CN101330917A - Fixed ratio drug combination treatments for solid tumors - Google Patents
Fixed ratio drug combination treatments for solid tumors Download PDFInfo
- Publication number
- CN101330917A CN101330917A CNA2006800447790A CN200680044779A CN101330917A CN 101330917 A CN101330917 A CN 101330917A CN A2006800447790 A CNA2006800447790 A CN A2006800447790A CN 200680044779 A CN200680044779 A CN 200680044779A CN 101330917 A CN101330917 A CN 101330917A
- Authority
- CN
- China
- Prior art keywords
- floxuridine
- irinotecan
- tumor
- cancer
- dosage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Abstract
Provided herein are methods for treating cancer by administering a pharmaceutical composition comprising a fixed, non-antagonistic molar ratio of irinotecan and floxuridine. Such methods are particularly useful in the treatment of cancer patients with advanced solid tumors.
Description
Related application
The application requires the priority of No. the 60th, 730,199, the U. S. application of submitting on October 25th, 2005 and the U. S. application of submitting on January 12nd, 2006 the 60th, 759, No. 225, and each applies for all intactly being combined in herein in the reference mode.
Technical field
The present invention relates to have the method for the medicine coupling of the medication of improvement and therapeutic effect.More specifically, the present invention relates to the floxuridine (floxuridine) of fixed ratio and the medication of Irinotecan coupling.
Technical background
In vitro study shows that the coupling cytotoxic drug can strengthen anti-tumor activity.This discovery guiding drug combination clinically exceedes the several years, and therefore in the cancer chemotherapy of many forms, the cytotoxic drug coupling is the method for standard now.New anti-cancer drug is used for patient with single medicine earlier usually.After the maximum tolerance of single medicine is determined, add second kind of medicine, and adjust the dosage of single or two kinds of medicines according to toxicity.The development of these scheme of combination drug therapy at that time is based on experience, determines according to toleration.Yet, external---can control the ratio of coupling medicine, proved already a certain ratio show synergistic drug combination may other ratio show simple accumulative action or or even antagonism (Mayer, L.D. etc., Mol.Cancer Ther. (2006) 5:1854-63; Chou, T-C. etc., Adv.Enzyme Reg. (1984) 22:27-55).When free drug was individually dosed, each medicine diversity was in vivo handled, and the result makes the distribution variation of single medicine on tumor sites, and this can cause not good enough or invalid medicine ratio.Therefore, often depend on specific medicine ratio, so the activity in vivo of administering drug combinations depends on the medicine ratio of keeping synergism or accumulative action and avoiding antagonism at the synergistic activity of extracorporeal anti-tumor medicine.Like this, the development of concrete chemotherapy regimen can be according to the most effective medicine ratio, rather than empirically according to toxicity.
The fluorine pyrimidine reached for three more than ten years as the treatment foundation stone of advanced colorectal cancer.5-fluorouracil (5-FU) is considered the standard systemic amic therapy method (Eur.J.Cancer (1998) 34:296-306, Coutinho, A.K. is etc., Cancer Control (2003) 10:224-238 for Van Laar, J.A.M. etc.) of this indication.As if the therapeutic evaluation to 5-FU is incorporated among the RNA with respect to 5-FU, relevant with the activity that suppresses the sweet acid enzyme of breast more.For this reason, study intravenous injection floxuridine (derivant of the dezyribonucleoside of 5-FU) clinically at the beginning of the sixties in 19th century, and the proposition hypothesis thinks that floxuridine is better than 5-FU (Young in treatment, C.W. etc., Cancer Chemother.Repts. (1960) 6:17-20, Ansfield, F.J. etc., CancerChemother.Repts. (1963) 32:101-105, Reitemeier, R.J. etc., CancerChemother.Repts. (1965) 44:39-43, east cooperative association, JAMA (1967) 200:101-118).These researchs carry out at leading oncology center, have utilized the experimental design under the technology at that time.Though floxuridine clearly has activity in these researchs, there is not clinical evidence proof 5-FU to have different significantly with floxuridine.As if floxuridine more effective unlike 5-FU.5-FU more easily produces, and is easier to obtain, so except specific clinical research (Creaven, P.J. etc., Cancer Chemother.Pharmacol. (1994) 34:261-265), the most normal use 5-FU in systemic treatment.Proved when giving patient's hepatic artery ligation floxuridine of hepatic metastases, floxuridine has activity, and be used for this indication (Anonymous at U.S.'s approved floxuridine, J.Natl.Cancer Inst. (1996) 88:252-258, Kemeny, N. etc., Lancet Oncol. (2001) 2:418-428).
Granted since Irinotecan in 1996, the drug combination of Irinotecan and 5-FU has become the standard embolic chemotherapy of a line and second line treatment metastatic colorectal cancer.The most frequently used scheme is that FOLFIRI and Irinotecan are individually dosed at present.Irinotecan has two kinds of instructions of taking usually.A kind of scheme is per 21 days intravenous injection 350mg/m
2Irinotecan surpasses 30 minutes (Rougier P. etc., J.Clin.Oncol. (1997) 15:25l-60) at every turn.Another kind of scheme is, the 1st, 8, and 15 and 22 days intravenous injection 125mg/m
2Irinotecan surpasses 90 minutes at every turn, repeats in per 42 days (Pitot H.C. etc., J.Clin.Oncol (1997) 2910-19).FOLFIRI is usually included in the 1st, the 2 day about 180mg/m of intravenous injection
2Irinotecan, 100-500mg/m
2Folinic acid (LV), 24 or 48 hours venoclysis 2300-3000mg/m
25-FU or inject 400mg/m
2Infusion 600mg/m behind the 5-FU
25-FU 22 hours, per two weeks repeat.IFL comprises weekly intravenous injection 70 or 125mg/m fast
2Irinotecan, 20-200mg/m
2Folinic acid, and 450-500mg/m
25-FU around continuing, had a rest for two weeks.The less usefulness of IFL, because its possibility toxicity is bigger, and what are poorer than the FOLFIRI effect.
Though use the medicinal mixture of coupling that a plurality of advantages are arranged, various shortcomings have still limited their therapeutic use.For example, giving the free drug mixture often causes a kind of or whole medicine just to be removed fast before arriving tumor sites.If various medicines only have optimum efficiency in the mixture in the narrow ratio of itself and another medicine, a kind of medicine is removed fast but situation that another medicine does not have may reduce the general effect of administering drug combinations, has also often increased toxicity simultaneously.This may cause toxicity to increase sometimes, obtains bigger curative effect because will increase the dosage of single medicine.Fluorine pyrimidine such as 5-FU and floxuridine all can be eliminated fast, therefore adopt the long infusion time for improving active the trial, with effectiveness and the toxicity curve that improves these medicines.Common this infusion time of administration can be 24 hours or longer time.Therefore, be starved of the dosage regimen that to keep best drug regimen ratio,, and can not increase treatment toxicity because it can reduce administration number of times.Improved plan also can realize the overall dose that the patient is higher like this, and during with other dosage regimen dosage owing to the toxicity reason is restricted.
Summary of the invention
On the one hand, provided herein is one treat method for cancer for the experimenter, described method comprises to described experimenter takes the Irinotecan that comprises fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, and wherein, the mol ratio of described fixed, non-antagonist was kept in blood plasma at least about 4 hours.In another embodiment, the mol ratio of fixed, non-antagonist in blood plasma, keep at least about 8 hours, at least about 16 hours or at least about 24 hours.Usually, Irinotecan and floxuridine and delivery vehicle stable bond.In one embodiment, delivery vehicle is a liposome.
On the other hand, provided herein is one described method comprises to described patient takes the Irinotecan that comprises fixed, non-antagonist molar and the pharmaceutical composition of floxuridine for the experimenter treats method for cancer, wherein, described compositions is passed through intravenously administrable.In some embodiments, the pharmaceutical composition administration time is at least about 30 minutes, and is no more than 3 hours.In a concrete embodiment, about 90 minutes of pharmaceutical composition administration time.
On the one hand, provided herein is one treat method for cancer for the experimenter, described method comprises to described patient takes the Irinotecan that comprises fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, and wherein, floxuridine is to give less than 0.001 mole/square metre/dosage.In a concrete embodiment, floxuridine gives with about 0.001 mole/square metre/dosage.
On the other hand, provided herein is one treat method for cancer for the experimenter, described method comprises to described patient takes the Irinotecan that comprises fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, wherein, takes floxuridine less than 0.01 mole/square metre/month.In a special embodiment, take about 0.0006 mole/square metre/month of floxuridine.
In the method that provides herein, the Irinotecan of fixed, non-antagonist molar and the ratio of floxuridine can be between about 5: 1 to 1: 5.In a concrete embodiment, the Irinotecan of fixed, non-antagonist approximately is 1: 1 than the ratio of floxuridine.Usually, the Irinotecan and the floxuridine of fixed, non-antagonist ratio are encapsulated in the liposome.
In some embodiments, cancer is an advanced solid tumor.Advanced solid tumor can be tumor stomach, tumor of kidney, breast tumor, colon tumor, esophageal tumor, prostate tumor, pancreas tumor, ovarian tumor, osteosarcoma or sphenoid sinus tumor.Sometimes, cancer is a relapsed cancer.The patient can live through at least a antitumor scheme in the past.Sometimes, the antitumor scheme is the multiple medicines scheme for combining.
Also consider to use to comprise the Irinotecan of fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, wherein said fixed, non-antagonist molar in blood plasma, keep at least about 4 hours with the treatment cancer patient, as described herein.On the other hand, provided herein is, the pharmaceutical composition of described Irinotecan that comprises fixed, non-antagonist molar and floxuridine is used for the treatment of application in the medicine of cancer in preparation, wherein said fixed, non-antagonist molar in blood plasma, keep at least about 4 hours with the treatment cancer patient, as described herein.
Summary of drawings
Fig. 1 has shown the anti-tumor activity of patient CPX-1.
After the Irinotecan and floxuridine of liposome taken in Fig. 2 demonstration, the fixed Irinotecan of keeping in the blood plasma was than the mol ratio of floxuridine.A: venoclysis 30-270 unit/square metre CPX-1 after, until 24 hours, the mol ratio of Irinotecan and floxuridine in patient's blood plasma.(concentration is measured with LC/MS/MS; Every line is all represented a patient; N=26).B: intravenous injection 210 units/square metre CPX-1 after, the mol ratio of Irinotecan and floxuridine in patient's blood plasma was represented than the last time with the ratio in the blood plasma.(concentration is measured with LC/MS/MS; Every line is all represented a patient; N=6).
The invention implementation method
Unless otherwise defined, all technology of Shi Yonging all have the identical meaning with scientific terminology herein, as one skilled in the art of the present invention are common understand.The application of all patents of this paper reference, application, announcement and other publication are all with complete being combined in herein of mode of list of references.If it is opposite or inconsistent in others that the definition of Ti Chuing herein and mode with list of references are combined in the definition that proposes in the application of herein patent, application, announcement and other publication, the definition of Ti Chuing so herein has precedence over the definition in the list of references.
" one " meaning of herein using is " at least one " or " one or more ".
For Irinotecan and floxuridine, between 5: 1 and 1: 5, the mol ratio of finding 1: 1 is best (Mayer, L.D. etc., Mol.Cancer Ther. (2006) 5:1854-63) in external non-antagonistic molar ratio.Therefore, the term " Irinotecan of non-antagonistic molar ratio and floxuridine " that herein uses refer to Irinotecan than the molar ratio range of floxuridine between about 5: 1 to about 1: 5.In some embodiments, non-antagonistic molar range is about 1: 1 Irinotecan: floxuridine.
Method provided herein strengthens anti-tumor activity by Irinotecan and the floxuridine of taking non-antagonistic molar ratio, has the advantage of quick administration, dosage increase and restriction toxicity simultaneously.In brief, at the external non-antagonism ratio of determining chemotherapeutics by screening method.If the medicine of these same ratio gives (for example, not having the conventional aqueous-based pharmaceutical formulations of liposome delivery) respectively with the free drug form of mixtures, can not keep this ratio, because the distribution of medicine is separate with removing, cause ratio constantly to change.The method of the common entrapped drug of use liposome provided herein, can realize administration after non-antagonistic ratio can keep for a long time.Liposomal formulation is sent every kind of medicine by the individual pharmacokinetics of controlling every kind of medicine with appropriate ratio, thereby keeps non-antagonistic ratio.
Usually, continue to send need be bigger dosage, to keep in the blood plasma and the effective treatment concentration in the final tumor.The administration in long-time scope of this heavy dose often is one day or a couple of days, needs the long-term infusion process of being in hospital and/or depending on prolongation, and this has increased the risk of complication, as infecting and inject obstacle.Another shortcoming is the toxicity that higher dosage is brought, and this may hinder medicine to reach best plasma concentration.If common administered agents is only effective in a specific mutual ratio ranges, then the free drug mixture is more unfavorable.For example, (＜5: 1 and＞1: 5), can resist mutually unexpectedly, this depends on it is which kind of tumor cell line than the ratio of floxuridine at specific Irinotecan for Irinotecan and floxuridine.
CPX-1 is the Irinotecan HCl of fixed 1: 1 mol ratio and the Liposomal formulation of floxuridine, compare with the free drug of form of mixtures, and compare with independent liposome medicament, having proved in the model of its colorectal carcinoma in cell culture and body has enhanced curative effect.Referring to the United States Patent (USP) of submitting on April 2nd, 2004 of owning together and awaiting the reply jointly 2004/0265368.Can adopt any suitable Irinotecan HCl and floxuridine.In one embodiment, Irinotecan HCl is (+)-7-ethyl-10-hydroxycamptothecine 10-(1,4 ' two piperidines)-1 '-carboxylate, mono-hydrochloric salts, and trihydrate, floxuridine are 2 '-'-Deoxy-5-fluorouridines.
Can adopt any suitable delivery vehicle, the Irinotecan that makes fixed, non-antagonist molar provided herein discharges lastingly than the compositions of floxuridine.In some embodiments, adopt Liposomal formulation.Liposome is designed to make entrapped medicine to be delivered to tumor locus enduringly with fixed ratio.In one embodiment, Irinotecan and floxuridine and liposome stable bond.Usually, the diameter of liposome is less than 300nm, sometimes less than 200nm.In one embodiment, the nominal size of these liposomees approximately is 110nm, and by 0.2 μ m filter filtration sterilization.In a specific embodiment, liposome membrane is made up of with 7: 2: 1 mol ratio distearoyl phosphatidylcholine (DSPC), distearyl phosphatidyl glycerol (DSPG) and cholesterol (CHOL).In one embodiment, liposome prepares by water in oil derived liposome method, and the liposome of extruding is suspended in sucrose-phosphate buffer of pH7.0.Can adopt any suitable method that pharmaceutical composition is encapsulated in the liposome.In a concrete embodiment, employing is encapsulated into Irinotecan and floxuridine in the liposome such as loading method based on copper gluconate/triethanolamine, whereby, Irinotecan since complexing in preformed liposome inner accumulated, simultaneously floxuridine is passive seals.
Method provided herein is all useful to any experimenter, particularly to cancer or advanced solid tumor patient.The malignant cell that cancer comprises unusually, grows uncontrollably.This cell has numerous characteristics, as increment uncontrollably, immortality, transitivity, growth and multiplication rate and some typical morphological feature fast.Usually, cancerous cell exists with the form of tumor, but this cell also may exist in mammal separately, perhaps may be the cancerous cell of non-tumorigenic, as the aleukemic leukemia cell.Identification of cancer cell has many kinds of methods, include but not limited to, detect exist (as by clinical or radiologic method) of tumor, check that tumor is interior or from the cell (Tathagata self-organizing biopsy) of other biological sample, the blood marker of measuring the indication cancer is (as CA125, PAP, PSA, CEA, or the like), and/or the genotype of detection indication cancer (as TP53, ATM, or the like).Term " solid tumor " refers to except that aleukemic leukemia or lymphoma (being neoplastic hematologic disorder), forms the tumor of the entity material of cancerous cell.Herein the term of Shi Yonging " advanced solid tumor " refer to transfer or partly late period inoperable malignant tumor.Solid tumor can be any origin, includes but not limited to adrenal carcinoma, bladder cancer, osteocarcinoma, the brain cancer, breast carcinoma, cervical cancer, colon cancer, esophageal carcinoma, carcinoma of gallbladder, neuroganglion cancer, gastrointestinal cancer, head and neck cancer, heart cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, muscle cancer, ovarian cancer, cancer of pancreas, parathyroid carcinoma, carcinoma of prostate, rectal cancer, salivary-gland carcinoma, hole cancer, skin carcinoma, soft tissue cancer, spleen cancer, carcinoma of testis, thymic carcinoma, thyroid carcinoma or uterus carcinoma.
Method described herein can keep the Irinotecan of non-antagonistic molar ratio and floxuridine continue send.For example, after single gave pharmaceutical composition, the Irinotecan of non-antagonistic molar ratio and floxuridine were kept at least about 24 hours in the blood plasma, at least about 16 hours, and at least about 12 hours, at least about 8 hours, and often at least about 4 hours.In addition, the plasma drug level of the liposomal encapsulated lasting concentration ratio free drug mixture combination of pharmaceutical composition in blood plasma wants big.
This method is also impelled the significantly more floxuridine of taking than reported in the past of low dosage intensity, keeps its therapeutic effect simultaneously.Referring to table 1 and 2.
The molar dose that table 1 floxuridine or 5-FU and Irinotecan make up and the comparison of dose intensity
| Gram/agent is (m 2) | Mw | Mole/square metre/dosage | Mole/square metre/month | |
| CPX-1270 unit/square metre (floxuridine) | 0.0972 | 246.2 | 0.0004 | 0.0008 |
| CPX-1210 unit/square metre (floxuridine) | 0.0756 | 246.2 | 0.0003 | 0.0006 |
| FOLFIRI(5FU)Tournigand | 3.2 | 130.08 | 0.0246 | 0.0492 |
| IFL(5FU)Salz | 0.5 | 130.08 | 0.0038 | 0.0154 |
| FOLFIRI(5FU)NCCN/Italians | 1 | 130.08 | 0.0077 | 0.0154 |
| DeGramont scheme (5FU/LV) | 1 | 130.08 | 0.0077 | 0.0154 |
| Capecitabine | 5 | 359.35 | 0.0139 | 0.2922 |
The molar dose of the Irinotecan among table 2CPX-1 and the FOLFIRI (Tournigand) and the comparison of dose intensity
| Gram/dosage (m 2) | mw | Mole/square metre/dosage | Mole/square metre/month | |
| CPX-1 (Irinotecan) | 0.21 | 677.19 | 0.0003 | 0.0006 |
| FOLFIRI(5FU) Tournigand | 0.18 | 677.19 | 0.0003 | 0.0005 |
For example, to need dose intensity be the fluorine pyrimidine (present embodiment is 5-FU) of 0.0246 mole/square metre/dosage or 0.0492 mole/square metre/month to the FOLFIRI scheme of 5-FU and Irinotecan.Notice that 5-FU and floxuridine all are the fluorine pyrimidines, the death that it comes inducing tumor cell by identical activatory intermediate, proved already when they during with similar molar ratio administration, clinical meaning is suitable.It is the fluorine pyrimidine of 0.0038 mole/square metre/day or 0.0154 mole/square metre/month that the IFL drug regimen of 5-FU, Irinotecan and LV needs dose intensity.On the contrary, when taking CPX-1, the dose intensity of fluorine pyrimidine in Irinotecan and the floxuridine drug regimen (present embodiment is a floxuridine) can be approximately less than 0.0035 mole/square metre/dosage, approximately less than 0.0025 mole/square metre/dosage, less than 0.0010 mole/square metre/dosage or less than 0.005 mole/square metre/dosage, can keep therapeutic effect simultaneously.Usually, only took a dosage in one day.In a concrete embodiment, the dose intensity of fluorine pyrimidine is about 0.0003 mole/square metre/dosage in Irinotecan and the floxuridine drug regimen.In some embodiments, the dose intensity of fluorine pyrimidine approximately less than 0.0150 mole/square metre/month, approximately less than 0.0100 mole/square metre/month, approximately less than 0.0050 mole/square metre/month, perhaps approximately less than 0.0020 mole/square metre/month.In a concrete embodiment, the dose intensity of fluorine pyrimidine is about 0.0006 mole/square metre/month in Irinotecan and the floxuridine drug regimen.
Use method provided herein, the dosage of taking uracil (as floxuridine) lacks than the drug dose of the aqueous matrix preparation of non-liposome taking respectively, can keep therapeutic effect simultaneously.
Described method also provides the Irinotecan of the treatment effective dose that a kind of method sends fixed molar ratio fast and the method for floxuridine pharmaceutical composition.The Liposomal formulation of CPX-1 also has another advantage to be, the intravenously administrable required time is than prior art shorter (therefore faster).Usually, liposomal encapsulated Irinotecan and floxuridine pharmaceutical composition can pass through intravenously administrable, and administration time is at least about 30 minutes and less than about 3 hours.In one embodiment, liposomal encapsulated Irinotecan and floxuridine pharmaceutical composition are by intravenously administrable, and administration time was at least about 90 minutes.On the contrary, other scheme adopts the free drug mixture of Irinotecan and floxuridine, then needs at least 24 hours (Douillard J.Y. etc., Lancet (2000) 355:1041-47), and wants infusion sometimes until 48 hours.(Tournigand C. etc., Proc ASCO (2000) 1 9:245a (summary 949); TournigandC. etc. .1.Clin.Oncol. (2004) 22 (2): 229-37).This helps the expense as minimizing hospital, thereby avoids long-term being in hospital to improve patient's quality of life, avoids injecting fault and the infection chance of minimizing in this hospital stay.
Described method is effective in cure to the treatment relapsed cancer." relapsed cancer " refers to treatment in the past and effectively and wholly or in part alleviates afterwards the cancer of recurrence again.Recurrence can be confirmed in any way, comprise by clinical, radiologic or biochemical mensuration, or the concentration of tumor marker increases the reproduction of detected tumor or regeneration.Treatment in the past can include but not limited to chemotherapy, Biotherapeutics, radiotherapy and bone marrow transplantation.
In some embodiments, treated in the past, fail or other is treated the drug-fast patient of generation with the patient of method described herein treatment.For example, after the patient accepted or any chemotherapy and biotherapy produced drug resistance, still can treat with method described herein.In some cases, the patient accepted the platiniferous therapeutic regimen in the past.In one embodiment, the patient accepted FOLFIRI, FOLFOX (5-FU and oxaliplatin) or IFL treatment in the past.
Method described herein can also be as the first-line treatment of the cancer of not treating in the past.
Response to described Therapeutic Method comprises any tangible clinically positive change that takes place under the tumor disease state.Such response can comprise the increase of total life cycle and the increase of life cycle of getting nowhere.The response of disease is estimated by any suitable method.In one embodiment, adopt RECIST (solid tumor therapeutic evaluation standard) standard to estimate disease (Therasse, P. etc., J.Natl Cancer Inst. (2000) 92:205-16).The best response taxonomy of research is as follows now: (CR) in full force and effect: all of tumor are clinical all to disappear with radiological evidence.Part is (PR) effectively: compare with the baseline total amount of longest diameter, target focus longest diameter total amount is reduced by at least 30%.Stable disease (SD): the steady statue of disease.Tumor had not both had enough dwindling to meet PR, did not have enough increases again to meet PD.PD (PD): the minimum total amount of the longest diameter that is recorded with treatment beginning is compared the focus longest diameter total amount increase at least 20% that detects.The appearance of new focus also constitutes PD.Under special environment, the clearly progress of the non-focus that measures also can be regarded the evidence of progression of disease as.
Pharmaceutical composition provided herein is to take to any suitable patient, preferred cancer patient.Pharmaceutical composition among the present invention preferably passes through intravenously administrable.The dosage of delivery vehicle formulations depends on the ratio of medicine and lipid and the doctor in charge suggestion based on patient age, body weight and state.
The pharmaceutical composition that comprises delivery vehicle of the present invention prepares according to standard method, water, buffered water, 0.9% saline, 0.3% glycine, 5% glucose etc. be may comprise, stable glycoprotein that uses of raising such as albumin, lipoprotein, globulin or the like also are included as.These compositionss may be sterilized with general sterilizing methods common to all.Obtained aqueous solution can be packed and use or filtration and lyophilizing under aseptic condition, and lyophilized formulations mixes the back administration with aseptic aqueous solution.Because need be near physiological condition, compositions can comprise pharmaceutically acceptable auxiliary substance, as pH additive and buffering reagent, tension adjustment reagent or the like, for example sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride or the like.In addition, the suspension of delivery vehicle also can comprise lipid protection reagent, and the protection lipid is avoided the destruction of free radical and lipid superoxides between the storage life.The lipotropy radical scavenger also is suitable as alpha-tocopherol and water-soluble iron specificity chelating agen such as ferrum oxygen amine.Folinic acid also can be taken the life-span of taking fluorine pyrimidine patient with raising by standard method with compositions of the present invention.
The concentration of delivery vehicle in pharmaceutical preparation can be different to a great extent, as about 0.05% from being less than according to weight, usually about or at least about 2-5%, up to 10% to 30%, and according to the specific administration pattern of selecting, mainly by selections such as liquid volume, viscosity.For example, can increase concentration and reduce the liquid load relevant with treatment.Perhaps, the delivery vehicle that the zest lipid is formed can be diluted to low concentration, to alleviate the inflammatory reaction of administration place.For ease of diagnosis, the amount of the delivery vehicle that gives depends on the morbid state of employed particular marker, diagnosis and clinician's judgement.
The 1 clinical I phase of embodiment treats
CPX-1 (Irinotecan HCl: floxuridine) development of lipidosome injection is based on 1) adopts the screening test based on cell, limit two active parts---the non-antagonism sex rate of Irinotecan HCl and floxuridine, with 2) the design lipidosome drug carrier, to keep the ratio behind the intravenously administrable.This ratio is not based on the scheme with the experience source that is used for Irinotecan HCl and fluorine pyrimidine at present.More accurate is, this ratio depends on the therapeutic effect of cancer therapy drug Irinotecan and fluorine pyrimidine, and the principle of supposing is that these medicines are fixed on the carrier to improve the therapeutic activity that has reached at present with these compositionss.Expection is that CPX-1 has enhanced therapeutic effect in the cancer to Irinotecan and fluorine pyrimidine sensitivity.Before vitro human gastroenteric tumor cell line clinical in data and the body modelling verification of Mus colorectal carcinoma select the principle of medicine according to the medicine ratio.
The initial purpose of this research is to determine the II phase clinical dosage (being defined as maximum tolerated dose (MTD) in this experimental design) of the CPX-1 of recommendation, and this dosage can be used for carrying out with fortnightly scheme the advanced solid tumor patient of infusion.This research has also been estimated with this scheme and has been given preliminary curative effect information behind the advanced solid tumor patient CPX-1, and gives the safety of CPX-1 and the pharmacokinetic parameter of dose-limiting toxicity (DLT) and CPX-1 with this scheme.
Physics, chemistry with the information of pharmacy
(Irinotecan HCl: floxuridine) lipidosome injection is antineoplastic agent Irinotecan HCl ((+)-7-ethyl-10-hydroxycamptothecin 10-(1 that is used for the Liposomal formulation of venoclysis to CPX-1,4 ' two piperidines)-1 '-carboxylate, mono-hydrochloric salts, trihydrate) and the fixed ratio compositions of floxuridine (2 '-deoxidation-5-fluorouracil).These two kinds of medicines are included in the liposome with 1: 1 mol ratio, its no antagonistic activity of proof in preclinical study.Liposome membrane is made up of with 7: 2: 1 molar ratio distearoyl phosphatidylcholine (DSPC), distearyl phosphatidyl glycerol (DSPG) and cholesterol (CHOL).The CPX-1 expection is to come intravenously administrable by slow infusion.(Irinotecan HCl: floxuridine) lipidosome injection is aseptic, apyrogeneity, gobelin, opaque to the CPX-1 that provides, and is divided in the disposable liquid medicine bottle.CPX-1 is stored frozen (20 ℃), melts 60 minutes in room temperature earlier before dilution and administration.Before giving patient's intravenously administrable, the medicine with packing dilutes so that injection with normal saline or glucose earlier.
(Irinotecan HCl: floxuridine) lipidosome injection provides 25mg Irinotecan HCl trihydrate and 9.1mg floxuridine to each disposable bottled CPX-1.The composition that the medicine of every milliliter of thawing comprises is as shown in the table.
The composition of table 3CPX-1 lipidosome injection
| Composition | Molecular weight | Every ml quantity |
| Irinotecan HCl trihydrate | 677.19 | 5.0mg |
| Floxuridine | 246.19 | 1.8mg |
| Distearoyl phosphatidylcholine (DSPC) | 790.16 | 29.2mg |
| Distearyl phosphatidyl glycerol (DSPG) | 801.07 | 8.5mg |
| Cholesterol (CHOL) | 386.66 | 2.0mg |
| Copper gluconate, USP | 453.85 | 4.3mg |
| Triethanolamine, NF | 149.19 | ＜2.7mg |
| Sucrose, NP | 342.3 | 102.7mg |
| The monobasic sodium phosphate, USP (NaH 2PO4) | 120 | 1.7mg |
| Binary sodium phosphate, USP (Na 2HPO4) | 141.96 | 7.0mg |
| Water for injection USP, an amount of | 18 | 1.0ml |
The CPX-1 of described all dosage refers to, is included in the inclusions Irinotecan HCl trihydrate in the CPX-1 injection and the dosage of floxuridine.For example, the CPX-1 of dosage 50/18mg/kg refers to, and the Irinotecan HCl trihydrate that is included in the 50mg/kg among the CPX-1 adds the 18mg/kg floxuridine.The dosage of CPX-1 can also refer to the unit of CPX-1.The CPX-1 of a unit comprises 1mg Irinotecan HCl trihydrate and 0.36mg floxuridine.
Clinical research
Initial dose
For the cytotoxicity antineoplastic agent, the initial dose commonly used when the people treats for the first time is the surface area (mg/m according to human body
2) calculate, generally be Rodents LD
101/10th (if this dosage is not very deleterious words at non-Rodents), or 1/3rd (the producing the minimum dosage of the pathological change of drug induced hematological, chemical, clinical or morphologic parameter) of " TDL " of most of intolerant species, if this dosage of twice can fatal and can not cause serious, irreversible toxicity.For CPX-1 (Irinotecan HCl: lipidosome injection floxuridine), do not identify its Rodents LD as yet
10Proof maximum dose level (100mg/kg Irinotecan HCl is in rat) does not cause any death.In Canis familiaris L., (Irinotecan HCl: floxuridine) TDL of lipidosome injection is 5mg/kg Irinotecan HCl (+1.8mg/kg floxuridine) to CPX-1, is equivalent to 100mg/m
2Irinotecan HCl.This dosage of twice can be not fatal.From toxicology information, the initial dose level that this I phase that calculates is studied is CPX-133:12mg/m
2Briefly, for quantitatively convenient, initial dose CPX-130:10.9mg/m
2In this research, the CPX-1 of a unit comprises 1mg Irinotecan and 0.36mg floxuridine.
Scheme
Select per 14 days dosage regimen according to 1) the use convention of Irinotecan (with the fluorine pyrimidine), 2) animal pharmacokinetics and 3 of CPX-1) require to avoid cumulative toxicity.The Irinotecan scheme that approval is used comprises 125mg/m weekly
2Irinotecan around keeping, was had a rest for two weeks, and " European proposal " of Irinotecan, per three all 300-350mg/m
2Irinotecan (300mg/m
2Dosage be proposed to be used in patient greater than 70 years old or 2 grades of performance statuses).FOLFIRI scheme (Tournigand, C. etc., J.Clin.Oncol. (2004): 22:229-237) be another Irinotecan/5-FU/ folinic acid scheme of often using, 180mg/m
2The Irinotecan of dosage, per two all administrations.
The infusion time
A large amount of, accept the liposome chemotherapeutics (
Ortho Biotech Produces L.P. company (2001) and
Gilead Sciences company (2002) package insert) in patient's the clinical trial, recorded acute infusion correlated response (as flushing, rapid breathing, headache, shiver with cold, backache, chest constriction and/or hypotension).To Most patients, disappear in a few hours to one after these are reflected at infusion and finish day.To some patients, the infusion velocity that slows down, loss for reaction.The amount that has compared lipid among several liposome products and the CPX-1 in the following form.Based on this information, select 90 minutes infusion time.
The amount of lipid in table 4 liposome product
Suppose:
According to heavy 70kg, body surface area 1.8m
2The patient calculate.
More than the dosage of Jia Ding CPX-1 is 125: 45.5mg/m
2Dosage.
There is the evidence proof patient of record that cancer refractory, late period, that shift or recurrence is arranged.
Table 5 method of administration
| Medicine | Dosage | The path | Time | Scheme |
| CPX-1 | The dosage level that sees table | Vein | 90 minutes | Per 14 days |
Dosage level
Individual patient is not increased in proportion the dosage of CPX-1.Increase scheme according to following dosage, increase dosage one by one in proportion according to toxicity.
The dosage of the CPX-1 that table 6 adopts in each test group patient
| Test group # | The factor (fibonacci series of hanging oneself and revising) | Dosage (the mg/m of Irinotecan among the CPX-1 2) | Dosage (the mg/m of floxuridine among the CPX-1 2) |
| 1 | 1 | 30 | 10.8 |
| 2 | 2 | 60 | 21.6 |
| 3 | 3.3 | 100 | 35.6 |
| 4 | 5 | 150 | 54.0 |
| 5 | 7 | 210 | 75.6 |
| 6 | 9 | 270 | 97.2 |
If desired, subsequent dose can increase by 1/3 on every group of dosage.Yet expection is possible DLT occur in the 5th test group, and the dosage that the 5th test group is accepted is slightly larger than the dosage of Irinotecan given in 14 day regimen of FOLFIRI.
Drug-delivery preparation
(Irinotecan HCl: floxuridine) lipidosome injection is the antineoplastic agent Irinotecan HCl trihydrate of Liposomal formulation and the fixed ratio compositions of floxuridine to CPX-1.These two medicines are included in the liposome with 1: 1 molar ratio.Liposome membrane is made up of with 7: 2: 1 molar ratio distearoyl phosphatidylcholine (DSPC), distearyl phosphatidyl glycerol (DSPG) and cholesterol (CHOL).These liposomees prepare with a water-in-oil derived liposome method, and the liposome of extruding are suspended in sucrose-phosphate buffer of pH 7.0.The nominal size of these liposomees approximately is 110nm; And by 0.22 μ m filter filtration sterilization.
The CPX-1 lipidosome injection that provides is aseptic, apyrogeneity, gobelin, opaque, is divided in the disposable 5ml Brown Glass Brown glass bottles and jars only.The dosage of CPX-1 refers to, and is included in the inclusions Irinotecan HCl trihydrate in the CPX-1 injection and the dosage of floxuridine.For example, dosage 50: 18mg/m
2CPX-1 refer to, be included in the 50mg/m among the CPX-I
2Irinotecan HCl trihydrate adds 18mg/m
2Floxuridine.
Administrable CPX-1 (Irinotecan HCl: lipidosome injection treatment floxuridine), by 90 minutes intravenous infusion administration.The principle of selection infusion time as mentioned above.(Irinotecan HCl: floxuridine) lipidosome injection is to finish by periphery or central vein conduit to infusion CPX-1, uses infusion pump to finish infusion to guarantee medicine in specified time bar.Comprise doser, the material of use is a non-PVC, as Hi-fax.Do not use internal ramp.
The definition of dose-limiting toxicity (DLT): adopt the 3rd edition " NCI adverse events name the universal standard ", only the toxicity that occurs when treat in the first round defines patient's DLT.Dose-limiting toxicity is defined as any 3 grades or 4 grades, the non-blood toxicity (except the nausea and vomiting of chance) that occurs when treating in the first round.Dose limitation blood toxicity is defined as and surpasses 7 days absolute neutrophil count (ANC)＜0.5 * 10
9/ L, the fever type neutrophilic granulocytopenia (is defined as ANC＜500 * 10
9/ L, or generate heat simultaneously above 38.5 degree, or hospitalization fever type neutrophilic granulocytopenia), platelet count＜25 * 10
9/ L (have or do not have hemorrhage) perhaps follows 3 grades of hemorrhage thrombocytopenia (platelet＜50 * 10
9/ L and＞25 * 10
9/ L).ALT or AST have been the patient of liver transplantation of 3 to 5 times (CTCAE is defined as 2 grades) of upper limits of normal when participating in research, and 3 grades ALT or AST toxicity do not constitute DLT.
The definition of maximum tolerated dose (MTD): maximum tolerated dose (MTD) is defined as and makes the dosage that is less than 1/3 patient experience DLT, and this is to be only second to 1/3 or the low dosage of the test group of more patient experience DLT simultaneously.
If in the treatment of at least 28 days treatment phases, under given dosage level, do not have patient experience DLT among 3 or 4 patients, so just in 3 or 4 patients of another test group, study next dosage level.
If under given dosage level, 1 patient experience DLT is arranged among 3 or 4 patients, so just increase patient's sum to 6, and with identical dosage level treatment.If 1 experience DLT among 6 patients just continues to increase in proportion patient's sum.If under given dosage level, 2 or more experience DLT among 6 patients just do not continue to increase this horizontal dosage.In order to ensure the effectiveness of this dosage as II phase clinical dosage, probe into the active primary evidence of proof antitumor antibiotic simultaneously, also have other 3 to 12 patients acceptance dosage level in the past.
Pharmacokinetic analysis
Use effective, specific high speed liquid chromatography mass spectrum algoscopy, Irinotecan in the analysed for plasma and SN-38, and floxuridine and 5-FU.At each patient, plasma concentration-time diagram of Irinotecan, SN-38, floxuridine and 5-FU is arranged all.Determine pharmacokinetic parameter from plasma concentration-time diagram of all valuable experimenters.Use non-chamber model and WinNonlin
TMProfessional version (4.0 editions or higher) is calculated pharmacokinetic parameter, includes but not limited to following parameter:
C
MaximumThe Cmax that observes
T
MaximumC
MaximumThe time that occurs
λ
zNormal by the elimination speed that final time data on linear regression nature log (ln) the conversion concentration ratio obtains
Number (only after administration in the 1st day, occurring)
t
1/2T1/2, calculating formula are ln (2)/λ z
AUC
(0-is last)When plasma concentration-time graph extends to last time of administration point from the zero-time point, wherein can decide
Area under the time period of amount plasma concentration; Obtain by linear rhomboid method
AUC
(0-is infinite)When plasma concentration-time graph when zero-time point extends to infinitely-great time point, the face under the curve
Long-pending
CL System Cleaning rate, calculating formula is dosage/AUC
(0-is infinite)(only being used for Irinotecan and floxuridine)
Summarize the plasma concentration and the PK parameter of each therapeutic test group with descriptive statistics (average, standard deviation, CV%, intermediate value, minima and maximum).
The result: (16 men: 10 woman), median age 58 years old (50-79) was all accepted treatment to 26 experimenters in the past, joined in 6 test group, and the 5th test group expands to 6 experimenters.
Diagnosis: 8 colorectal, 3 pancreas, 3 ovaries, 2 thymus, 2 stomaches, 2 esophaguses, 2 sarcomas, 1 nephrocyte, 1 nonsmall-cell lung cancer and 1 sphenoid sinus.7 patients (4 men: 3 woman), all accepted treatment in the past and suffered from colorectal carcinoma, is registered in the extension phase of this research by median age 58 years old (50-79).Referring to Fig. 1.
Nearly allly be in the patient that this research dosage increases the stage, all suffer from late malignant tumour and many-sided treatment was arranged in the past.Therefore, we are low to being contemplated to be of the getting nowhere life cycle of goal treatment effect and prolongation (PFS＞5 month).
We observe two patients part goal treatment effect.First place patient is a colon cancer, and his curative effect has continued 4 first quarter moons.Metastatic disease has appearred in this experimenter, and accepted the tumor that treatment has former of excision, afterwards with the treatment of Irinotecan Jia Aosha platinum profit and the metastasis of liver is dwindled, trial property the pathological changes that hepatectomizes residual and find obstinate disease of lymph node, at last with capecitabine treatment, all these be enter the I phase study before to treatment.Although contacted in the past fluorine pyrimidine of this patient and Irinotecan have therapeutic effect.
Second place patient is a nonsmall-cell lung cancer, and therapeutic effect has continued 3 months.This patient accepted the treatment of Ramulus et folium taxi cuspidatae terpene, cisplatin, etoposide and gefitinib in the past.Treat such cancer without the fluorine pyrimidine as usual, but may use Irinotecan that therapeutic effect is arranged.
In addition, we observed 5 months or 9 patients of longer stable phase, also had 3 patients' the progresson free survival phase (PFS) may surpass 5 months durations in the near future in addition.Great majority among these patients were accepted the chemotherapy of too high dose in the past.The treatment that these experimenters accepted in the past is summarized in the following table:
The treatment that table 7 patient accepted in the past
| Dosage level U/m 2 | Tumor type | PFS (moon) | Chemotherapy in the past |
| 60 | Stomach | 5.7 | Capecitabine |
| 100 | Ovary | 16.4+ | Ramulus et folium taxi cuspidatae terpene+carboplatin (adjuvant); |
| 100 | Colon | 11.8 | 5FU/LV, capecitabine, Irinotecan, oxaliplatin, ALVAC- |
| 210 | Pancreas | 7.4 | 5FU/LV, |
| 210 | Colon | 7.4 | 5FU/LV (adjuvant); FOLFOX; FOLFIRI |
| 210 | Colon * | 5.6 | 5FU/LV; XRT pelvis (pelvis); The FOLFOX+ bevacizumab; FOLFIRI; Cetuximab; The dust network is for Buddhist nun (erlotinib) |
| 210 | Colon * | 7.0+ | XRT; |
| 210 | Colon * | 5.4 | XRT；5FU/LV；FOLFOX，PTK787， |
| 270 | The sphenoid sinus tumor | 7.9 | Paclitaxel; Cisplatin; Carboplatin; Gemcitabine; Nvelbine |
Safety: observing DLT:4 position experimenter at the 6th dosage level has DLT:3 diarrhoea (one because dehydration/acute renal failure causes death), and 1 neutrophilic granulocyte reduces.Other 3 grades of may be correlated with and 4 grades of incidents, wherein each incident is one: 3 grades of diarrhoea, 3 grades of vomitings, 3 grades of neutrophilic granulocytes reduce, 3 grades of fatigue, 3 grades of compression fracturees and arthralgia and 4 grades of pulmonary infarction.
PK: pharmacokinetic analysis is presented among Fig. 2.Among 26 experimenters of all of data analysis, the IRT of 1: 1 molar ratio kept 24 hours than FLOX, metabolite 5-FU and SN-38 occurred in the blood plasma simultaneously.Compare result of this clinical trial and the data that clinical trial is in the past announced below.
The PK of Irinotecan when table 8 is relatively taken conventional medicine or CPX-1
A kind of new method of CPX1 representative development pharmaceutical composition, the ratio of its Chinese medicine is to come preselected in the activity of external antitumor antibiotic according to the best, and in the pharmacokinetics monitoring, and in whole pharmacokinetics control, can both keep to general this ratio.II phase project is used 210 units (the U)/m that recommends
2CPX-1.
Obviously those skilled in the art can not break away from the spirit and scope of the present invention, make many corrections of the present invention and change.The specific embodiment described herein only provides in an exemplary fashion, and the present invention simultaneously is subject to the term in the appended claims, also has the four corner of the equivalent of claims tax power thus; And the invention is not restricted to the described specific embodiment that provides in an exemplary fashion.
Quoting of above publication and file is intended to neither permit that above-mentioned any content all is relevant prior art, also do not constitute any approval to the interior perhaps date of these publications and file.In view of the above, the United States Patent (USP) quoted of this paper and other publication are combined in herein in the mode of list of references.
Claims (18)
1. one kind for the experimenter treats method for cancer, and described method comprises: give described experimenter and comprise the Irinotecan of fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, wherein, described fixed, non-antagonist molar was kept in blood plasma at least about 4 hours.
2. the method for claim 1 is characterized in that, described fixed, non-antagonist molar was kept in blood plasma at least about 8 hours.
3. the method for claim 1 is characterized in that, described fixed, non-antagonist molar was kept in blood plasma at least about 16 hours.
4. one kind for the experimenter treats method for cancer, and described method comprises: give described experimenter and comprise the Irinotecan of fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, wherein, described compositions intravenous administration.
5. method as claimed in claim 4 is characterized in that, described compositions administration time is 30 minutes to 3 hours.
6. method as claimed in claim 4 is characterized in that, described compositions administration time is about 90 minutes.
7. treat method for cancer for the experimenter for one kind, described method comprises: give described experimenter and comprise the Irinotecan of fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, wherein, the dosage level that gives floxuridine is not more than 0.001 mole/square metre/agent.
8. method as claimed in claim 7 is characterized in that, gives floxuridine 0.0003 mole/square metre/agent.
9. one kind for the experimenter treats method for cancer, and described method comprises: give described experimenter and comprise the Irinotecan of fixed, non-antagonist molar and the pharmaceutical composition of floxuridine, wherein, the dosage level that gives floxuridine is not more than 0.01 mole/square metre/month.
10. method as claimed in claim 9 is characterized in that, gives 0.0006 mole/square metre/month of floxuridine.
11., it is characterized in that the Irinotecan of described fixed, non-antagonist molar and the ratio of floxuridine are between about 5: 1 to about 1: 5 as each described method among the claim 1-10.
12. method as claimed in claim 11 is characterized in that, the Irinotecan of described fixed, non-antagonist molar and the ratio of floxuridine are about 1: 1.
13., it is characterized in that described cancer is an advanced solid tumor as each described method among the claim 1-10.
14. method as claimed in claim 13 is characterized in that, described advanced solid tumor is tumor stomach, tumor of kidney, breast tumor, colon tumor, esophageal tumor, prostate tumor, pancreas tumor, ovarian tumor, osteosarcoma or sphenoid sinus tumor.
15., it is characterized in that the Irinotecan and the floxuridine of described fixed, non-antagonist molar are encapsulated in the liposome as each described method among the claim 1-10.
16., it is characterized in that described cancer is the cancer of recurrence as each described method among the claim 1-10.
17., it is characterized in that described experimenter's past experience is crossed at least a antitumor scheme as each described method among the claim 1-10.
18. method as claimed in claim 17 is characterized in that, described antitumor scheme is the multiple medicines scheme for combining.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US73019905P | 2005-10-25 | 2005-10-25 | |
| US60/730,199 | 2005-10-25 | ||
| US60/759,225 | 2006-01-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101330917A true CN101330917A (en) | 2008-12-24 |
Family
ID=40206355
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800447790A Pending CN101330917A (en) | 2005-10-25 | 2006-10-25 | Fixed ratio drug combination treatments for solid tumors |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101330917A (en) |
-
2006
- 2006-10-25 CN CNA2006800447790A patent/CN101330917A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7842676B2 (en) | Fixed ratio drug combination treatments for solid tumors | |
| JP7463329B2 (en) | Methods for treating metastatic pancreatic cancer using combination therapy comprising liposomal irinotecan and oxaliplatin - Patent Application 20070123333 | |
| EP3076972B1 (en) | Cancer treatment with combination of plinabulin and taxane | |
| US11071726B2 (en) | Treating gastric cancer using combination therapies comprising liposomal irinotecan, oxaliplatin, 5-fluorouracil (and leucovorin) | |
| CN102006875A (en) | Use of picoplatin and bevacizumab to treat colorectal cancer | |
| JP2020528880A (en) | Combination cancer therapy | |
| CN101686971A (en) | Methods of treating multiple myeloma using combination therapies based on anti-cs1 antibodies | |
| TW201701880A (en) | Methods for improving the pharmacokinetics and therapeutic index of sustained release drug therapies | |
| Hara et al. | Double-conditioning regimens consisting of thiotepa, melphalan and busulfan with stem cell rescue for the treatment of pediatric solid tumors | |
| JP2013521338A (en) | Methods for treating small cell lung cancer | |
| CN101687104A (en) | The cancer treatment combination therapy that comprises vinflunine and trastuzumab | |
| Gelmon et al. | A phase 1 study of OSI-211 given as an intravenous infusion days 1, 2, and 3 every three weeks in patients with solid cancers | |
| CN113116895B (en) | Quinoline derivatives for the treatment of neuroblastoma | |
| Gershenson et al. | A phase I study of a daily× 3 schedule of intravenous vinorelbine for refractory epithelial ovarian cancer | |
| TWI817958B (en) | Compositions and methods for treating liver cancer | |
| KR20070037498A (en) | Epothilone combinations | |
| Murray et al. | Brief intensive chemotherapy for metastatic non-small-cell lung cancer: a phase II study of the weekly CODE regimen | |
| CN101330917A (en) | Fixed ratio drug combination treatments for solid tumors | |
| Pronzato et al. | Carboplatin and vinorelbine in advanced non-small-cell lung cancer | |
| US20130338129A1 (en) | Method of treating refractory cancer | |
| Malik et al. | Phase II trial of merbarone in patients with malignant brain tumors | |
| Treat et al. | Elliptinium: phase II study in advanced measurable breast cancer | |
| Ito et al. | Dose-finding phase I study of simultaneous weekly infusion with doxorubicin and docetaxel in patients with advanced breast cancer | |
| Hütter et al. | Phase I/II trial of topotecan given as continuous infusion in combination with oxaliplatin in 5-FU-pretreated patients with colorectal cancer | |
| Brack et al. | Application for the Inclusion of Vinorelbine for the Treatment of Rhabdomyosarcoma as first line treatment on the WHO Essential Medicines List for Children 2021 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20081224 |