective amount” means the concentration of a compound that is sufficient to elicit the desired therapeutic effect.
The phrases “conjoint administration,” “administered conjointly,” “receiving conjoint treatment,” and grammatical variations refer to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still therapeutically effective in the body (e.g., the two compounds are simultaneously therapeutically effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly (i.e., at substantially the same time) or sequentially (i.e., with one compound administered first and the other compound administered at a later time). In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 7 days, 14 days or 15 days of one another, or
wherein the different therapeutic compounds are administered within the same treatment cycle as one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include one or more selected moieties that are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates ( e.g ., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, some or all of the compounds of the invention in a formulation represented above can be replaced with the corresponding suitable prodrug (e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester).
Tesetaxel and its preparation are described in U.S. Patent No. 6,677,456, which is incorporated by reference in its entirety. Various crystal forms of tesetaxel are described in U.S. Patent No. 7,410,980, which is hereby incorporated by reference in its entirety.
An “indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor” is the recommended tesetaxel dose on a prescribing information label, which may either be the recommended starting dose or a dose that has been modified as described on the label (exclusive of any modifications for concomitant administration with a CYP3A inhibitor). For example, the indicated dose may be reduced from the starting dose following the occurrence
of neutropenia or other adverse reaction. In certain embodiments, the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 6-27 mg/m2 tesetaxel, preferably 18- 27 mg/m2 tesetaxel. In certain embodiments, the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 18, 21, 24, or 27 mg/m2 tesetaxel, preferably 27 mg/m2 tesetaxel.
The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a human. When administered, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as a tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system ( e.g ., a skin patch). The composition can also be present in a solution suitable for topical administration, such as an eye drop.
A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, to increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-
microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit-risk ratio.
The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally ( e.g ., as drenches in aqueous or non-aqueous solutions or suspensions, tablets, capsules [including sprinkle capsules and gelatin capsules], boluses, powders, granules or pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (e.g., as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as,
for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount will range from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water- in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.
To prepare solid dosage forms for oral administration (capsules [including sprinkle capsules and gelatin capsules], tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate;
(8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high-molecular-weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder ( e.g ., gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose) or surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example,
filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, oral spray or oral ointment.
Alternatively, or additionally, compositions can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum or intestine.
Formulations that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that may be required.
The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal
fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration ( e.g ., topical administration, such as eye drops, or administration via an implant).
The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in
turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5%, more preferably, 0.5 to 90%, of active ingredient in combination with a pharmaceutically acceptable carrier.
Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors, including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
In general, a suitable daily dosage of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to
produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
If desired, the effective daily dosage of the active compound may be administered as 1 , 2, 3, 4, 5, 6 or more sub-doses (or divided doses) administered separately at appropriate intervals throughout a day, optionally, in unit dosage forms. In preferred embodiments of the present invention, an active compound may be administered one or two times daily on the days on which it is administered.
In certain embodiments, the methods of the invention may be used alone or the compounds administered may be used conjointly with another type of therapeutic agent.
This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra- alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl (morpholine, piperazine, potassium, 1 -(2-hydroxy ethyl)pyrrolidine, sodium, triethanolamine, tromethamine and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxyl- naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene- 1, 5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic
acid, L-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid and undecylenic acid salts.
The pharmaceutically acceptable acid-addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal- chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
EXEMPLIFICATION
The invention now being generally described will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
Example 1 : Clinical Studv
Patients with any histologically or cytologically confirmed solid tumor for which no standard therapy exists were recruited. Patients were administered each of the following treatment regimens:
In Cycle 1, patients were treated with tesetaxel capsules (15 mg/m2) orally once on the morning of Day 1 of a 21 -day cycle.
In Cycle 2, patients were treated with tesetaxel capsules (15 mg/m2) orally once on the morning of Day 1 of a 21 -day cycle, and itraconazole solid dosage form (200 mg) orally once
daily on Days -3 to -1 (corresponding to Cycle 1, days 19-21 if no dosing delay) and Days 1 to 14.
Patients were treated for two 21 -day cycles and permitted to continue onto an optional treatment extension, wherein tesetaxel capsules were administered orally on Day 1 of each 21- day cycle at a starting dose not to exceed 27 mg/m2. Treatment continued until the disease progressed or unacceptable toxicity was observed in the patient.
The primary endpoint of the study was the ratio of the geometric mean Cmax for tesetaxel in the presence and absence of itraconazole and the ratio of the geometric mean AUCo-336h for tesetaxel in the presence and absence of itraconazole. Secondary endpoints included the ratio of the geometric mean Cmax for tesetaxel metabolites (t-butyl-OH tesetaxel, 5 -hydroxy pyridine tesetaxel, and N-desmethyl tesetaxel) in the presence and absence of itraconazole and the ratio of the geometric mean AUCo-336h for tesetaxel metabolites (t-butyl-OH tesetaxel, 5-hydroxypyridine tesetaxel, and N-desmethyl tesetaxel) in the presence and absence of itraconazole, the ratio of the geometric mean AUCo-t for tesetaxel in the presence and absence of itraconazole and the ratio of the geometric mean AUCo-inf for tesetaxel in the presence and absence of itraconazole, and the ratio of the geometric mean AUCo-t for tesetaxel metabolites (t-butyl-OH tesetaxel, 5-pyridine- OH tesetaxel, and N-desmethyl tesetaxel) in the presence and absence of itraconazole and the ratio of the geometric mean AUCo-inf for tesetaxel metabolites (t-butyl-OH tesetaxel, 5- hydroxypyridine tesetaxel, and N-desmethyl tesetaxel) in the presence and absence of itraconazole.
All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the compounds and methods of use thereof described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. Those skilled in the art will also recognize that all combinations of embodiments described herein are within the scope of the invention.
Claims
1. A method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising: administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
2. A method for safely treating cancer in a patient receiving treatment with a CYP3A inhibitor, comprising: administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle, wherein the first dose of tesetaxel is 20-80% of an indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
3. The method of claim 1 or claim 2, further comprising: administering a second dose of tesetaxel to the patient on day 1 of a second 21 -day cycle, wherein the second dose of tesetaxel is 20-80% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
4. The method of any one of claims 1-3, wherein the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 6-27 mg/m2.
5. The method of claim 4, wherein the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 27 mg/m2.
6. The method of any one of the preceding claims, wherein the first dose is 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
7. The method of claim 6, wherein the first dose is 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
8. The method of any one of the preceding claims, wherein the second dose is 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
9. The method of claim 8, wherein the second dose is 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
10. The method of any one of claims 1-9, wherein the first dose of tesetaxel comprises 1-24 mg/m2 tesetaxel.
11. The method of any one of claims 1-10, wherein the first dose of tesetaxel comprises 6, 9,
12, 15, 18, or 21 mg/m2 tesetaxel.
12. The method of any one of claims 1-11, wherein the first dose of tesetaxel comprises 9 mg/m2 tesetaxel.
13. The method of any one of claims 1-11, wherein the first dose of tesetaxel comprises 12 mg/m2 tesetaxel.
14. The method of any one of claims 1-11, wherein the first dose of tesetaxel comprises 15 mg/m2 tesetaxel.
15. The method of any one of claims 1-11, wherein the first dose of tesetaxel comprises 18 mg/m2 tesetaxel.
16. The method of any one of claims 1-11, wherein the first dose of tesetaxel comprises 21 mg/m2 tesetaxel.
17. The method of any one of claims 3-16, wherein the second dose of tesetaxel comprises 6- 24 mg/m2 tesetaxel.
18. The method of any one of claims 3-17, wherein the second dose of tesetaxel comprises 6, 9, 12, 15, 18, or 21 mg/m2 tesetaxel.
19. The method of any one of claims 3-18, wherein the second dose of tesetaxel comprises 9 mg/m2 tesetaxel.
20. The method of any one of claims 3-18, wherein the second dose of tesetaxel comprises 12 mg/m2 tesetaxel.
21. The method of any one of claims 3-18, wherein the second dose of tesetaxel comprises 15 mg/m2 tesetaxel.
22. The method of any one of claims 3-18, wherein the second dose of tesetaxel comprises 18 mg/m2 tesetaxel.
23. The method of any one of claims 3-18, wherein the second dose of tesetaxel comprises 21 mg/m2 tesetaxel.
24. The method of any one of claims 3-23, wherein the first dose and the second dose are equal.
25. The method of any one of claims 1-24, wherein the treatment with the CYP3A inhibitor comprises: administering a dose of the CYP3A inhibitor on one or more days of the first 21 -day cycle.
26. The method of claim 25, wherein the treatment with the CYP3A inhibitor further comprises: administering a dose of the CYP3A inhibitor on one or more days of the second 21 -day cycle.
27. A method for safely administering tesetaxel to a patient receiving treatment with a CYP3A inhibitor, comprising: administering a first dose of tesetaxel to the patient on day 1 of a first 21 -day cycle wherein the first dose is an indicated tesetaxel dose for a patient not receiving treatment with a
CYP3A inhibitor; and administering a second dose of tesetaxel to the patient on day 1 of a second 21 -day cycle, wherein the second dose of tesetaxel is 20-80% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
28. The method of claim 27, wherein the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 6-27 mg/m2 tesetaxel.
29. The method of claim 28, wherein the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor is 27 mg/m2 tesetaxel.
30. The method of any one of claims 27-29, wherein the second dose of tesetaxel is 40-60% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
31. The method of claim 30, wherein the second dose of tesetaxel is 50% of the indicated tesetaxel dose for a patient not receiving treatment with a CYP3A inhibitor.
32. The method of any one of claims 27-31, wherein the second dose of tesetaxel comprises 6-24 mg/m2 tesetaxel.
33. The method of any one of claims 27-32, wherein the second dose of tesetaxel comprises 6, 9, 12, 15, 18, or 21 mg/m2 tesetaxel.
34. The method of any one of claims 27-33, wherein the second dose of tesetaxel comprises 6 mg/m2 tesetaxel.
35. The method of any one of claims 27-33, wherein the second dose of tesetaxel comprises 9 mg/m2 tesetaxel.
36. The method of any one of claims 27-33, wherein the second dose of tesetaxel comprises 12 mg/m2 tesetaxel.
37. The method of any one of claims 27-33, wherein the second dose of tesetaxel comprises 15 mg/m2 tesetaxel.
38. The method of any one of claims 27-33, wherein the second dose of tesetaxel comprises 18 mg/m2 tesetaxel.
39. The method of any one of claims 27-33, wherein the second dose of tesetaxel comprises 21 mg/m2 tesetaxel.
40. The method of any one of claims 27-39, wherein the treatment with the CYP3A inhibitor comprises: administering a dose of the CYP3A inhibitor on one or more of days 2-21 of the first 21 -day cycle.
41. The method of any one of claims 27-40, wherein the treatment with the CYP3A inhibitor comprises: administering a dose of the CYP3A inhibitor on one or more days of the second 21 -day cycle.
42. The method of any one of the preceding claims, wherein the CYP3A inhibitor is a strong
CYP3A inhibitor.
43. The method of claim 42, wherein the second dose of tesetaxel comprises 13.5 mg/m2 tesetaxel.
44. The method of any one of claims 1-41, wherein the CYP3A inhibitor is boceprevir, ceritinib, clarithromycin, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit, grapefruit juice, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, nefazodone, nelfinavir, lopinavir and ritonavir, paritaprevir and ritonavir (and ombitasvir and/or dasabuvir), pomegranate, pomegranate juice, posaconazole, ribociclib, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, tucatinib, and voriconazole, or a combination of any of the foregoing.
45. The method of claim 44, wherein the CYP3A inhibitor is itraconazole.
46. The method of any one of the preceding claims, wherein CYP3A metabolism in the patient is inhibited.
47. The method of any one of the preceding claims, further comprising administering an antiemetic agent.
48. The method of claim 47, wherein the anti emetic agent is dexamethasone, ondansetron, dolasetron, or palonosetron, or rolapitant, or a combination of any of the foregoing.
49. The method of any one of the preceding claims, further comprising administering a therapeutically effective amount of capecitabine.
50. The method of any one of the preceding claims, wherein the patient has been diagnosed with a cancer.
51. The method of claim 50, wherein the cancer is breast cancer.
52. The method of claim 50 or claim 51, wherein the cancer is locally advanced or metastatic breast cancer.
53. The method of claim 52, wherein the cancer is locally advanced breast cancer.
54. The method of claim 52, wherein the cancer is metastatic breast cancer.
55. The method of claim 51 , wherein the breast cancer is hormone receptor positive.
56. The method of any one of claims 51-55, wherein the breast cancer is estrogen receptor positive.
57. The method of any one of claims 52-56, wherein the breast cancer is estrogen receptor negative.
58. The method of any one of claims 51-57, wherein the breast cancer is progesterone receptor positive.
59. The method of any one of claims 51-57, wherein the breast cancer is progesterone receptor negative.
60. The method of any one of claims 51-59, wherein the breast cancer is HER2-negative.
61. The method of any one of claims 51-59, wherein the breast cancer is HER2-positive.
62. The method of any one of claims 51-59, wherein the breast cancer is hormone receptor positive and HER2-negative.
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Non-Patent Citations (6)
Title |
---|
A.DOMÍNGUEZ-GIL HURLÉ, A.SÁNCHEZ NAVARRO, M.J.GARCÍA SÁNCHEZ: "Therapeutic drug monitoring of itraconazole and the relevance of pharmacokinetic interactions", CLINICAL MICROBIOLOGY AND INFECTION, vol. 12, no. Suppl.7, 1 December 2006 (2006-12-01), pages 97 - 106, XP055975349 * |
ANONYMOUS: "CYP3A4 Inhibitor/Inducer Drug-Drug Interactions - All Kinase Inhibitors | OncologyPRO", INTERNET ARCHIVE WAYBACK MACHINE, 28 July 2019 (2019-07-28), pages 1 - 7, XP055975342, Retrieved from the Internet <URL:https://web.archive.org/web/20190728221558/https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/drug-drug-interactions-with-kinase-inhibitors/types-of-drug-drug-interactions/cyp3a4-inhibitor-inducer> [retrieved on 20221027] * |
ANONYMOUS: "History of Changes for Study: NCT04312282 The Effect of Tesetaxel on the QTc Interval and the Effect of Food, Itraconazole, and Rifampin on Tesetaxel Pharmacok With Advanced Solid Tumors ", CLINICALTRIALS.GOV, 13 January 2021 (2021-01-13), pages 1 - 5, XP055975337, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/history/NCT04312282?V_3=View#StudyPageTop> [retrieved on 20221027] * |
DAVID A. FLOCKHART, SALLY USDIN YASUDA, PETER HONIG, CURTIS ROSEBRAUGH, RAYMOND L. WOOSLEY : "Preventable Adverse Drug Reactions: A Focus on Drug Interactions | FDA", 3 June 2018 (2018-06-03), pages 1 - 39, XP055975347, Retrieved from the Internet <URL:https://www.fda.gov/drugs/drug-interactions-labeling/preventable-adverse-drug-reactions-focus-drug-interactions> [retrieved on 20221027] * |
ENGELS F: "Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel", CLINICAL PHARMACOLOGY AND THERAPEUTICS, NATURE PUBLISHING GROUP, US, vol. 75, no. 5, 1 May 2004 (2004-05-01), US , pages 448 - 454, XP055975339, ISSN: 0009-9236, DOI: 10.1016/j.clpt.2004.01.001 * |
MUHAMMAD WASIF SAIF; JOHN SARANTOPOULOS; AMITA PATNAIK; ANTHONY W. TOLCHER; CHRIS TAKIMOTO; MURALI BEERAM: "Tesetaxel, a new oral taxane, in combination with capecitabine: a phase I, dose-escalation study in patients with advanced solid tumors", CANCER CHEMOTHERAPY AND PHARMACOLOGY, SPRINGER, BERLIN, DE, vol. 68, no. 6, 6 May 2011 (2011-05-06), Berlin, DE , pages 1565 - 1573, XP019980114, ISSN: 1432-0843, DOI: 10.1007/s00280-011-1639-3 * |
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