WO2003033012A1 - Composes a base de kahalalide utilisables en therapie anticancereuse - Google Patents

Composes a base de kahalalide utilisables en therapie anticancereuse Download PDF

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Publication number
WO2003033012A1
WO2003033012A1 PCT/GB2002/004735 GB0204735W WO03033012A1 WO 2003033012 A1 WO2003033012 A1 WO 2003033012A1 GB 0204735 W GB0204735 W GB 0204735W WO 03033012 A1 WO03033012 A1 WO 03033012A1
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Prior art keywords
dose
kahalalide
mcg
day
compound
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PCT/GB2002/004735
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English (en)
Inventor
José Jimeno
Lázaro Luis LOPEZ
Ana Ruiz Casado
Miguel Angel Izquierdo
Luis Paz-Ares
Jose Manuel Trigo
Jan Schellens
Original Assignee
Pharma Mar, S.A.
Ruffles, Graham, Keith
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Priority claimed from PCT/GB2001/004821 external-priority patent/WO2002036145A2/fr
Priority claimed from GB0222409A external-priority patent/GB0222409D0/en
Application filed by Pharma Mar, S.A., Ruffles, Graham, Keith filed Critical Pharma Mar, S.A.
Priority to EP02801430A priority Critical patent/EP1435990A1/fr
Priority to CA002462639A priority patent/CA2462639A1/fr
Priority to MXPA04003672A priority patent/MXPA04003672A/es
Priority to US10/492,670 priority patent/US20050054555A1/en
Priority to AU2002334203A priority patent/AU2002334203C1/en
Publication of WO2003033012A1 publication Critical patent/WO2003033012A1/fr
Priority to EP03779140A priority patent/EP1572726B1/fr
Priority to MXPA05004133A priority patent/MXPA05004133A/es
Priority to AU2003285911A priority patent/AU2003285911B2/en
Priority to DE60335292T priority patent/DE60335292D1/de
Priority to KR1020057006480A priority patent/KR101149095B1/ko
Priority to UAA200504629A priority patent/UA80992C2/uk
Priority to JP2005501483A priority patent/JP4430009B2/ja
Priority to SI200331948T priority patent/SI1572726T1/sl
Priority to PCT/US2003/033207 priority patent/WO2004035613A2/fr
Priority to CN200380101647A priority patent/CN100591691C/zh
Priority to NZ539093A priority patent/NZ539093A/en
Priority to BR0315489-0A priority patent/BR0315489A/pt
Priority to RU2005115102/04A priority patent/RU2356908C2/ru
Priority to DK03779140.7T priority patent/DK1572726T3/da
Priority to PL377056A priority patent/PL209129B1/pl
Priority to CNA2007101122538A priority patent/CN101077885A/zh
Priority to AT03779140T priority patent/ATE490975T1/de
Priority to PT03779140T priority patent/PT1572726E/pt
Priority to KR1020117020121A priority patent/KR20110114690A/ko
Priority to ES03779140T priority patent/ES2357644T3/es
Priority to CA2501089A priority patent/CA2501089C/fr
Priority to IL167724A priority patent/IL167724A/en
Priority to ZA200502926A priority patent/ZA200502926B/xx
Priority to NO20052379A priority patent/NO333448B1/no
Priority to HK06102999.1A priority patent/HK1082261A1/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to the use of kahalalide compounds in the treatment of cancer.
  • the kahalalide compounds are peptides isolated from a Hawaiian herbivorous marine species of mollusc, Elysia rufescens. Kahalalides A-F are described in EP 610 078 and Hamman et al., J. Am. Chem. Soc, 1993, 115, 5825-5826.
  • Kahalalide A-G are described in Hamann, M. et al., J. Org. Chem, 1996, 61, 6594-6600: "Kahalalides: bioactive peptides from a marine mollusk Elysia rufescens and its algal diet Bryopsis sp.”
  • Kahalalide H and J are described in Scheuer P.J. et al., J. Nat. Prod. 1997, 60, 562-567: "Two acyclic kahalalides from the sacoglossan mollusk Elysia rufescens" .
  • Kahalalide 0 is described in Scheuer P.J. et al., J. Nat. Prod. 2000, 63(1) 152-4 : A new depsipeptide from the sacoglossan mollusk Elysia ornata and the green alga Bryopsis species".
  • Kan, Y. et al., J. Nat. Prod. 1999 62(8) 1169-72 "Kahalalide K: A new cyclic depsipeptide from the hawaiian green alga bryopsis species".
  • Kahalalide F is the most promising because of its antitumoural activity.
  • Kahalalide F now known to have the structure:
  • Kahalalide F is a tridecapeptide with a ring shape side and a lateral side, containing a fatty acid group connected to the latter. Its activity against in vitro cell cultures of human lung carcinoma A-549 and human colon carcinoma HT-29 were reported in EP 610 078.
  • WO 02 36145 describes pharmaceutical compositions containing kahalalide F and new uses of this compound in cancer therapy.
  • the antitumoural compound Kahalalide F acts on cell lysosomes.
  • kahalalide F exhibited low cardiac and skeletal muscle toxicities and also low myeolotoxicity.
  • the main toxicities found were tubular nephrotoxicity and CNS (central nervous system) neurotoxicity, and hints of hepatotoxicity. Therefore the expected toxicities were renal and neurologic with a marked threshold.
  • MTD central nervous system
  • the present invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a therapeutically effective amount of kahalalide compound, or a pharmaceutical composition thereof. More preferably the kahalalide compound is kahalalide F.
  • the dose limiting toxicity in the treatment with a kahalalide compound is liver toxicity with grade 4 transaminase elevation. This toxicity is asymptomatic, manageable and reversible if the proper dosages and schedules are selected. Transaminases peak 4-5 hours after kahalalide infusion.
  • the present invention provides a pharmaceutical composition containing a recommended dose of a kahalalide compound and a pharmaceutically acceptable carrier.
  • the present invention provides a procedure for establishing the amount of a kahalalide compound to be recommended for dosing to patients, which procedure comprises administering the compound in a series of escalating doses to a cohort of humans, monitoring for transaminase elevation as the dose-limiting toxicity, determining a maximum tolerated dose, and establishing a recommended dose.
  • the maximum tolerated dose is suitably set as one in which a proportion of the cohort encounter dose-limiting toxicity.
  • the proportion is typically 2 out of 6.
  • the recommended dose can then be established in accordance with familiar principles. Usually the recommended dose is the dose below the maximum tolerated dose, but sometimes rules are applied regarding the proportion of the cohort which encounter dose-limiting toxicity at the proposed recommended dose.
  • the procedure for clinical trials enables a method of preparing a pharmaceutical composition containing a kahalalide compound, the method comprising carrying out the procedure to establish the recommended dose, and formulating the kahalalide compound with a pharmaceutically acceptable carrier to give a dosage form which contains the recommended dose of the kahalalide compound.
  • the invention further provides for the use of kahalalide compounds in the preparation of a composition for the procedures and methods of this invention.
  • the present invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a kahalalide compound at a dose below 1200 mcg/m2/day, preferably below 930 mcg/m2/day and more preferably below 800 mcg/m2/day.
  • the dose is at least 320 mcg/m2/day.
  • the dose is in the range of 400-900 mcg/m2/day, preferably 500-800 mcg/m2/day, more preferably 600-750 mcg/m2/day.
  • doses of about 650-700 mcg/m2/day are especially preferred.
  • the selected schedule is important to allow for a reversion of the liver toxicity. If a daily 1 hour intravenous infusion is used during 5 days, the dose limiting toxicity is reached at 930 mcg/m2/day. Thereafter a rest period of 2 weeks is needed to reverse the toxicity effects.
  • the invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a kahalalide compound daily during 5 days at a dose below 930 mcg/m2/day, followed by a resting period of from 1 to 4 weeks in which the kahalalide compound is not administered.
  • the dose is preferably 650-750 mcg/m2/day, more preferably about 700 mcg/m2/day.
  • the infusion time is preferably between 1 and 24 hours, more preferably between 1 and 3 hours. Especially preferred is an infusion time of about 1 hour.
  • the resting period is preferably 2-3 weeks, more preferably about 2 weeks.
  • the present invention provides a method for treating a human patient afflicted with cancer, comprising administering to said patient a kahalalide compound once weekly at a dose below 800 mcg/m2/day.
  • the dose is preferably 600-700 mcg/m2/day, more preferable 650 mcg/m2/day.
  • the infusion time is preferably between 1 and 24 hours, more preferably between 1 and 3 hours. Especially preferred is an infusion time of about 1 hour.
  • kahalalide compounds and in particular kahalalide F is effective in the treatment of advanced solid tumours (AST), including metastatic tumours.
  • Tumours that are preferably treated are hormone independent prostate cancer, hepatocarcinoma, epithelial carcinomas, non small cell lung cancer and mesothelioma.
  • a medical kit for administering a kahalalide compound comprising printed instructions for administering the kahalalide compound according to the dosing schedules set forth above, and a supply of kahalalide compound in dosage units for at least one cycle, wherein each dosage unit contains the appropriate amount of kahalalide compound for the treatments as defined above and a pharmaceutically acceptable carrier.
  • kahalalide compound includes natural compounds, their mixtures and new compounds as defined in WO 01 58934 which is incorporated herein in its entirety by reference. Especially preferred is the compound kahalalide F.
  • the present invention employs a natural kahalalide such as kahalalide F or a mimic of a natural kahalalide.
  • the mimic compounds may differ in one or more amino acids, and one or more components of the acyl side chain. Preferably they differ in one or more components of the acyl side chain.
  • Examples of the kahalalide compound for use in this invention particularly include the compound identified as kahalalide F with a 5- methylhexyl sidechain, compounds differing only in the sidechain such as the 4-methylhexyl analogue, and mixtures thereof.
  • the mimics have at least one of the following features to differentiate from a parent naturally occurring kahalalide:
  • 1 to 10 especially 1 to 6, more especially 1 to 3, most especially 1 or 2, additional methylene groups in the side chain acyl group of the parent compound; 1 to 10, especially 1 to 6, more especially 1 to 3, most especially 1 or
  • amino acid addition or omission can be in the cyclic ring or in the side chain.
  • mimic comopunds are compounds related to kahalalide F, and having the formula:
  • Aaai, Aaa 2 , Aaa 3 , Aaa , Aaa ⁇ , and Aaa are independently ⁇ -amino acids of L or D configuration, if applies;
  • Ri, R2, R3, R4, R5, R6, R7 are each independently H or an organic group selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, and their substituted derivatives with an hydroxy group, a mercapto group, an amino group, a guanidino group, a halogen group;
  • Xl is independently O, S, or N;
  • R2 is, if applies, independently H or an organic group selected from the group consisting of an alkyl group and an aralkyl group;
  • Aaa5 is independently an amino acid of L or D configuration, if applies; wherein X2 is independently an organic group selected from the group consisting of an alkenyl, an alkyl group, an aryl group, an aralkyl group, and their substituted derivatives with an hydroxy group, a mercapto independently H or an organic group selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, and their substituted derivatives with an hydroxy group, a mercapto group, an amino group, a guanidino group, a halogen group; wherein R ⁇ is independently of the following formulae III, IV, or V:
  • R9, RlO, and Ru are each independently H or an organic group selected from the group consisting of an alkyl group, an aryl group, an aralkyl group, and their substituted derivatives with an hydroxy group, a mercapto group, an amino group, a guanidino group, a carboxyl group, a carboxamido group, a halogen group; R9 and RlO can form part of the same cycle; R9 can confer S or R configuration, if applies, to the carbon attached to; and n is 0 to 6.
  • the definitions of the amino acids can also be varied to allow for proline and analogous amino acids including hydroxyproline.
  • the formulae (III), (IV) and (V) can be intermixed to give a side chain made up of repeat units in more than one of these formulae.
  • one or more of the ring amino acids Aaa-6 and Aaa- 5 of the hexaamino acid cycle is omitted or an amino acid Aaa-7 is added between Aaa-6 and Aaa- 1, in order to arrive at rings having four, five or seven ring amino acids.
  • Six ring amino acids is preferred.
  • the treaments of the invention are useful in preventing the risk of developing tumours, in promoting tumour regression, in stopping tumour growth and/or in preventing metastasis.
  • Administration of the compounds or compositions of the present invention is by intravenous infusion. Infusion times of up to 72 hours can be used, more preferably 1 to 24 hours, with either about 1 or about 3 hours most preferred. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. However, infusion may be around 24 hours or even longer if required.
  • the correct dosage of the compound will vary according to the particular formulation, the mode of application, and the particular situs, host and tumour being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
  • the Recommended Dose is the highest dose which can be safely administered to a patient producing tolerable, manageable and reversible toxicity according to the Common Toxicity Criteria (CTC) established for example by the National Cancer Institute, (USA) typically with no more than 2 out of 6 patients presenting any dose limiting toxicities (DLT).
  • CTC Common Toxicity Criteria
  • DLT dose limiting toxicities
  • Guidelines for cancer therapy frequently call for administration of chemotherapeutic agents at the highest safe dose at which toxicity is manageable in order to achieve maximum efficacy (DeVita, V. T. Jr., Hellman, S. and Rosenberg, S. A., Cancer: Principles and Practice of Oncology, 3rd ed., 1989, Lipincott, Philadelphia).
  • the recommended doses are as defined above and set forth in the examples.
  • the administration is performed in cycles, in the preferred application method, an intravenous infusion of kahalalide compounds given to the patients the first week of each cycle, the patients are allowed to recover for the remainder of the cycle.
  • the preferred duration of each cycle is of either 1 , 3 or 4 weeks; multiple cycles can be given as needed.
  • Dose delays and/or dose reductions and schedule adjustments are performed as needed depending on individual patient tolerance of treatments, in particular dose reductions are recommended for patients with higher than normal serum levels of liver transaminases or alkaline phosphatase.
  • compositions of kahalalide compound that can be used include liquid (solutions, suspensions or emulsions) with suitable composition for intravenous administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. Further guidance concerning the pharmaceutical compositions can be found in WO 02 36145 which is incorporated herein by reference in its entirety.
  • a combination of a non-ionic surfactant and an organic acid is suited for use with a bulking agent to give a lyophilised form of a kahalalide compound suited for reconstitution.
  • Reconstitution is preferably effected with a mix of emulsifying solubiliser, alkanol and water.
  • the lyophilised composition preferably comprises mainly the bulking agent, such as at least 90 % or at least 95 % bulking agent.
  • bulking agents are well known and include sucrose and mannitol. Other bulking agents can be employed.
  • the non-ionic surfactant in the lyophilised composition is preferably a sorbitan ester, more preferably a polyethylene sorbitan ester, such as a polyoxyethylene sorbitan alkanoate, especially a polyoxyethylene sorbitan mono-oleate, for example polysorbate 80.
  • the non-ionic surfactant typically comprises a few % of the composition, such as 0 to 5 % of the composition, for instance 2 to 3 or 4 % of the composition.
  • the organic acid in the lyophilised composition is typically an aliphatic acid, preferably a hydroxycarboxylic acid and more preferably a hydroxypolycarboxylic acid, notably citric acid.
  • the organic acid typically comprises a few % of the composition, such as 0 to 5 % of the composition, for instance 2 to 3 or 4 % of the composition.
  • the amount of kahalalide compound in the lyophilised composition is typically less than 1 %, or often less than 0.1 %, of the mix.
  • a suitable amount is in the range 50 to 200 ⁇ g, say about 100 ⁇ g, per 100 mg of composition.
  • the emulsifying solubiliser for the reconstituting agent suitably comprises an polyethylene glycol ester, notably an ester of a fatty acid, more preferably a PEG oleate such as PEG-35 oleate.
  • the emulsifying solubiliser is suitably 0 to 10 % of the reconstituting agent, typically about 3 to 7 %, say about 5 %.
  • the alkanol is usually ethanol, and is suitably 0 to 10 % of the reconstituting agent, typically about 3 to 7 %, say about 5 %.
  • the remainder of the reconstituting agent is water, and gives a reconstituted solution suited for intravenous injection.
  • the lyophilised composition comprises 150 ⁇ g kahalalide F; 150 mg sucrose; 3 mg anhydrous citiric acid; and 3 mg of polysorbate 80.
  • the preferred reconstituting agent then comprises 2 to 7 %, say about 5 %, emulsifying solubiliser; 2 to 7 %, say about 5 %, alcohol; and remainder water.
  • kits comprising separate containers containing the lyophilised composition and the reconstituting agent. Methods of reconstitution are also provided.
  • the present invention further provides a method of treating any mammal, notably a human, affected by cancer which comprises administering to the affected individual a therapeutically effective amount of a pharmaceutical composition thereof prepared by reconstitution of a lyophilised composition of this invention.
  • the present invention can be employed particularly for treatment of patients with refractory cancers that do not respond favourably to other treatments.
  • the compositions of this invention can be employed after other chemotherapy has been tried and not worked.
  • the reconstituted solution is prepared for infusion and is administered in a 3-hour infusion on concentrations of up to around 20 or 25 ⁇ g/ml, typically up to 15 ⁇ g/ml.
  • Suitable infusion equipment preferably includes a glass container, rather than one of polyethylene.
  • Tubing is preferably of silicone.
  • infusion times of up to 24 hours are used, and as explained we prefer an infusion time of about 1 hour.
  • the infusion time is 2- 12 hours, such as 2-6 hours. Short infusion times which allow treatment to be carried out without an overnight stay in hospital are especially desirable. However, infusion may be 12 to 24 hours or even longer if required. Infusion may be carried out at suitable intervals of say 2 to 4 weeks.
  • the kahalalide compound such as kahalalide F is administered for say about 1 hour for 5 consecuvitve days every 3 weeks.
  • Other protocols can be devised as variations.
  • the compounds and compositions of this invention may be used with other drugs to provide a combination therapy.
  • the other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or a different time.
  • the identity of the other drug is not particularly limited.
  • the rate of subject entry and escalation to the next dose level will depend upon assessment of the safety profile of patients entered at each dose level. Toxicity will be evaluated and graded according to the Common Toxicity Criteria, version 2.0.
  • a single patient will be treated per dose level with 100% dose escalation in the absence of any toxicity G2 (excluding alopecia) during their first course of treatment.
  • the dose level is expanded to three patients with only 50% incremental increase in dosage in advancing to the next dose level.
  • the dose level should be expanded up to six patients. This second cohort of 3 patients will be included consecutively. If the first or second patient develops dose limiting toxicities no further patients will be treated at this dose level, it will be defined as MTD and the accrual will begin at a lower dose level. If only one DLT occurs at this dose level another 3 patients will be included at the next dose level with an increase of 25% only.
  • the maximum tolerated dose is defined as the dose at which at least 2 out of 3 or more than 3 patients experience DLT. However, it is possible that additional patients may experience DLT due to the timing of patient enrollment into that dose level. Once an MTD level is established, subsequent patients should be treated at the next lower dose level. Intermediate doses may be used in some instances and flexibility is an integral part of the protocol.
  • DLTs Dose limiting toxicities
  • CTC Common Toxicity Criteria
  • DLTs Dose limiting toxicities
  • Kahalalide F is one of a family of novel dehydroaminobutyric acid-containing peptides isolated from the Hawaiian herbivorous marine species of mollusk, Elysia rufescens. KF displays both in vitro and in vivo anti-tumour activity in various solid tumour models including breast, colon, non-small cell lung, and in particular prostate cancer. On the basis of its selectivity, KF is now further developed as a potential anticancer agent against androgen independent prostate tumours.
  • OBJECTIVE In the present phase I clinical and pharmacokinetic (PK) study the toxicity profiles PK and anti-tumour activity of KF are investigated.
  • KF is administered as an intravenous infusion over one hour, during five consecutive days every three weeks in patients with advanced or metastatic androgen refractory prostate cancer.
  • a starting dose of 20 ⁇ g/m2/day was selected, which is equivalent to a total dose of 100 ⁇ g/m2.
  • PK of KF were determined in plasma during the first course.
  • Bioanalysis of KF was performed by LC- MS/MS. LDH, AF and especially PSA levels of each patient were also evaluated during the study to determine the activity of KF. RESULTS AND
  • DISCUSSION At present 7 patients have been registered. Patients had a median age of 66 years (range 54-75). One patient per level was entered at
  • PSA level 050% associated to clinical improvement (pain relief).
  • Two additional patients experienced minor PSA reductions, one still ongoing after two cycles.
  • the maximum tolerated dose has not been reached yet and the study is ongoing.
  • KHF-A-001-00 Phase I Clinical and Pharmacokinetic study to determine the safety of kahalalide F administered as a daily x 5 over 1 hour Infusion every 21 days in patients with advanced or metastatic prostate cancer.
  • a dose of 20 mcg/m2 was considered a safe starting dose on the basis of acute toxicity studies in animals.
  • the trial was designed as an accelerated dose escalation (pharmacokinetically guided).
  • Bilirubin 10 0 0 0 0
  • liver toxicity was the most commonly seen as grade 4 transaminases elevation in the MTD (GOP, GPT levels). Patients also complain of puncture or prick on hands palms during the infusion.
  • This trial was addressed to any solid tumours and was designed as a classical escalation.
  • the starting dose was higher because we had some information from the first trial, and this allowed us to skip the first steps.
  • One cycle in this trial means a week, so 4 cycles mean 1 month of treatment.
  • the second dose level (400) was expanded because of two unrelated adverse events: grade 3 diarrhea and death due to gastrointestinal bleeding. This was also the reason why the next escalation was only 32.5% instead of 50%. No toxicities were reported in this level and the following escalation was 50% again.
  • the DLT was identified at 1200 mcg/m2, and was grade 4 hypertransaminasemia non reversible by day 21.
  • the time of onset was located at 5 hours after the infusion. This was not a scheduled determination and that was why the dose was descalated looking for previously unidentified grade 4 hypertransaminasemia.
  • the 4th level was reexplored and this second time, grade 4 hypertransaminasemia was identified as DLT again at this dose level.
  • KHF was supposed to be a non myelosuppressor agent. This prediction seems to have been confirmed in the clinical programme. Grade 1 -2 neutropenia was seen in 10% of patients. No grade 3-4 toxicities were reported.
  • a grade 4 ALT is a marker of hepatocellular injury.
  • HIPERSENSITIVITY Probably the most frequent toxicity observed with KHF is the palm hand prick referred by patients while the infusion. Sometimes this complaint was accompanied by other symptoms like erythema or pruritus in other locations.
  • dose limiting toxicity for Kahalalide F was grade 4 hypertransaminasemia as in the previous example with a different schedule. It is an asymptomatic and reversible feature that appears 4-5 hours after the infusion of KHF. Hypersensitivity reactions with cutaneous features were commonly reported at highest levels.

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Abstract

L'invention concerne des procédures d'essais cliniques pour composés à base de kahalalide, visant à élaborer de nouvelles formulations de ce type de composé.
PCT/GB2002/004735 2001-10-19 2002-10-18 Composes a base de kahalalide utilisables en therapie anticancereuse WO2003033012A1 (fr)

Priority Applications (30)

Application Number Priority Date Filing Date Title
EP02801430A EP1435990A1 (fr) 2001-10-19 2002-10-18 Composes a base de kahalalide utilisables en therapie anticancereuse
CA002462639A CA2462639A1 (fr) 2001-10-19 2002-10-18 Composes a base de kahalalide utilisables en therapie anticancereuse
MXPA04003672A MXPA04003672A (es) 2001-10-19 2002-10-18 Compuestos de kahalalida para uso en terapia de cancer.
US10/492,670 US20050054555A1 (en) 2001-10-19 2002-10-18 Kahalalide compounds for use in cancer therapy
AU2002334203A AU2002334203C1 (en) 2001-10-19 2002-10-18 Kahalalide compounds for use in cancer therapy
KR1020117020121A KR20110114690A (ko) 2002-10-18 2003-10-20 4-메틸헥사노 카할라리드 ｆ 화합물
ES03779140T ES2357644T3 (es) 2002-10-18 2003-10-20 Compuesto 4-metilhexanoico kahalalido f.
CA2501089A CA2501089C (fr) 2002-10-18 2003-10-20 Composes antitumoraux
SI200331948T SI1572726T1 (sl) 2002-10-18 2003-10-20 4-metilheksanoiäśna kahalalid f spojina
DK03779140.7T DK1572726T3 (da) 2002-10-18 2003-10-20 4-methylhexansyre-kahalalid F-forbindelse
AU2003285911A AU2003285911B2 (en) 2002-10-18 2003-10-20 4-methylhexanoic kahalaide F compound
DE60335292T DE60335292D1 (de) 2002-10-18 2003-10-20 4-methylhexanoic kahalalide f verbindung
KR1020057006480A KR101149095B1 (ko) 2002-10-18 2003-10-20 4-메틸헥사노 카할라리드 ｆ 화합물
UAA200504629A UA80992C2 (en) 2002-10-18 2003-10-20 Kahalaide antitumoral compound, use thereof and process for the preparation
JP2005501483A JP4430009B2 (ja) 2002-10-18 2003-10-20 新規な抗腫瘍化合物
EP03779140A EP1572726B1 (fr) 2002-10-18 2003-10-20 Composes 4-methylhexanoic kahalalide f
PCT/US2003/033207 WO2004035613A2 (fr) 2002-10-18 2003-10-20 Composes antitumoraux
CN200380101647A CN100591691C (zh) 2002-10-18 2003-10-20 新型抗肿瘤化合物
NZ539093A NZ539093A (en) 2002-10-18 2003-10-20 4-methylhexanoic kahalaide F compound
BR0315489-0A BR0315489A (pt) 2002-10-18 2003-10-20 Composição antitumorais
RU2005115102/04A RU2356908C2 (ru) 2002-10-18 2003-10-20 Новые противоопухолевые соединения
MXPA05004133A MXPA05004133A (es) 2002-10-18 2003-10-20 Nuevos compuestos antitumorales.
PL377056A PL209129B1 (pl) 2002-10-18 2003-10-20 Nowe związki przeciwnowotworowe
CNA2007101122538A CN101077885A (zh) 2002-10-18 2003-10-20 新型抗肿瘤化合物
AT03779140T ATE490975T1 (de) 2002-10-18 2003-10-20 4-methylhexanoic kahalalide f verbindung
PT03779140T PT1572726E (pt) 2002-10-18 2003-10-20 Composto kahalalide f 4-metil-hexanóico
IL167724A IL167724A (en) 2002-10-18 2005-03-29 Kahalalide derivatives and pharmaceutical compositions containing the same
ZA200502926A ZA200502926B (en) 2002-10-18 2005-04-11 4-Methylhexanoic kahalaide F compound.
NO20052379A NO333448B1 (no) 2002-10-18 2005-05-13 Nye 4-metylheksansyre kahalalid F forbindelser, fremgangsmate for deres fremstilling, deres anvendelse for fremstilling av et medikament fortrinnsvis for behandling av kreft, farmasoytiskpreparat omfattende forbindelsene, og et sett som inneholder et farmasoytisk preparat omfattendeforbindelsene.
HK06102999.1A HK1082261A1 (en) 2002-10-18 2006-03-08 4-methylhexanoic kahalalide f compound

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US34844901P 2001-10-19 2001-10-19
US60/348,449 2001-10-19
GBPCT/GB01/04821 2001-10-31
PCT/GB2001/004821 WO2002036145A2 (fr) 2000-10-31 2001-10-31 Kahalalide f
GB0222409.5 2002-09-26
GB0222409A GB0222409D0 (en) 2002-09-26 2002-09-26 Use of antitumoral compounds in cancer therapy

Publications (1)

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AU (1) AU2002334203C1 (fr)
CA (1) CA2462639A1 (fr)
WO (1) WO2003033012A1 (fr)

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WO2004035613A2 (fr) * 2002-10-18 2004-04-29 Pharma Mar, S.A.U. Composes antitumoraux
WO2005023846A1 (fr) * 2003-09-09 2005-03-17 Pharma Mar, S.A.U. Nouveaux composes anti-tumoraux
US7323444B2 (en) 2003-02-26 2008-01-29 Pharma Mar, S.A.U. Use of kahalalide compounds for the manufacture of a medicament for the treatment of psoriasis
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US7507708B2 (en) 2003-02-26 2009-03-24 Pharma Mar, S.A.U. Antitumoral compounds
WO2009095480A1 (fr) * 2008-01-30 2009-08-06 Pharma Mar, S.A. Traitements antitumoraux améliorés
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US10538535B2 (en) 2017-04-27 2020-01-21 Pharma Mar, S.A. Antitumoral compounds

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WO2004035613A3 (fr) * 2002-10-18 2004-07-29 Pharma Mar Sau Composes antitumoraux
WO2004035613A2 (fr) * 2002-10-18 2004-04-29 Pharma Mar, S.A.U. Composes antitumoraux
AU2003285911B2 (en) * 2002-10-18 2009-11-19 Pharma Mar, S.A.U. 4-methylhexanoic kahalaide F compound
US7507708B2 (en) 2003-02-26 2009-03-24 Pharma Mar, S.A.U. Antitumoral compounds
US7683028B2 (en) 2003-02-26 2010-03-23 Pharma Mar, S.A.U. Kahalalide compositions
US7323444B2 (en) 2003-02-26 2008-01-29 Pharma Mar, S.A.U. Use of kahalalide compounds for the manufacture of a medicament for the treatment of psoriasis
EP2280025A2 (fr) 2003-09-09 2011-02-02 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
JP2012031188A (ja) * 2003-09-09 2012-02-16 Pharma Mar Sau 新規な抗腫瘍化合物
EP1918296A3 (fr) * 2003-09-09 2009-06-24 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
EP2664623A1 (fr) 2003-09-09 2013-11-20 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
AU2011202286B2 (en) * 2003-09-09 2013-08-01 Pharma Mar, S.A.U. New antitumoral compounds
JP2007526904A (ja) * 2003-09-09 2007-09-20 ファーマ・マール・エス・アー・ウー 新規な抗腫瘍化合物
JP2012051899A (ja) * 2003-09-09 2012-03-15 Pharma Mar Sau 新規な抗腫瘍化合物
EP2280026A2 (fr) 2003-09-09 2011-02-02 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
WO2005023846A1 (fr) * 2003-09-09 2005-03-17 Pharma Mar, S.A.U. Nouveaux composes anti-tumoraux
EP2280027A2 (fr) 2003-09-09 2011-02-02 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
EP2280027A3 (fr) * 2003-09-09 2011-05-04 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
EP2280025A3 (fr) * 2003-09-09 2011-05-25 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
EP2280026A3 (fr) * 2003-09-09 2011-05-25 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
AU2004270471B2 (en) * 2003-09-09 2011-06-02 Pharma Mar, S.A.U. New antitumoral compounds
JP4874796B2 (ja) * 2003-09-09 2012-02-15 ファーマ・マール・エス・アー・ウー 新規な抗腫瘍化合物
JP2012031187A (ja) * 2003-09-09 2012-02-16 Pharma Mar Sau 新規な抗腫瘍化合物
EP1918296A2 (fr) 2003-09-09 2008-05-07 Pharma Mar, S.A.U. Nouveaux composés antitumoraux
JP2008506633A (ja) * 2004-04-22 2008-03-06 ファーマ・マール・エス・アー・ウー カハラリド化合物類の収束的合成
US20100323021A1 (en) * 2008-01-30 2010-12-23 Pharma Mar, S.A. Antitumoral treatments
WO2009095480A1 (fr) * 2008-01-30 2009-08-06 Pharma Mar, S.A. Traitements antitumoraux améliorés
US10538535B2 (en) 2017-04-27 2020-01-21 Pharma Mar, S.A. Antitumoral compounds
US11332480B2 (en) 2017-04-27 2022-05-17 Pharma Mar, S.A. Antitumoral compounds
US11339180B2 (en) 2017-04-27 2022-05-24 Pharma Mar, S.A. Antitumoral compounds
US11713325B2 (en) 2017-04-27 2023-08-01 Pharma Mar, S.A. Antitumoral compounds

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CA2462639A1 (fr) 2003-04-24
AU2002334203B2 (en) 2008-01-24

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