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WO2008033039A1 - Traitement du cancer - Google Patents

Traitement du cancer Download PDF

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Publication number
WO2008033039A1
WO2008033039A1 PCT/NZ2007/000266 NZ2007000266W WO2008033039A1 WO 2008033039 A1 WO2008033039 A1 WO 2008033039A1 NZ 2007000266 W NZ2007000266 W NZ 2007000266W WO 2008033039 A1 WO2008033039 A1 WO 2008033039A1
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WIPO (PCT)
Prior art keywords
compound
formula
gemcitabine
pharmaceutically acceptable
derivative
Prior art date
Application number
PCT/NZ2007/000266
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English (en)
Inventor
Adam Vorn Patterson
William Robert Wilson
Original Assignee
Adam Vorn Patterson
William Robert Wilson
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Adam Vorn Patterson, William Robert Wilson filed Critical Adam Vorn Patterson
Publication of WO2008033039A1 publication Critical patent/WO2008033039A1/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
    • A61K31/095—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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • 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 for 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 chemotherapeutic agent Gemcitabine (Gemzar®) 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 (T)
  • 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 W) 2 or —
  • 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 Gemcitabine.
  • 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 die 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 Gemcitabine.
  • the compound of Formula (T) or salt or derivative thereof and Gemcitabine 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 Gemcitabine, 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 die effect is therapeutically superior to the effect achievable with a compound of Formula (I) or Gemcitabine 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 Gemcitabine alone.
  • die 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 Gemcitabine 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 Gemcitabine.
  • “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,_ 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-mediylglucamine, 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 Gemcitabine, 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 Gemcitabine.
  • 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) Gemcitabine in a second unit dosage form; and c) ' container means for containing said first and second dosage forms.
  • Figures 1-5 graphically represent the effect of various treatment regimes (single agent and combinations) in the Panc-1 human pancreatic tumor xenograft model using Gemcitabine and the preferred compound of Formula (I), PR-104, and
  • Figure 6 is a Kaplan-Meier plot of A2780 xenograft bearing CD-I nude mice treated with
  • PR-104 gemcitabine or a combination of PR-104 and Gemcitabine.
  • This invention is primarily based upon the surprising finding of synergism between anticancer agents.
  • One agent is the chemo therapeutic agent Gemcitabine (Gemzar®; chemical name 4-amino-l -[3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-l H- pyrimidin-2-one) which is commercially available from Eli Lilly.
  • 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 die second agent should not be such as to lose the benefit of die combination dierapy.
  • the agents may also be in any appropriate form for administration.
  • die agents will be formulated for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • odier 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 die 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 Gemcitabine) employed in current clinical practice for eidier agent or for both. More commonly, however, die dose of one or botii agents will be reduced below single-agent clinical practice, bodi to reflect the dierapeutic benefit of die combination and to minimise die 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 die 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 chemodierapeutic 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 carboplatin 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 Research, 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 the anti-erbBl antibody cetuximab), Class I receptor tyrosine kinase inhibitors (for example inhibitors of the epiderma
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab 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-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-l-ylpropoxy)quinazoune (AZD2171; within WO 00/47212), vatalanib (PTK787; WO 98/35985) and SUl 1248 (WO 01/60814));
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab and VEGF receptor
  • 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.
  • 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 O.lGy 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 (Lot#MPD-A- 124(1)) was received from Proacta via Albany Molecular Research, Inc. and stored at -2O 0 C until use. PR- 104 was solubilized in a PBS solution containing one equivalent sodium bicarbonate at appropriate concentrations to achieve proper doses. PR-104 was prepared fresh and sterile filtered prior to injections. Gemcitabine (Lot#8SE30M, Eli Lilly) was received from Eli Lilly, reconstituted according to manufacturer's guidelines, and diluted in saline to working concentrations. Sodium bicarbonate (Lot#045K0187) was received from Sigma (St Louis, MO), and PBS (Lot# 1289515) was obtained from Gibco (Carlsbad, CA).
  • Panc-1 tumor cell line was received from American Type Tissue Collection (ATCC, Manassas, Va). Cultures were maintained in DMEM supplemented with 10% fetal bovine serum, and 5% CO 2 atmosphere. The cultures were expanded in T225 tissue culture flasks until the appropriate number of cells could be harvested for inoculation.
  • ICR SCID mice Ici ⁇ ac:ICR-Prkde sad' were supplied by Taconic (Hudson, NY). Mice were received at five weeks of age and were acclimated seven days prior to handling. Animals are housed in an ammonia-free environment in individually isolated cages. All procedures were carried out under the institutional guidelines of the TGen Drug Development Services Institutional Animal Care and Use Committee.
  • mice Five week old female ICR SCID mice were received from Taconic (Hudson, NY). The mice were placed in individually isolated cages and allowed to acclimate for seven days. Following acclimation, mice were randomized into eight groups of five mice each. On Day 0, mice were weighed and weights recorded. On Day 1, mice were administered PR-104 or Gemcitabine via intraperitoneal (IP) route on Days 1, 5 and 9 (Table 1). Mice were observed daily and weighed twice weekly following initial injections.
  • IP intraperitoneal
  • mice Five week old female ICR SCID mice were received From Taconic. The mice were placed in individually isolated cages and allowed to acclimate for seven days. Following acclimation, mice were randomized to five groups of five mice each. On Day 1, mice were weighed prior to dosing. Mice received PR-104 and Gemcitabine intraperitoneally (described in Table 2). The Gemcitabine dose was administered within fifteen minutes of the PR-104 dose. Mice were weighed twice weekly and observed daily for overt signs of toxicity.
  • mice Five to six week old female ICR SCID mice were received from Taconic. The mice were allowed to acclimate for seven days prior to tumor cell inoculation. Each mouse was inoculated subcutaneously with 0.1ml of a 50% RPMI/ 50% MatrigelTM mixture containing a suspension of tumor cells (10 x 10 6 ) cells/mouse).
  • Tumor weight (a x b 2 /2) where 'b' is the smallest diameter and 'a' is the largest diameter.
  • PR- 104 was prepared as described at concentrations required to deliver an IP dose of 400, 500, 600, and 700 mg/kg. PR-104 was well tolerated at all dose levels. PR- 104 700 mg/kg exhibited maximum body weight loss of 5.9% recorded on Day 12. Positive weight gain was noted by Day 16. No clinical signs of overt toxicity were observed at any of the dose levels. Gemcitabine was tested intraperitoneally at 80, 100, 120, and 160 mg/kg. All doses were tolerated with no weight loss recorded at any dose levels. No clinical signs of toxicity were observed.
  • PR-104 600 IP q4dx3 1 0 06 -1 0 63 0 dPR-104 ⁇ "' 700 ,IP q4dx3 -20 Us -59 1 2 0 '
  • PR-104 Doses of 400 ' and 600 mg/kg of PR-104 were chosen to be administered in combination with Gemcitabine at doses of 100 and 160 mg/kg.
  • the PR-104 400 mg/kg and Gemcitabine 100 mg/kg combination was well-tolerated with a maximum weight loss of 4.9% recorded at Day 8. Weight was regained by Day 19 with animals showing no obvious signs of toxicity.
  • PR-104 given at 400 mg/kg in conjunction with a Gemcitabine dose of 160 mg/kg produced a sustained weight loss at or above 7.0% with maintained weight gain of 3.8% by Day 19. Though moderate weight loss was observed, animals preserved normal activity with no other clinical signs of toxicity.
  • the combination regimen of PR-104 600 mg/kg with Gemcitabine 100 mg/kg displayed weight loss of 9.3% four days following initial injections and mice continued to lose substantial weight over the dosing period with a maximum weight loss of 17.2% noted on Day 8.
  • One mouse showed additional weight loss as compared to other mice in the cohort and was found dead on Day 10. Animals still maintained normal motility and activity. Evidence of emaciation was noted but not confirmed by gross necropsy. Weight gain was sustained by Day 19.
  • the PR-104 600 mg/kg / Gemcitabine 160 mg/kg combination displayed the most weight loss as compared to the other cohorts with a 19.0% weight loss at Day 12. All mice survived treatment with no effects on normal activity; however emaciation was evident but not confirmed by gross necropsy. Other overt signs of toxicity were not observed and a positive weight gain trend was noted.
  • Panc-l human pancreatic tumor xenograft is a moderate growing tumor; the vehicle control group produced a median survival of 30 days to the 1500mg end-point.
  • the tumor burden added no observable overall effect to the animals' health.
  • the antitumor activity of PR-104 300 mg/kg as a single agent produced a tumor growth inhibition (TGI) of 51.7% at Day 27 and an overall median survival of 41 days (Min: 34 days, Max: 48 days). The length of survival is significantly different than vehicle control (P ⁇ 0.001). A maximum weight loss of approximately 1.0% was observed at Day 5 and was promptly recovered in subsequent days. No signs of clinical toxicity were observed.
  • TGI tumor growth inhibition
  • Single agent PR-104 500 mg/kg generated a TGI of 82.6% (Day 27) and a median survival of 51 days (Min: 44 days, Max: 65 days). The difference in the length of survival as compared to vehicle control is statistically significant (P ⁇ 0.0001). The maximum weight loss of 3.0% was observed at Day 12 with recovering recorded by Day 15. All animals maintained normal activity and no indications of toxicity were recorded.
  • the combination regimen of PR-104 300 mg/kg and Gemcitabine 100 mg/kg demonstrated mean tumor shrinkage of 57.5% occurring in 8 of 9 animals.
  • the treatment regimen was generally well-tolerated with a maximum weight loss of approximately 8.4% which was rapidly regained by Day 15. One death did occur; treatment related death was not confirmed by necropsy. The remaining mice exhibited no additional signs of toxicity and maintained normal activity.
  • PR-104 600 mg/kg and Gemcitabine combinations exhibited a more robust interaction.
  • These combination dose levels of PR-104 and Gemcitabine can be defined as immediately above the maximum doses that can be administered utilizing the q4dx3 schedule.
  • TGI in-study tumor growth inhibition
  • PR-104 displayed impressive activity as a monotherapy agent and more so in a combination capacity. Both combination regimens tested can be considered generally nontoxic while demonstrating synergistic tumor response.
  • Treatment size Mean diameter 7.0-9.9mm (average: 8.0mm); volume 118-440mm 3 ; average 236+72mm 3 (mean ⁇ S.D.)
  • End-point After treatment, tumor size and body weights were measured regularly and mice were culled either when the average diameter of the tumor reached 15 mm (end- point), the tumor ulcerated or when the body weight change reached -15%. Experiment was ended and all remaining mice culled 120 days after treatment.
  • End-points will be expressed as TTE 50 , Median RTV 4 and plotted in Kaplan- Meier Plots and analysed by Log Rank P statistical test. Weight loss nadir will be compared between schedules.
  • Gemzar 237 213 q4d x3 9 0 -56+1 5 0 32 33 0 0000217

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Abstract

L'invention concerne une polythérapie pour le traitement du cancer. L'invention concerne en particulier une méthode pour le traitement du cancer chez un animal à sang chaud, par exemple l'être humain, qui consiste à administrer à celui-ci une dose efficace d'un composé de formule (I), dans laquelle : X représente dans n'importe quelle position disponible de l'anneau -CONH-, -SO2NH-, -O-, -CH2-, -NHCO- ou -NHSO2-; R représente un alkylène C1-6 inférieur substitué par un ou plusieurs groupes comprenant hydroxyle, amino et N-oxydes de ceux-ci ou dialkylamino et N-oxydes de celui-ci; Y représente dans n'importe quelle position disponible de l'anneau -N-aziridinyle, -N(CH2CH2W)2 ou -N(CH2CHMeW)2, dans lesquels W est indépendamment sélectionné entre halogène ou -OSO2Me; Z représente dans n'importe quelle position disponible de l'anneau -NO2, -halogène, -CN, -CF3 ou -SO2Me; ou un sel ou un dérivé acceptable sur le plan pharmaceutique de celui-ci, avant, après ou simultanément à l'administration d'une dose efficace de Gemcitabine.
PCT/NZ2007/000266 2006-09-11 2007-09-11 Traitement du cancer WO2008033039A1 (fr)

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NZ549799 2006-09-11

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Citations (2)

* 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
WO2007041546A2 (fr) * 2005-10-03 2007-04-12 Genetix Pharmaceuticals, Inc. Methode de depletion selective de cellules hypoxiques

Patent Citations (2)

* 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
WO2007041546A2 (fr) * 2005-10-03 2007-04-12 Genetix Pharmaceuticals, Inc. Methode de depletion selective de cellules hypoxiques

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