CN112294814A

CN112294814A - Quinoline derivatives for the treatment of glioblastoma

Info

Publication number: CN112294814A
Application number: CN202010760358.XA
Authority: CN
Inventors: 陈媛媛; 王诚倩
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2019-07-31
Filing date: 2020-07-31
Publication date: 2021-02-02

Abstract

The present application belongs to the field of medical technology and relates to quinoline derivatives for the treatment of glioblastoma. In particular, the present application relates to the use of quinoline derivatives in combination with at least one chemotherapeutic agent for the treatment of glioblastoma; quinoline derivative the chemical name of compound I is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine.

Description

Quinoline derivatives for the treatment of glioblastoma

Technical Field

The present application relates to quinoline derivatives for the treatment of glioblastoma, in particular to the use of quinoline derivatives in combination with at least one chemotherapeutic drug for the treatment of glioblastoma.

Background

Gliomas are tumors originating from glial cells, also known as gliomas, and are the most common primary intracranial tumors. The WHO classification of central nervous system tumors classified gliomas as WHO grade I-IV, I, II grade low grade gliomas, and III, IV grade high grade gliomas.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, accounting for 6% and 54% of gliomas, respectively. Glioblastomas are the most lethal brain tumors, with only one third of patients having a survival of 1 year and < 5% over 5 years.

IDH mutation detection has become an important indicator of glioma classification, suggesting the prognosis of the patient. The TP53 gene mutation was found in more than 50% of secondary glioblastoma, but was less present in oligodendrogliomas. Most invasive astrocytomas express both IDH and TP53 mutations, whereas IDH wild-type also less expresses TP53 mutations. In the new glioma classification, the chromosomal 1p/19q co-deletion combined with the IDH mutation is defined as a subtype of oligodendroglioma. In addition, glioma is involved in mutations such as ATRX and TERT mutations, histone mutations, MGMT promoter methylation, BRAF mutations. With the continuous and deep research, the biological behaviors of various types of gliomas can be further understood deeply, and the development of new anti-tumor drugs can be guided.

The glioblastoma is mainly treated by surgical resection of tumors and combined with radiotherapy, chemotherapy and other comprehensive treatment methods. The main chemotherapy drugs include temozolomide, nitrosoureas, procarbazine, platinum, vinblastine and camptothecin drugs. After surgery, temozolomide synchronous radiotherapy combined with adjuvant chemotherapy becomes a standard treatment scheme for newly diagnosing GBM. New therapies such as new molecular targeted drug therapy, immunotherapy, gene therapy and the like are tried in glioblastoma treatment, but the curative effect needs to be verified by clinical tests.

Summary of The Invention

In one aspect, the present application provides a method of treating glioblastoma comprising administering to a patient in need thereof a therapeutically effective amount of: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one chemotherapeutic agent; and optionally radiation therapy.

In a second aspect, the present application provides a pharmaceutical combination of compound I or a pharmaceutically acceptable salt thereof and at least one chemotherapeutic agent, and its use in the manufacture of a medicament for the treatment of glioblastoma.

In a third aspect, the present application provides a pharmaceutical combination comprising: a first compartment comprising a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof; and the second compartment contains at least one chemotherapeutic drug.

In a fourth aspect, the present application provides a kit for treating glioblastoma comprising (a) a pharmaceutical composition containing at least one unit dose of compound I or a pharmaceutically acceptable salt thereof, (b) a pharmaceutical composition containing at least one chemotherapeutic drug as an active ingredient, and (c) instructions for treating glioblastoma.

In a fifth aspect, the treatment method, the pharmaceutical composition and the use thereof in preparing a medicament for treating glioblastoma, or the kit provided by the present application, may further comprise at least one small molecule targeted anti-tumor drug, an immunotherapy drug, or a macromolecular antibody drug.

In a sixth aspect, the application also provides a pharmaceutical combination of compound I or a pharmaceutically acceptable salt thereof and at least one small-molecule targeted antitumor drug and/or immunotherapeutic drug and/or macromolecular antibody drug, and its use in the preparation of a drug for treating glioblastoma.

Disclosure of Invention

In a second aspect, the present application provides the use of compound I, or a pharmaceutically acceptable salt thereof, in combination with at least one chemotherapeutic agent, in the manufacture of a medicament for the treatment of glioblastoma.

In some embodiments of the present application, the glioblastoma includes, but is not limited to, primary glioblastoma and secondary glioblastoma. In some embodiments of the present application, the glioblastoma includes, but is not limited to, a giant cell glioblastoma, an epithelial-like glioblastoma, and a glioblastoma that includes primitive neuronal components.

In some embodiments of the present application, the glioblastoma includes, but is not limited to, locally advanced, and/or advanced glioblastoma. In some embodiments, the glioblastoma is a glioblastoma that failed prior treatment. In some embodiments, the glioblastoma is a glioblastoma that failed prior surgical removal of the tumor. In some embodiments, the glioblastoma is a glioblastoma that has failed treatment with radiation and/or chemotherapeutic drugs. In some embodiments, the glioblastoma is a progression or recurrence of glioblastoma prior to treatment with at least one chemotherapeutic agent. In some embodiments, the glioblastoma is a glioblastoma that is intolerant of chemotherapeutic drugs. The chemotherapeutic drugs are imidazole tetrazine ketone drugs. In some embodiments, the glioblastoma is a glioblastoma previously treated with temozolomide.

In some embodiments, the glioblastoma is IDH wild-type glioblastoma. In some embodiments, the glioblastoma is an IDH mutant glioblastoma. In some embodiments, the glioblastoma is IDH1 and/or IDH2 mutant glioblastoma, including but not limited to IDH1R132, IDH2R172 at specific sites. In some embodiments, the glioblastoma is an EGFR gene-amplified glioblastoma. In some embodiments, the glioblastoma is a PTEN gene mutant glioblastoma. In some embodiments, the glioblastoma is a TP53 gene mutant glioblastoma. In some embodiments, the glioblastoma is a glioblastoma with a mutant version of the RAD50 gene.

In some aspects of the present application, the patient has previously received surgery, chemotherapy, and/or radiation therapy. In some embodiments, the patient experiences disease progression again after achieving complete remission following surgery, chemotherapy, and/or radiation therapy. In some embodiments, the patient has failed to complete remission or partial remission following surgery, chemotherapy, and/or radiation therapy.

In some embodiments of the present application, the patient has not previously received systemic chemotherapy. In some embodiments, the patient has previously received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the patient has not previously received systemic chemotherapy, but has received surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the patient experiences disease progression again after complete remission following surgical treatment, radiation therapy, induced chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the patient fails to provide complete or partial remission following surgical treatment, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy. In some embodiments, the cancer metastasizes after the patient has undergone surgical treatment, radiation therapy, induced chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy.

In some embodiments of the methods of treatment or use, compound I or a pharmaceutically acceptable salt thereof is administered in combination with at least one chemotherapeutic agent. Wherein the chemotherapy medicine is one or more of imidazole tetrazine ketone medicine, nitrosourea medicine, procarbazine, platinum medicine, vinblastine medicine and camptothecin medicine. In certain embodiments, the chemotherapeutic agent is one or more of temozolomide, carmustine, cyclazamide, methlomustine, pyrinurine, carmustine, lomustine, fotemustine, nimustine, ranimustine, streptozotocin, procarbazine, oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, camptothecin, hydroxycamptothecin, irinotecan, topotecan, vinorelbine, vinblastine, vincristine, vindesine, vinblastine. In some embodiments, the chemotherapeutic agent is temozolomide.

In some embodiments of the present application, the compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 6mg, 8mg, 10mg, or 12mg once daily; 2 weeks with continuous dosing and 1 week off dosing schedule; and/or, in a dosing regimen of 2 weeks on continuous dosing, and 2 weeks off.

In some embodiments of the present application, the chemotherapeutic agent is administered at 5-250mg/m once daily²The dosage of (a), a continuous dosing regimen. In some embodiments of the present application, the chemotherapeutic agent is administered at 5, 20, 50, 75, 100, 120, 140, 150, 180, 200, and/or 250mg/m once daily²The dose of (4) is administered for 5, 7, 10, 21, 35 or 42 consecutive days. In some specific embodiments, the chemotherapeutic agent is administered at 75mg/m once daily²The dose of (4), administered for 42 consecutive days. In some specific embodiments, the chemotherapeutic agent is administered at 75mg/m once daily²The dose of (4), administered for 42 consecutive days. In some specific embodiments, the chemotherapeutic agent is administered at 100mg/m once daily²The dose of (4), administered continuously for 5 days. In some specific embodiments, the chemotherapeutic agent is administered at 150mg/m once daily²The dose of (4), administered continuously for 5 days. In some specific embodiments, the chemotherapeutic agent is administered at 200mg/m once daily²The dose of (4), administered continuously for 5 days. In some specific embodiments, the chemotherapeutic agent is administered at 100mg/m once daily²The dose of (4), administered continuously for 7 days.

In some embodiments, the chemotherapeutic agent and compound I or a pharmaceutically acceptable salt thereof each have different treatment cycles, one treatment cycle for e.g. 21 days, 28 days, 35 days, 42 days, or one treatment cycle every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks, respectively. In some specific embodiments, the chemotherapeutic agent and compound I or a pharmaceutically acceptable salt thereof have the same treatment cycle, e.g., one treatment cycle for 21 days, 28 days, 35 days, or 42 days, or one treatment cycle for every 3 weeks, 4 weeks, 5 weeks, or 6 weeks.

In some specific embodiments, the treatment cycle for the chemotherapeutic agent and compound I or a pharmaceutically acceptable salt thereof is one treatment cycle every 3 weeks. In some specific embodiments, the treatment cycle for the chemotherapeutic agent and compound I or a pharmaceutically acceptable salt thereof is one treatment cycle for 21 days. In some specific embodiments, the treatment cycle for the chemotherapeutic agent and compound I or a pharmaceutically acceptable salt thereof is one treatment cycle every 4 weeks. In some specific embodiments, the treatment cycle for the chemotherapeutic agent and compound I or a pharmaceutically acceptable salt thereof is one treatment cycle for 28 days.

In some particular embodiments of the methods or uses of treatment, wherein the temozolomide is administered at 50-200mg/m once daily²Is administered to the patient, e.g., at a dose of 50, 75, 100, 110, 120, 130, 140, 150 and/or 200mg/m²Is administered to the patient. In some specific embodiments, wherein said temozolomide is present at 75mg/m once daily²The dose of (a) is administered to the patient for 42 consecutive days. In some embodiments, the temozolomide is administered concurrently with radiation therapy. In some embodiments, wherein said temozolomide is treatable as an adjunct to chemotherapy. In some embodiments, wherein said temozolomide is present at 100-²The dose of (a) is administered to the patient for 5 consecutive days, followed by 23 days of discontinuation, with a cycle of every 28 days. In some embodiments, wherein said temozolomide is present at 100mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, followed by 23 days off, 28 days being a cycle. In some embodiments, wherein said temozolomide is present at 150mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, followed by 23 days off, 28 days being a cycle. In some specific embodiments, wherein said temozolomide is present at 200mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, followed by 23 days off, 28 days being a cycle.

In some embodiments, wherein the temozolomide is administered every three weeks for a single dosing cycle. In some embodiments, wherein said temozolomide is present in an amount of 75-100mg/m²The dose of (a) is administered to the patient for 21 consecutive days, followed by 7 days off, 28 days being a cycle. In some embodiments, wherein said temozolomide is present at 100mg/m once daily²The dose of (a) is administered to the patient for 21 consecutive days, followed by 7 days off, 28 days being a cycle. In some embodiments, wherein the temozolomide is administered on a weekly dosing schedule. In some embodiments, wherein said temozolomide is present at 100-150mg/m once daily²The dose of (a) is administered to the patient on days 1-7 and days 15-21, with a cycle every 28 days.

In some embodiments, the compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 6mg, 8mg, 10mg, or 12mg once daily; 2 weeks with continuous dosing and 1 week off dosing schedule; in combination with temozolomide, wherein the temozolomide is administered in a regimen selected from the group consisting of any one or more of: i) at a dose of 100mg/m once a day²The dose of (a) is administered to the patient for 21 consecutive days, followed by 7 days off, 28 days being a cycle; ii) 75mg/m once daily²The dose of (a) is administered to the patient for 21 consecutive days, followed by 7 days off, 28 days being a cycle; iii) 150mg/m once daily²The dose of (a) is administered to the patient for 21 consecutive days, followed by 7 days off, 28 days being a cycle; iv) at once daily 100mg/m²The dose of (a) is administered to the patient for 5 consecutive days, followed by 23 days off, 28 days being a cycle; v) 150mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, followed by 23 days off, 28 days being a cycle; vi) at 200mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, followed by 23 days off, 28 days being a cycle; vii) at once daily 100mg/m²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days; viii) at 150mg/m once daily²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days; ix) to 75mg/m once daily²The dose of (a) is administered to the patient for 42 consecutive days; x) at 75mg/m once daily²Is administered to the patient for no more than 63 consecutive days.

In some embodiments, there is provided a method of treating glioblastoma by simultaneous chemoradiotherapy, wherein the simultaneous chemoradiotherapy is a simultaneous administration of a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent and radiation to a patient in need thereof. In some embodiments, there is provided a method of treating glioblastoma by means of sequential radiotherapy, wherein the sequential radiotherapy is a first administration of a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof, followed by radiotherapy, to a patient in need thereof.

In some embodiments, there is provided a method of treating glioblastoma by simultaneous chemoradiotherapy followed by adjunctive chemotherapy, wherein the simultaneous chemoradiotherapy is administered to a patient in need of treatment simultaneously, sequentially or intermittently, a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent and radiation therapy, and the adjunctive chemotherapy is administered simultaneously to a patient in need of treatment simultaneously, a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent. In some embodiments, there is provided a method of treating glioblastoma by simultaneous chemoradiotherapy, followed by adjuvant chemotherapy and then maintenance therapy, wherein the simultaneous chemoradiotherapy is a simultaneous administration of a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent and radiation to a patient in need of treatment, the adjuvant chemotherapy is a simultaneous administration of a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent to a patient in need of treatment, and the maintenance therapy is a administration of a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.

In some embodiments, a method is provided for treating glioblastoma by concurrent chemoradiotherapy of compound I or a pharmaceutically acceptable salt thereof and temozolomide, followed by adjuvant chemotherapy of compound I or a pharmaceutically acceptable salt thereof and temozolomide, followed by maintenance therapy of compound I or a pharmaceutically acceptable salt thereof.

In a specific embodiment, the compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 8mg once daily, continuously during the concurrent chemoradiotherapy periodsDosing with a dosing regimen of 2 weeks, rest 1 week; temozolomide at 75mg/m once a day²The dose of (c), administered on a 42 day continuous schedule; while receiving radiation therapy. In the adjuvant chemotherapy phase, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 8mg once daily for 2 weeks, on a 1-week rest schedule; temozolomide at 150mg/m once a day²The dose of (3) is administered on a cyclic dosing schedule of 5 consecutive days, 23 days apart, and 28 days apart. During the maintenance treatment period, compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 8mg once daily for 2 weeks, with a dosing schedule of 1 week off.

In a specific embodiment, there is provided a method of treating a glioblastoma in a patient, comprising three treatment phases in sequence: (1) compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 8mg once daily for 2 weeks on a dosing schedule of 1 week off; temozolomide at 75mg/m once a day²The dose of (c), administered on a 42 day continuous schedule; simultaneously receiving radiation therapy; (2) compound I or a pharmaceutically acceptable salt thereof is administered at a dose of 8mg once daily for 2 weeks on a dosing schedule of 1 week off; temozolomide at 150mg/m once a day²The dose of (a), administered continuously for 5 days followed by 23 days off, 28 days being a cyclic dosing schedule; and (3) Compound I or a pharmaceutically acceptable salt thereof, is administered at a dose of 8mg once daily for 2 weeks with a dosing schedule of 1 week off.

In a third aspect, the present application provides a pharmaceutical combination comprising: the first compartment comprises a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof; and the second compartment contains at least one chemotherapeutic drug.

In some embodiments of the present application, the pharmaceutical combination comprises: (i) a pharmaceutical composition comprising compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one pharmaceutical composition comprising a chemotherapeutic agent.

In some embodiments, there is provided a pharmaceutical combination for treating glioblastoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) at least one chemotherapeutic agent, optionally in combination with radiation therapy. In some specific embodiments, there is provided a pharmaceutical combination for treating glioblastoma comprising: (i) compound I or a pharmaceutically acceptable salt thereof; and (ii) temozolomide.

In some specific embodiments, there is provided a pharmaceutical combination for treating glioblastoma comprising: (i) a pharmaceutical composition having a unit dose of 6mg, 8mg, 10mg and/or 12mg of compound I or a pharmaceutically acceptable salt thereof; and (ii) the administration dose is 5-250mg/m²The pharmaceutical composition of temozolomide.

In some specific embodiments, there is provided a pharmaceutical combination for treating glioblastoma comprising: (i) a pharmaceutical composition with a single dose of 6mg, 8mg, 10mg and/or 12mg of compound I or a pharmaceutically acceptable salt thereof; and (ii) administered in a dose of 5, 20, 50, 75, 100, 140, 150, 180, 200 and/or 250mg/m²The pharmaceutical composition of temozolomide.

In some specific embodiments, there is provided a pharmaceutical combination for treating glioblastoma comprising: (i) a single dose of 6mg, 8mg, 10mg and/or 12mg of a pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof; and (ii) administered at a dose of 5, 20, 100, 140, 180 and/or 250mg/m²The pharmaceutical composition containing temozolomide.

In a fifth aspect, the pharmaceutical composition and the use thereof in the preparation of a medicament for treating glioblastoma, or a kit provided by the present application, may further comprise at least one of a small molecule targeted anti-tumor drug, an immunotherapy drug, and a macromolecular antibody drug.

Glioblastoma

In the present application, the glioblastoma includes, but is not limited to, primary glioblastoma and secondary glioblastoma. According to different molecular generation mechanisms, the molecular change of the primary glioblastoma is mainly based on the amplification and over-expression of an Epidermal Growth Factor Receptor (EGFR); the molecular change of secondary glioblastoma is mainly due to p53 gene mutation. In some embodiments, the glioblastoma is grade III glioblastoma, according to the WHO classification. In some embodiments, the glioblastoma is grade IV glioblastoma. In some embodiments, the glioblastoma is a highly malignant glioblastoma.

In some embodiments, the glioblastoma is glioblastoma multiforme. In some embodiments, the glioblastoma is a primary glioblastoma. In some embodiments, the glioblastoma is a secondary polymorphic sarcoma. In some embodiments, the glioblastoma is a giant cell glioblastoma. In some embodiments, the glioblastoma is an epithelial-like glioblastoma (Ep-GBM). In some embodiments, the glioblastoma is a glioma. In some embodiments, the Glioblastoma is a Glioblastoma with a primary neural component (GBM-PNC) containing primitive neuronal components.

In some embodiments, the glioblastoma is IDH wild-type glioblastoma. In some embodiments, the glioblastoma is an IDH mutant glioblastoma. In some embodiments, the glioblastoma is a glioblastoma of undetermined classification (NOS). In some embodiments, the glioblastoma is IDH1 and/or IDH2 mutant glioblastoma, and the specific sites can be IDH1R132 and IDH2R 172.

In some embodiments, the glioblastoma is an EGFR gene-amplified glioblastoma. In some embodiments, the glioblastoma is an EGFR gene mutant glioblastoma. In some embodiments, the glioblastoma is wild-type glioblastoma of the EGFR gene. In some embodiments, the glioblastoma is a TP53 gene mutant glioblastoma. In some embodiments, the glioblastoma is a TP53 gene wild-type glioblastoma. In some embodiments, the glioblastoma is a PTEN gene mutant glioblastoma. In some embodiments, the glioblastoma is a PTEN gene wild-type glioblastoma. In some embodiments, the glioblastoma is an ATRX gene mutant glioblastoma. In some embodiments, the glioblastoma is a glioblastoma of the wild type of the ATRX gene. In some embodiments, the glioblastoma is a glioblastoma with mutations in the TERT gene promoter at position C250T/C228T. In some embodiments, the glioblastoma is a TERT gene promoter mutant glioblastoma. In some embodiments, the glioblastoma is a TERT gene promoter wild-type glioblastoma. In some embodiments, the glioblastoma is a TERT gene promoter-fused glioblastoma. In some embodiments, the glioblastoma is a glioblastoma with methylation of the MGMT gene promoter. In some embodiments, the glioblastoma is one in which the MGMT gene promoter is unmethylated. In some embodiments, the glioblastoma is a SMARCAL1 gene mutant glioblastoma. In some embodiments, the glioblastoma is a SMARCAL1 gene wild-type glioblastoma. In some embodiments, the glioblastoma is a glioblastoma with a mutant ERBB2 gene. In some embodiments, the glioblastoma is a glioblastoma of the ERBB2 gene wild type. In some embodiments, the glioblastoma is a MET gene mutant glioblastoma. In some embodiments, the glioblastoma is a MET gene wild-type glioblastoma. In some embodiments, the glioblastoma is a BRAF gene mutant glioblastoma. In some embodiments, the glioblastoma is a wild-type glioblastoma of the BRAF gene. In some embodiments, the glioblastoma is a KRAS gene mutant glioblastoma. In some embodiments, the glioblastoma is a KRAS gene wild-type glioblastoma. In some embodiments, the glioblastoma is an ALK gene mutant glioblastoma. In some embodiments, the glioblastoma is a glioblastoma of the ALK gene wild type. In some embodiments, the glioblastoma is a RET gene mutant glioblastoma. In some embodiments, the glioblastoma is a RET gene wild-type glioblastoma. In some embodiments, the glioblastoma is a ROS1 gene mutant glioblastoma. In some embodiments, the glioblastoma is a ROS1 gene wild-type glioblastoma. In some embodiments, the glioblastoma is a glioblastoma with a mutant version of the RAD50 gene. In some embodiments, the glioblastoma is wild-type glioblastoma of the RAD50 gene. In some embodiments, the glioblastoma is a histone mutated glioblastoma. In some embodiments, the glioblastoma is a histone wild-type glioblastoma.

In some specific embodiments, the glioblastoma is a glioblastoma with a mutant EGFR1 gene, specifically at exon 14. In some specific embodiments, the glioblastoma is a PTEN gene mutant glioblastoma with exon 5 as the specific site. In some specific embodiments, the glioblastoma is a TP53 gene mutant glioblastoma with a specific site of exon 5. In some specific embodiments, the glioblastoma is a glioblastoma with a mutant RAD50 gene, with a specific site of exon 5.

Glioblastoma described herein, including but not limited to locally advanced, and/or advanced glioblastoma. In some embodiments, the glioblastoma is a glioblastoma that failed prior treatment. In some embodiments, the glioblastoma is a glioblastoma that failed prior surgical removal of the tumor. In some embodiments, the glioblastoma is a glioblastoma that has failed treatment with radiation and/or chemotherapeutic drugs. In some embodiments, the glioblastoma is a progression or recurrence of glioblastoma prior to treatment with at least one chemotherapeutic agent. In some embodiments, the glioblastoma is a glioblastoma that is intolerant of chemotherapeutic drugs.

Chemotherapy medicine

In the present application, the chemotherapeutic drug includes, but is not limited to, one or more of alkylating agents, podophyllum, camptothecin, taxus, antimetabolites, and antibiotic antineoplastic drugs. Examples that may be enumerated include, but are not limited to, imidazotetrazinones (e.g., temozolomide), platinoids (e.g., oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin (dicycloprotein), ledaplatin (Lobaplatin), triplatin tetranitrate, phenanthroline, picoplatin, satraplatin), nitrosoureas (e.g., carmustine (BCNU), cyclazamide (CCNU), methrocyclonitrosourea (Me-CCNU), pyriminoxuron (ACNU), carmustine, lomustine (semustine), fotemustine, nimustine, ramustine, streptozotocin), camptothecins (e.g., camptothecin, hydroxycamptothecin, irinotecan, topotecan), vinblastines (e.g., vinorelbine, vinblastine, vincristine, vindesine, vinflunine (vinflunine)), procarbazine, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, estramustine, mechlorethamine, one or two or three of triamcinolone, melphalan, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, thiotepa), alkyl sulfonates (e.g., busulfan, mannosulfan, busulfan), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, fluorouracil, difurofluorouracil, doxifluridine, tegafur, carmofur, trifluridine), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, paclitaxel liposomes, and docetaxel), pemetrexed, etoposide, irinotecan, mitomycin, cytarabine, azacitidine, amrubicin, methotrexate, epirubicin, doxorubicin, Sapacitabine, plinabulin (plinabulin), troxsulalfan (treosulfan), dipivefrin hydrochloride (tipicil hydrochloride), oxychlorocidine, and octenidar.

In certain embodiments, the chemotherapeutic agent is one or more of an imidazotetrazine drug, a nitrosourea drug, procarbazine, a platinum drug, a vinca alkaloid drug, and a camptothecin drug.

In certain embodiments, the chemotherapeutic agent is one or more of temozolomide, carmustine, cyclazamide, methlomustine, pyrinurine, carmustine, lomustine, fotemustine, nimustine, ranimustine, streptozotocin, procarbazine, oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, camptothecin, hydroxycamptothecin, irinotecan, topotecan, vinorelbine, vinblastine, vincristine, vindesine, vinblastine.

In certain embodiments, the chemotherapeutic agent is temozolomide.

In certain embodiments, the chemotherapeutic agent is temozolomide concurrently with the radiation therapy.

In certain embodiments, the chemotherapeutic agent is a STUPP regimen. Wherein the STUPP regimen is specifically a simultaneous chemoradiotherapy: temozolomide 75mg/m²D, 42 days; adjuvant chemotherapy: administration of temozolomide 150-²And/d, continuous administration for 5 days, once a day, with 23-day intervals, and 28-day cycle.

In some embodiments of the present application, the chemotherapy isThe medicine is 5-250mg/m once a day²The dosage of (a), a continuous dosing regimen. In some embodiments of the present application, the chemotherapeutic agent is administered at 5, 20, 50, 75, 100, 120, 140, 150, 180, 200, and/or 250mg/m once daily²The dose of (4) is administered for 5, 7, 10, 21, 35 or 42 consecutive days. In some specific embodiments, the chemotherapeutic agent is administered at 75mg/m once daily²The dose of (4), administered for 42 consecutive days. In some specific embodiments, the chemotherapeutic agent is administered at 75mg/m once daily²The dose of (4), administered for 42 consecutive days. In some specific embodiments, the chemotherapeutic agent is administered at 100mg/m once daily²The dose of (4), administered continuously for 5 days. In some specific embodiments, the chemotherapeutic agent is administered at 150mg/m once daily²The dose of (4), administered continuously for 5 days. In some specific embodiments, the chemotherapeutic agent is administered at 200mg/m once daily²The dose of (4), administered continuously for 5 days. In some specific embodiments, the chemotherapeutic agent is administered at 100mg/m once daily²The dose of (4), administered continuously for 7 days.

In some embodiments, the chemotherapeutic agent is one treatment cycle, including but not limited to 21 days, 28 days, 35 days, 42 days, every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, or every 6 weeks. In some specific embodiments, the treatment cycle of the chemotherapeutic agent is one treatment cycle every 3 weeks. In some specific embodiments, the treatment cycle for the chemotherapeutic agent is one treatment cycle for 21 days. In some specific embodiments, the treatment cycle of the chemotherapeutic agent is one treatment cycle every 4 weeks. In some specific embodiments, the treatment cycle for the chemotherapeutic agent is one treatment cycle for 28 days.

In some particular embodiments of the methods of treatment or use, wherein the temozolomide is administered at 50 to 200mg/m once daily²Is administered to the patient, e.g., at a dose of 50, 75, 100, 110, 120, 130, 140, 150 and/or 200mg/m²Is administered to the patient. In some specific embodiments, wherein said temozolomide is present at 75mg/m once daily²Is administered to a patient in a continuous doseAnd (5) 42 days. In some embodiments, the temozolomide is administered concurrently with radiation therapy. In some embodiments, wherein said temozolomide is treatable as an adjunct to chemotherapy. In some embodiments, wherein said temozolomide is present at 100-²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 28 days at 23-day intervals. In some embodiments, wherein said temozolomide is present at 100mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 28 days at 23-day intervals. In some embodiments, wherein said temozolomide is present at 150mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 28 days at 23-day intervals. In some specific embodiments, wherein said temozolomide is present at 200mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 28 days at 23-day intervals. In some embodiments, wherein the temozolomide is administered on a weekly dosing schedule. In some embodiments, wherein said temozolomide is present at 100-150mg/m once daily²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days. In some embodiments, wherein said temozolomide is present at 100mg/m once daily²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days. In some embodiments, wherein said temozolomide is present at 150mg/m once daily²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days. In some embodiments, wherein the temozolomide is administered on a three week dosing schedule. In some embodiments, wherein said temozolomide is present at 75-100mg/m once daily²The dose of (a) is administered to the patient for 21 consecutive days, with 7 days being the interval, and 28 days being a cycle. In some embodiments, wherein said temozolomide is present at 100mg/m once daily²The dose of (a) is administered to the patient for 21 consecutive days, with 7 days being the interval, and 28 days being a cycle.

Small molecule targeted antitumor drug and immunotherapy drugSubstance, macromolecule antibody medicine

In some embodiments, the small molecule targeted anti-tumor drugs described herein include, but are not limited to, protein kinase inhibitors. Wherein, the protein kinase inhibitor includes but is not limited to tyrosine kinase inhibitor, serine and/or threonine kinase inhibitor, Poly ADP Ribose Polymerase (PARP), poly ADP-ribose polymerase inhibitor, the target of the inhibitor includes but is not limited to Fascin-1 protein, HDAC (histone deacetylase), Proteasome (Proteasome), CD38, SLAMF7(CS1/CD319/CRACC), RANKL, EGFR (epidermal growth factor receptor), Anaplastic Lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signal path, DDR2 (discoid death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene; the target of the small molecule targeted antitumor drug also comprises COX-2 (cyclooxygenase-2), APE1 (apurinic apyrimidinic endonuclease), VEGFR (vascular endothelial growth factor receptor), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor), Ezrin, PEDF (pigment epithelium derived factor), AS, ES, OPG (osteoprotegerin), Src and IFN, ALCAM (leukocyte activated adhesion factor), HSP, jis 1, GSK-3 (glycogen synthase kinase 3 sugar), CyclinD1 (cell cycle regulatory protein), CDK4 (cyclin dependent kinase), TIMP1 (tissue metalloproteinase inhibitor), THBS3, PTHR1 (parathyroid hormone-related protein receptor 1), TEM7 (human tumor vascular endothelial marker 7), COPS3, cathepsin K. Examples of small molecule targeted antineoplastic agents include, but are not limited to, Imatinib (Imatinib), Sunitinib (Sunitinib), Nilotinib (Nilotinib), bosutinib (bosutinib), saratinib (Saracatinib), Pazopanib (Pazopanib), trabectedidine (Trabectedin), Regorafenib (Regorafenib), Cediranib (Cediranib), Bortezomib (Bortezomib), Panobinostat (Panobinostat), Carfilzomib (Carfilzomib), ixazomide (Ixazomib), apatinib (traatinib), Erlotinib (Erlotinib), Afatinib (Afatinib), Crizotinib (critinib), Ceritinib (ceratinib), tracintinib (veitinib), Erlotinib (grittinib), Gefitinib (grittinib), gefit, Icotinib (icotinib), Lapatinib (Lapatinib), Vandetanib (Vandetinib), semetinib (Selumetinib), Sorafenib (Sorafenib), tematinib (Olmutinib), Wolinib (Savoltinib), furoquintinib (Fruquintinib), ententinib (Entretinib), Dasatinib (Dasatinib), Ensartinib (Ensartinib), Lenvatinib (Lenvatinib), itacetinib, piritinib (Pyrotinib), bimetinib (Binitetinib), erdasatinib (Erdaitinib), Acitinib (Axitinib), lenatinib (Neitinib), bicininib (Cometinib), Acatinib (LOpsinib), Farnetinib-803, Maspininib (L-1205), Lluminaib, Lpininib (L-1205), Lluminaib, Lpintinib-L), Lluminanib (Lluminanib), Lbtinib (Lbtinib), Lpininib (Lbtain, Lpintinib), Lpintinib-L-1205, Lpintinib, Lf-L-D, Lpintinib, Lf-D, Lpintinib (Lf-L-D), Lpintinib, Lf-D-L-R-L-D, Lf-L-E, L-D, L-E-D-L-E-L-E, L-E-L-E, L-E (L-E, L-E-, Capivastrib, SH-1028, metformin, seliciclib, OSE-2101, APL-101, berzostrib, idelalisib, lerociclib, ceralasertib, PLB-1003, tomiveritb, AST-2818, SKLB-1028, D-0316, LY-3023414, allitinib, MRTX-849, AP-32788, AZD-4205, lifirafenib, vactorib, mivebressib, napubulin, sitatinvaib, TAS-114, molibresib, CC-223, rivoceranib, 254-101, LXH-CK, simotinib, GSK-3368715, TAS-8, sitaiib, tepetinib, 102-96, SAF-4544, ASN-101, ASN-53, AZH-CK, silmurafenib-0735, ASN-379, SANgutid-0735, SANTIA-53, SANgrain-3, SANgutisb, SANgurtib, SANgutisib, SANgutisb-369, SANgutisib, SANgutisb-3, SANgutisb, SANgutisib, SANgutise-3, SANgutisb, SANgutis0, SANgutisib, SANgutisb, SANgutisib, SANgutise-3, CT-707, epitinib succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosystem, DV-281, Siremaddlin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, bortezomib, tucidinostat, vorinostat, reminiostat, epatadinostat, tazemetostat, entinostat, mocetinostat, quisinostat, LCL-161, KML-001.

In some embodiments, the small molecule targeted antineoplastic agent is one or more of sorafenib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacomitinib, ocitinib, erlotinib, brigatinib, loratinib, tremetinib, treetinib, larotinib, erlotinib, lapatinib, vandetanib, semertinib, tematinib, wallitinib, furazitinib, enretinib, dasatinib, ennatinib, lenvatinib, itatinib, pyrrole, bimetinib, erlotinib, axitinib, lenatinib, cobitinib, acartinib, acartitinib, famitinib, masitinib, ibrutinib, and nintedanib.

In some embodiments, the immunotherapeutic agents described herein include, but are not limited to, one or more of interferons (interferon alpha, interferon alpha-1 b, interferon alpha-2 b), interleukins, sirolimus (temsirolimus), everolimus (everolimus), ridaforolimus (ridaforolimus), and temsirolimus.

In some embodiments, the targets targeted by the macroantibody drugs described herein include, but are not limited to, any one or more of PD-1, PD-L1, cytotoxic T lymphocyte antigen 4 (cytoxic T-lymphocyte antigen 4, CTLA-4), platelet derived growth factor receptor alpha (PDGFR- α), Vascular Endothelial Growth Factor (VEGF), human epidermal growth factor receptor-2 (HER2), Epidermal Growth Factor Receptor (EGFR), ganglioside GD2, B cell surface protein CD20, B cell surface protein CD52, B cell surface protein CD38, B cell surface protein CD319, B cell surface protein CD30, B cell surface protein CD19/CD 3.

In some embodiments, the antibody drug is an inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1; in some embodiments, the antibody agent is a cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor. In some embodiments, the antibody drug is a platelet-derived growth factor receptor alpha (PDGFR-alpha) inhibitor.

In some embodiments, the inhibitor of the interaction between the PD-1 receptor and its ligand PD-L1 is an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-1) and/or inhibits PD-1 activity, or an antibody or antigen-binding portion thereof that binds programmed death receptor 1(PD-L1) and/or inhibits PD-L1 activity, such as an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, the antibody or antigen-binding portion thereof is (a) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-1 and blocks the binding of human PD-L1 to human PD-1; or (b) a monoclonal antibody, or antigen-binding fragment thereof, that specifically binds to human PD-L1 and blocks the binding of human PD-L1 to human PD-1.

In some embodiments, the anti-PD-1 or PD-L1 antibody is an anti-PD-1 or PD-L1 monoclonal antibody.

In some embodiments, the anti-PD-1 or PD-L1 antibody is a human or murine antibody.

In some embodiments, the anti-PD-1 antibody may be selected from any one or more of Nivolumab, palboceprizumab (Pembrolizumab), debarville mab (Durvalumab), teriepril mab (toriplalimab, JS-001), Cedilizumab (IBI308), Carelix strain mab (Camrelizumab), Tirley strain mab (BGB-A317), AK105 (Compton), Jennuzumab (GB226), Lilizumab (M009), HLX-10, BAT-1306, AK103(HX008), AK104 (Compton), CS1003, SCT-I10A, F520, SG001, GLS-010.

In some embodiments, the anti-PD-L1 antibody may be selected from any one or more of Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, BGB-333, JS003, STI-A1014(ZKAB0011), KN035, MSB2311, HLX-20, CS-1001.

In some specific embodiments, the anti-PD-1 antibody is tereprimab.

In some specific embodiments, the anti-PD-1 antibody is pabollizumab.

In some embodiments, the inhibitor of cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is an anti-CTLA-4 monoclonal antibody.

In some embodiments, the anti-CTLA-4 antibody may be selected from any one or more of Ipilimumab (Iplimumab), Tremelimumab (Tremelimumab), AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI 310.

In some specific embodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the platelet-derived growth factor receptor alpha (PDGFR-alpha) inhibitor is an anti-PDGFR alpha antibody. In some embodiments, the anti-PDGFR α antibody is an anti-PDGFR α monoclonal antibody.

In some specific embodiments, the anti-PDGFR α antibody is Olaratumab (olarataumab).

In some specific embodiments, the antibody drug may further include, but is not limited to, Bevacizumab (Bevacizumab), Ramucirumab (Ramucirumab), Pertuzumab (Pertuzumab), trastuzumab (trastuzumab), cetuximab (Cotuximab), Nimotuzumab (Nimotuzumab), Panitumumab (Panitumumab), Nimotuzumab (Necitumumab), dinuximab (Necitumumab), dinituximab, Rituximab (Rituximab), Ibritumomab (Ibritumomab), ofazumab ozitumomab (ofamab), Obinutuzumab (Alemtuzumab), daratuzumab (Daratumumab), Gemtuzumab (Gemtuzumab), rituzumab (Rituximab), present antibody (brentuzumab), Rituximab (biotuzumab), or any one or more of them.

Compound I or a pharmaceutically acceptable salt thereof

Compound I has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the following structural formula:

in the application, all references to erlotinib refer to compound I.

Compound I can be administered in its free base form, as well as in the form of its salts, hydrates, and prodrugs, which convert in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the present application and can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments, compound I is administered as the hydrochloride salt of compound I. In some embodiments, compound I is administered as the monohydrochloride salt of compound I. In some embodiments, compound I is administered as the dihydrochloride salt. In some embodiments, the compound I is administered as a crystalline form of the hydrochloride salt of compound I. In a particular embodiment, compound I dihydrochloride is administered as a crystalline form.

Compound I or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent, may be administered by a variety of routes including, but not limited to, a route selected from: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal. In a particular embodiment, administration is by oral administration.

The amount of compound I or a pharmaceutically acceptable salt thereof, chemotherapeutic agent administered may be determined by the severity of the disease, the response to the disease, any treatment-related toxicities, the age and health of the patient. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 3 mg to 30 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 5mg to 20 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 8mg to 16 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 10mg to 14 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 8 mg. In a particular embodiment, compound I or a pharmaceutically acceptable salt thereof is administered in a daily dose of 10 mg. In a particular embodiment, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 12 mg. In this application, for example, with respect to tablets or capsules, "12 mg of compound I on a unit dose basis" means that each tablet or each capsule ultimately produced contains 12mg of compound I.

The compound I or a pharmaceutically acceptable salt thereof, a chemotherapeutic agent may be administered once or more times daily. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, is administered once daily. In one embodiment, the oral solid formulation is administered once daily.

In the above-mentioned therapeutic methods, the administration method can be comprehensively determined depending on the activity and toxicity of the drug, the tolerance of the patient, and the like. Preferably, compound I or a pharmaceutically acceptable salt thereof is administered at intervals. The intermittent administration includes a dosing period during which compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day and a rest period. For example, compound I or a pharmaceutically acceptable salt thereof is administered daily during a dosing period, then the administration is stopped for a period of time during a rest period, followed by a dosing period, then a rest period, and so on, which may be repeated multiple times. Wherein the ratio of the administration period to the withdrawal period in days is 2: 0.5-5, preferably 2: 0.5-3, more preferably 2: 0.5-2, and still more preferably 2: 0.5-1.

In some embodiments, the administration is discontinued for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 14 days off; followed by 1 administration per day for 14 days and then 14 days, so that the administration may be repeated several times at 2-week intervals.

In some embodiments, the administration is discontinued for 1 week for 2 weeks. In some embodiments, administration is 1 time per day for 14 days followed by 7 days of discontinuation; the administration is followed 1 time per day for 14 days and then discontinued for 7 days, so that the administration is repeated multiple times at 1 week intervals for 2 weeks of continuous administration.

In some embodiments, the administration is continued for 5 days and discontinued for 2 days. In some embodiments, administration is 1 time per day for 5 days, followed by 2 days off; the administration is followed 1 time per day for 5 days and then discontinued for 2 days, and the administration may be repeated multiple times at intervals of 5 consecutive days and 2 discontinued days.

In certain particular embodiments, the administration is oral at a dose of 12mg once daily for 2 weeks with 1 week rest.

Pharmaceutical combination

Each component of the pharmaceutical combination described herein may optionally be used in combination with one or more pharmaceutically acceptable carriers, wherein the components may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient. The pharmaceutical combinations described herein may be formulated separately from each other or some or all of them may be co-formulated. Preferably, the components of the pharmaceutical combination are formulated separately or each is formulated as a suitable pharmaceutical composition. In some embodiments, the pharmaceutical combination of the present application may be formulated as a pharmaceutical composition suitable for single or multiple administration. In some particular embodiments, the pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof may be selected from solid pharmaceutical compositions including, but not limited to, tablets or capsules.

The components of the pharmaceutical combination of the present application may each be administered separately, or some or all of them may be co-administered. The components of the pharmaceutical combination of the present application may be administered substantially simultaneously, or some or all of them may be administered substantially simultaneously.

The components of the pharmaceutical combination of the present application may be administered independently of each other, or some or all of them together in a suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may be administered orally or parenterally, each independently, or some or all of them together, for example intravenously or intraperitoneally.

The components of the pharmaceutical combination of the present application may each independently, or some or all of them together be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained release formulations for oral or non-oral administration.

In some embodiments of the present application, the pharmaceutical combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

In some embodiments of the present application, the pharmaceutical combination is a non-fixed combination. In some embodiments, the chemotherapeutic agent and the compound of formula I in the non-fixed combination are each in the form of a pharmaceutical composition.

In certain embodiments, compound I is combined with surgical resection and/or radiation therapy.

In some embodiments, compound I is administered simultaneously or sequentially with one or more chemotherapeutic agents. In certain embodiments, one or more chemotherapeutic agents have been administered to the patient prior to administration of compound I or prior to combination with compound I. In certain embodiments, the one or more chemotherapeutic agents are administered to the patient again after administration of compound I or after combination with compound I. In certain embodiments, compound I has been administered to the patient prior to administration of the one or more chemotherapeutic agents or prior to combination with the one or more chemotherapeutic agents. In certain embodiments, compound I is administered to the patient again after administration of or in combination with one or more chemotherapeutic agents. In certain embodiments, the one or more chemotherapeutic drugs are not effective in treating cancer. In some embodiments, the chemotherapeutic agent is any anti-cancer agent described herein or known in the art.

In some embodiments, compound I, a chemotherapeutic drug, is formulated in a formulation suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalational, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal administration; preferably suitable for oral administration, including tablet, capsule, powder, granule, dripping pill, paste, powder, etc., preferably tablet and capsule. Wherein the tablet can be common tablet, dispersible tablet, effervescent tablet, sustained release tablet, controlled release tablet or enteric coated tablet, and the capsule can be common capsule, sustained release capsule, controlled release capsule or enteric coated capsule. The oral preparation can be prepared by a conventional method using a pharmaceutically acceptable carrier well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. Fillers include starch, lactose, mannitol, microcrystalline cellulose, and the like; the absorbent comprises calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include water, ethanol, and the like; the binder comprises hypromellose, polyvidone, microcrystalline cellulose, etc.; the disintegrating agent comprises croscarmellose sodium, crospovidone, surfactant, low-substituted hydroxypropyl cellulose, etc.; the lubricant comprises magnesium stearate, pulvis Talci, polyethylene glycol, sodium laurylsulfate, silica gel micropowder, pulvis Talci, etc. The medicinal adjuvants also include colorant, sweetener, etc.

In some embodiments of the present application, the pharmaceutical combination is a non-fixed combination. In some embodiments, the chemotherapeutic agent and compound I in the non-fixed combination are each in the form of a pharmaceutical composition.

In some embodiments, a kit of pharmaceutical compositions for treating glioblastoma is also provided, comprising (a) a first pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a kit of pharmaceutical compositions for treating glioblastoma is also provided, comprising (a) a first pharmaceutical composition comprising an imidazotetrazine as an active ingredient; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient. In some embodiments, a kit of pharmaceutical compositions for treating glioblastoma is also provided, comprising (a) a first pharmaceutical composition comprising temozolomide as an active ingredient; and (b) a second pharmaceutical composition containing compound I or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, and for purposes of this application, the following terms used in the specification and claims shall have the following meanings, unless otherwise indicated.

As used herein, the term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.

As used herein, the term "treatment failure" refers to intolerance of toxic side effects, disease progression during treatment, or relapse after treatment is concluded.

As used herein, the term "patient" is a mammal, preferably a human.

A "recurrent" cancer is a cancer that regenerates at the primary site or a distant site in response to an initial treatment (e.g., surgery). A "locally recurrent" cancer is one that occurs at the same location after treatment as a previously treated cancer.

The term "pharmaceutically acceptable" is intended 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 problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts of the base ion with the free acid or salts of the acid ion with the free base, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt and the like. In the present application, when forming a pharmaceutically acceptable salt, the molar amount of free acid to base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1: 8. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1: 8.

The term "fixed combination" means that the active ingredients (e.g. the chemotherapeutic drug or compound I) are administered to a patient simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

The term "non-fixed combination" means that two or more active ingredients are administered to a patient as separate entities (e.g. pharmaceutical compositions, formulations) simultaneously, concurrently or sequentially and without specific time constraints, wherein the active ingredients are administered to the patient at a therapeutically effective amount level. An example of an unfixed combination is cocktail therapy, e.g. 3 or more active ingredients are administered. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as a completely separate pharmaceutical composition. The term "non-fixed combination" also includes the use of "fixed combinations" in between, or "fixed combinations" in combination with, any one or more of the individual entities of the active ingredients.

As used herein, "in combination" or "in combination" means that two or more active substances may be administered to a patient sequentially, in any order, together in a mixture, simultaneously as a single formulation, or as a single formulation.

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application (e.g., a chemotherapeutic agent or compound I) or a pharmaceutical combination thereof with pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application or pharmaceutical combinations thereof to a patient.

The term "Complete Remission (CR)": refers to complete mitigation as defined by the RANO standard.

The term "Partial Remission (PR)": refers to partial mitigation as defined by the RANO standard.

The term "disease Progression (PD)": refers to disease progression as defined by the RANO standard.

The term "disease Stable (SD)": refers to disease stabilization as defined by the RANO standard.

Detailed Description

The present application is further described below with reference to specific examples, which, however, are only for illustration and do not limit the scope of the present application. Likewise, the present application is not limited to any particular preferred embodiment described herein. It will be understood by those skilled in the art that equivalents may be made to the features of the present application or modifications may be made thereto without departing from the scope of the invention. The reagents used in the following examples are commercially available products, and the solutions can be prepared by techniques conventional in the art, except where otherwise specified.

Example 1 therapeutic efficacy of Arotinib in combination with temozolomide on relapsed glioblastoma patients

Patient, male, 55 years old, 2018, 2 months and 1 day, general anesthesia descent "left temporal placeholderectomy", postoperative pathological diagnosis was (left temporal lobe) glioblastoma, graded as grade IV according to WHO. The synchronous radiotherapy and chemotherapy (STUPP scheme) comprises the following specific steps: temozolomide 75mg/m²D, 42 days; PTV 60Gy/2 Gy/30F. Then auxiliary chemotherapy is carried out, in particular to temozolomide 150-²Once daily for 5 consecutive days, with 23 days intervals. Five cycles after adjuvant chemotherapy regimen dosing, disease progression (PD, RANO criteria) occurred and the patient occasionally experiencedThe occipital pain is persistent dull pain accompanied by dizziness, and new focus appears after relapse.

Administration of temozolomide 100mg/m²Once daily for 21 consecutive days with 7 days intervals, and every 28 days as a treatment cycle; 12mg/d of erlotinib, once daily for 14 days, and one treatment cycle is every three weeks after the drug is stopped. After the patient takes the erlotinib for one period, the headache is obviously relieved. According to the RANO standard, PR was obtained after 1 month of administration of Arotinib, CR was obtained after 2 months of administration of Arotinib, and CR was obtained after 3 months of administration of Arotinib.

Example 2 results of clinical trials of Arotinib in combination with STUPP regimen for treatment of newly diagnosed glioblastoma patients

For 20 primary-treated patients with glioblastoma confirmed by post-operative pathology (where post-operative treatment refers to 2-6 weeks after surgery and the surgical incision is well healed, and there are lesions evaluable according to the RANO standard), the treatment regimen of anitinib in combination with STUPP was performed, including the synchronized radiotherapy phase, the adjuvant chemotherapy phase, and the maintenance treatment phase. The primary observation that the combined treatment regimen had an effect on Progression Free Survival (PFS) in glioblastoma patients was other observations including: (1) disease Control Rate (DCR); (2) overall survival of treatment (OS); (3) a treatment failure mode; (4) treatment-related toxicity. (5) Quality of life; (6) intellectual state and cognitive function. The specific treatment protocol is as follows:

1) concurrent chemoradiotherapy phase (42-63 days): the oral administration of the nilotinib is started on the first day, 8mg each time and once a day, and the oral administration is carried out before breakfast. The medicine is taken continuously for 2 weeks, and the medicine is stopped for 1 week, namely 3 weeks (21 days) are taken as a cycle. First day temozolomide 75mg/m²Once a day; simultaneously receiving radiotherapy 5 days a week, 1.8-2.0Gy each time once a day, and 54-60Gy total dose.

2) 4 weeks after the end of the concurrent chemoradiotherapy phase treatment, the adjuvant chemotherapy phase is started: anrotinib administered orally at 8mg once a day, once a breakfast, began the first day of this period. The drug administration is continued for 2 weeks, and the drug is stopped for 1 week, i.e. 3 weeks (21 days) are 1 cycle of the anitinib treatment. The initial dose of temozolomide is 150mg/m²The medicine is stopped for 23 days after 5 days of continuous administration, namely 4 weeks (28 days) are 1 cycle of chemotherapy treatment, and the temozolomide dosage is increased to 150mg/m per day according to the patient early reaction from the 2 nd cycle²～200mg/m²。

The adjuvant chemotherapy stage is 24 weeks in total, namely 8 dosing cycles of the aniotinib treatment and 6 dosing cycles of the chemotherapy treatment.

3) And (3) maintaining the treatment stage: after 1 week of the last anitinib in the adjuvant chemotherapy stage, the anitinib is orally taken, 8mg each time, once a day and before breakfast. The medicine is taken continuously for 2 weeks, and the medicine is stopped for 1 week, namely 3 weeks (21 days) are 1 cycle. Maintenance treatment was terminated as soon as disease progression was assessed by RANO criteria.

Until now, the new statistical data show the results of efficacy evaluation in 15 patients as shown in the following table, and the treatment cycles in each stage are calculated as the treatment cycles of aniotinib, except for patients 1 and 2, the rest of patients are still receiving drug treatment.

Claims

1. The use of a pharmaceutical combination of compound I or a pharmaceutically acceptable salt thereof and at least one chemotherapeutic agent for the preparation of a medicament for the treatment of glioblastoma,

2. the use according to claim 1, wherein the glioblastoma comprises, but is not limited to, primary glioblastoma, secondary glioblastoma.

3. The use of claim 1, wherein the glioblastoma includes, but is not limited to, a giant cell glioblastoma, an epithelial-like glioblastoma, and a glioblastoma containing primitive neuronal components.

4. Use according to any one of claims 1 to 3, wherein the glioblastoma is a glioblastoma that failed prior treatment, preferably a glioblastoma that failed prior surgical removal of the tumor, or a glioblastoma that failed treatment with radiation and/or chemotherapeutic drugs.

5. The use according to any one of claims 1 to 4, wherein the glioblastoma is a glioblastoma that has progressed or recurred after prior treatment with at least one chemotherapeutic, a glioblastoma that is intolerant to chemotherapeutic, preferably a glioblastoma that has been previously treated with an imidazoletetrazinone drug, and more preferably a glioblastoma that has been previously treated with temozolomide.

6. The use according to any one of claims 1 to 5, wherein said glioblastoma comprises, but is not limited to, IDH wild-type glioblastoma, IDH mutant glioblastoma, preferably IDH1 and/or IDH2 mutant glioblastoma, more preferably glioblastoma with IDH1R132, IDH2R172 mutant sites.

7. The use according to any one of claims 1 to 6, wherein the glioblastoma includes, but is not limited to, EGFR gene amplification type glioblastoma, PTEN gene mutant glioblastoma, TP53 gene mutant glioblastoma, RAD50 gene mutant glioblastoma.

8. Use according to any one of claims 1 to 7, wherein the chemotherapeutic agent includes, but is not limited to, one or more of alkylating agents, podophyllotoxins, camptothecins, taxanes, antimetabolites, antibiotic antineoplastic agents, and examples include, but are not limited to, imidazotetrazinones, such as temozolomide; platinum drugs such as oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, leplatin, triplatin tetranitrate, phenanthroline, picoplatin, satraplatin; nitrosoureas, such as carmustine, cyclitrourea, methylcyclonitrosourea, pyrimiditrourea, carmustine, lomustine, fotemustine, nimustine, ramustine, streptozotocin; camptothecins, such as camptothecin, hydroxycamptothecin, irinotecan, topotecan; vinblastines such as vinorelbine, vinblastine, vincristine, vindesine, vinflunine; procarbazine; nitrogen mustards, such as nitrogen mustards, mechlorethamine, cyclophosphamide, ifosfamide, estramustine, trofosfamide, melphalan, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, thiotepa; alkyl sulfonates such as busulfan, mannosulfan, threosulfan; fluoropyrimidine derivatives such as gemcitabine, capecitabine, fluorouracil, difurfurofluorouracil, doxifluridine, tegafur, carmofur, trifluridine; taxanes, such as paclitaxel, albumin-bound paclitaxel, paclitaxel liposomes, and docetaxel; one or two or three of pemetrexed, etoposide, irinotecan, mitomycin, cytarabine, azacitidine, amrubicin, methotrexate, epirubicin, doxorubicin, Sapacitabine, plinabulin, troosufen, dipivefrin hydrochloride, tegafur and encequidar.

9. The use according to any one of claims 1 to 8, wherein the compound I or the pharmaceutically acceptable salt thereof is administered in a daily dose of 3 mg to 30 mg, preferably 5mg to 20 mg, more preferably 8mg to 16 mg, even more preferably 8mg to 14 mg, most preferably 8mg, 10mg or 12 mg.

10. The use according to any one of claims 1 to 9, wherein compound I or a pharmaceutically acceptable salt thereof is administered at intervals between a dosing period and a rest period; the ratio of the administration period to the withdrawal period in days is preferably 2: 0.5-5, more preferably 2: 0.5-3, even more preferably 2: 0.5-2, and still more preferably 2: 0.5-1; as a further preferred mode of administration at intervals, one of the following modes is used: stopping the drug for 2 weeks after 2 weeks of continuous administration, for 1 week after 2 weeks of continuous administration, or for 2 days after 5 days of continuous administration; the intermittent administration mode may be repeated a plurality of times.

11. The use according to any one of claims 1 to 10, wherein the chemotherapeutic agent is temozolomide, to be administered in an amount of 50 to 200mg/m once daily²Is administered to the patient, e.g., at a dose of 50, 75, 100, 110, 120, 130, 140, 150 and/or 200mg/m²Is administered to the patient; preferably, the temozolomide is present at 75mg/m once daily²Is administered to the patient for 42 consecutive days, or temozolomide is administered at 100-200mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 23 days, 28 days; or temozolomide in an amount of 75-100mg/m once a day²The dose of (a) is administered to the patient for 21 consecutive days, with 7 days intervals, and 28 days as a cycle; or temozolomide at 100-150mg/m once a day²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days.

12. The use according to any one of claims 1 to 11, wherein the compound I or the pharmaceutically acceptable salt thereof is administered at a dose of 6mg, 8mg, 10mg or 12mg once daily; 2 weeks with continuous dosing and 1 week off dosing schedule; a temozolomide dosing regimen in combination with any one of the following chemotherapeutic agents: i) at a dose of 100mg/m once a day²The dose of (a) is administered to the patient for 21 consecutive days, with 7 days intervals, and 28 days as a cycle; ii) 75mg/m once daily²The dose of (a) is administered to the patient for 21 consecutive days, with 7 days intervals, and 28 days as a cycle; iii) 150mg/m once daily²Is administered to a patient in a dosage of (a),the administration is carried out continuously for 21 days, and the interval is 7 days, and 28 days are a period; iv) at once daily 100mg/m²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 23 days, 28 days; v) 150mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 23 days, 28 days; vi) at 200mg/m once daily²The dose of (a) is administered to the patient for 5 consecutive days, with a period of 23 days, 28 days; vii) at once daily 100mg/m²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days; viii) at 150mg/m once daily²Is administered to the patient on days 1-7 and 15-21, with a cycle of 28 days; ix) to 75mg/m once daily²The dose of (a) is administered to the patient for 42 consecutive days; x) at 75mg/m once daily²Is administered to the patient for no more than 63 consecutive days.

13. The use according to any one of claims 1 to 12, wherein the pharmaceutical combination further comprises at least one small molecule targeted antineoplastic, immunotherapeutic, macromolecular antibody drug;

the small molecule targeted antitumor drug includes but is not limited to imatinib, sunitinib, nilotinib, bosutinib, secatinib, pazopanib, trabectedin, regorafenib, cediranib, bortezomib, panobinostat, carfilzomib, ixazomide, apatinib, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib, dabrafenib, cabozantinib, gefitinib, dacetinib, oxitinib, orletinib, ibrutinib, brutinib, loratinib, trametinib, laratinib, lapatinib, vandetanib, sematinib, sorafenib, tematinib, wolitinib, furatinib, emtinib, dasatinib, emtinib, erlotinib, irvatinib, ivatinib, itatinib, piritinib, erlotinib, acatinib, famitinib, masitinib, ibrutinib, rociletinib, nintedanib, lenalidomide, LOXO-292, Vorolanib, bemcentinib, caplatinib, entritinib, TAK-931, ALT-803, Pabosini, famitinib L-malatate, LTT-462, BLU-667, ninetinib, tipifarnib, poziotiib, DS-1205, capivalitib, SH-1028, metformin, selicicliib, OSE-2101, APL-101, berzostitib, idelisib, lerocicliib, ceraratertiib, PLB-1003, tomivosertib, AST-2818, LB-1026, SKPTID-03183, MRB-788, MRB-3544, TAcinetilib-4208, SALK1-848, TAlasertinib-3514, TAlasertinib-1028, MRB-358, TAlasertinib, TAI-3514, TAI-223, TAI-3, TAI-D-3, TAI-1, TAI-D-7, TAI-D, TAI-1, TAI-D, TAI-7, TAI-D-7, TAI-D, TAI, One or more of galenisertib, ASN-003, gedatolisib, defatinib, lazerttinib, CKI-27, S-49076, BPI-9016M, RF-A-089, RMC-4630, AZD-3759, antroquinonol, SAF-189S, AT-101, TTI-101, naputinib, LNP-3794, HH-SCC-244, ASK-120067, CT-707, epitinib succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, parotin, veliparib, talazoparib, DV-281, Siremamandin, telaglendast, MP-0250, G-TL, G-0812, borteosinst, vitreosidin 801, beta-161, beta-sulfatide, beta-161, beta-200, beta-0812, beta-sulfatide, beta-beta;

the immunotherapy drug comprises one or more of but not limited to interferon alpha, interferon alpha-1 b, interferon alpha-2 b, interleukin, sirolimus, everolimus, diphospholimus and temsirolimus;

the macromolecular antibody drug includes but is not limited to nivolumitumumab, palivizumab, Devolumab, Terepritumomab, Cedilitumumab, Ribrizumab, AK105, Jennuzumab, Rilizumab, HLX-10, BAT-1306, AK103, AK104, CS1003, SCT-I10A, F520, SG001, GLS-010, Atezolizumab, Avelumab, Durvalumab, KL-A167, SHR-1316, SHB-333, JS003, STI-A1014(ZKAB0011), KN035, MSB2311, HLX-20, CS-1001, ipilimumab, AGEN-1884, BMS-986249, BMS-986218, AK-104, IBI310, Diolaritumumab, Rituzumab, pertuzumab, Rituzumab, rituxorubib, rituximab, Nutuximab, Rituximab, Bestub, Rituzumab, Rituximab, Rituzumab, one or more of ibritumomab tiuxetan, ofatumumab, Obinutuzumab, alemtuzumab, daratumumab, gemtuzumab ozotakizumab, erlotintuzumab, present-tuximab, oximtuzumab and bonatuzumab.