PHARMACEUTICAL COMPOSITION COMPRISING PROTEIN KINASE INHIBITOR AND CHEMOTHERAPEUTIC DRUG AND USE THEREOF

Abstract

The present invention relates to the field of biotechnology, and in particular relates to a pharmaceutical composition comprising a protein kinase inhibitor and a chemotherapeutic drug and use thereof. It is found that in the treatment of platinum-refractory/drug-resistant relapsed advanced ovarian cancer, the remission rates of etoposide or paclitaxel in combination with chiauranib is respectively 40% and 50%, while the remission rate of etoposide alone is about 27%, and the remission rate of paclitaxel alone is about 21%, indicating that the combination of chiauranib and etoposide or paclitaxel in the treatment of platinum-refractory/drug-resistant relapsed advanced ovarian cancer has achieved unexpected synergistic effects.

Claims

1. A pharmaceutical composition comprising a protein kinase inhibitor and a chemotherapeutic drug, wherein the protein kinase inhibitor is a compound of formula (I): ##STR00005## or free form, salt form, enantiomer or diastereomer thereof, wherein Z is CH or N; R.sup.1, R.sup.2 and R.sup.3 are independently hydrogen, halogen, methyl, methoxy or trifluoromethyl; R.sup.4 is ##STR00006## X is a benzene ring or a pyridine ring; R.sup.5 is one or more substituents selected from the group consisting of hydrogen, halogen, methyl, methoxy or trifluoromethyl.

2. The pharmaceutical composition according to claim 1, wherein the protein kinase inhibitor is a compound of formula (II): ##STR00007##

3. The pharmaceutical composition according to claim 1, wherein the chemotherapeutic drug comprises topoisomerase II inhibitors or paclitaxel and derivatives thereof; wherein the topoisomerase II inhibitors comprise etoposide or teniposide; the paclitaxel and derivatives thereof comprise paclitaxel, docetaxel and nab-paclitaxel.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for the treatment and/or prevention of cancer, preferably ovarian cancer comprising malignant epithelial ovarian cancer, fallopian tube cancer and primary peritoneal carcinoma, more preferably platinum-refractory/platinum-resistant relapsed ovarian cancer, most preferably platinum-refractory/platinum-resistant relapsed advanced ovarian cancer.

5. The pharmaceutical composition according to claim 1, wherein the protein kinase inhibitor is used at an amount within the range of 1-100 mg, the topoisomerase II inhibitor is used at an amount within the range of 1-100 mg, and the paclitaxel and derivatives thereof are used at an amount within the range of 10-200 mg/m.sup.2.

6. (canceled)

7. A method for treating and/or preventing cancer, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 1 to a patient in need, wherein the cancer is ovarian cancer comprising malignant epithelial ovarian cancer, fallopian tube cancer and primary peritoneal carcinoma, preferably platinum-refractory/platinum-resistant relapsed ovarian cancer, most preferably platinum-refractory/platinum-resistant relapsed advanced ovarian cancer.

8. A kit, comprising the pharmaceutical composition according to claim 1.

9. The kit according to claim 8, wherein the protein kinase inhibitor, the topoisomerase II inhibitor or paclitaxel and derivatives thereof are respectively unit preparations with the same or different specifications, and the protein kinase inhibitor is preferably an oral preparation, the topoisomerase II inhibitor is preferably an oral preparation, and the paclitaxel and derivatives thereof are preferably an intravenous drip preparation.

10. The kit according to claim 8, wherein the protein kinase inhibitor, the topoisomerase II inhibitor or paclitaxel and derivatives thereof are respectively provided in separate containers.

11. A method for treating platinum-refractory/platinum-resistant relapsed advanced ovarian cancer, comprising administering a therapeutically effective amount of the compound of formula (II) to a patient in need: ##STR00008##

Description

DETAILED DESCRIPTION

[0050] The present disclosure discloses a pharmaceutical composition comprising a protein kinase inhibitor and a chemotherapeutic drug and use thereof, and those skilled in the art can learn from the content of this document and make appropriate improvements. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, which are deemed to be included in the present disclosure. The application of the present disclosure has been described through the preferred embodiments, and it is obvious that relevant persons can make modifications or appropriate changes and combinations to the applications described herein without departing from the content, thought and scope of the present disclosure to implement and apply the technology of the present disclosure.

[0051] The present disclosure is further illustrated below by non-limiting examples, which is not intended to limit the scope encompassed by the present disclosure.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art. For the purpose of the present disclosure, the following terms are defined below.

[0053] The term “about” when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5% less than the specified numerical value and an upper limit that is 5% greater than the specified numerical value.

[0054] The term “adverse event” (AE) refers to an adverse medical event that occurs after a patient or clinical trial subject receives a drug/substance, but it is not necessarily causally related to the treatment. The relapse of pre-existing other disease that occurs during the course of the clinical study is included, whether or not its occurrence is related to the treatment. Invasive clinical examinations per se are not considered as adverse events, but the reasons for these examinations should be considered as adverse events.

Example 1 A Single-Arm, Multi-Center, Non-Randomized, Open-Label Clinical Trial to Explore the Efficacy and Safety of Chiauranib Capsules for the Treatment of Relapsed and Refractory Ovarian Cancer

[0055] 1. Trial Design

[0056] A single-arm, multi-center, non-randomized, open-label phase Ib trial.

[0057] Main inclusion criteria: Patients with histologically diagnosed epithelial ovarian cancer, fallopian tube cancer or primary peritoneal carcinoma; patients who had received platinum-based chemotherapy regimens, and platinum-resistant patients who achieved progressive or relapsed disease after had received ≥2 different chemotherapy regimens; platinum-sensitive patients who achieved progressive or relapsed disease after had received ≥2 different chemotherapy regimens, or who refused to receive further chemotherapy.

[0058] Medication regimen: 50 mg of chiauranib was taken orally every morning on an empty stomach, once a day, every 28 days as a treatment cycle, and there was no drug withdrawal interval between the treatment cycles. The treatment was continued until any of the following conditions occurred (whichever occurred first): progressive disease, intolerable toxicity reaction, death, withdrawal of informed consent, or loss to follow-up.

[0059] Efficacy indicators: The efficacy indicators were evaluated by investigators and imaging experts according to RECIST1.1 criteria.

[0060] Main: Objective response rate (ORR).

[0061] Secondary: Progression-free survival (PFS), time to progression (TTP), 16-week disease control rate (16W-DCR), duration of response (DOR) of disease, overall survival (OS).

[0062] 2. Subject Population

[0063] Twenty-five patients with relapsed and refractory ovarian cancer were enrolled in the study, and the number of previous treatment regimens they had received was ≥3. 3 cases (12.0%) were sensitive to the last platinum-containing chemotherapy, and 22 cases (88.0%) were refractory or resistant to the last platinum-containing chemotherapy. As of the cut-off date for trial data (Mar. 20, 2019), 16 patients (64.0%) discontinued the treatment due to progressive disease, 3 patients (12.0%) discontinued the treatment due to adverse events, and other reasons for the discontinuation of the treatment comprised voluntary withdrawal of subjects, end of trial and loss to follow-up.

[0064] The full analysis set (FAS) and safety data set (SS) were used for analysis, and 25 subjects were included in each data set.

[0065] 3. Efficacy Results

[0066] The evaluation of various efficacy indicators is shown in Table 1. Among the 25 subjects, the confirmed best efficacy was partial response (PR) in 1 case (4.0%), stable disease (SD) in 14 cases (56.0%), progressive disease (PD) in 7 cases (28.0%), and not evaluable (NE) in 3 cases (12.0%). ORR was 4.0%.

[0067] As of the cut-off date for trial data (Mar. 20, 2019), 12 study events (progressive disease or death) had achieved PFS, with a median PFS of 3.7 (95% CI, 1.8˜NE) months. The median TTP was 3.7 (95% CI, 1.8˜NE) months, the 16W-DCR was 32.0%, and the median DOR and OS could not be estimated so far.

TABLE-US-00001 TABLE 1 Efficacy results of chiauranib capsule in the treatment of relapsed and refractory ovarian cancer N = 25 Best efficacy assessment, n(%) CR  0 PR 1 (4.0) SD 14 (56.0) PD 7 (28.0) NE 3 (12.0) Objective response rate, % (95% CI) 4.0 (0.10%, 20.35%) 16-week disease control rate, % (95% CI) 32.0 (15.0%, 53.5%) Progression-free survival, median(95% CI), 3.7 (1.8, NE) month Event 12 Censoring 13 Time to progression, median(95% CI), 3.7 (1.8, NE) month Event 11 Censoring 14 Duration of response, median(95% CI), NE (NE, NE) month Event  0 Censoring  2 Overall survival, median(95% CI), month NE (6.0, NE) Event 11 Censoring 14

[0068] 4. Efficacy Conclusion

[0069] In subjects with platinum-refractory/resistant relapsed ovarian cancer who had received multiple chemotherapies, chiauranib single-agent showed primary efficacy of tumor response.

[0070] 5. Safety Evaluation

[0071] The safety indicators comprised adverse events, vital signs, ECG and abnormal laboratory results, which were evaluated according to CTCAE V4.03. Twenty-five patients with relapsed and refractory ovarian cancer were enrolled in the study and included in the safety data set (SS) for analysis. The results are shown in Table 2.

TABLE-US-00002 TABLE 2 Safety evaluation results of chiauranib capsule in the treatment of relapsed and refractory ovarian cancer By severity By frequency of occurrence Adverse event leading to death Common adverse event One patient (4.0%) died due to the “multiple All 25 (100%) subjects experienced at least organ dysfunction syndrome”. Cause of death: one common adverse event. The adverse the patient with advanced ovarian cancer had events with relatively high incidence were: multiple relapses in the postoperative diarrhea in 18 cases (72.0%), loss of chemotherapy and was insensitive to appetite in 16 cases (64.0%), fatigue in 16 chemotherapy with change of chemotherapy cases (64.0%), proteinuria in 15 cases regimens; the patient was admitted to hospital (60.0%), weight loss in 14 cases (56.0%), for loss of consciousness with no obvious abdominal pain in 13 cases (52.0%), incentive, and still presented multiple organ hypertension in 11 cases (44.0%), etc. failure after active treatment. This event was judged to be undetermined with chiauranib. Serious adverse event 9 cases of serious adverse events occurred in 8 patients (32.0%), and 5 cases were judged to be related to chiauranib (definitely related, possibly related, undetermined), which were respectively 1 case of liver function damage, 1 case of bile duct obstruction, 1 case of electrolyte disturbance, 1 case of hypokalemia, and 1 case of death (multiple organ failure) mentioned above. Liver function damage is a known adverse event of chiauranib, and chiauranib has caused the adverse event of hyponatremia in the past. Adverse event leading to the discontinuation of the treatment 3 patients (12.0%) discontinued chiauranib therapy due to adverse events, which were respectively 1 case of multiple organ dysfunction syndrome, 1 case of bile duct obstruction, and 1 case of electrolyte disturbance. Adverse event leading to the reduction of the dosage of chiauranib One patient (4.0%) had a dosage reduction of chiauranib due to an adverse event, which was an increase in serum creatine phosphokinase MB. Adverse event leading to the suspension of chiauranib 11 patients (40.7%) suspended chiauranib due to adverse events, which were 2 cases of decreased platelet count, 3 cases of hypertension, 2 cases of proteinuria, 1 case of increased alanine aminotransferase, 1 case of increased aspartate aminotransferase, 1 case of ventricular dysfunction, 1 case of infection, 1 case of decreased appetite and 1 case of palmoplantar erythema syndrome.

[0072] The current data suggest that the toxicity characteristics of chiauranib single-agent therapy are similar to those reported in VEGFR target drugs (eg: sorafenib, sunitinib, etc.), which can be tolerated by most subjects, and are safe controllably.

Example 2 A Phase II Multi-Center Clinical Trial of Chiauranib in Combination with Chemotherapy in the Treatment of Platinum-Refractory/Platinum-Resistant Relapsed Advanced Ovarian Cancer

[0073] 1. Trial Design

[0074] A multi-center, randomized, and open-label phase II trial.

[0075] The subjects were stratified according to whether or not the treatment-free interval (TFI) was more than or equal to 3 months at the time of screening, and the stratified subjects were randomly assigned to chiauranib in combination with etoposide group (CE group) or chiauranib in combination with paclitaxel group (CP group) according to a ratio of 1:1.

[0076] The trial was divided into two phases: pre-trial and formal trial. Before the start of the formal trial, 3 subjects were enrolled into each group for the pre-trial to preliminarily evaluate the safety of chiauranib in combination with chemotherapeutic drugs, and analyze the potential effects of chemotherapy drugs on the pharmacokinetics of chiauranib. After the first cycle of safety and pharmacokinetic evaluation was completed in all pre-trial subjects, the enrollment of the formal trial began.

[0077] Main inclusion criteria: Patients with histologically or cytologically diagnosed epithelial ovarian cancer, fallopian tube cancer or primary peritoneal carcinoma; patients with platinum-refractory or platinum-resistant relapsed ovarian cancer; patients who had previously received ≥1 line of platinum-containing chemotherapy (platinum-containing treatment for at least 4 treatment cycles), and patients with platinum-refractory or platinum-resistant cancer who had received ≤2 lines of therapy.

[0078] Medication regimen: The medication regimen comprised two treatment stages, a stage of chiauranib in combination with chemotherapy and a stage of maintenance by chiauranib single-agent. All subjects were treated until progressive disease, intolerable toxicity, withdrawal of informed consent or death occurred (whichever occurred first).

[0079] Stage of chiauranib in combination with chemotherapy: CE group: Chiauranib capsule: In the pre-trial phase, it was orally administered at 25 mg, once a day. After the sampling of the pharmacokinetics study at the time point specified in the protocol was completed, the investigator decided whether or not to increase the administration to 50 mg orally, once a day by observing the tolerance and preliminary efficacy comprehensively; in the formal trial phase, it was orally administered at 50 mg on an empty stomach every morning, once a day, and administered continuously. Etoposide soft capsule: It was orally administered at 50 mg every morning on an empty stomach, continuously administered for 21 days and withdrawn for 7 days. Every 28 days was a treatment cycle, with a maximum of 6 treatment cycles. CP group: The administration regimens of chiauranib in the pre-trial and formal trial phases were the same as that in the CE group. Paclitaxel injection: It was administered at 60 mg/m.sup.2 via intravenous infusion, once a week (d1, d8, d15), and every 3 weeks was a treatment cycle, with a maximum of 6 treatment cycles.

[0080] Stage of maintenance by chiauranib single-agent: CE group and CP group both received maintenance therapy of chiauranib single-agent.

[0081] Efficacy indicators: The efficacy evaluation was performed using the RECIST version 1.1 (2009) criteria for solid tumors.

[0082] Main: Progression free survival (PFS).

[0083] Secondary: Objective response rate (ORR), overall survival (OS), time to progression (TTP), duration of response (DOR) of disease.

[0084] 2. Subject Population

[0085] As of Dec. 26, 2019, a total of 21 patients (10 in CE group and 11 in CP group) were enrolled. The duration of treatment for the enrolled subjects was between 0-5 cycles, and the following efficacy results were based on the evaluable data before the cut-off date.

[0086] 3. Efficacy Results

[0087] The evaluation of various efficacy indicators is shown in Table 3. 11 of the 21 subjects had efficacy evaluation record (5 in the CE group and 6 in the CP group). The best efficacy response showed that in the CE group, 2 cases (40.0%) achieved PR, and 3 cases achieved SD; in the CP group, 3 cases (50.0%) achieved PR, 2 cases achieved SD, and 1 case achieved PD.

TABLE-US-00003 TABLE 3 Efficacy results of chiauranib capsule in combination with chemotherapy in the treatment of relapsed and refractory advanced ovarian cancer Best efficacy response CE (N = 10) CP (N = 11) No efficacy evaluation 5 5 Efficacy evaluation 5 6 CR (complete response) 0 0 PR (partial response) 2 (40.0) 3 (50.0) SD (stable disease) 3 (60.0) 2 (33.3) PD (progressive disease) 0 1 (16.7)

[0088] 4. Efficacy Conclusion

[0089] Historical data show that in the treatment of platinum-refractory/resistant relapsed advanced ovarian cancer, the response rate of etoposide single-agent is about 27%, and the response rate of paclitaxel single-agent is about 21%. The current data suggest that the response rates of etoposide and paclitaxel in combination with chiauranib respectively are respectively 40% and 50%, indicating that the combination of chiauranib with etoposide or paclitaxel has achieved an unexpected synergistic effect in the treatment of platinum-refractory/resistant relapsed advanced ovarian cancer. According to the actual situation of the enrolled cases, it shows that the combination of chiauranib with etoposide or paclitaxel has an excellent effect in the treatment of platinum-refractory/resistant relapsed advanced (stage III and IV) malignant epithelial ovarian cancer, especially the malignant epithelial ovarian cancer at stage III and stage IV with metastasis.

[0090] 5. Safety Evaluation

[0091] The safety indicators comprised various vital signs, adverse events and laboratory inspection indicators, which were detected or observed for safety evaluation. The severity of adverse events was judged according to CTCAE V4.03 criteria.

[0092] As of Dec. 26, 2019, a total of 21 patients (10 in CE group and 11 in CP group) were enrolled. The duration of treatment for the enrolled subjects was between 0-5 cycles, and the safety results were based on the evaluable data before the cut-off date. The results are shown in Table 4.

TABLE-US-00004 TABLE 4 Safety evaluation results of chiauranib capsule in combination with chemotherapy in the treatment of relapsed and refractory advanced ovarian cancer Safety results By severity By frequency of occurrence Adverse event leading to death Common adverse event None. CE group: All 10 (100%) subjects had at Serious adverse event least one adverse event. The adverse events One serious adverse event occurred, which with relatively high incidence were: nausea in was grade III gastrointestinal dysfunction 7 cases (70.0%), decreased white blood cell (nausea, vomiting), which was judged to be count in 7 cases (70.0%), decreased possibly related to chiauranib and possibly neutrophil count in 6 cases (60.0%), related to paclitaxel. Nausea and vomiting decreased appetite in 6 cases (60.0%), fatigue are known adverse events of chiauranib. in 5 cases (50.0%), vomiting in 5 cases Adverse event of special concern (50.0%) and so on. None. CP group: 8 out of 11 subjects (72.7%) had at least one adverse event. The adverse events with relatively high incidence were: decreased neutrophil count in 6 cases (54.5%), decreased white blood cell count in 6 cases (54.5%), anemia in 4 cases (36.4%), hypertension in 4 cases (36.4%) and so on.

[0093] The current data suggest that the types of adverse events of etoposide and paclitaxel in combination with chiauranib respectively are similar to those reported in each chemotherapeutic drug single-agent and chiauranib single-agent, and no new safety signals have been found. The incidence of adverse events has increased, but most patients can tolerate it, no treatment has been terminated due to adverse events, and the safety is controllable.

[0094] The present disclosure has been introduced in detail above, and the principles and implementations of the present disclosure are described herein by using specific examples. The descriptions of the above examples are only used to help understand the method and core idea of the present disclosure, including the best mode. It also enables any person skilled in the art to practice the present disclosure, including making and using any devices or systems, and implementing any combined methods. It should be noted that for those skilled in the art, several improvements and modifications can also be made to the present disclosure without departing from the principle of the present disclosure, and these improvements and modifications also fall within the protection scope of the claims of the present disclosure. The scope of patent protection of the present disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. If such other examples have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal expressions of the claims, they are also intended to be within the scope of the claims.