OA16269A - An antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative. - Google Patents
An antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative. Download PDFInfo
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- OA16269A OA16269A OA1201200508 OA16269A OA 16269 A OA16269 A OA 16269A OA 1201200508 OA1201200508 OA 1201200508 OA 16269 A OA16269 A OA 16269A
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- ombrabulin
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- 229950003600 Ombrabulin Drugs 0.000 title claims abstract description 84
- IXWNTLSTOZFSCM-YVACAVLKSA-N Ombrabulin Chemical compound C1=C(NC(=O)[C@@H](N)CO)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 IXWNTLSTOZFSCM-YVACAVLKSA-N 0.000 title claims abstract description 81
- 230000000259 anti-tumor Effects 0.000 title claims abstract description 30
- 150000003057 platinum Chemical class 0.000 title abstract description 6
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 26
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 40
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- 229930003347 taxol Natural products 0.000 claims description 32
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 30
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- 229960003668 docetaxel Drugs 0.000 claims description 28
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- OHJKXVLJWUPWQG-IUYNYSEKSA-J (4S,6R)-6-[(2R,4R)-4,6-dihydroxy-5-(sulfonatoamino)-2-(sulfonatooxymethyl)oxan-3-yl]oxy-3,4-dihydroxy-5-sulfonatooxyoxane-2-carboxylate Chemical compound O[C@@H]1C(NS([O-])(=O)=O)C(O)O[C@H](COS([O-])(=O)=O)C1O[C@H]1C(OS([O-])(=O)=O)[C@@H](O)C(O)C(C([O-])=O)O1 OHJKXVLJWUPWQG-IUYNYSEKSA-J 0.000 description 1
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Abstract
The invention concerns an antitumoral combination comprising ombrabulin, a taxane derivative and a platinum derivative and its use in the treatment of advanced solid tumors.
Description
AN ANTITUMORAL COMBINATION COMPRISING QMBRABULIN, A TAXANE DERIVATIVE AND A PLATINUM DERIVATIVE
The invention concems an antitumoral combination comprising ombrabuiin, a taxane dérivative and a platinum dérivative and its use In the treatment of advanced solid tumors.
[Prior art and problam to be solved]
WO 99/51246 discloses the ombrabulin/platinum sait combination.
WO 2004/037258 discloses the combination of ombrabuiin with various antitumoral agents including taxanes (Taxol®, Taxotere®).
There is still a need to find and optimize new therapeutic options to treat patients with advanced solid tumors.
The invention meet this need by providing a new pharmaceutical antitumoral combination comprising ombrabuiin, a taxane dérivative and a platinum dérivative for which doses of each component and a suitable administration protocol has been determined, to obtain a well tolerated combination which does not exacerbate the toxicity of each of the antitumoral agents and which allows the treatment of advanced solid tumors either by stabilizing or by inducing a partial or a complété régression of the tumor.
[Description of the Invention]
The invention concems an antitumoral combination comprising ombrabuiin, a taxane dérivative and a platinum dérivative, these therapeutic components being In the form of a free base or of an addition sait with a pharmaceutical acceptable acid, or in the form of a hydrate or of a solvaté, where this antitumoral combination is well tolerated, does not exacarbate the toxicity of each of the antitumoral agents and which allows the treatment of advanced solid tumors either by stabilizing or by inducing a partial or a complété régression of the tumor.
Ombrabuiin (AVE8062) belongs to the iamily of combretastatins and has the formula:
«L
(it is the Z isomer)
It is an antivascular agent (or VDA, Vascuiar Disrupting Agent). It has the chemical name: (Z)-N-[2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)vinyl]phenyl|-L-serinamide.
This compound, which is described in EP 731085 B1, may be prepared according to the method described in WO 03/084919. Ombrabulin may be administered in base form (ci. above formula) or in the form of a sait of a pharmaceutically acceptable acid, for example in the form of the hydrochloride, represented below:
Once administered, ombrabulin releases in vivo the active métabolite (Z)-1-(3-amino-4· methoxy phenyl )-2-(3,4,5-trimethoxyphenyl)ethene, which has the formula;
It is therefore also possible to substitute, for ombrabulin, another combretastatin of formula:
in base form or in the form of a sait of a pharmaceutically acceptable acid, in which Y représente an amino acid, which releases in vivo this métabolite.
The taxane dérivative may for exempte be chosen from paclitaxel or docetaxel.
The platinum dérivative may for example be chosen from cisplatin or carboplatin.
The oombination comprises an effective quantity of ombrabulin, an effective quantity of a taxane dérivative and an effective quantity of a platinum dérivative.
Ombrabulin may be administered by perfusion at a dose comprised between 15 and 35 mg/m2, for example chosen from the following doses: 15.5; 20 ; 25 ; 30 and 35 mg/m2. Docetaxel may be administered by perfusion at a dose of 60 or 75 mg/m2.
Paclitaxel may be administered by perfusion at a dose of 175 or 200 mg/ml Cisplatin may be administered by perfusion at a dose of 75 mg/m2.
Carbopiatin may be administered by perfusion at a dose of AUC 5 and AUC 6.
Preferentially, ombrabulin may be used in combination with docetaxel and cisplatin or in combination with paclitaxel and carbopiatin.
Preferentially, ombrabulin may be used in combination with docetaxel and cisplatin.
In this case, ombrabulin may be administered at a dose of 20 mg/m3, docetaxel at a dose of 75 mg/m2 and cisplatin at a dose of 75 mg/m2.
In this case, ombrabulin may also be administered at a dose of 35 mg/m2, docetaxel at a dose of 75 mg/m2 and cisplatin at a dose of 75 mg/m2.
Preferentially, ombrabulin may be used in combination with paclitaxel and carbopiatin.
In this case, ombrabulin may be administered at a dose of 35 mg/m2, paclitaxel at a dose of 175 mg/m2 and carbopiatin at a dose of 5 AUC.
In this case, ombrabulin may also be administered at a dose of 35 mg/m2, paclitaxel at a dose of 200 mg/m2 and carbopiatin at a dose of 6 AUC.
The cycle of administration of the three antitumoral agents is repeated with an interval between two administrations of three weeks.
The invention also concerns the use of ombrabulin, a taxane dérivative and a platinum dérivative for the préparation of an antitumoral combination here above disclosed.
The invention also concerns the above disclosed antitumoral pharmaceutical combination comprising ombrabulin, a taxane dérivative and a platinum dérivative, these agents being in the form of a free base or of an addition sait with a pharmaceutical acceptable acid, or in the form of a hydrate or of a solvaté, for its use as a médicament in the treatment of advanced solid tumors.
The invention also concems a method of treating advanced solid tumors in a patient in need thereof, said method comprising administrating to said patient therapeutically effective amounts of the above disclosed antitumoral pharmaceutical combination comprising ombrabulin, a taxane dérivative and a platinum dérivative, these agents being in the form of a free base or of an addition sait with a pharmaceutical acceptable acid, or în the form of a hydrate or of a solvaté.
Examples of solid tumors that may be treated with the combination of the invention are but not exclusively - lung tumors, ovarian tumors and breast tumors including triple négative breast tumors.
In another aspect the invention provides for an article of manufacture comprising:
• a packaging material • the above disclosed antitumoral pharmaceutical combination comprising ombrabulin, a taxane dérivative and a platinum dérivative, these agents being in the form of a free base or of an addition sait with a pharmaceutical acceptable acid, or in the form of a hydrate or of a solvaté, and • a label or package insert contained within said packaging material Indicating that said antitumoral pharmaceutical combination is administered to the patient at a recommended dose, and in a plurality of subséquent doses at a recommended dose separated in time from each other by three weeks.
The recommended doses are as described in the following study.
Définitions • pharmaceutically acceptable acid: organic or inorganic acid having a low toxicity (see Pharmaceutical salts J.Pharm.Sci. 1977, 66, 1-19);
• effective amount: amount of a pharmaceutical compound that produces an effect on the treated tumour.
advanced solid tumors: locally advanced or metastatic solid tumors ie tumors which are not opérable any more.
The oomblnation is administered repeatedly in a course of several cycles according to a protocol that dépends on the nature and on the stage of the cancer to be treated and also on the patient to be treated (âge, weight, previous treatment(s), etc.).
Examples of cycles and doses are given in the study below.
An open-label, non-randomized, dose escalation, safety and pharmacokinetics phase l study of ombrabulin in combination with platinum salts (cisplatin or carboplatin) and taxanes (docetaxel or paclitaxel), every 3 weeks, in patients with advanced solid tumors has been done.
STUDY OBJECTIVE(S)
Primary objective
The primary objective of the study is to détermine the recommended dose (RD) based on the incidence of dose limiting toxicity (DLT), the maximum administered dose (MAD), and the maximum tolerated dose (MTD) of ombrabulin in combination with platinum salts and taxanes, every 3 weeks in patients with advanced solid tumors for which platinum-taxane doublet has been approved or constitutes mainstay of care.
Thus, the primary endpoint of the study is:
Dose Limiting Toxicity (DLT) at cycle 1.
Seoondary objectives
The secondary objectives of the study are:
To assess the overall safety profile of the combination.
To characterize at Cycle 1 the pharmacokinetic (PK) profile of ombrabulin given with platinum salts and taxanes following different schedules.
To evaluate anti-tumor activity of the tritherapy combination.
To evaluate potentia! prédictive biomarkers.
Thus, the secondary endpoints of the study are:
TEAE (Treatment Emergent Adverse Event), post-TEAE, SAE (Serious Adverse Event) and laboratory abnormalities.
• At cycle 1 : pharmaookinetic (PK) parameters of ombrabulin given with platinum salts and taxanes foltowing different schedules.
♦ Objective tumor response as defined by the RECIST criteria.
STUDY DESIGN
Two groups of patients will be treated: one with docetaxel-cisplatin doublet (group 1 ) and the second with paclitaxel-carboplatin doublet (group 2), both in combination with ombrabulin.
The combination will be started with the following schedule (schedule A) for group 1:
Dav 1: ombrabulin as a 30 minutes i.v. infusion immediately followed by 120 minutes i.v. infusion of cisplatin, and
Dav 2: docetaxel administered as a 60 minutes i.v. infusion 24 hours apart ombrabulin infusion end and for the first 4 dose levels (I, II, III, IV).
Cohorts of 3 or 6 patients will reçoive escalating doses of ombrabulin (15.5, 20 and 25 mg/m2) with a fixed dose of cisplatin at 75 mg/m2 on Day 1, followed by docetaxel on Day 2, given either at 60 mg/m2 for the ombrabulin doses of 15.5 and 20 mg/m2 or at 75 mg/m2 for the ombrabulin doses of 20 and 25 mg/m2.
Taking into considération the recommended dose of the combination ombrabulin and cisplatin administered the same day (25 mg/m2 and 75 mg/m2 respectively) every 3 weeks, after dose level IV, even if MAD not reached at this dose level, dose escalation of ombrabulin will be stopped and the combination will be administered with the following schedule /schedule B) in the 2 groups:
Dav 1: ombrabulin as a 30 minutes i.v, infusion, and
Dav 2:
Group 1 : docetaxel administered as a 60 minutes i.v. infusion followed by cisplatin as a 120 minutes i.v. infusion, 24 hours apart ombrabulin infusion end.
VL·
Group 2: paclitaxel administered as a 180 minutes i.v. infusion followed by carboplatin as a 30 minutes i.v. infusion, 24 hours apart ombrabulin infusion end.
At each level, cohorts of 3 or 6 patients will receive escalating doses of ombrabulin (20,
25, 30, 35... mg/m2) followed at Day 2 by a fixed dose of cisplatin at 75 mg/m2 or carboplatin AUC 5 or 6 in combination with docetaxel given at 75 mg/m2 or paclitaxel either at 175 (regimen A) or 200 mg/m2 (regimen B).
Group 1 (ombrabulln/docetaxel/clsplatln):
| Dos· escalation: ombrabulin with cisplatin (CDDP) and docetaxel (TXT) | ||||
| Schedule A | Dose- | ombrabulin | CDDP | TXT |
| (ombrabulin | Levais | mg/m2 | mg/m2 | mg/m2 |
| and CDDP | l | 15.5 | 75 | 60 |
| Day1.TXT Day 2) | II | 20 | 75 | 60 |
| III | 20 | 75 | 75 | |
| IV | 25 | 75 | 75 | |
| Schedule B | V* | 20 | 75 | 75 |
| (ombrabulin | VI | 25 | 75 | 75 |
| Day 1. CDDP and TXT Day | VII | 30 | 75 | 75 |
| 2) | Vlil | 35 | 75 | 75 |
| * if 2 DLTs at this dose level, possibility to test ombrabulin at 15.5 mg/m2 - docetaxel 75 | ||||
| mg/m2 - cisplatin 75 mg/m2 | ||||
| Group 2 (ombrabulln/paclltaxel/carboplatln): | ||||
| Dose escalation: ombrabulin with carboolatln fCb) and paclitaxel (PXL): Reolmen A |
| Schedule B | Dose- | ombrabulin | Cb | PXL |
| (ombrabulin Day | Levels | mg/m2(D1) | AUC | mg/m2 (D2) |
| 1, Cb and PXL | (D2) | |||
| Day 2) | la* | 20 | 5 | 175 |
| la’ | 20 | 6 | 175 |
Dose escalation: ombrabulin with carboplatin (Cb) and paclitaxel (PXL): Regimen A
| lia | 25 | 5 | 175 |
| Ilia | 30 | 5 | 175 |
| IVa | 35 | 5 | 175 |
*if 2 DLTs at this dose level, possibility to test ombrabulin at 15.5 mg/m2
In group 2, dose escalation could be continued by increasing ombrabulin of 20% from previous dose for a maximum of 50 mg/m2 (which is the recommended dose of the drug in monotherapy), provided that tested dose levels had not shown 2 or more DLTs.
In group 1, dose escalation will be stopped after dose level 35 mg/m2 for ombrabulin, taking into account the recommended dose that has been reached with the bi-therapy (ombrabulin 35 mg/m2 and docetaxel 75 mg/m2) in an on-going phase I trial.
Patients will then be followed for 21 days for safety assessment. After at least 21 days, patients will receive additional courses at every 21-day intervals in the absence of disease progression, unacceptable toxicity, or other study treatment criteria.
Thus, a cycle is defïned as a 3 week-period including one ombrabulin, platinum sait and taxane administration.
Recrultment in groups 1 and 2 could be run in paraltel. The first dose levels to be tested in group 2 will be:
- ombrabulin 20 mg/m2 - Carboplatin AUC 5 - Paclitaxel 175 mg/m2 (dose level la), followed by
- ombrabulin 20 mg/ms - Carboplatin AUC 6 - Paclitaxel 175 mg/m2 (dose level la’) followed by
- ombrabulin 20 mg/m2 - Carboplatin AUC 6 - Paclitaxel 200 mg/m2 (dose level Ib) Then dose levels lla-llla-IVa (regimen A) and llb-lllb-IVb (regimen B) could be run in parallel. Once the MAD is reached in each group and regimen with schedule B, additional patients to complets a subset of at least 15 patients, will be treated at the immédiate lower dose of ombrabulin with both platinum-taxane doublets chemotherapy (MTD) schedule B, mainly patients with non small cell lung cancer and ovarian cancer.
? L·
Dose escalatlon: ombrabulin with carboplatin (Cb) and paclitaxel (PXL): Reglmen B
| Schedule B | Dose- | ombrabulin | Cb | PXL |
| (ombrabulin | Levels | mg/m2 (D1) | AUC (D2) | mg/m2 (D2) |
| Day 1, Cb | ||||
| and PXL | Ib | 20 | 6 | 200 |
| Day 2) |
llb 25 6
200
| lllb | 30 | 6 | 200 |
| IVb | 35 | 6 | 200 |
NB: The first dose level to be tested in group 2 will be la, followed by la' then Ib. Then dose levels lla-llla-IVa and llb-lllb-IVb could be run in parallel; dose escalation could be continued by increasing ombrabulin of 20% from previous dose, provided that tested dose levels had not shown 2 or more DLTs θύ
Cohorts of 3 or 6 patients will be screened and treated at each dose level. When the first three patients of a cohort hâve completed the first cycle, i.e. should hâve received at least one treatment course and should hâve been observed for acute toxicity for at least a 3-week follow-up period (or shorter period provided that a DLT has been observed), dose escalation strategy will be as follows:
In the absence of DLT at first cycle, three patients will be treated at the next dose level.
If DLT is observed at first cycle in 1 out of 3 patients, three further patients will be included at the same dose level and possibly at the same time.
Then, if DLT i$ observed at first cycle in 1 out 6 patients, the next dose level will be tested. Otherwise, if 2 out 6 patients présent with a DLT at first cycle, the MAD is considered to be achieved.
If DLT is observed at first cycle in 2 out of the 3 patients, the MAD is considered to hâve been reached.
The Maximum Administered Dose (MAD) will be reached at the dose at which ï 2 out of
3-6 patients develop a DLT at the first cycle.
The dose limiting toxicities ( DLTs) that are events to be watched and which allow to drive the escalation of dose, were predefined in the protocol in agreement with the scale of classification NCI-CTCAE version 3.
Route(s) of administration;
ombrabulin, cisplatin, carboplatin, paclitaxel and docetaxel will be administered by intravenous infusion
STUDY POPULATION
Main inclusion criteria
- Advanced neoplastic disease (i.e. metastatic or locally advanced disease) for which platinum-taxane doublet regimens are approved or constitutes the mainstay of care such as non small cell lung cancer, épithélial ovary cancer, gastric cancer, transitional cell and bladder cancer and head and neck cancer.
- First or second line of metastatic disease.
- & 18 years old.
- ECOG performance status of 0 to 1.
- No brain métastasé or carcinomatous leptomeningitis.
- No peripheral neuropathy grade > 1.
AC
Main exclusion criteria
- Related to the Methodology (concurrent treatment with any other anticancer therapy, absence of histologically or cytologicaily proven cancer at the first diagnosis, washout period of less than 3 weeks from prior anti-tumor therapy like chemotherapy, targeted agents, immunotherapy and radlotherapy or any investigational treatment, of less than 6 weeks from prior therapy with nitrosoureas or mitomycin).
- Related to the study drugs (previous carboplatin dose higher than 3000 mg/m2 or cisplatîn higher than 600 mg/m1; more than 1 line of previous chemotherapy as treatment for advanced cancer disease, neoadjuvant treatment excluded; severe hypersensitivity due to taxanes, polysorbate 80 and any other compound of the study combination; unadequate organ function including: neutrophils < 1.5 x 109/L; platelets < 100 x 109/L; creatinine έ 1.5 mg/dl, total bilirubin not within normal limit and ALT/AST/AP > 2.5 times the upper normal limite of the institutional norms).
- Cardiovascular exclusion criteria (documented medical history of myocardial infarction. documented angina pectoris, arrhythmia especially severe conduction disorder such as second or third-degree atrio-ventricular block, stroke, or history of artériel or venous thrombo-embolism within the past 6 months requiring anticoagulants; patient with a LVEF < 50% by echocardiography; patient with unconlrolled hypertension and patient with organ damage related to hypertension such as left ventricular hypertrophy or grade 2ocularfunduscopic changes or kidney impairment; 12-lead ECG: infarction Q-wave (at least in 2 contiguous dérivations, duration > 40 msec, amplitude > 20% of QRS complex), ST segment dépréssion or élévation a 1 mm in at least 2 contiguous leads; untreated hypertension defined as systolic BP > 140 mmHg ordiastolic BP > 90 mmHg on two repeated measurements at 30 minutes interval).
RESULTS:
T (docetaxel D or paclitaxel P) and PS (cisplatin C or carboplatin Cb respectively) Ob = ombra bu lin pt = patient; pts = patients d - day
Sixty-nine patients (23 males and 46 females), médian âge 49 (range 24-74), including chemonaive patients, were treated in 4 cohorte:
- Cohort I (Ob/C75 mg/m2 d1, D60 or 75 mg/m2 d2 -13 pts)
- Cohort II (Ob d1, C75/D75 d2 - 19 pts)
- Cohort III (Ob d1, CbAUC5/P175d2- 18 pts)
- Cohort IV (Ob d 1, CbAUC6/P200 d2 - 19 pts).
Dose levels (DL) tested for Ob were: 15.5, 20, 25, 30, 35 mg/m2.
Granulocyte growth factors were systematically administered as primary prophylaxie in cohort I and II.
The most common tumor types were lung (n= 14), breast (n=19, including 5 triple négative pts) and ovarian (n= 9).
Conceminq cohort I:
- the médian number of cycles was 6 (range 1-16);
- the RD is Ob20/C75/D75 mg/m2.
Two DLTs (febrile neutropenia and grade 4 pulmonary embolism) were reported at cycle of dose levels 25/75/75 mg/m2.
The most frequent TEAEs were: asthenîa (12 pts including 1 grade 3), nausea (11 pts), paresthesia (10 pts), diarrhea (7 pts including 1 grade 3). Other related grade % TEAEs were: 1 grade 3 drug hypersensitivity. Related cardiovascular events consistée! on: grade thrombo-phlebitis (3 2 pts), grade 1 sinusal bradycardia (1 pt), grade 2 deep venous thrombosis (1 pt) and grade 1 orthostatic hypotension (1 pt).
Hematotoxicity was typical for D and C combinations.
Objective responses were observed: on 11 évaluable pts, there were 4 partial responses (including 1 epidermoid lung cancer).
Conceminq cohort II
- the médian number of cycles was 6 (range 2-15);
- the maximum administered dose was reached at 35 mg/m2 for ombrabulin;
- the RD is Ob35/C75/D75 mg/m2; only 1 DLT (grade 3 transaminase increase) was observed at the first dose levai (20/75/75)
The most frequent TEAEs were: asthenîa (19 pts, including 1 grade 3), nausea (17 pts), paresthesia (13 pts), stomatitis (10 pts), vomiting (12 pts), alopecia (13 pts). Other related grade % TEAEs were 1 grade 3 drug hypersensitivity and 2 grade 3 pulmonary embolism. Related cardiovascular events not listed as grade % consisted on: grade 2 hypertension (1 pt), grade 1 orthostatic hypotension (1 pt) and grade 2 LVEF decrease (1 pt).
Hematotoxicity was typical for D and C combination.
Objective responses were observed: on 18 évaluable pts, 6 partial responses (2 lung including 1 epidermoid lung cancer, 2 breast and 1 utérus cancer) were obtaîned.
Concemino cohort III
- the médian number of cycles was 2 (range 1-8);
- the maximum administered dose was reached at 35 mg/m2 for ombrabulin;
the RD is Ob35mg/m2 /Cb5 AUC /P175 mg/m2; no DLT was observed.
The most frequent TEAEs were: asthénie (16 pts), alopecia (13 pts), vomiting (12 pts), nausea (11 pts), paresthesia (11 pts) and stomatitis (9 pts). Related grade % TEAEs were: 1 grade 3 drug hypersensitivity. Related cardiovascular events consisted on: grade 3 hypertension (1 pt).
Hematotoxidty was typical for P and Cb combination.
Objective responses were observed: on 17 évaluable pts, 1 complété response (triple négative breast cancer) and 2 partial responses (ovarian lung cancer) were obtained.
Conceminq cohort IV
- the médian number of cycles was 4 (range 1-12);
- the maximum administered dose was reached at 35 mg/m2 for ombrabulin; the RD is Ob35mg/m2 /Cb6 AUC /P200 mg/m2;
- only 1 DLT was observed: grade 3 toe ischemia at the first dose level tested ( Ob20 mg/m2/Cb6 AUC /P200 mg/m2).
The most frequent TEAEs were: decrease apetite (11 pts), vomiting (10 pts), asthenia (17 pts including 1 grade 3), nausea (11 pts including 1 grade 3), alopecia (11 pts) and paresthesia (15 pts). Other related grade % TEAEs were: 1 grade 3 peripheral neuropathy. Related cardiovascular events consisted on: grade 1 sinusal bradycardia (1 pt), grade 2 hypertension (2 pts).
Hematotoxidty was typical for P and Cb combination.
Objective responses were observed: on 18 évaluable pts, 3 partial responses (lung, ovary and thymoma).
Thus, these results confirm that the combination of Ob with T and PS is feasible and well tolerated, with preliminary encouraging evidence of anti-tumor activity.
Pharmacokinetic studv
Blood samples for pharmacokinetic analysis were obtained from ail patients on Day 1, 2 and 3 at Cycle 1.
Qr9MP1
AVE8062
A sériés of 2-mL blood samples were collected in heparinized (lithium heparinate) tubes as follows:
-immediately prior to the end of infusion;
-at 5,10, 25,45 and 60 minutes post infusion;
-at 2, 4, 6,8,10 and 24 hours post infusion (i.e a total of 24 mLof blood).
Cisplatin
A sériés of 5-mL blood samples were collected in heparinized (sodium heparinate) tubes as follows:
-immediately prior to the end of infusion;
-at 30 and 60 minutes post infusion;
-at 2,4, 6, 8 and 22 hours post infusion (i.e a total of 40 mL of blood).
Docetaxel
A sériés of 2-mL blood samples were collected in heparinized (lithium heparinate) tubes as follows:
-15 minutes before the end of docetaxel infusion;
-at 15 and 45 minutes post docetaxel infusion;
-at 2 and 5 hours post docetaxel infusion (i.e. a total of 10 mL of blood).
Group 2
AVE8062
A sériés of 2-mL blood samples were collected in heparinized (lithium heparinate) tubes as follows:
-immediately prior to the end of infusion;
-at 5, 10, 25,45 and 60 minutes post infusion;
-at 2,4, 6, 8,10 and 24 hours post infusion (i.e a total of 24 mL of blood).
Paclitaxel
A sériés of 2-mL blood samples were collected in EDTA tubes as follows
- 90 minutes and immediately prior to the end of infusion
- at 0.5,1, 2, 4, 6, 8 and 24 hours post infusion (i.e. a total of 18 mL of blood)
P’C
Carboplatin
A sériés of 3-mL blood samples were collected as follow:
- immediately prior to the end of infusion;
- at 0.5, 1.5, 3.5, 5,5, 7.5 and 23.5 hours post infusion (i.e. a total of 21 mL of blood)
Résulte :
Ombrabulin clearance was high (72.9 Uh/m2) and the volume of distribution at steady state was small (25.0 L/ m2), corresponding to a short terminal élimination half-life (17 min).
Ombrabulin was rapidly converted to ils active métabolite which has a terminal élimination half-life of around 11 h.
Métabolite exposure was found to be about 2-fold higher than ombrabulin.
The table 1 shows mean ombrabulin pharmacokinetic parameters at cyciel.
The table 2 shows mean ombrabulin métabolite pharmacokinetic parameters at cyciel.
Table 1: Mean ombrabulin pharmacokinetic parameters at cycle 1.
CO θ E
S «jT
| <si ΓΣ & | f2 «2 | <ZZ» K ’W— θ' | B | |
| 03' <=> Îf S- | CO* K~ s> <=> g ç5_ | co’ θ ™ ç5. | S* es *^r gS. | ίο S> θ es. |
| CO | «si | CM | CO | tn |
| 40 u5 | <zz* CM | tn CM | 40 CO |
Table 2: Meanombrabulin métabolite pharmaookinetic parameters at cycle*!.
Biomarkers studv
Tumor biopsies were performed on 11 patients, immunohistochemical and RT-PCR methods were used.
On 11 patients, 3 had high score for CD31 (ovary, utérus and liver cancer), 9 for CD34 (mainly ovarian, breast, Itvar cancer) and 1 for CD 105 (ovarian cancer). Ali cases were stained in intratumoral vessels, indicating that these tumors présent a high grade of vascularisation.
One patient showed high expression of Hif-1a, Fli*1 and Pax2 and high score for CD34 10 in intratumoral vessels.
6 NOV. 201?
YAO
Cameroun
Claims (21)
1. An antitumoral combination comprising ombrabulin, a taxane dérivative and a platinum dérivative, these therapeutic components being in the form of a free base or of an addition sait with a pharmaceutical acceptable acid, or in the form of a hydrate or of a solvaté, where this antitumoral combination is well tolerated, does not exacerbate the toxicity of each of the antitumoral agents and which allows the treatment of ad va need solid tumors either by stabilizing or by inducing a partial or a complété régression of the tumor.
2. Combination according to claim 1 where ombrabulin is in the form of the hydrochloride sait.
3. Combination according to claim 1 where the taxane dérivative is chosen from paclitaxel or docetaxel.
4. Combination according to claim 1 where the platinum dérivative is chosen from cisplatin or carboplatin.
5. Combination according to any one of daims 1 to 4 where ombrabulin is in combination with docetaxel and cisplatin or in combination with paclitaxel and carboplatin.
6. Combination according to any one of claims 1 to 5 comprising an effective quantity of ombrabulin, an effective quantity of a taxane dérivative and an effective quantity of a platinum dérivative.
7. Combination according to claim 6 where ombrabulin is administered at a dose comprised between 15 and 35 mg/m2,
8. Combination according to claim 7 where ombrabulin is administered at a dose chosen from: 15.5; 20 ; 25 ; 30 and 35 mg/m2.
9. Combination according to claim 6 where the taxane dérivative is docetaxel and is administered at a dose of 60 or 75 mg/m2.
>6 L
10. Combination according to claim 6 where the taxane dérivative is paclitaxel and Is administered at a dose of 175 or 200 mg/m®.
11. Combination according to claim 6 where the platinum dérivative is cisplatin and is administered at a dose of 75 mg/m®.
12. Combination according to claim 6 where the platinum dérivative is carboplatin and is administered at a dose of AUC 5 or 6.
13. Combination according to claim 5 or 6 where ombrabulin is in combination with docetaxel and cisplatin and where ombrabulin is administered at a dose of 20 mg/m®, docetaxel is administered at a dose of 75 mg/m® and cisplatin is administered at a dose of 75 mg/m®.
14. Combination according to claim 5 or 6 where ombrabulin is in combination with docetaxel and cisplatin and where ombrabulin is administered at a dose of 35 mg/m®, docetaxel is administered at a dose of 75 mg/m® and cisplatin is administered at a dose of 75 mg/m®.
15. Combination according to claim 5 or 6 where ombrabulin is in combination with paclitaxel and carboplatin and where ombrabulin is administered at a dose of 35 mg/m®, paclitaxel is administered at a dose of 175 mg/m® and carboplatin is administered at a dose of 5 AUC.
16. Combination according to claim 5 or 6 where ombrabulin is in combination with paclitaxel and carboplatin and where ombrabulin is administered at a dose of 35 mg/m®, paclitaxel is administered at a dose of 200 mg/m® and carboplatin is administered at a dose of 6 AUC.
17. Combination according to any one of daims 1 to 16, where the cycle of administration of the three antitumoral agents is repeated with an interval between two administrations of three weeks.
18. Article of manufacture comprising:
• a packaging material • an antitumoral pharmaceutical combination comprising ombrabulin, a taxane dérivative and a platinum derivalive, these agents being in the form of a free
5 base or of an addition sait with a pharmaceutical acceptable acid, or in the form of a hydrate or of a solvaté, and • a label or package insert contained within said packaging material indicating that said antitumoral pharmaceutical combination is administered to the patient at a recommended dose, and in a plurality of subséquent doses at a
10 recommended dose separated in time from each other by three weeks.
19. Article of manufacture according to claim 18 where the antitumoral pharmaceutical combination is as defined in any one of claims 1 to 17 and the recommended dose indicated on the label or package insert is as defined in claim 13, 14,15 or 16.
15
20. Use of ombrabulin, a taxane dérivative and a platinum dérivative for the préparation of an antitumoral combination as claimed in claims 1 to 17.
21. An antitumoral pharmaceutical combination comprising ombrabulin, a taxane dérivative and a platinum dérivative, these agents being tn the form of a free base or of 2 0 an addition sait with a pharmaceutical acceptable acid, or in the form of a hydrate or of a solvaté, where this antitumoral combination is well tolerated, does not exacerba te the toxicity of each of the antitumoral agents and which allows the treatment of advanced solid tumors either by stabilizîng or by inducing a partial or a complété régression of the tumor, for its use as a médicament in the treatment of advanced solid tumors.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10305653.7 | 2010-06-18 | ||
| EP10306256.8 | 2010-11-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA16269A true OA16269A (en) | 2015-04-24 |
Family
ID=
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