WO2016073669A1 - Thérapie combinée associant des composés inhibiteurs de la protéine hsp90 et des inhibiteurs de la protéine mtor - Google Patents

Thérapie combinée associant des composés inhibiteurs de la protéine hsp90 et des inhibiteurs de la protéine mtor Download PDF

Info

Publication number
WO2016073669A1
WO2016073669A1 PCT/US2015/059148 US2015059148W WO2016073669A1 WO 2016073669 A1 WO2016073669 A1 WO 2016073669A1 US 2015059148 W US2015059148 W US 2015059148W WO 2016073669 A1 WO2016073669 A1 WO 2016073669A1
Authority
WO
WIPO (PCT)
Prior art keywords
sarcoma
inhibitor
patients
sirolimus
ganetespib
Prior art date
Application number
PCT/US2015/059148
Other languages
English (en)
Inventor
Vojo Vukovic
Original Assignee
Vojo Vukovic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vojo Vukovic filed Critical Vojo Vukovic
Publication of WO2016073669A1 publication Critical patent/WO2016073669A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • HSPs Heat shock proteins
  • HSPs are a class of chaperone proteins that are up- regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins), facilitate their proper folding and repair and aid in the refolding of misfolded client proteins.
  • client proteins There are several known families of HSPs, each having its own set of client proteins.
  • the Hsp90 family is one of the most abundant HSP families accounting for about 1-2% of proteins in a cell that is not under stress, increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in the degradation of its client proteins via the ubiquitin proteasome pathway.
  • the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer.
  • Ganetespib is a selective inhibitor of Hsp90.
  • Hsp90 client proteins including proteins involved in "oncogene addiction” (ALK, HER2, mutant BRAF and EGFR, androgen receptor, estrogen receptor, and JAK2); proteins involved in resistance to chemotherapy and radiation therapy (ATR, BCL2, BRCAl/2, CDKl/4, CHK1, survivin, and WEE1); proteins involved in angiogenesis (HIF-lalpha, VEGFR, PDFGR, and VEGF); and proteins involved in metastasis (MET, RAF, AKT, MMPs, HIF-lalpha, and IGF-1R).
  • inhibition of Hsp90 by ganetespib results in the inactivation, destabilization, and eventual degradation of these cancer-promoting proteins.
  • Ganetespib is being evaluated in trials in lung cancer, breast cancer, and other tumor types.
  • MPNSTs Malignant peripheral nerve sheath tumors
  • MPNSTs are soft tissue sarcomas arising from peripheral nerve or show nerve sheath differentiation and are associated with a high risk of local recurrence and metastasis.
  • MPNSTs account for 10% of all soft tissue sarcomas, and carry the highest risk for sarcoma specific death among all the soft tissue sarcoma histologies .
  • complete surgical resection is the only curative treatment for MPNST.
  • MPNSTs are at high risk for local recurrence (32-65%) 5 and metastasis (40%).
  • Hsp90 inhibitors in particular Ganetespib, in combination with mTOR inhibitors, in particular sirolimus (rapamycin), are demonstrated herein to be particularly effective in specific dosing regimens for treating pediatric patients with sarcomas. It is also demonstrated herein that those Hsp90 inhibitors in combination with mTOR inhibitors, in particular sirolimus, are particularly effective in treating refractory sarcomas, including malignant peripheral nerve sheath tumors (MPNSTs). It is a surprising and unexpected finding of the present invention that drugs that target Hsp90 and mTOR show synergistic activity in treating sarcomas, and in particular MPNSTs. The particular dosing regimens disclosed herein demonstrate potency against these certain specific types of cancer, while showing minimal side effects.
  • the invention provides methods of treating or preventing a sarcoma in a subject, comprising administering a therapeutically effective amount of an Hsp90 inhibitor in combination with an mTOR inhibitor, wherein the subject is selected as being of 16 years of age or less.
  • the invention provides methods of reducing or inhibiting the progression of a sarcoma in a subject, comprising administering a
  • an Hsp90 inhibitor in combination with an mTOR inhibitor wherein the subject is selected as being of 16 years of age or less.
  • the Hsp90 inhibitor is ganetespib (5-[2,4-dihydroxy-5-(l- methylethyl)phenyl]-2,4-dihydro-4-(l-methyl-lH-indol-5-yl)-3H-l,2,4-triazole-3-one), or a pharmaceutically acceptable salt or a tautomer thereof.
  • the mTOR inhibitor is sirolimus (3S,6R ,7E,9R, 10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a- hexadecahydro-9,27-dihydroxy-3-[(lR)-2-[(lS,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l- methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,l-c][l,4] oxaazacyclohentriacontine-1,5, 11,28,29 (4H,6H ,31H)-pentone.
  • the sarcoma is a refractory sarcoma, e.g., a bone or soft tissue sarcoma.
  • the sarcoma is a malignant peripheral nerve sheath tumor (MPNST), e.g., an unresectable or metastatic sporadic or neurofibromatosis type-1 associated MPNST.
  • MPNST peripheral nerve sheath tumor
  • the sarcoma was previously treated and not responsive.
  • the sarcoma is a recurrent sarcoma.
  • the amount of the Hsp90 inhibitor administered is from 100- 200 mg/m 2 . In another embodiment, the amount of the Hsp90 inhibitor administered is from 150-200 mg/m 2 . [0013] In one embodiment, the Hsp90 inhibitor is administered intravenously. In another embodiment, the Hsp90 inhibitor is infused over 60 minutes.
  • the amount of mTOR inhibitor administered is 2-12 mg. In another embodiment, the amount of mTOR inhibitor administered is 2-4 mg.
  • the mTOR inhibitor is administered orally.
  • the Hsp90 inhibitor and mTOR inhibitor are administered over a 28 day cycle.
  • the 28 day cycle is repeated one or more times.
  • the Hsp90 inhibitor is administered on days 1, 8 and 15.
  • the mTOR inhibitor is administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.
  • the invention provides methods of treating or preventing a sarcoma in a subject, comprising administering a therapeutically effective amount of ganetespib (5-[2,4-dihydroxy-5-(l-methylethyl)phenyl]-2,4-dihydro-4-(l-methyl-lH-indol-5- yl)-3H-l,2,4-triazole-3-one), or a pharmaceutically acceptable salt or a tautomer thereof, in combination with sirolimus (3S,6R ,7E,9R, 10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(lR)- 2-[(lS,3R,4R)-4
  • the invention provides methods of reducing or inhibiting the progression of a sarcoma in a subject, comprising administering a therapeutically effective amount of ganetespib (5-[2,4-dihydroxy-5-(l-methylethyl)phenyl]-2,4-dihydro-4-(l-methyl- lH-indol-5-yl)-3H-l,2,4-triazole-3-one), or a pharmaceutically acceptable salt or a tautomer thereof, in combination with sirolimus (3S,6R ,7E,9R, 10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27- dihydroxy-3-[(lR)-2-[(lS,3R,4
  • the invention provides kits to practice any one of the methods described herein.
  • the invention provides compositions comprising an Hsp90 inhibitor and an mTOR inhibitor.
  • the Hsp90 inhibitor is ganetespib (5- [2,4-dihydroxy-5-(l-methylethyl)phenyl]-2,4-dihydro-4-(l-methyl-lH-indol-5-yl)-3H-l,2,4- triazole-3-one), or a pharmaceutically acceptable salt or a tautomer thereof.
  • the mTOR inhibitor is sirolimus (3S,6R ,7E,9R, 10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27- dihydroxy-3-[(lR)-2-[(lS,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l-methylethyl]-10,21- dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,l-c][l,4]
  • the amount of the Hsp90 inhibitor is between 100-500 mg/m 2 . In another embodiment, the amount of the Hsp90 inhibitor is between 100-200 mg/m 2 , preferably 150-200 mg/m 2 .
  • the amount of mTOR inhibitor is between 2-12 mg. In another embodiment, the amount of mTOR inhibitor is between 2-4 mg.
  • the compostion comprising the combination of the Hsp90 inhibitor and the mTOR inhibitor exhibits therapeutic synergy.
  • the present invention provides novel combinations of drugs that target Hsp90 and mTOR to treat refractory sarcomas, and in particular MPNSTs, in pediatric patients. It is a surprising and unexpected finding of the present invention that drugs that target Hsp90 and mTOR show synergistic activity in treating sarcomas, and in particular MPNSTs. DEFINITIONS
  • the term "about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1 %, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • administer As used herein, the terms “administer,” “administering” or
  • administration include any method of delivery of a pharmaceutical composition or agent into a subject's system or to a particular region in or on a subject.
  • an agent is administered intravenously,
  • an agent is administered intravenously.
  • Administering an agent can be performed by a number of people working in concert.
  • Administering an agent includes, for example, prescribing an agent to be administered to a subject and/or providing instructions, directly or through another, to take a specific agent, either by self-delivery, e.g., as by oral delivery, subcutaneous delivery, intravenous delivery through a central line, etc.; or for delivery by a trained professional, e.g., intravenous delivery,
  • agent refers to any active agent that affects any biological process. Active agents that are considered drugs for purposes of this application are agents that exhibit a pharmacological activity. Examples of agents include active agents that are used in the prevention, diagnosis, alleviation, treatment or cure of a disease condition. In an exemplary embodiment, an agent is a chemotherapeutic agent.
  • the term "in combination” refers to the use of more than one therapeutic agent (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more).
  • the use of the term “in combination” does not restrict the order in which the therapeutic agents are administered to a subject afflicted with cancer.
  • a first therapeutic agent such as a compound described herein, can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second
  • diagnosing is meant to refer to a clinical or other assessment of the condition of a subject based on observation, testing, or circumstances for identifying a subject having a disease, disorder, or condition based on the presence of at least one indicator, such as a sign or symptom of the disease, disorder, or condition.
  • diagnosing using the method of the invention includes the observation of the subject for multiple indicators of the disease, disorder, or condition in conjunction with the methods provided herein. Diagnostic methods provide an indicator that a disease is or is not present. A single diagnostic test typically does not provide a definitive conclusion regarding the disease state of the subject being tested.
  • identify or “select” refer to a choice in preference to another.
  • identify a subject or select a subject is to perform the active step of picking out that particular subject from a group and confirming the identity of the subject by name or other distinguishing feature.
  • recur refers to the re-growth of tumor or cancerous cells in a subject in whom primary treatment for the tumor has been administered.
  • the tumor may recur in the original site or at another site.
  • refractory cancer or tumor is understood as a malignancy which is either initially unresponsive to chemo- or radiation therapy, or which becomes unresponsive over time.
  • a cancer refractory to on intervention may not be refractory to all interventions.
  • a refractory cancer is typically not amenable to treatment with surgical interventions.
  • Exemplary refractory cancers or tumors of the invention include refractory sarcomas, for example refractory bone and soft tissue sarcomas, and in particular MPNSTs.
  • the term "sarcoma” is meant to refer to a broad group of cancers that includes tumors that form in the bones and in the soft tissues.
  • the sarcoma is a refractory sarcoma, which may be a bone or soft tissue sarcoma.
  • the sarcoma is a malignant peripheral nerve sheath tumor (MPNST).
  • subject As used herein, terms “subject”, “patient” and “mammal” are used interchangeably.
  • the terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non- primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human.
  • a non- primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In another embodiment, the subject is a human.
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • the subject is a human.
  • the term "synergistic” or “synergy” refers to a combination of compounds described herein, which, when taken together, is more effective than the additive effects of the individual therapies.
  • a synergistic effect of a combination of therapies ⁇ e.g., a combination of therapeutic agents) permits the use of lower dosages of one or more of the therapeutic agent(s) and/or less frequent
  • a disease or disorder e.g., a proliferative disorder.
  • the ability to utilize lower the dosage of one or more therapeutic agent and/or to administer the therapeutic agent less frequently reduces the toxicity associated with the administration of the agent to a subject without reducing the efficacy of the therapy in the treatment of a disease or disorder.
  • a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disease or disorder, e.g. cancer.
  • a synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of either therapeutic agent alone.
  • a "therapeutically effective amount” is that amount sufficient to treat a disease in a subject.
  • a therapeutically effective amount can be administered in one or more administrations.
  • the terms “treat,” “treating” or “treatment” refer, preferably, to an action to obtain a beneficial or desired clinical result including, but not limited to, alleviation or amelioration of one or more signs or symptoms of a disease or condition, diminishing the extent of disease, stability (i.e., not worsening) state of disease, amelioration or palliation of the disease state, diminishing rate of or time to progression, and remission (whether partial or total), whether detectable or undetectable.
  • “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment does not need to be curative.
  • compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.
  • MPNSTs Malignant peripheral nerve sheath tumors
  • MPNSTs are soft tissue sarcomas arising from peripheral nerve or show nerve sheath differentiation and are associated with a high risk of local recurrence and metastasis (1).
  • MPNSTs account for 10% of all soft tissue sarcomas, and carry the highest risk for sarcoma specific death among all the soft tissue sarcoma histologies (2).
  • complete surgical resection is the only curative treatment for MPNST (3,4).
  • MPNSTs are at high risk for local recurrence (32-65%) (5) and metastasis (40%) (6).
  • MPNST The most frequent sites of metastasis of MPNSTs are lung, liver, brain, soft tissue, bone, lymph nodes, and retroperitoneum (7).
  • the outcome for unresectable, recurrent, or metastatic MPNST is dismal.
  • Neurofibromatosis Type 1 and MPNST
  • NF1 is a common autosomal dominant tumor predisposition syndrome.
  • the gene responsible for NF1 encodes for a protein called neurofibromin, which includes a GTPase activating protein that regulates hydrolysis of Ras-GTP to Ras-GDP (9,10).
  • Patients with NF1 have decreased levels of neurofibromin, which can lead to dysregulated Ras and tumorigenesis (11).
  • MPNSTs are the most common NF1- associated malignancy.
  • the lifetime risk of MPNST in NF1 is 8-13% compared to 0.001% in the general population (7,8).
  • the majority of NFl-associated MPNSTs arise within pre-existing plexiform neurofibromas (12).
  • NF1 associated MPNSTs are frequently more located in the trunk (13,14) as opposed to extremity location seen more commonly in sporadic MPNSTs, tend to be large (>5cm) (15), and may have a greater propensity to metastasize ( 7). These may be potential reasons why NFl-associated MPNSTs appear to have a worse outcome than sporadic MPNSTs.
  • Hsp90 inhibitors have demonstrated benefit in a variety preclinical of bone and soft tissue sarcomas, including synovial sarcoma (21, 32) Ewing Sarcoma (33), osteosarcoma (34, 35), and rhabdomyosarcoma (36, 37). Disruptions of the PI3K-Akt-mTOR signaling pathway are associated with different sarcoma types (38). Rapamycin and other mTOR inhibitors have demonstrated inhibition of growth in a variety of in vitro and in vivo sarcoma preclinical models (39-43).
  • mTOR was found to be activated in both NF1 deficient primary human and mouse cells as well as in human and genetically-engineered Nf 1 mouse tumor models. This aberrant activation was dependent on Ras and PI3 kinase/AKT signaling (64,65).
  • Nf 1 loss in mouse embryonic fibroblasts (65) and primary mouse astrocytes (64) was shown to result in Ras- and PI3K-dependent mTOR pathway activation, which could be inhibited with sirolimus.
  • Nf 1-/- astrocytes are highly sensitive to sirolimus treatments that have no effect on normal astrocyte growth (64).
  • a transgenic mouse model (67) carrying compound mutations in the Nfl and p53 tumor suppressors on the same chromosome develop aggressive MPNSTs that are histologically indistinguishable from human MPNSTs. Tumors grow with consistent and rapid kinetics, and on average mice only survive 10.7 days after the tumor is detected.
  • This model was used to test the role of mTOR in tumorigenesis in vivo and assess the therapeutic utility of rapamycin (27). Animals with palpable tumors (approximately 300 mm 3 ) were injected LP. with 5 mg/kg rapamycin per day. Control mice died on average in 12.2 days, and tumors grew 9.7-fold.
  • rapamycin potently suppressed MPNST growth, and allowed the animals to survive. Inhibition of S6 phosphorylation was observed in tumor and non-tumor tissue, demonstrating that rapamycin was effectively suppressing the mTOR pathway in vivo. Moreover rapamycin mediated its anti-tumor effects within 24 hours by potently suppressing proliferation, as assessed by BrDU incorporation in control and rapamycin treated tumors. Consistent with in vitro observations, apoptotic and senescent cells were not detected. As such, tumor growth was dependent on continued exposure to rapamycin, as tumors re-exhibited S6 phosphorylation and resumed growing at a rate comparable to control treated tumors following
  • Tumor cells often exhibit specific stress-related phenotypes caused by insults such as excessive DNA damage as well as replicative, metabolic, and proteotoxic stress (68). Agents that further enhance or sensitize cancer cells to these stresses could thus be developed as potential anti-cancer therapies (69,70).
  • ER stress Proteotoxic or endoplasmic reticulum (ER) stress is induced when unfolded proteins accumulate in the ER (28). Cancer cells frequently exhibit high levels of ER stress caused by a multitude of factors (69,70). Oncogenic RAS also causes ER stress (29). Aneuploidy in particular has been shown to induce proteotoxic stress in cells (71). ER stress activates a signal transduction pathway called the unfolded protein response (UPR) (28). The UPR is an initially protective mechanism to reduce protein accumulation, however, when ER stress levels become insurmountable, cell death ensues (28).
  • UPR unfolded protein response
  • Hsp90 maintains protein homeostasis by folding newly synthesized and misfolded proteins, assembling and dissembling protein complexes and resolving protein aggregates (47). Hsp90 also directly stabilizes two key stress sensing components of UPR: IREl and pPERK/PERK 72. Therefore Hsp90 inhibitors would expect to promote ER stress in cancer cells directly by impairing global protein folding in already compromised tumor cells and inactivating subsequent adaptive responses of UPR.
  • MPNSTs are highly aneuploid and are driven by constitutive activation of Ras. They were demonstrated to have much higher levels of ER stress when compared to normal peripheral nerve as confirmed by three markers of UPR activation (BiP upregulation, eukaryotic translational initiation factor 2a (eIF2a) phosphorylation, and accumulation of the spliced active form of XBP-1 (sXBP-1). In addition, agents that induced ER stress triggered cell death at concentrations that did not affect the viability of normal cells. [0056] To date, no previous targeted agents have been shown capable of causing tumor regression in the highly aggressive genetically engineered MPNST model or in human tumors (see Table 1).
  • Table 1 Completed and select ongoing clinical trials with targeted for refractory MPNST.
  • Ganetespib is a potent, next generation Hsp90 inhibitor that has shown superior activity to first generation agents in preclinical studies. It has a favorable safety profile and promising anti-tumor activity over a broad range of tumor types in early clinical trials.
  • Sirolimus is commercially available, oral, and relatively inexpensive. It has a long safety record, demonstrated efficacy in preclinical cancer models, and was used in the transgenic MPNST mouse model.
  • the present application proposes a multi-institutional open label phase I/II trial of ganetespib in combination with sirolimus in patients with refractory MPNST, and other sarcoma types.
  • compositions comprising an Hsp90 inhibitor and an mTOR inhibitor. It is a surprising finding of the present invention that the combination of a Hsp90 inhibitor and an mTOR inhibitor show synergistic activity.
  • the Hsp90 inhibitor is ganetespib (5-[2,4-dihydroxy-5-
  • Ganetespib (formerly called STA-9090) is a novel, injectable resorcinolic triazolone small molecule inhibitor of Hsp90 (46).
  • Hsp90 is a molecular chaperone that regulates posttranslational folding, stability, and function of its client proteins, many of which play critical roles in cell growth, differentiation, and survival (47,48).
  • Ganetespib is shown as Formula (I) below:
  • solvates e.g., hydrates
  • solvent molecules are incorporated into the crystal lattice during crystallization.
  • Solvates may include water or nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate.
  • water is the solvent molecule incorporated into the crystal lattice of a solvate, it is typically referred to as a "hydrate”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.
  • Ganetespib inhibits Hsp90 chaperone activity by binding to its N-terminal adenosine triphosphate (ATP) pocket. Hsp90 inhibition causes its client proteins to adopt aberrant conformations, which are then targeted for ubiquination and degradation by the proteosome (49). Hsp90 client proteins include wild type and mutated forms of many important signaling proteins associated with cancer, such as BCR-ABL, BRAF, CDK4, KIT, c-MET, c-SRC, EGFR, LCK, HER2 and VEGFR.
  • Ganetespib is currently being investigated in adults with a broad range of tumor types. It is being explored in both once weekly and twice weekly schedule, and has been generally well tolerated. Most frequent adverse events were gastrointestinal or constitutional in nature, and were generally mild to moderate in severity.
  • the mTOR inhibitor is sirolimus (3S,6R ,7E,9R, 10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)-
  • Sirolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor that has been FDA approved for immunosuppression following kidney transplantation (52).
  • mTOR is a serine/threonine kinase, which belongs to
  • PI3K phosphatidylinositol-3 kinase
  • PIKKs phosphatidylinositol-3 kinase
  • Sirolimus inhibited tumor growth in preclinical models by inducing cell cycle arrest and apoptosis, leading to recognition of the mTOR pathway as a target for cancer therapy (53,54).
  • Rapamycin analogs such as temsirolimus (55), an intravenous soluble ester (pro drug) of sirolimus and everolimus (56), and oral mTOR inhibitor, have been FDA approved for the treatment of advanced renal cell carcinoma. At this time, it is unclear whether one compound will have advantage over the others in a particular tumor type.
  • the amount of the Hsp90 inhibitor is between 100-500 mg/m 2 , between 100-200 mg/m 2 , and preferably between 150-200 mg/m 2 .
  • the amount of mTOR inhibitor is between 2-12 mg, preferably between 2-4 mg.
  • the present invention relates to methods of treating or preventing a sarcoma in a subject, comprising administering a therapeutically effective amount of an Hsp90 inhibitor in combination with an mTOR inhibitor, wherein the subject is selected as being of 16 years of age or less.
  • the invention also relates to methods of reducing or inhibiting the progression of a sarcoma in a subject, comprising administering a therapeutically effective amount of an Hsp90 inhibitor in combination with an mTOR inhibitor, wherein the subject is selected as being of 16 years of age or less.
  • the Hsp90 inhibitor is ganetespib (5-[2,4- dihydroxy-5-(l-methylethyl)phenyl]-2,4-dihydro-4-(l-methyl-lii-indol-5-yl)-3ii- l,2,4-triazole-3-one).
  • the mTOR inhibitor is sirolimus (3S,6R ,7E,9R, 10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3- [(lR)-2-[(lS,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l-methylethyl]-10,21- dimethoxy-6,8, 12, 14,20,26-hexamethyl-23,27-epoxy-3H-pyrido [2, 1-c] [1,4]
  • the sarcoma is a refractory sarcoma.
  • the refractory sarcoma may be a bone or soft tissue sarcoma.
  • the sarcoma is a malignant peripheral nerve sheath tumor (MPNST).
  • the MPNST may be an unresectable or metastatic sporadic or neurofibromatosis type-1 associated MPNST.
  • the sarcoma may be a sarcoma that was previously treated and not responsive, or the sarcoma may be a recurrent sarcoma.
  • the invention includes methods of administering the Hsp90 inhibitor and mTOR inhibitor disclosed herein for therapeutic purposes for any sarcoma. As such, the invention provides methods of treating an individual afflicted with a sarcoma.
  • compositions described herein are formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, intranasal ⁇ e.g., inhalation), transdermal (topical), transmucosal, and rectal.
  • Effective dosages and schedules for administering the compositions of the invention may be determined empirically, and making such determinations is within the skill in the art.
  • the dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms/disorder are/is affected.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex and extent of the disease in the patient, route of administration, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any counterindications.
  • Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
  • Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • guidance in selecting appropriate doses for antibodies can be found in the literature on therapeutic uses of antibodies, e.g., Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, N.J., (1985) ch. 22 and pp. 303-357; Smith et al., Antibodies in Human
  • the amount of the Hsp90 inhibitor administered is from 100-200 mg/m 2 . In further embodiments, the amount of the Hsp90 inhibitor administered is from 150-200 mg/m 2 .
  • the Hsp90 is preferably administered intravenously, over a period of 60 minutes.
  • the amount of mTOR inhibitor administered is 2-12 mg. In further embodiments, the amount of mTOR inhibitor administered is 2-4 mg. Preferably , the mTOR inhibitor is administered orally.
  • the Hsp90 inhibitor is administered on days 1, 8 and 15.
  • the mTOR inhibitor is preferably administered on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28.
  • the Hsp90 inhibitor and mTOR inhibitor may be administered over a cycle of days, for example a cycle of 28 days.
  • the 28 day cycle may be repeated one or more times.
  • the therapeutic agents of the combination therapies described herein can be administered sequentially or concurrently. In one embodiment, the
  • the administration of the Hsp90 inhibitor and the mTOR inhibitor are done separately. In another embodiment, the administration of the Hsp90 inhibitor and the mTOR inhibitor are done sequentially. In one embodiment, the administration of the Hsp90 inhibitor and the mTOR inhibitor are done until the sarcoma is cured or stabilized or improved.
  • the efficacy of the therapeutic peptide can be assessed in various ways well known to the skilled practitioner.
  • compositions disclosed herein may be also administered
  • kits and pharmaceutical packages that are drawn to reagents or components that can be used in practicing the methods disclosed herein.
  • the kits can include any material or combination of materials discussed herein or that would be understood to be required or beneficial in the practice of the disclosed methods.
  • the kits could include a peptide of the invention, or one or more additional active agents.
  • a kit can include a set of instructions for using the components of the kit for its therapeutic and/or diagnostic purposes.
  • Example 1-- A Phase I/II Trial of ganetespib in combination with the mTOR inhibitor sirolimus for pediatric patients with unresectable or metastatic malignant peripheral nerve sheath tumors (MPNSTs)
  • Ganetespib is a novel, injectable, small molecule inhibitor of Hsp90 and is currently being
  • Ganetespib has been studied in preclinical in vivo models with a variety of targeted agents with no marked apparent
  • Sirolimus is a commercially available orally administered mTOR inhibitor and is the active metabolite of temsirolimus, which is FDA approved agent for advanced metastatic renal cell carcinoma. Sirolimus has been studied and tolerated in combination with multiple cytotoxic and targeted agents in a variety of tumor types.
  • a pediatric patient population is meant to refer to a particular sub -population of subjects less than 16 years of age.
  • Phase I To assess the safety, tolerability, and maximum tolerated dose (MTD)/ recommended dose of ganetespib when administered in combination with sirolimus in patients aged 16 years of less with refractory or relapsed sarcomas including unresectable or metastatic sporadic or neurofibromatosis type 1 (NF1) associated MPNST.
  • MTD maximum tolerated dose
  • NF1 neurofibromatosis type 1
  • Phase II To determine the clinical benefit of ganetespib in combination with sirolimus for patients aged 16 years or less with unresectable or metastatic sporadic or NF1 associated MPNST.
  • Phase I To describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in combination therapy [0097] Phase I/II: To determine changes in pharmacodynamic parameters including phospho-S6, phosphorylated eIF2 alpha, Akt Phosphorylation, Hsp70, and G6PD in tumor tissue and peripheral blood mononuclear cells at baseline and during treatment and correlate with changes in clinical or radiologic outcome.
  • Phase I/II To assess patient-reported pain severity and the impact of pain on daily activities before and during treatment with ganetespib and sirolimus and to correlate with changes in clinical or radiologic outcome.
  • Phase I/II To evaluate the utility of three-dimensional MRI (3D-MRI) analysis in comparison to 1-dimensional and 2-dimensional measurements as a method to more sensitively monitor response.
  • the study will be a multi-institutional open label phase I/II trial of ganetespib in combination with sirolimus in patients with refractory sarcoma including MPNST.
  • the primary objective of the initial phase I component is to evaluate the safety and tolerability of this combination, and to determine the maximum tolerated dose (MTD)/recommend dose for this combination.
  • MTD maximum tolerated dose
  • the present trials are designed for a particular subset of patients aged 16 years or less, with sarcomas, in particular refractory sarcoma including MPNSTs.
  • phase I component will be open to the identified patient population with refractory sarcomas. Secondary objectives of this portion will be to describe the plasma pharmacokinetic profile of ganetespib and sirolimus when administered in this combination therapy.
  • the starting dose and escalation schema are as described below.
  • the recommended phase II dose of weekly single agent ganetespib is 200 mg/m 2 /dose IV over one hour x 3 weeks; 1 week off.
  • the starting dose of Ganetespib selected is a 25% dose decrease and used previously in the docetaxel combination trials (49).
  • the starting dose for sirolimus was selected using similar doses derived from earlier phase I single and combination studies (59, 61, 62) with sirolimus trough levels ranging from 5-10 ng/mL. There will be no plans to exceed the recommended doses of either agent (Dose level 2). Three to six patients will be entered per dose level using standard 3+3 design. Patients will be closely evaluated for the
  • phase II component will open.
  • the primary objective of the phase II portion will be to determine the clinical benefit rate (CR, PR, or stable disease > 4 months using WHO criteria) of ganetespib in combination with sirolimus for patients with refractory sporadic or NF1 associated MPNST. Additional sarcoma strata may be considered directed by preclinical findings and rationale.
  • Ten patients will be enrolled on the first stage, with no further accrual if no response (CR, PR, or stable disease > 4 months) is observed. If at least one response is observe, accrual will continue until a total of 20 patients have been enrolled.
  • this regimen will be considered active and could provide a therapeutic upfront strategy for this malignancy.
  • Sites of measureable disease will be evaluated within 4 weeks prior to starting therapy and then every 2 cycles. Patients will be able to remain on treatment as long as they do not experience progressive disease or unacceptable toxicity up to a maximum of 13 cycles (1 year). Response will be determined by WHO criteria.
  • MPNSTs are typically complex, non-spherical tumors and 2-D may thus reflect changes in tumor size better than 1-D (RECIST).
  • previous and ongoing trials of refractory phase II MPNST trials have used WHO criteria and will allow for direct comparisons. Secondary objectives will be to determine changes in
  • pharmacodynamic parameters including phospho-S6, AKT phosphorylation, pEIF2cc, Hsp70, and G6PD in tumor tissues from diagnosis/recurrence, and on treatment if feasible. These markers will also be evaluated in peripheral blood mononuclear cells at baseline and during treatment. Changes in patient reported pain and impact of pain on daily activities will also be assessed before and during treatment.
  • Phase I Patients with unresectable, recurrent, or metastatic histologically confirmed soft tissue or bone sarcoma of one of the following subtypes:
  • MPNST Malignant peripheral nerve sheath tumor
  • Alveolar soft part sarcoma Malignant giant cell tumor of bone Desmoplastic small round blue cell tumor Synovial Sarcoma Undifferentiated sarcoma
  • Phase II Patients with unresectable or metastatic histologically confirmed sporadic or NF1 associated high grade MPNST who have experienced progression after one or more prior regimens of cytotoxic chemotherapy. Patients who have refused cytotoxic chemotherapy or for whom treatment on this protocol prior to receiving cytotoxic chemotherapy is felt to be in the best interest for the patient by the local investigator will also be eligible.
  • a distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex)
  • Patients must have measurable disease, defined as at least one tumor that is measurable (defined as those that can be accurately measured in at least two dimensions (longest diameter > 20 mm with conventional techniques or > 10 mm using spiral CT scan) in two dimensions on CT or MRI scan.
  • measurable disease defined as at least one tumor that is measurable (defined as those that can be accurately measured in at least two dimensions (longest diameter > 20 mm with conventional techniques or > 10 mm using spiral CT scan) in two dimensions on CT or MRI scan.
  • Baseline radiologic scans must be performed within 4 weeks of starting treatment.
  • Adequate hematologic function as shown by: ANC > 1.0 x 10 9 /L, Platelets > 75,000 x 10 9 /L, Hgb > 9 g/dL (transfusion of packed red blood cells allowed).
  • QTcF ⁇ 480 ms. Note: Patients with Grade 1 prolonged QTcF (450-480 msec) at the time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e. electrolytes, medications).
  • Prior therapy Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy. Recovery is defined as a toxicity ⁇ grade 2 (CTCAE v 4.0), unless otherwise specified in the inclusion/exclusion criteria.
  • Myelosuppressive chemotherapy Patients must have not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study.
  • Biologic agent At least 7 days after the last dose of biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time which adverse events are known to occur.
  • Immunotherapy At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines.
  • Monoclonal antibodies Patients may not have received monoclonal antibodies within 3 weeks of enrollment onto this study.
  • Radiation At least 14 days after local palliative XRT (small port); or at least 4 weeks otherwise.
  • Hematopoietic growth factors At least 7 days must have elapsed since completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim.
  • Effective methods of birth control includes: surgically sterile, barrier device (condom, diaphragm), contraceptive coil, abstinence, or oral contraception.
  • Severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value corrected for hemoglobin and alveolar volume and/or O2 saturation that is 88% or less at rest on room air.
  • respiratory symptoms e.g. dyspnea at rest, known requirement for
  • vascular disease e.g. aortic aneurysm, symptomatic peripheral vascular disease
  • HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
  • sirolimus e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection.
  • BHT butylhyroxytoluene/butylated hydroxytoluene
  • magnesium stearate lactose monohydrate, hypromellose/hydroxypropyl methylcellulose, crospovidone, lactose anhydrous.
  • CYP3A4/CYP2C19 substrates Patients should not have received these medications within 1 week of entry and is not allowed while on study.
  • Enzyme inducing anticonvulsants Patients may not be taking enzyme - inducing anticonvulsants, and may not have received these medications within 1 week of entry, as these patients may experience different drug disposition. These medications include:
  • Phenobarbitol Phenytoin (Dilantin) Primidone (Mysoline) Oxcarbazepine (Trileptal)
  • Ganetespib is commercially available. Ganetespib will be diluted to appropriate dose in D5W prior to administration. Ganetespib will be given at hour 0 on days 1, 8, and 15 intravenously over 1 hour. Loperamide 2 mg should be given 1 to 2 hours prior to ganetespib administration and then every 4 hours for 12 hours post infusion to all patients as prophylactic diarrhea management. *A11 efforts should be made to adhere to this schedule. However, to provide some flexibility to changes in patients' schedules and holidays for long-term treatment, +/- 1 day in changes will not be considered a protocol deviation and will not require reporting to the NCI, IRB, or FDA.
  • Sirolimus will be purchased commercially (2 mg tablets) and administered once daily. On cycle 1, on day 1 a loading dose of sirolimus will be given orally x 1. Subsequent doses of sirolimus will be given once daily continuously with no breaks in between cycles. On days when sirolimus and ganetespib are given together, they should begin at hour 0 together. Sirolimus should be taken at approximately the same time every day, preferably in the morning, consistently with or without food. If a patient misses a dose, the dose may be taken within 6 hours of missed dose. Otherwise, patient must wait until the next day's dose. If a patient vomits after a dose of sirolimus it will not be repeated. All doses prescribed and dispensed to the patient and all dose changes during the study will be recorded in a patient diary.
  • a cycle of therapy is considered to be 28 days.
  • Ganetespib drug doses should be adjusted based on BSA determined prior to the beginning of each cycle.
  • a cycle may be repeated every 28 days if the patient has at least stable disease, has not experienced dose-limiting toxicity, and has recovered from the prior cycle as evidenced by return to baseline eligibility.
  • a cycle can be extended by an additional 14 days (to day 42) to allow for recovery without modifying the dose of the drug on subsequent cycles if toxicity did not meet dose limiting criteria.
  • Patient must not met one of the off protocol therapy or off study criteria defined in section 5.8 and 5.9.
  • a cycle may be administered a maximum of 13 times.
  • DLT Dose Limiting Toxicity
  • Toxicity will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
  • CTCAE Common Terminology Criteria for Adverse Events
  • a copy of the CTCAE version 4.0 can be downloaded from the CTEP website (http://ctep.cancer.gov). Any suspected or confirmed dose-limiting toxicity should be reported within 24 hours to the overall study Principal Investigator.
  • DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to ganetespib or sirolimus.
  • the DLT observation period for the purposes of dose escalation will be the first cycle of therapy.
  • Dose limiting hematological and non-hematological toxicities are defined below:
  • Grade 3 ALT/ AST that returns to meet initial eligibility criteria within 7 days of study drug interruption and that do not recur upon study re-challenge.
  • Grade 2 non-hematological toxicity that persists for > 7 days and is considered sufficiently medically significant or intolerable by patients that it requires treatment interruption. Any adverse event requiring interruption of study drug for > 7 days or which recurs upon drug challenge.
  • Intra-patient dose escalation is not allowed.
  • the MTD is defined as the dose level immediately below the dose at which > 33% of patients in a cohort experience a DLT.
  • At least 3 patients in a cohort must be evaluable for the definition of the MTD in order to escalate.
  • a patient will be considered evaluable for definition of the MTD if at least 70% of the prescribed sirolimus dose has been administered to the patient during the first treatment cycle based on diary review and pill count of returned drug, and patient must have received all 3 doses of ganetespib in the cycle. If a discrepancy occurs, pill count will be used for adherence measurement. If a patient has less than 70% adherence, the patient will be replaced in the cohort. In addition, anyone who receives one or more doses and experiences a DLT will be considered evaluable for definition of MTD. Dosing for Phase II component
  • immunosuppressive agent for example, cyclosporine
  • Concurrent cancer therapy including chemotherapy, radiation therapy, immunotherapy, or biologic therapy may not be administered.
  • trimethoprim/sulfamethoxazole as per institutional guidelines, or inhaled pentamidine.
  • inhaled pentamidine for example: trimethoprim/sulfamethoxazole as per institutional guidelines, or inhaled pentamidine.
  • Growth Factors that support platelet or white cell number or function can only be administered for culture proven bacteremia, clinical sepsis, or invasive fungal infection with neutropenia. ASCO guidelines and regulatory authority labeling for providing growth factor support are recommended.
  • Vaccinations Patients receiving immunosuppressants, including sirolimus, should not be administered live vaccines.
  • the response to vaccines (non-live) administered while the patient is immunosuppressed can be variable, and clinicians should check titers following for response if a non-live vaccine must be administered during this time.
  • the antiviral treatment should continue throughout the entire study period and for at least 4 weeks after the last dose of study drug.
  • Treatment may continue for a maximum of 1 year (13 cycles) in the absence of disease progression or unacceptable adverse events. [00205] Duration of Follow Up
  • Ganetespib may be restarted at dose reduction (Section 6.3) when QTcF is ⁇ Grade 1. While the QTcF
  • Severe Symptoms such as hypotension, angioedema, respiratory distress, or generalized uticaria:
  • the suggested treatments are topical analgesic mouth treatments (i.e., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in Orabase®).
  • topical analgesic mouth treatments i.e., local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol
  • topical corticosteroids such as triamcinolone oral paste 0.1% (Kenalog in Orabase®).
  • sirolimus will be held, and restarted with a dose reduction by 1 dose level after recovery from toxicity to grade 1 or less.
  • Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth ulcers. It is preferable to avoid these agents.
  • Antifungal agents must be avoided unless a fungal infection is diagnosed.
  • systemic imidazole antifungal agents ketoconazole, fluconazole, itraconazole, etc.
  • topical antifungal agents are preferred if an infection is diagnosed.
  • antiviral agents such as acyclovir should be avoided unless a viral infection is diagnosed.
  • Treatment of hyperlipidemia should take into account the pre-treatment status and dietary habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 or greater hypercholesterolemia (> 300 mg/dL or 7.75 mmol/L) or Grade 2 or greater hypertriglyceridemia (> 300 mg/dL or > 3.42 mmol/L) should be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitor (e.g., atorvastatin, pravastatin) or appropriate lipid-lowering medication, in addition to diet.
  • HMG 3-hydroxy-3-methyl-glutaryl
  • HMG-CoA reductase inhibitors Patients should be monitored clinically and through serum biochemistry for the development of rhabdomyolysis and other adverse events as required in the product label/data sheets for HMG-CoA reductase inhibitors.
  • Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is associated with an increased risk of a rare but serious skeletal muscle toxicity manifested by rhabdomyolysis, markedly elevated creatinine kinase (CPK) levels and myoglobinuria, acute renal failure and sometimes death.
  • CPK creatinine kinase
  • myoglobinuria acute renal failure and sometimes death.
  • the risk versus benefit of using this therapy should be determined for individual patients based on their risk of cardiovascular
  • Grade 4 hypercholesterolemia (> 500 mg/dL or > 12.92 mmol/L) hold sirolimus until cholesterol is ⁇ Grade 4. If triglycerides > 500- 1,000, and HDL is low, consider fibrate or niacin. For triglycerides > 1000 mg/dL or >11.4mmol/L, hold sirolimus while instituting fibrate or niacin therapy until triglycerides are ⁇ Grade 4.
  • Non-infectious pneumonitis is a class effect of rapamycin derivatives. Cases of non-infectious pneumonitis (including interstitial lung disease) have also been described in patients taking sirolimus. Some of these have been severe and on rare occasions, a fatal outcome was observed.
  • a diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate
  • Grade 3 CT scan with lung Prescribe Hold treatment until windows and pulmonary corticosteroids if recovery to ⁇ Grade 1.
  • function testing including: infective origin is ruled May restart protocol spirometry, DLCO, and out. Taper as medically treatment within 2 room air 02 saturation at indicated. weeks at a reduced dose rest; Repeat each if evidence of clinical subsequent Cycle until benefit.
  • Ganetespib chemical name: 5-[2,4-dihydroxy-5-(l-methylethyl)phenyl]-
  • 2,4-dihydro-4-(l-methyl-lH-indol-5-yl)-3H-l,2,4-triazole-3-one is a novel triazolone heterocyclic compound. Its molecular formula is C20H20N4O3. Ganetespib is a white to off-white powder with a molecular weight of
  • the current ganetespib investigational product is a concentrate for solution for infusion provided in a single-use vial containing 300 mg /vial of ganetespib, as described in the Pharmacy Manual.
  • the concentration of ganetespib is 25 mg/mL in a polyethylene glycol 300 (PEG 300), polysorbate 80 (Tween-80) and dehydrated alcohol non-aqueous solvent system.
  • the drug product is a clear, colorless-to-pale-yellow solution, essentially free of visible particles.
  • Ganetespib Drug Product 25 mg/mL, 300 mg/vial (identified with a dark blue color cap and applicable product label): Each vial contains 12 mL of deliverable volume (12.84 mL total including an overage per USP requirements) equivalent to 300 mg of ganetespib at a concentration of 25 mg/mL in a PEG 300, polysorbate 80, and dehydrated alcohol non-aqueous solvent system.
  • the drug product as noted, is a clear, colorless-to-pale-yellow solution.
  • the amount of ganetespib administered will depend upon the patient's body surface area. The drug product is diluted before infusion.
  • Ganetespib must be diluted prior to administration.
  • the appropriate drug administration instructions per the preparation guidelines must be carefully followed prior to use. Refer to the Pharmacy Manual for detailed ganetespib preparation guidelines.
  • VADs vascular access devices
  • PICCS peripherally-inserted central catheters
  • the ganetespib drug product is provided in a 30 mL type I amber glass vial fitted with a 20 millimeter stopper and sealed with an aluminum crimp and flip-off cap..
  • Sirolimus is a macrocyclic lactone produced by Streptomyces
  • sirolimus also known as rapamycin
  • the chemical name of sirolimus is (3S,6R ,7E,9R ,10R,12R ,14S,15E ,17E,19E ,21S,23S ,26R,27R ,34aS)- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3- [(lR)-2-[(lS,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-l-methylethyl]-10,21- dimethoxy-6,8, 12, 14,20,26-hexamethyl-23,27-epoxy-3H-pyrido [2, 1-c] [1,4] oxaazacyclohentriacontine-1,5, 11,28,29 (4H,6H ,31H)-pentone. Its molecular formula is
  • Tablets should be stored at 20° to 25°C (USP Controlled Room
  • Evaluable for toxicity for Phase I component A patient will be considered evaluable for definition of the MTD if at least 70% of the prescribed sirolimus dose has been administered to the patient during the first treatment cycle based on diary review and pill count of returned drug [if a discrepancy occurs, pill count will be used for adherence measurement] and all 3 doses of ganetespib in the first cycle. If a patient has less than 70% adherence, the patient will be replaced in the cohort. In addition, anyone who receives one or more doses and experiences a DLT will be considered evaluable for definition of MTD.
  • phase II component Patients who have received at least one dose of study drug will be considered evaluable for toxicity from the time of their first dose of ganetespib and sirolimus until the last evaluation on trial.
  • Measurable disease Measurable lesions are defined as those that can be accurately measured in at least two dimensions (longest diameter > 20mm with conventional techniques or >10 mm using spiral CT scan). All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).
  • Non-measurable disease All other lesions (or sites of disease), including small lesions (longest diameter ⁇ 20mm with conventional techniques or ⁇ 10 mm using spiral CT scan), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all non-measurable.
  • any patient who is enrolled and receives at least one dose of sirolimus and ganetespib will be considered evaluable for response provided: (1) the patient demonstrates progressive disease or death while on protocol therapy; (2) the patient is observed on protocol therapy for at least one cycle and the tumor is not removed surgically prior to the time complete response or partial response is confirmed; or (3) the patient demonstrates a complete or partial response or stable disease as confirmed according to protocol criteria. Patients who electively terminate therapy before receiving all ganetespib doses and > 80% of the required sirolimus doses during the first treatment cycle and do not expire within 28 days from start of treatment will be replaced. Disease Parameters
  • Index lesions should be selected on the basis of their measurability in two dimensions and their suitability for accurate repeated measurements (by imaging techniques CT or MRI). A sum of the product(s) of the longest diameter (LD) and greatest perpendicular diameter of all index lesions will be calculated and reported as the baseline sum. The baseline sum will be used as a reference by which to characterize the objective tumor response.
  • Non-index Lesions All other lesions (or sites of disease) including any measurable lesions over and above the index lesions should be identified as non- index lesions and should also be recorded at baseline. Measurement of these lesions is not required, but the presence or absence of each should be noted throughout follow-up.
  • Imaging-based evaluation is preferred to evaluation by clinical examination when both methods have been used to assess the antitumor effect of a treatment.
  • MPNSTs are typically complex non spherical tumors, and 2- dimensional measurements may thus better reflect changes in tumor size than 1- dimensional measurements (RECIST).
  • Complete Response Disappearance of all known disease, determined by two consecutive observations not less than 4 weeks apart.
  • Partial Response A > 50% decrease in the total tumor load of the lesions that have been measured to determine the effect of therapy not less than four weeks apart. The observations must be consecutive.
  • Bidimensionally measurable single lesion, > 50% decrease in tumor area (multiplication of longest diameter by the greatest perpendicular diameter); multiple lesions, a 50% decrease in the sum of the products of the perpendicular diameters of the multiple lesions.
  • Stable Disease A 50% decrease in total tumor area cannot be established nor has a 25% increase in the size of one or more measurable lesions been demonstrated.
  • Progressive Disease A > 25% increase in the area of one or more measurable lesions or the appearance of new lesions.
  • Partial Response Estimated decrease in tumor area of > 50% for at least four weeks.
  • Stable Disease No significant change for at least four weeks. This includes stable disease, estimated decrease of ⁇ 50%, and lesions with estimated increase of ⁇ 25%.
  • Progressive Disease Appearance of any new lesions not previously identified or an estimated increase of > 25% in existent lesions.
  • Duration of overall response The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, best response scan).
  • the duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented.
  • Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started.
  • PFS is defined as the duration of time from start of treatment to time of objective progression or death.
  • phase I component a conventional dose-escalation design is used.
  • the initial starting dose of ganetespib is approximately 1 dose level below the recommended phase 2 weekly dose in combination with the recommended adult dose of sirolimus of 4 mg once daily. This will be followed by one dose escalation to the ganetespib weekly recommended phase 2 dose and sirolimus recommended adult dose.
  • the total number of dose levels will likely only be 2, with the possibility of 2 dose de-escalations. Cohorts of 3 to 6 patients will be treated per dose level.
  • the MTD/Recommended dose will be defined as the dose level immediately below the level at which >33% of patients in a cohort experience a DLT based on toxicities observed in the first treatment cycle.
  • the primary endpoint will be clinical benefit rate, which will be defined as a CR, PR, or stable disease >4 months.
  • a completed trial of erlotinib in patients with refractory MPNST demonstrated a median time to progression of 48 days and progressive disease in the first response evaluation after completion of 2 treatment cycles in 19/20 patients— .
  • stable disease > 4 months can be considered potentially beneficial and worthy of further investigation.
  • An evaluable patient will be classified a responder (success) for the primary endpoint if the patient achieves a PR, CR or stable disease at > 4 months.
  • the target clinical benefit rate will be 25%, and a clinical benefit rate ⁇ 5% will be considered
  • the first stage will require 10 patients, with no further accrual if 0 of 10 respond. If >1/10 patients respond, accrual will continue until a total of 20 patients have been enrolled. If >3/20 patients respond, this combination will be considered of sufficient activity.
  • this design has a one sided alpha of 0.07 and a power of 88% for detecting a true success probability of at least 25% versus the null hypothesis success rate of 5% or less.
  • Any patient who experiences DLT at any time during protocol therapy is considered evaluable for adverse effects.
  • Patient without DLT who receive at least 85% of the prescribed sirolimus dose per protocols guidelines and had the appropriate toxicity monitoring performed are also considered evaluable for adverse effects.
  • Patients who are not evaluable for adverse effects at a given dose level will be replaced.
  • any eligible patient who is enrolled and receives at least one dose of drug will be considered evaluable for response provided: 1) the patient demonstrates progressive disease or death while on protocol therapy or 2) the patient is observed on protocol therapy for at least one cycle and the tumor is not removed surgically prior to the time complete response or partial response or stable disease is confirmed, or 3) patient demonstrates a complete or partial response or stable disease per protocol criteria.
  • the evaluation period for determination of best response will be 6 treatment cycles. All other patients will be considered non- responders
  • Phase I 3 to 6 patients per cohort with 1 dose escalations (potential for 2 de-escalation). Thus a minimum of 6 patients to a maximum of 18 patients will be enrolled.
  • Phase II 10 patients in first stage with an additional 10 patients in the second stage for a total of 20 patients.
  • the maximum number of patients for entire study will be 38. It is expected that 15-25 patients be enrolled per year, and enrollment is expected to be completed in approximately 2.5 years.
  • Pharmacokinetic analysis will be conducted using non-compartmental methods and estimated pharmacokinetic parameters including AUC, clearance, half- life and volume of distribution presented for each dose level using summary statistics (mean, standard deviation, median and range).
  • Pharmacodynamic parameters including phospho-S6, phospho-S6, phosphorylated eIF2 alpha, Akt Phosphorylation, Hsp70, and G6PD will be evaluated in surrogate tissue (peripheral blood mononuclear cells) and tumor tissue (when feasible) at baseline and during treatment. Changes in these parameters will be correlated to radiographic response using logistic regression analysis.
  • the plasma pharmacokinetic profile of ganetespib and sirolimus will be described when administered in combination therapy. Pre-therapy levels will be drawn at baseline. Pharmacokinetic analysis will occur on cycle 1, day 15 as to capture steady state sirolimus levels. Ganetespib has previously demonstrated no accumulation. On day 15: Ganetespib will be collected at hours 0, 1 hr (at the end of infusion), 2, 4, 6, 8, and 24 hours. Sirolimus will be collected at hours 0, 1, 2, 4, and 24 hours. All patients enrolled in the phase I portion will be required to participate in pharmacokinetic testing. In the phase II component, up to 10 patients will have optional pharmacokinetic analysis performed for broader experience at the
  • sirolimus trough levels There are no additional required sirolimus trough levels. However, sirolimus trough levels can be drawn if concerns for toxicity or any other clinical indication, and recommendations to be discussed with principal investigator.
  • Hsp 70 levels increase when Hsp90 is effectively inhibited and has been used as a pharmacodynamic response to Hsp90 inhibitors (73).
  • Phospho-S6 is the marker of choice in mTOR PD studies (59, 74) and recent data indicate that baseline expression could have predictive value (75).
  • the limited clinical efficacy of mTOR inhibitors have been proposed to result from AKT activation that can occur via the negative feedback pathways (76).
  • Sirolimus did not induce AKT activation in MPNSTs in vivo(27), and combined rapamycin/IPI-504 did not suppress AKT phosphorylation or expression levels in the mouse model, indicating that this combination is not more effective because it inhibits AKT (30).
  • EIF2cc phosphorylation is a marker of UPR activation (28) and was observed in the preclinical model as a marker of ER stress (30). Hsp90 inhibition appears to stimulate ROS production, and sirolimus appears to enhance these effects by suppressing endogenous anti-oxidants (30).
  • G6PD Glucose 6-phosphate dehydrogenase
  • Pain associated with a mass was found to be greatest risk factor associated with the development of MPNSTs in NF1 (12). Pain may also serve a surrogate marker for tumor response and clinical benefit.
  • Patient reported pain severity and the impact of pain on daily activities will be assessed prior to treatment and during treatment prior to cycles 3, 5, 9 and 13. The relationship in the change in pain with radiologic response will be examined.
  • the patient-reported pain evaluation will consist of two validated scales.
  • the Numerical Rating Scale-11 (NRS-11) will be used to assess pain severity
  • the Pain Interference Scale from the Brief Pain Inventory will be used to assess the impact of pain on daily activities. These scales have been placed on a single page to simplify administration. Total administration time is less than 3 minutes.
  • the Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11- point numeric scale that assesses pain severity(81). It consists of a horizontal line with 0 representing "no pain” at the right end of the line and 10 representing "worst pain you can imagine” at the left end. Patients are asked to circle the one number from 0 to 10 that best describes how much their "most important tumor pain” hurt during the past week. It takes less than 1 minute to complete.
  • the Brief Pain Inventory is a 7-item self-report questionnaire that measures the extent to which pain interferes with daily functioning (82). Patients are asked to indicate how much pain interfered with various activities (general activity, mood, walking, normal work, relations with other people, sleep, and enjoyment of life) in the past week, with scores ranging from 0 (does not interfere) to 10
  • a total score is obtained by taking the mean of the scores for all 7 items; thus, the total pain interference score can range from 0 to 7. This scale takes less than 2 minutes to complete.
  • Volumetric MRI analysis has become the standard method to evaluate the growth rate of plexiform neurofibromas on clinical trials (83, 84). This method may have utility for MPNSTs, which are typically large and have a complex shape.
  • Volumetric MRI analysis will be performed centrally at the NIH as a secondary objective and compared to standard response evaluation with ID-and 2D- measurements. MRI studies performed for response evaluation will be used for volumetric analysis, and no MRI sequence other than STIR MRI (Short Tl inversion recovery), which is commonly used in the evaluation of sarcomas and does not require contrast administration, will be required.
  • STIR MRI Short Tl inversion recovery
  • phase I component a conventional 3+3 dose-escalation design is used.
  • the initial starting dose of ganetespib is 150 mg/m 2 , approximately 1 dose level below the recommended phase 2 weekly dose, in combination with the recommended adult dose of sirolimus of 4 mg once daily. This will be followed by one dose escalation of the ganetespib to 200 mg/m 2 weekly (recommended phase 2 dose) and sirolimus recommended adult dose.
  • MTD dose-limiting toxicity
  • the primary endpoint will be clinical benefit rate, which will be defined as a CR, PR, or stable disease > 4 cycles.
  • An evaluable patient will be classified as a responder (success) for the primary endpoint if the patient achieves a PR, CR or stable disease at > 4 months.
  • the target clinical benefit rate will be 25%, and a clinical benefit rate ⁇ 5% will be considered uninteresting.
  • the first stage will require 10 patients, with no further accrual if 0 of 10 respond. If >_1/10 patients respond, accrual will continue until a total of 20 patients have been enrolled. If >_3/20 patients respond, this combination will be considered of sufficient activity. Assuming the number of successes is binomially distributed, this design has a one sided alpha of 0.07 and a power of 88% for detecting a true success probability of at least 25% versus the null hypothesis success rate of 5% or less.
  • Ron D Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519-29.
  • G6PD glucose 6-phosphate dehydrogenase

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des méthodes de traitement ou de prévention d'un sarcome chez un sujet, comprenant l'administration d'une quantité thérapeutiquement efficace d'un inhibiteur de la protéine Hsp90 en combinaison avec un inhibiteur de la protéine mTOR, le sujet ne devant pas être âgé de plus de 16 ans. La présente invention concerne également des compositions comprenant un inhibiteur de la protéine Hsp90 et un inhibiteur de la protéine mTOR, et des nécessaires en comprenant.
PCT/US2015/059148 2014-11-05 2015-11-05 Thérapie combinée associant des composés inhibiteurs de la protéine hsp90 et des inhibiteurs de la protéine mtor WO2016073669A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201462075581P 2014-11-05 2014-11-05
US62/075,581 2014-11-05

Publications (1)

Publication Number Publication Date
WO2016073669A1 true WO2016073669A1 (fr) 2016-05-12

Family

ID=55909780

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/059148 WO2016073669A1 (fr) 2014-11-05 2015-11-05 Thérapie combinée associant des composés inhibiteurs de la protéine hsp90 et des inhibiteurs de la protéine mtor

Country Status (1)

Country Link
WO (1) WO2016073669A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120128665A1 (en) * 2010-11-18 2012-05-24 Synta Pharmaceuticals Corp. Preselection of subjects for therapeutic treatment based on hypoxic status
WO2012162372A1 (fr) * 2011-05-24 2012-11-29 Synta Pharmaceuticals Corp. Thérapie combinée par des composés inhibiteurs de hsp90 et des inhibiteurs de mtor/p13k
WO2013170182A1 (fr) * 2012-05-11 2013-11-14 Synta Pharmaceuticals Corp. Traitement d'un cancer au moyen d'un composé inhibiteur de hsp90
US20140135370A1 (en) * 2011-05-11 2014-05-15 Synta Pharmaceuticals Corp. Treating cancer with an hsp90 inhibitory compound

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120128665A1 (en) * 2010-11-18 2012-05-24 Synta Pharmaceuticals Corp. Preselection of subjects for therapeutic treatment based on hypoxic status
US20140135370A1 (en) * 2011-05-11 2014-05-15 Synta Pharmaceuticals Corp. Treating cancer with an hsp90 inhibitory compound
WO2012162372A1 (fr) * 2011-05-24 2012-11-29 Synta Pharmaceuticals Corp. Thérapie combinée par des composés inhibiteurs de hsp90 et des inhibiteurs de mtor/p13k
WO2013170182A1 (fr) * 2012-05-11 2013-11-14 Synta Pharmaceuticals Corp. Traitement d'un cancer au moyen d'un composé inhibiteur de hsp90

Similar Documents

Publication Publication Date Title
RU2747788C2 (ru) Комбинированная терапия ингибиторами notch и cdk4/6 для лечения рака
US8110550B2 (en) HDAC inhibitors and hormone targeted drugs for the treatment of cancer
JP6705828B2 (ja) 腎癌の処置に使用するためのアピリモド
Yang et al. Liposomal honokiol induced lysosomal degradation of Hsp90 client proteins and protective autophagy in both gefitinib-sensitive and gefitinib-resistant NSCLC cells
JP6716585B2 (ja) 結腸直腸癌の処置に使用するためのアピリモド
Lin et al. Metformin sensitizes anticancer effect of dasatinib in head and neck squamous cell carcinoma cells through AMPK-dependent ER stress
EA033573B1 (ru) Комбинированное лечение меланомы, включающее введение кобиметиниба и вемурафениба
US20210236500A1 (en) Inhibition of autophagy using phospholipase a2 inhibitors
EP3576794A1 (fr) Méthodes de traitement du cancer au moyen d'inhibiteurs de hsp90
US20170071903A1 (en) Use of eribulin and mtor inhibitors as combination therapy for the treatment of cancer
Patel et al. Autophagy and senescence in cancer therapy
TW201306837A (zh) 使用ｐｉ３ｋ抑制劑及ｍｅｋ抑制劑用於治療癌症之組成物及方法
Anwer et al. Future of personalized therapy targeting aberrant signaling pathways in multiple myeloma
US10786471B2 (en) Methods and products related to glutaminase inhibitors
Wolfson et al. Enhancing FTS (Salirasib) efficiency via combinatorial treatment
WO2021048417A1 (fr) Polythérapies comprenant du dasatinib, destinées au traitement du cholangiocarcinome
WO2016073669A1 (fr) Thérapie combinée associant des composés inhibiteurs de la protéine hsp90 et des inhibiteurs de la protéine mtor
US20220409582A1 (en) Combination therapies comprising panobinostat for the treatment of cholangiocarcinoma
JP2019502707A (ja) 癌をアピリモドで処置するためのバイオマーカー
EP3164122A1 (fr) Prédiction de réponse à une thérapie anticancéreuse
CN112336864A (zh) 原黄素在肺癌治疗中的应用
KR20150003786A (ko) Pi3k 저해제 및 mek 저해제를 이용한 암 치료 방법
US20220071982A1 (en) Methods and uses for treating cancer
WO2021048418A1 (fr) Polythérapies comprenant du bortézomib pour le traitement du cholangiocarcinome
CA3240993A1 (fr) Inhibiteur de cdk4 pour le traitement du cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15856660

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15856660

Country of ref document: EP

Kind code of ref document: A1