WO2008033041A1 - Traitement contre le cancer - Google Patents

Traitement contre le cancer Download PDF

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Publication number
WO2008033041A1
WO2008033041A1 PCT/NZ2007/000268 NZ2007000268W WO2008033041A1 WO 2008033041 A1 WO2008033041 A1 WO 2008033041A1 NZ 2007000268 W NZ2007000268 W NZ 2007000268W WO 2008033041 A1 WO2008033041 A1 WO 2008033041A1
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bevacizumab
day
compound
formula
administered
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PCT/NZ2007/000268
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English (en)
Inventor
Adam Vorn Patterson
Paul Adrian Cossum
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Auckland Uniservices Limited
Proacta Inc.
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Publication of WO2008033041A1 publication Critical patent/WO2008033041A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention is directed to methods fot treating cancer and to compositions for use therein.
  • Cancer is a significant cause of death, particularly in industrialised countries. While there are a number of anti-cancer therapies now available, there remains a need for new approaches to treating cancer which offer better outcomes for patients. It is towards one such approach that the present invention is directed.
  • the present invention is broadly based upon the unexpected and surprising finding that compounds of Formula (I) and their salts as defined in WO 2005/042471 used in combination with anti-VEGF agent bevacizumab (Avastin®) produces significantly better effects than either agent alone.
  • a method for the production of an anti-cancer effect in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of a compound of Formula (I)
  • X represents at any available ring position -CONH-, -SO 2 NH-, -O-, -CH 2. , -NHCO- or -NHSO 2 -;
  • R represents a lower Cl -6 alkylene optionally substituted with one or more groups including hydroxy, amino and N-oxides therefrom or dialkylamino and N-oxides therefrom;
  • Y represents at any available ring position — N-aziridinyl, -N(CH 2 CH 2 N)C) 2 or — N(CH 2 CHMeW) 2 , where each W is independently selected from halogen or -OSO 2 Me;
  • Z represents at any available ring position -NO 2 , -halogen, -CN, -CF 3 or -SO 2 Me; or a pharmaceutically acceptable salt or derivative thereof, before, after or simultaneously with an effective amount of bevacizumab.
  • Anti-cancer effects include, but are not limited to, anti-tumor effects, the response rate, the time to disease progression and the survival rate.
  • Anti-tumor effects include but are not limited to, inhibition of tumor,-growth, tumor growth delay, regression of tumor, shrinkage of tumor, increased time to regrowth of tumor' on cessation of treatment and slowing of disease progression.
  • an "effective amount” includes amounts of the compound which provide an anti-cancer effect on their own as well as amounts of the compound which, while being less than a therapeutic dose for the compound as a monotherapy, do provide an anti-cancer effect when the second compound is administered in combination.
  • a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt or derivative thereof, before, after or simultaneously with an effective amount of bevacizumab.
  • the compound of Formula (I) or salt or derivative thereof and bevacizumab may each be administered together with a pharmaceutically acceptable excipient or carrier.
  • a therapeutic combination treatment comprising the administration of an effective amount of a compound of Formula (I) as defined above or a pharmaceutically acceptable salt or derivative thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and the simultaneous, sequential or separate administration of an effective amount of bevacizumab, optionally together with a pharmaceutically acceptable excipient or carrier, to a warm-blooded animal such as a human in need of such therapeutic treatment.
  • Such therapeutic treatment includes an anti-cancer effect and an anti-tumor effect.
  • a combination treatment of the present invention as defined herein may be achieved by way of the simultaneous, sequential or separate administration of the individual components of said treatment.
  • a combination treatment as defined herein may be applied as a sole therapy or may involve surgery or radiotherapy or an additional chemotherapeutic agent in addition to a combination treatment of the invention.
  • Surgery may comprise the step of partial or complete tumor resection, prior to, during or after the administration of the combination treatment described herein.
  • the effect of a combination treatment of the present invention is expected to be a synergistic effect.
  • a combination treatment is defined as affording a synergistic effect if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one or other of the components of the combination treatment at its conventional dose.
  • the effect of the combination treatment is synergistic if the effect is therapeutically superior to the effect achievable with a compound of Formula (I) or bevacizumab alone.
  • the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to a compound of Formula (I) or bevacizumab alone.
  • the effect of the combination treatment is defined as affording a synergistic effect if one of the components is dosed at its conventional dose and the other component(s) is/are dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent to that achievable on dosing conventional amounts of the components of the combination treatment.
  • synergy is deemed to be present if the conventional dose of compound of Formula (I) or bevacizumab may be reduced without detriment to one or more of the extent of the response, the response rate, the time to disease progression and survival data, in particular without detriment to the duration of the response, but with fewer and/or less troublesome side effects than those that occur when conventional doses of each component are used.
  • Combination treatments of the present invention may be used to treat cancer, particularly a cancer involving a solid tumor.
  • combination treatments of the invention are expected to slow advantageously the growth of primary and recurrent solid tumors of, for example, the ovary, colon, stomach, brain, thyroid, adrenal, pituitary, pancreas, bladder, breast, prostate, lungs, kidney, liver, head and neck (including esophageal), cervix, endometrium, vulva, skin and connective tissues or bone.
  • More especially combination treatments of the present invention are expected to slow advantageously the growth of tumors in colorectal cancer and in lung cancer, for example mesothelioma and non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • combination treatments of the invention are expected to inhibit any form of cancer associated with VEGF including leukaemia, multiple myeloma and -lymphoma and also, for example, to inhibit the growth of those primary and recurrent solid tumors which are associated with VEGF, especially those tumors which are significantly dependent on VEGF for their growth and spread, including for example, certain tumors of the kidney, ovary, colon (including rectum), brain, thyroid, pancreas, bladder, breast, prostate, lung, vulva, skin and particularly NSCLC.
  • the therapeutic combination of the invention may be administered in the form of a combination product or a pharmaceutical composition. Therefore, according to one further aspect of the present invention there is provided a combination product comprising a compound of Formula (I) as defined above or a pharmaceutically acceptable salt or derivative thereof, and bevacizumab.
  • “Pharmaceutically acceptable” is to be understood as meaning that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • esters include carboxylic acid esters in which the non-carbonyl moiety of the ester grouping is selected from straight or branched chain C 1-6 alkyl, (methyl, n-propyl, n-butyl or t-butyl); or C 3-6 cyclic alkyl (e.g. cyclohexyl), or a chain of from one to three D- or L- aminoacids.
  • Amides include non-substituted and mono- and di-substituted derivatives.
  • Such derivatives may be prepared by techniques known per se in the art of pharmacy.
  • “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.
  • Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like; or salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g.
  • Acceptable organic bases include ethanolamine, diethanolamine, N-methylglucamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • a pharmaceutical composition which comprises a compound of Formula (I) as defined above or a pharmaceutically acceptable salt or derivative thereof, and bevacizumab, in association with a pharmaceutically acceptable excipient or carrier.
  • Kits may also be provided. According to a further aspect of the present invention there is provided a kit comprising a compound of Formula (I) as defined above or a pharmaceutically acceptable salt or derivative thereof, and bevacizumab.
  • kits comprising: a) a compound of Formula (I) as defined above or a pharmaceutically acceptable salt or derivative thereof in a first unit dosage form; b) bevacizumab in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or derivative thereof and bevacizumab in the preparation of a medicament for producing an anti-cancer effect in a warm-blooded animal such as a human.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or derivative thereof and bevacizumab in the preparation of a medicament for the treatment of cancer in a warm-blooded animal such as a human.
  • Figures 1-6 graphically represent the effect on tumor weight of various treatment regimes (single agent and combinations) in the HT-29 human colon tumor xenograft model using bevacizumab (Avastin®) and the preferred compound of Formula (I), PR-104; and Figures 7 and 8 graphically represent the effect on percent survival on various treatment regimes (single agent and combinations) in the HT-29 human colon tumor xenograft model using bevacizumab (Avastin®) and the preferred compound of Formula (I), PR-104.
  • This invention is primarily based upon the surprising finding of synergism between anticancer agents.
  • One agent is the anti-VEGF agent bevacizumab (Avastin) which is commercially available from Genentech, Inc under the trade name Avastin ®.
  • the second agent is a compound of Formula (I) as defined and described in PCT/NZ2004/000275 (published as WO 2005/042471), with the compound 2-[2-bromoethyl)-2,4-dinitro-6-[[[2- phosphonooxy)ethyl]amino]-carbonyl]anilino]ethyl methane sulfonate (known as PR-104) being representative.
  • the agents are administered in combination. It is to be understood that “combination” encompasses the simultaneous or sequential administration of the agents, with “sequential” meaning either agent can be administered before or after the other provided only that the delay in administering the second agent should not be such as to lose the benefit of the combination therapy.
  • the agents may also be in any appropriate form for administration. Commonly, the agents will be formulated for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion. However, other formulations are in no way excluded.
  • compositions described herein may be prepared in a conventional manner using conventional excipients and/or carriers, including liposomal or albumin carriers.
  • the component agents can be formulated in accordance widi manufacturer's instructions or as described below in the experimental section.
  • the dosages and schedules of administration of the component agents may be varied according to the particular disease state and overall condition of the patient. Administration may be at single-agent dosages (up to 100 mg/m 2 for Avastin®) employed in current clinical practice for either agent or for both. More commonly, however, the dose of one or both agents will be reduced below single-agent clinical practice, both to reflect the therapeutic benefit of the combination and to minimise the potential for toxicity. Any and all such dose combinations can be employed subject to the component agents being present in amounts which combine to produce an anti-cancer effect.
  • the final dose, and dose scheduling will be determined by the practitioner treating the particular patient using professional skill and knowledge.
  • a combination treatment of the present invention is most desirably a sole therapy but is not limited to that - it may in addition involve surgery or radiotherapy or the administration of a chemotherapeutic agent.
  • Chemotherapeutic agents for optional use with the combination treatment of the present invention may include, for example, the following categories of therapeutic agent:
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology for example carbop latin and cisplatin
  • cytostatic agents for example inhibitors of growth factor function such as growth factor antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab and the anti-erbBl antibody cetuximab), Class I receptor tyrosine kinase inhibitors (for example inhibitors of the epidermal growth factor family), Class II receptor tyrosine kinase inhibitors (for example inhibitors of the insulin growth factor family such as IGFl receptor inhibitors as described, for example, by Chakravarti et al., Cancer ⁇ search, 2002, 62: 200-207), serine/threonine kinase inhibitors, farnesyl transferase inhibitors and platelet- derived growth factor inhibitors;
  • growth factor function such as growth factor antibodies, growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab and
  • VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4- ylmethoxy)quinazoline (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro- 2-rnethylindol-5-yloxy)-6-rnethoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (WO 01/60814));
  • vascular damaging agents such as the compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, ⁇ ••; • • WO 02/04434 and WO 02/08213;
  • biological response modifiers for example interferon
  • a bisphosphonate such as tiludronic acid, ibandronic acid, incadronic acid, risedronic acid, zoledronic acid, clodronic acid, neridronic acid, pamidronic acid and alendronic acid.
  • Radiotherapy may be administered according to the known practices in clinical radiotherapy.
  • the dosages of ionising radiation will be those known for use in clinical radiotherapy.
  • the radiation therapy used will include for example the use of ⁇ -rays, X-rays, and/or the directed delivery of radiation from radioisotopes.
  • Other forms of DNA damaging factors are also included in the present invention such as microwaves and UV- irradiation.
  • X-rays may be dosed in daily doses of 1.8-2.0Gy, 5 days a week for 5-6 weeks. Normally a total fractionated dose will lie in the range 45-60Gy.
  • Single larger doses, for example 5-1 OGy may be administered as part of a course of radiotherapy.
  • Single doses may be administered intraoperatively.
  • Hyperfractionated radiotherapy may be used whereby small doses of X-rays are administered regularly over a period of time, for example 0.1Gy per hour over a number of days. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and on the uptake by cells.
  • PR- 104 was tested as a single agent and in combination with Avastin ® in the HT-29 human colon tumor xenograft model.
  • An initial combination dose toleration study was completed to assess the safety of coadministered PR-104 and Avastin ®.
  • Efficacy was determined by the in-study tumor growth inhibition and survival for single agent and combination treatment regimens.
  • PR-104 (Lot#309-01-001) was prepared using the methods described in WO 2005/042471 and stored as single use 400 mg vials at -20° C until used. Immediately prior to use, 2.0 ml of Water for Injection (WFI) (Baxter, Deerfield, IL) was added to reconstitute the preservative- free lyophilized cake. PR-104 was further diluted with PBS (Gibco, Carlsbad, CA) to working concentrations of 10, 15, 18, 60 and 70 mg/ml. Avastin® (Lot#M46866, Genentech) was diluted with 0.9% NaCI solution immediately prior to dosage administration to working concentrations of 0.625 and 1.0 mg/ml. Cell Culture
  • the HT-29 tumor cell line (Miknyoczki, SJ, et al. Chemopotentiation of Temozolomide, Irinotecan, and Cisplatin Activity by CEP-6800, a Poly(ADP-Ribose) Polymerase Inhibitor. MoI. Cancer Ther. 2:371-382, 2003.) was received from American Type Tissue Collection (ATCC, Manassas, VA). Cultures were maintained in RPMI 1640 (Mediatech, Herdon, VA) supplemented with 10% fetal bovine serum (Mediatech) and incubated in a 37°C, 5% CO 2 atmosphere.
  • ATCC Manassas, VA
  • mice Female ICR SCID mice, IcrTac:ICR-Pri ⁇ ⁇ s ⁇ d> were supplied by Taconic (Hudson,
  • mice were received at five weeks of age and were acclimated seven days prior to handling. Animals were housed in an ammonia-free environment in individually isolated cages. Mice were provided sterile food and water ad libitum. All procedures were carried out under appropriate animal care and use guidelines.
  • mice were randomized into nine treatment groups of five mice as described in Table 1. Prior to treatment initiation each mouse was weighed. Following initial treatment, each mouse was weighed daily and monitored twice daily during the dosing period. Each mouse was assessed individually for any gross signs of toxicity. After 32 days, mice were sacrificed with CO 2 .
  • mice were inoculated subcutaneously with 0.1 ml of a 50% RPMI / 50% Matrigel 1 M (BD Biosciences, San Jose, CA) mixture containing a suspension of tumor cells (1 x 10 7 cells/mouse).
  • a 50% RPMI / 50% Matrigel 1 M BD Biosciences, San Jose, CA
  • Tumor weight (mg) (a x b 2 /2) where 'b' is the smallest diameter and 'a' is the largest diameter (Britten CD, et al. Enhanced antitumor activity of 6- hydroxymethylacylfulvene in combination with irinotecan and 5-fluorouracil in the HT29 human colon tumor xenograft model. Cancer Res 59:1049-1053, 1999.).
  • the mice were pair-matched into the various treatment groups (Day 1). Body weights were recorded when the mice were pair-matched.
  • body weight measurements were taken twice weekly thereafter in conjunction with tumor measurements.
  • Avastin was administered intraperitoneally at 150 and 200 ⁇ g per dose.
  • PR-104 was administered intraperitoneally; initial doses were given on Days 2, 3, 4, and 6 as described below (Table 2).
  • individual tumors reached die end-point of 2000 mg, the mouse was sacrificed by asphyxiation with regulated CO 2 .
  • TGI Tumor Growth Inhibition
  • %TGI [1— — — ] X 100 ( Y Control(Final) — Y Contol(Dayl) ⁇
  • Survival fractions were calculated using the Kaplan-Meier method. Survival curves were compared using the log rank test and median survival was calculated and reported.
  • PR-104 in fourteen serial doses at 150 and 180 mg/kg resulted in maximum weight loss of 6.0% (Day 15) and 6.6% (Day 11), respectively.
  • PR-104 700 mg/kg administered Q7DX3 resulted in a maximum weight loss of 11.9% (Day 13). Mild lethargy was noted following PR-104 administration with one death occurring on Day 25. Remaining animals showed overall toleration of treatment. Combining the PR-104 700 m/kg dose with Avastin® 200 ⁇ g/dose (Q7DX3) demonstrated a maximum weight loss of 10.1% (Day 6). Mild lediargy was observed following PR-104 dose. One deadi occurred on Day 28; remaining animals maintained normal activity with no additional signs of toxicity. PR-104 500 and 600 mg/kg given in combination with Avastin® 200 ⁇ g/dose resulted in maximum weight losses of 6.6% and 7.2%, respectively. Mild lethargy was observed following doses of PR- 104 500 and 600 mg/kg. No further gross signs of toxicity were noted.
  • the HT-29 human colon tumor xenograft is a moderate growing tumor line; the vehicle control group reached a mean tumor weight of 967.3 mg by Day 15 and produced a median survival of 29 days to the 2000 mg endpoint (Figure 1, 2).
  • the antitumor activity of PR-104 150 mg/kg ( Figures 3, 5, and 7, Tables 4-7) as a single agent produced a mean tumor weight of 474.4 mg and a TGI of 62.6% at Day 15 and an overall median survival of 52 days (Min: 43 days, Max: 61 days). Mean tumor weight (Day 15) was reduced (P ⁇ 0.01) and there was an increase in survival compared to control (P ⁇ 0.0001). A maximum weight loss of approximately 9.6% was observed at Day 19 with minimal weight loss continuing with increasing tumor burden. Mice maintained normal activity and exhibited no gross signs of toxicity.
  • TGI 63.9% (Day 15) and a median survival of 50 days (Min: 47 days, Max: 120 days). The difference in the length of survival compared to vehicle control is statistically significant (P ⁇ 0.0001). The maximum weight loss of 9.4% was observed at Day 22.
  • a statistically significant improvement in survival (P ⁇ 0.01) and Day 15 mean tumor weight (P ⁇ 0.01) was achieved for this combination compared to the single agents when administered as monotherapy.
  • the animals tolerated the treatment with a maximum weight loss of 2.1% at Day 19. No overt signs of toxicity were observed and animals maintained normal activity.
  • a statistically significant improvement in survival (P ⁇ 0.01) and Day 15 mean tumor weight (P ⁇ 0.01) was observed for this combination compared to the single agents when administered as monotherapy.
  • mice exhibited no overt signs of toxicity and sustained normal activity.
  • PR-104 600 mg/kg (Day 4) and Avastin® 200 ⁇ g/dose ( Figures 4, 6, and 8, Tables 4-7) administered in combination produced tumor shrinkages in 4 of 12 animals with a mean of 43.7% and a TGI of 94.5% for the remaining animals.
  • Median survival was 76.5 days (Min: 64 days, Max: 120 days).
  • a statistically significant improvement in survival (P ⁇ 0.01) and Day 15 mean tumor weight (P ⁇ 0.01) was achieved for this combination compared to the single agents when administered as monotherapy.
  • the animals tolerated the treatment recording a maximum weight loss of 3.4%. No additional signs of toxicity were observed and animals maintained normal activity.
  • a dose toleration and efficacy determination of PR-104 delivered as a single agent and co-administered with the anti-angiogenic agent, Avastin® in the HT-29 human colon tumor xenograft model was completed.
  • Single agent PR-104 at 150 mg/kg (QDxl4) and ⁇ OO mg (Q7Dx3) demonstrated growth inhibition activity equivalent to single agent Avastin ® and superior to vehicle control (P ⁇ 0.01).
  • the PR-104 150 mg/kg / Avastin ® 125 ⁇ g/dose combination regimen significantly enhanced efficacy with increased growth inhibition and increase in survival fraction compared to single agent PR-104 and single agent Avastin ®.
  • PR-104 600 mg/kg was co-administered with Avastin® beginning on Days 2, 3, 4, or 6. All four combination regimens resulted in a significant decrease in mean tumor weight (P ⁇ 0.01) and increase in survival fractions (P ⁇ 0.01) compared to their single agent counterparts.
  • PR- 104 600 mg/kg (Day 2) produced a median survival of 82 days compared to 71.5, 76.5 and 75 days demonstrated by PR-104 600 mg/kg (Day 3), PR-104 600 mg/kg pay 4), and PR-104 600 mg/kg Day 6), respectively.

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Abstract

Cette invention concerne un procédé pour le traitement du cancer chez un animal à sang chaud tel qu'un être humain. Ledit procédé consiste à administrer audit animal, avant, après ou simultanément avec une quantité efficace de bevacizumba (Avastin®), une quantité efficace d'un composé représenté par la formule (I), dans laquelle : X représente à n'importe quelle position de cycle disponible -CONH-, -SO2NH-, -O-, -CH2, -NHCO- ou -NHSO2-; R représente un alkylène inférieur en C1-6 facultativement substitué par un ou plusieurs groupes comprenant hydroxyle, amino et N-oxydes de ceux-ci ou dialkylamino et N-oxydes de ceux-ci; Y représente à n'importe quelle position de cycle disponible, -N-aziridinyle -N(CH2CH2W)2 ou -N(CH2CHMeW)2, où chaque W est indépendamment choisi parmi un halogène ou -OSO2Me; Z représente à n'importe quelle position du cycle disponible -NO2, -halogène, -CN, -CF3 ou -SO2Me; ou un sel ou un dérivé dudit composé pharmaceutiquement acceptable.
PCT/NZ2007/000268 2006-09-11 2007-09-11 Traitement contre le cancer WO2008033041A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010044686A1 (fr) * 2008-10-17 2010-04-22 Auckland Uniservices Limited Akr1c3 utilisé comme biomarqueur, procédés de sélection et de traitement de patients sur la base d'un profil d'akr1c3 et composés utiles à cet effet
EP2593139A2 (fr) * 2010-07-12 2013-05-22 Threshold Pharmaceuticals, Inc. Administration de promédicaments activés par hypoxie et d'agents anti-angiogéniques pour le traitement du cancer
WO2014062856A1 (fr) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxie et hyaluronane et leurs marqueurs pour le diagnostic et la surveillance de maladies et de pathologies, et méthodes associées
US9226932B2 (en) 2005-06-29 2016-01-05 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US9254299B2 (en) 2011-12-22 2016-02-09 Threshold Pharmaceuticals, Inc. Administration of hypoxia activated prodrugs in combination with Chk1 inhibitors for treating cancer
US10071109B2 (en) 2013-11-06 2018-09-11 Molecular Templates, Inc. Predictive biomarker for hypoxia-activated prodrug therapy

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042471A1 (fr) * 2003-10-31 2005-05-12 Auckland Uniservices Limited Nouvelle moutarde nitrophenyle et nouveaux alcools nitrophenylaziridine, phosphates correspondants et utilisation de ces derniers en tant qu'agents cytotoxiques cibles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042471A1 (fr) * 2003-10-31 2005-05-12 Auckland Uniservices Limited Nouvelle moutarde nitrophenyle et nouveaux alcools nitrophenylaziridine, phosphates correspondants et utilisation de ces derniers en tant qu'agents cytotoxiques cibles

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9226932B2 (en) 2005-06-29 2016-01-05 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
WO2010044686A1 (fr) * 2008-10-17 2010-04-22 Auckland Uniservices Limited Akr1c3 utilisé comme biomarqueur, procédés de sélection et de traitement de patients sur la base d'un profil d'akr1c3 et composés utiles à cet effet
EP2593139A2 (fr) * 2010-07-12 2013-05-22 Threshold Pharmaceuticals, Inc. Administration de promédicaments activés par hypoxie et d'agents anti-angiogéniques pour le traitement du cancer
JP2013531038A (ja) * 2010-07-12 2013-08-01 スレッショルド ファーマシューティカルズ、インク． 癌の治療のための低酸素活性化プロドラッグおよび血管新生阻害剤の投与方法
EP2593139A4 (fr) * 2010-07-12 2013-11-27 Threshold Pharmaceuticals Inc Administration de promédicaments activés par hypoxie et d'agents anti-angiogéniques pour le traitement du cancer
EP3311835A1 (fr) * 2010-07-12 2018-04-25 Threshold Pharmaceuticals Inc. Administration de promédicaments activés par hypoxie et d'agents anti-angiogéniques pour le traitement du cancer
US9254299B2 (en) 2011-12-22 2016-02-09 Threshold Pharmaceuticals, Inc. Administration of hypoxia activated prodrugs in combination with Chk1 inhibitors for treating cancer
WO2014062856A1 (fr) 2012-10-16 2014-04-24 Halozyme, Inc. Hypoxie et hyaluronane et leurs marqueurs pour le diagnostic et la surveillance de maladies et de pathologies, et méthodes associées
US9278124B2 (en) 2012-10-16 2016-03-08 Halozyme, Inc. Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods
US10071109B2 (en) 2013-11-06 2018-09-11 Molecular Templates, Inc. Predictive biomarker for hypoxia-activated prodrug therapy

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