EP1496903A1 - Anhydrovinblastin zur krebsbehandlung - Google Patents

Anhydrovinblastin zur krebsbehandlung

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Publication number
EP1496903A1
EP1496903A1 EP03714568A EP03714568A EP1496903A1 EP 1496903 A1 EP1496903 A1 EP 1496903A1 EP 03714568 A EP03714568 A EP 03714568A EP 03714568 A EP03714568 A EP 03714568A EP 1496903 A1 EP1496903 A1 EP 1496903A1
Authority
EP
European Patent Office
Prior art keywords
cancer
use according
carcinoma
metastatic
lung
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03714568A
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English (en)
French (fr)
Inventor
Bruce Schmidt
Lawrence Mayer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Access Oncology Inc
Original Assignee
Access Oncology Inc
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Filing date
Publication date
Application filed by Access Oncology Inc filed Critical Access Oncology Inc
Publication of EP1496903A1 publication Critical patent/EP1496903A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention pertains to the field of cancer therapies and in particular to the use of the vinca alkaloid anhydrovinblastine as an anti-tumour agent.
  • Control of tumorous growth has been achieved to a certain degree using oncolytic vinca alkaloids as anti-tumour agents alone or in combination with other antineoplastic drugs in cancer chemotherapy for more than 20 years.
  • Approximately 30 alkaloids with a wide range of pharmacological activities have been extracted from the Vinca rosea (Catharanthus roseus), commonly known as the periwinkle plant.
  • Vinca rosea Catharanthus roseus
  • vinleurosine, vinrosidine, vinblastine and vincristine possess significant anti-tumour activity.
  • vinblastine and vincristine have been used widely as single agents and in combination with outer antineoplastic drugs-in cancer chemotherapy.
  • these vinca alkaloids have an asymmetric dimeric structure composed of 2 nuclei linked by a carbon-carbon bond; a dihydroindole nucleus (vindoline), which is the major alkaloid contained in the periwinkle, and the indole nucleus catharanthine ( Figure 1).
  • the structural difference between vincristine and vinblastine exists at the RI position while vinblastine and vindesine differ with regard to the R2 and R3 substituents.
  • This compound is less potent than vinblastine and vincristine against murine P388 and L1210 leukaemia but is active against cells derived from human lung cancer whereas the other vinca alkaloids are inactive (S. Cros, et al, Seminars in Oncology, 16:15-20, 1989).
  • clinical trials on ⁇ avelbineTM support its utility in treating non-small cell lung cancer (A. Depierre et al, Am. J. Clin. Oncol., 14:155- 119, 1991; A. Yokoyama et al, Am. Soc. Clin. Oncol, 11:957, 1992).
  • the toxicity profile of this agent appears similar to that of vinblastine, in that hematological toxicities and not neurological side effects are dose limiting.
  • Vincristine has proved particularly useful as an intravenously administered oncolytic agent in combination with other oncolytic agents for the treatment of various cancers including central- nervous-system leukaemia, Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, rhabdomyosarcoma, neuroblastoma, and Wilma tumour. It is for intravenous (TV) use only and the intrathecal administration is uniformly fatal. Following single weekly doses, the most common adverse reaction is hair loss; the most troublesome are neuromuscular in origin. When single weekly doses of the drug are employed, the adverse reactions of leukopenia, neuritic pain, constipation, and difficulty in walking can occur.
  • ⁇ avelbineTM (vinorelbine tartrate) is a vinca alkaloid in which the catheranthine unit is the site of structural modification. Its anti-tumour activity is also thought to be due primarily to its ability to interfere with microtubule activity thereby inhibiting mitosis at metaphase through its interaction with tubulin. It is indicated in the treatment of advanced non-small cell lung cancer as a single agent or in combination, administered by intravenous route only. Its side effects include phlebitia or extravasion injury as it is a moderate vasicant. Studies on adverse reactions based on use of NavelbineTM as a single agent indicate Granculocytopenia as the major dose-limiting toxicity, although it was generally reversible and not cumulative over time.
  • This compound has been shown to have decreased toxicity as compared to vincristine and to inhibit the growth of lymphomas and certain solid tumours, specifically cervical, lung, breast and colon cancer (see U.S. Patent Nos. 6,011,041 and 6,326,376).
  • An object of the present invention is to provide a use of 3 ',4'- anhydrovinblastine (AHVB) in the treatment of cancer, and in particular in the treatment of advanced cancer.
  • AHVB 3 ',4'- anhydrovinblastine
  • a therapeutically effective dose of 3', 4 '-anhydrovinblastine for the treatment of cancer in a mammal in need of such therapy, wherein said therapeutically effective dose is between about 2 and about 30 mg of 3', 4' -anhydrovinblastine (AHVB)/m 2 .
  • AHVB 3', 4' -anhydrovinblastine
  • a pharmaceutical composition comprising 3', 4'- anhydrovinblastine (AHVB) and one or more pharmaceutically acceptable, inert or physiologically active carriers, diluents or adjuvants, said AHVB being formulated for administration to a mammal at a dose of between about 2 and about 30 mg AHVB/m 2 .
  • AHVB 3', 4'- anhydrovinblastine
  • Figure 1 depicts the chemical structure of some vinca alkaloids.
  • Figure 2 depicts measured AHVB serum concentration over a 0 to 72 h time frame for individual patients in a Phase I clinical trial of AHVB.
  • Figure 3 depicts the clearance of AHVB for patients in a Phase I clinical trial at their respective dose level.
  • Figure 4 depicts the linear increase in AUC with Dose for patients enrolled in a Phase I clinical trial of AHVB.
  • Figure 5 depicts the increase in Half Life with Dose for patients enrolled in a Phase I clinical trial of AHVB.
  • Figure 6 depicts the linear increase in maximum plasma concentration (C max ) with Dose for patients enrolled in a Phase I clinical trial of AHVB.
  • Figure 7 depicts a Goodness of Fit Plot demonstrating the ability of a two-compartment pharmokinetic model to predict the pharmokinetic properties of AHVB.
  • Figure 8 depicts AHVB concentration-time profiles from a Phase I clinical trial of AHVB. The data are presented as mean + standard error.
  • the present invention provides for the use of AHVB in the treatment of cancer in a mammal.
  • Phase I clinical trials in which AHVB was administered to patients in dosages between about 2.5 mg/m 2 and about 30 mg/m 2 have demonstrated that AHVB is effective in the treatment of advanced cancers, including metastatic cancers.
  • variants for purposes of 3 ⁇ '-anhydrovinblastine means any chemical structure that is a derivative of 3',4'-anhydrovinblastine achieved through conservative substitution of side groups, yet still exhibits the same or similar antineoplastic properties as 3 ⁇ 4'-anhydrovinblastine.
  • time-to-progression or “progression free survival,” as used herein, refers to the time from the initiation of treatment (or randomisation, as the case may be) to the time of progression, or the time of death for patients who have died in the absence of progression, irrespective of the cause.
  • Treatment refers to an increase of at least 25% in the overall sum of measurable lesions as compared to nadir (ie. best response) and/or the appearance of new lesions.
  • Response status refers to a measurement of the behaviour of a tumour(s) or lesion(s) under chemotherapy, namely any observed growth (progression of disease), stability, or shrinkage (complete or partial response).
  • Advanced disease refers to overt disease in a patient, wherein such overt disease is not amenable to cure by local modalities of treatment, such as surgery or radiotherapy.
  • Advanced disease may refer to a locally advanced cancer or it may refer to metastatic disease.
  • metalstatic disease refers to a disease that has spread from " one part of the body to another.
  • Relapse refers to the relapse of a patient with advanced disease.
  • Relapse time refers to the time from the initial appearance of a primary cancer to the appearance of advanced disease requiring chemotherapy.
  • the term "aggressive cancer” refers to a rapidly growing cancer.
  • cancers such as breast cancer or prostate cancer
  • SCLC small cell lung carcinoma
  • the phrase "suspected of having an aggressive cancer,” refers to a situation wherein a patient has had a tumour or lesion, which tumour or lesion had features correlated with the development of advanced disease, for example, markers predictive of aggressive disease.
  • an indication of aggressive breast cancer is a tumour that is estrogen-receptor negative (ER-).
  • the tumour may be ER positive, but the patient may exhibit other markers predictive of aggressive disease, such as node positivity. In these situations adjuvant therapies may be applied.
  • adjuvant therapy refers to a treatment that is added to increase the effectiveness of a primary treatment.
  • adjuvant therapy usually refers to chemotherapy, hormonal therapy or radiation therapy after surgery (primary therapy) to increase the likelihood of killing all cancer cells.
  • neoadjuvant therapy refers to a treatment given before the primary treatment.
  • examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy.
  • hormone therapy refers to a treatment in which hormones or anti-hormone drugs are administered to a patient in order to slow or stop the growth of certain cancers (such as prostate and breast cancer) by blocking the body's natural hormones.
  • hormone-resistant cancer refers to a cancer that does not respond to hormone therapy
  • hormone-responsive cancer refers to a cancer that does respond to hormone therapy
  • leukaemia refers broadly to progressive, malignant diseases of the blood- forming organs.
  • Leukaemia is typically characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow but can also refer to malignant diseases of other blood cells such as erythroleukaemia, which affects immature red blood cells.
  • Leukaemia is generally clinically classified on the basis of (1) the duration and character of the disease - acute or chronic; (2) the type of cell involved - myeloid (myelogenous), lymphoid (lymphogenous) or monocytic, and (3) the increase or non-increase in the number of abnormal cells in the blood - leukaemic or aleukaemic (subleukaemic).
  • Leukaemia includes, for example, acute nonlymphocytic leukaemia, chronic lymphocytic leukaemia, acute granulocytic leukaemia, chronic granulocytic leukaemia, acute promyelocytic leukaemia, adult T-cell leukaemia, aleukaemic leukaemia, aleukocythemic leukaemia, basophylic leukaemia, blast cell leukaemia, bovine leukaemia, chronic myelocytic leukaemia, leukaemia cutis, embryonal leukaemia, eosinophilic leukaemia, Gross' leukaemia, hairy-cell leukaemia, hemoblastic leukaemia, hemocytoblastic leukaemia, histiocytic leukaemia, stem cell leukaemia, acute monocytic leukaemia, leukopenic leukaemia, lymphatic leukaemia, lymphoblastic leukaemia, lymphocytic leuk
  • tumour generally refers to a tumour which originates in connective tissue, such as muscle, bone, cartilage or fat, is made up of a substance like embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas include soft tissue sarcomas, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumour sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented haemorrhagic
  • AHVB is used to treat a patient with a sarcoma.
  • the sarcoma is a soft tissue sarcoma.
  • the sarcoma is a metastatic sarcoma or a metastatic sarcoma to the lungs.
  • melanoma is taken to mean a tumour arising from the melanocytic system of the skin and other organs.
  • Melanomas include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, and superficial spreading melanoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells, such growths frequently infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated in accordance with the present invention include, for example, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colorectal carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale
  • carcinomas that originate in cells that make organs which have glandular (secretory) properties or that originate in cells that line hollow viscera, such as the gastrointestinal tract or bronchial epithelia. Examples include, but are not limited to, adenocarcinomas of the breast, lung, pancreas and prostate.
  • AHVB is used to treat a patient with an adenocarcinoma.
  • the adenocarcinoma is breast cancer.
  • the adenocarcinoma is prostate cancer or pancreatic cancer.
  • Additional cancers encompassed by the present invention include, for example, Hodgkin's Disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, small-cell lung tumours, primary brain tumours, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, gliomas, testicular cancer, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, mesothelioma and medulloblastoma.
  • AHVB Anti-Tumour Activity has shown significant cytotoxic potential against a panel of human cancer cell lines, and significant activity against the human H460 non-small cell lung carcinoma tumour xenograph in SCID/Rag-2 Mice.
  • In vitro cytotoxicity assays utilizing the MTT cytotoxicity assay with a drug exposure time of 72 hours have shown that AHVB is an active cytotoxic drug with IC 50 values ranging from 20 - 24 nM against the H460 human non-small cell lung carcinoma, C-4 human cervical carcinoma, K562 human leukaemia, and the A431 human epidermoid cell lines.
  • AHVB was approximately 10-fold less active than NavelbineTM when tested in vitro against the same cell lines.
  • AHVB can be tested in Clinical Trials. As is known in the art, clinical trials progress through phases of testing, which are identified as Phases I, ⁇ , III, and TV.
  • Phase I trials were used to determine the best mode of administration (for example, by pill or by injection), the frequency of administration, and the toxicity for the compounds. Phase I studies frequently include laboratory tests, such as blood tests and biopsies, to evaluate the effects of a compound in the body of the patient.
  • Phase I trials a small group of cancer patients are treated with specific doses of AHVB. During the trial, the dose is typically increased group by group in order to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) associated with the compound. This process determines an appropriate dose to use in a subsequent Phase II trial.
  • MTD maximum tolerated dose
  • DLT dose-limiting toxicities
  • Phase II trial can be conducted to further evaluate the effectiveness and safety of AHVB.
  • AHVB is administered to groups of patients with either one specific type of cancer or with related cancers, using the dosage found to be effective in Phase I trials.
  • Phase III trials focus on determining how a compound compares to the standard, or most widely accepted, treatment.
  • patients are randomly assigned to one of two or more "arms".
  • one arm will receive the standard treatment (control group) and the other arm will receive AHVB treatment (mvestigational group).
  • Phase IV trials are used to further evaluate the long-term safety and effectiveness of a compound. Phase IV trials are less common than Phase I, II and III trials and will take place after AHVB has been approved for standard use.
  • Participant eligibility criteria can range from general (for example, age, sex, type of cancer) to specific (for example, type and number of prior treatments, tumour characteristics, blood cell counts, organ function). Eligibility criteria may also vary with trial phase. For example, in Phase I and II trials, the criteria often exclude patients who may be at risk from the mvestigational treatment because of abnormal organ function or other factors. In Phase II and III trials additional criteria are often included regarding disease type and stage, and number and type of prior treatments.
  • Phase I cancer trials usually comprise 15 to 30 participants for whom other treatment options have not been effective.
  • Phase II trials typically comprise up to 100 participants who have already received chemotherapy, surgery, or radiation treatment, but for whom the treatment has not been effective. Participation in Phase II trials is often restricted based on the previous treatment received.
  • Phase III trials usually comprise hundreds to thousands of participants. This large number of participants is necessary in order to determine whether there are true differences between the effectiveness of AHVB and the standard treatment.
  • Phase III may comprise patients ranging from those newly diagnosed with cancer to those with extensive disease in order to cover the disease continuum.
  • clinical trials should be designed to be as inclusive as possible without making the study population too diverse to determine whether the treatment might be as effective on a more narrowly defined population.
  • the more diverse the population included in the trial the more applicable the results could be to the general population, particularly in Phase III trials. Selection of appropriate participants in each phase of clinical trial is considered to be within the ordinary skills of a worker in the art.
  • ECOG PS Eastern Cooperative Oncology Group
  • ECOG PS Performance Status
  • ECOG PS is a widely accepted standard for the assessment of the progression of a patient' s disease as measured by functional impairment in the patient, with ECOG PS 0 indicating no functional impairment, ECOG PS 1 and 2 indicating that the patients have progressively greater functional impairment but are still ambulatory and ECOG PS 3 and 4 indicating progressive disablement and lack of mobility.
  • MQOL McGill Quality of Life Questionnaire
  • SDS Symptom Distress Scale
  • Patients can also be classified according to the type and/or stage of their disease and/or by tumour size.
  • AHVB is typically administered to the trial participants parenterally.
  • AHVB is admimstered by intravenous infusion.
  • Methods of administering drugs by intravenous infusion are known in the art. Usually intravenous infusion takes place over a certain time period, for example, over the course of 60 minutes.
  • a range of doses of AHVB can be tested.
  • the studies outlined above have indicated that AHVB can be safely administered at concentrations up to ten times the dosages typically used for vinblastine. Provided with this information and effective dosages of vinblastine known in the art, a skilled practitioner could readily determine appropriate dosages of AHVB for use in clinical trials.
  • An exemplary dose range for AHVB treatment includes dosages in the range 2.5 mg/m to 30 mg/m .
  • samples such as blood or urine
  • samples can be taken at regular intervals up until about 72 hours after the start of infusion.
  • samples are taken at 0, 0.33, 0.67, 1, 1.25, 1.5, 2, 4, 6, 8, 12, 24, 48 and 72 hours after the start of each infusion of AHVB.
  • samples can be placed on dry ice after collection and subsequently transported to a freezer to be stored at -70 °C until analysis can be conducted.
  • Samples can be prepared for analysis using standard techniques known in the art and the amount of AHVB present can be determined, for example, by high-performance liquid chromatography (HPLC).
  • Pharmacokinetic data can be generated and analyzed in collaboration with an expert clinical pharmacologist and used to determine, for example, clearance, half-life and maximum plasma concentration.
  • the endpoint of a clinical trial is a measurable outcome that indicates the effectiveness of a compound under evaluation.
  • the endpoint is established prior to the commencement of the trial and will vary depending on the type and phase of the clinical trial.
  • Examples of endpoints include, for example, tumour response rate - the proportion of trial participants whose tumour was reduced in size by a specific amount, usually described as a percentage; disease-free survival — the amount of time a participant survives without cancer occurring or recurring, usually measured in months; overall survival - the amount of time a participant lives, typically measured from the beginning of the clinical trial until the time of death.
  • disease stabilization the proportion of trial participants whose disease has stabilized, for example, whose tumour(s) has ceased to grow and/or metastasize, can be used as an endpoint.
  • Other endpoints include toxicity and quality of life.
  • Tumour response rate is a typical endpoint in Phase II trials. However, even if a treatment reduces the size of a participant's tumour and lengthens the period of disease-free survival, it may not lengthen overall survival. In such a case, side effects and failure to extend overall survival might outweigh the benefit of longer disease-free survival. Alternatively, the participant's improved quality of life during the tumour-free interval might outweigh other factors. Thus, because tumour response rates are often temporary and may not translate into long-term survival benefits for the participant, response rate is a reasonable measure of a treatment's effectiveness in a Phase II trial, whereas participant survival and quality of life are typically used as endpoints in a Phase III trial.
  • the present invention also provides pharmaceutical compositions containing AHVB in combination with one or more pharmaceutically acceptable, inert or physiologically active, carriers, diluents or adjuvants.
  • AHVB may be freeze dried and, if desired, combined with other pharmaceutically acceptable excipients to prepare formulations for administration.
  • the pharmaceutical compositions comprising AHVB may further comprise one or more other active ingredients, for example, other chemotherapeutic agents useful in the treatment of cancer.
  • These compositions are presented in a form appropriate for the administration route envisaged, In one embodiment of the invention, AHVB is formulated for parenteral administration. In another embodiment, AHVB is formulated for intravenous administration.
  • the pharmaceutical compositions When formulated as an injectable composition, the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous solution or suspension.
  • This solution/suspension may be formulated according to known art using suitable dispersing or wetting agents and agents for dissolution or suspension of the AHVB such as those mentioned below.
  • Aqueous suspensions contain AHVB in admixture with suitable excipients including, for example, suspending agents, such as sodium carboxymethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethyene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate.
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or r ⁇ -propyl -hydroxy-benzoate.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol Acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution, lactated Ringer's solution and isotonic sodium chloride solution.
  • a non-toxic parentally acceptable diluent or solvent for example, as a solution in 1,3- butanediol Acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution, lactated Ringer's solution and isotonic sodium chloride solution.
  • Other examples are, sterile, fixed oils which are conventionally employed as a solvent or suspending medium, and a variety of bland fixed oils including, for example, synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • AHVB When AHVB is administered parenterally in a sterile medium or vehicle, it can either be suspended or dissolved in the vehicle depending on the vehicle and concentration used.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle.
  • compositions may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions (as described above), dispersible powders or granules, emulsion hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with suitable non-toxic pharmaceutically acceptable excipients including, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • suitable non-toxic pharmaceutically acceptable excipients including, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch, or alginic acid; binding agents, such as starch, gelatine or acacia, and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • the tablets can be uncoated,
  • compositions for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous and oily suspensions containing AHVB may also contain one or more colouring agents, one or more flavouring agents or one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may further contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin, or it may be a mixtures of these oils.
  • Suitable emulsifying agents may be naturally-occurring gums, for example, gum acacia or gum tragacanth; naturally-occurring phosphatides, for example, soy bean, lecithin; or esters or partial esters derived from fatty acids and hexitol, anhydrides, for example, sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monoleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and/or flavouring and colouring agents.
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and/or flavouring and colouring agents.
  • AHVB may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in “Remington: The Science and Practice of Pharmacy,” Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, PA (2000) (formerly “Remingtons Pharmaceutical Sciences”).
  • the present invention also provides for formulation of AHVB into specific dosage units. Suitable dosages of AHVB determined from clinical trials are between about 2 mg/m 2 and about 30 mg/m 2 . Thus, pharmaceutical compositions formulated for administration at a dose of between about 2 and about 30 mg AHVB/m 2 are contemplated by the present invention.
  • the pharmaceutical compositions may be provided as single-dose units or as multi-dose units. In one embodiment, single dose units formulated for administration at a dose of between about 5 and about 25 mg AHNB/m 2 are provided. In another embodiment, single dose units formulated for administration at a dose of between about 10 and about 21 mg AHVB/m 2 are provided.
  • AHVB may be administered in a number of ways depending upon whether local or systemic treatment of the organism is desired. Administration may be pulmonary, e.g. by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal; intranasal; epidermal or transdermal; oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, or intracranial, e.g. intrathecal or intraventricular, administration.
  • AHVB or pharmaceutical compositions comprising AHVB are used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic as described above.
  • AHVB is admimstered by parenteral infusion.
  • AHVB is administered through intravenous (IV) infusion.
  • AHVB may be administered topically in a lotion or cream, for example, for application to the skin in order to treat a melanoma.
  • AHVB may be admimstered orally in dosage forms such as tablets, capsules and the like as described above.
  • the proportion of active ingredients in any solid and liquid composition will be at least sufficient to impart the desired activity to the individual being treated upon oral administration.
  • AHVB or pharmaceutical compositions comprising AHVB can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the dose of AHVB to be administered will vary and a dose regimen is designed based on such factors as the potency of the compound, the particular compositions employed, route of administration, size of the patient and the nature and severity of the patient's condition, amongst others.
  • the dosage to be administered is not subject to defined limits, but it will usually be an effective amount. It will also usually be the equivalent, on a molar basis, of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active free drug to achieve its desired pharmacological and physiological effects.
  • Dosage requirements can be determined by standard clinical techniques, known to a worker skilled in the art. Typically, treatment is initiated with small dosages less than the optimum dose of AHVB. Thereafter the dosage is increased until the optimum effect under the circumstances is reached.
  • AHVB or pharmaceutical compositions comprising AHVB are administered at a concentration that will generally afford effective results while minimizing harmful or deleterious side effects. Administration can be either as a single unit dose or, if desired, the dosage can be divided into convenient sub- units that are administered at suitable times throughout the day.
  • An oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, appropriate protocols for effective administration of the compounds of this present invention by referring to the earlier studies of vinblastine and its derivatives.
  • AHVB is admimstered at a dose between about 2 mg/m 2 and about 30 mg/m 2 .
  • AHVB is administered at a dose between about 2.5 mg/m 2 and about 25 mg/m 2 .
  • AHVB is administered at a dose between about 5 mg/m 2 and about 25 mg/m 2 , between about 10 mg/m 2 and about 25 mg/m 2 , between about 10 mg/m 2 and about 21 mg/m 2 and between about 16.5 mg/m 2 and about 21 mg/m 2 .
  • AHVB When AHVB is administered by intravenous infusion, the dose of AHVB is typically administered to the patient over a time period of between about 30 minutes and about 90 minutes. In one embodiment of the present invention, AHVB is administered by intravenous infusion over a time period of about 60 minutes.
  • Treatment regimens are typically designed such that the AHVB is administered to the. patient in cycles.
  • Treatment with AHVB in accordance with the present invention may be part of a treatment regimen that involves one cycle of administration or the regimen may involve more than one cycle.
  • the treatment regimen involves between about 2 and about 10 cycles.
  • the treatment regimen involves between about 4 and about 8 cycles.
  • the treatment regimen involves about 6 cycles.
  • a cycle is between about 1 and about 4 weeks. In one embodiment, the cycle is about 3 weeks.
  • the present invention also contemplates the use of AHVB in treatment regimens in conjunction with one or more chemotherapeutic agents ("combination therapies").
  • AHVB can be administered to the patient prior to, or after, administration of the one or more other chemotherapeutic agents, or it can be administered concomitantly.
  • AHVB When AHVB is administered prior to the one or more other chemotherapeutic agents, the length of time between administration of the AHVB and the other compound(s) will depend on the mode of administration and the size of the patient. Generally, AHVB will be administered to the patient for between about 30 minutes and about 90 minutes prior to administration of the other chemotherapeutic agent(s). Alternatively, AHVB and the other chemotherapeutic agent(s) are administered concurrently, in which case administration of the chemotherapeutic(s) may be initiated at the same time as, or at a suitable time after, initiation of administration of AHVB. Generally, administration of the other chemotherapeutic(s) is initiated about 30 minutes to about 90 minutes after administration of AHNB was initiated.
  • Suitable agents for use with AHVB in combination therapies include those chemotherapeutic agents which are specific for the treatment of a particular type of cancer as well as those which may be applicable to a range of cancers, for example doxorubicin, mitoxantrone, irinotecan (CPT-11).
  • chemotherapeutic agents suitable for the treatment of breast cancer include, but are not limited to, cyclophosphamide, ifosfamide, cisplatin, carboplatin, 5-fiuorouracil (5-FU), taxanes such as paclitaxel and docetaxel and various anthracyclines, such as doxorubicin and epi-doxorubicin (also known as epirubicin).
  • Combination therapies using standard cancer chemotherapeutics may also be used in conjunction with AHVB and are also well known in the art, for example, the combination of epirubicin with paclitaxel or docetaxel, or the combination of doxorubicin or epirubicin with cyclophosphamide, which are used for breast cancer treatments.
  • Polychemotherapeutic regimens are also useful and may consist, for example, of doxorubicin/cyclophosphamide/5-fluorouracil or cyclophosphamide/epirubicin/5- fluorouracil. Cyclophosphamide, mitoxantrone and estramustine are known to be suitable for the treatment of prostate cancer.
  • Cyclophosphamide doxorubicin and etoposide are used in the treatment of small cell lung cancer, as are combinations of etoposide with either cisplatin or carboplatin.
  • combinations of doxorubicin or epirubicin with cisplatin and 5-fluorouracil are useful.
  • CPT- 11 alone or in combination with 5-fluorouracil-based drags, or oxaliplatin in combination with 5-fluorouracil-based drugs can be used.
  • doxorubicin examples include the combination of cyclophosphamide, doxorubicin and prednisone in the treatment of non-Hodgkin's lymphoma; the combination of doxorubicin, bleomycin, vinblastine and DTIC in the treatment of Hodgkin's disease and the combination of cisplatin or carboplatin with any one or a combination of gemcitabine, paclitaxel, docetaxel, vinorelbine or etoposide in the treatment of non-small cell lung cancer.
  • AHVB was shown to be active in stabilising cancer in humans, in particular advanced and metastatic cancers.
  • Phase I clinical trials in which AHNB was administered to patients as a 60 minute intravenous infusion once every 3 weeks for up to 6 courses at a dose of 10 mg/m 2 demonstrated stable disease in one patient with metastatic sarcoma to the lungs.
  • dosage levels of 21 and 25 mg/m 2 stable disease was shown in three patients with metastatic ⁇ SCLC.
  • AHVB may be used as part of a neo-adjuvant therapy (to primary therapy), as part of an adjuvant therapy regimen, and/or for the treatment of locally advanced or metastatic disease. AHVB may also be used to treat refractory and/or advanced tumours. It is further contemplated that AHVB can be used to treat patients that have undergone one or more prior courses of chemotherapy.
  • Primary therapy is understood to encompass a first line of treatment upon the initial diagnosis of cancer in a patient. Exemplary primary therapies may involve surgery, a wide range of chemotherapies and radiotherapy.
  • Adjuvant therapy is understood to encompass any therapy, following a primary therapy such as surgery that is administered to patients at risk of relapsing. Adjuvant systemic therapy is begun soon after primary therapy to delay recurrence, prolong survival or cure a patient. It is contemplated that AHVB can be used alone or in combination with one or more other chemotherapeutic agents as part of an adjuvant therapy.
  • a patient's response status is monitored to determine the effectiveness of the therapy. Arising out such monitoring may be the observation of relapse in a patient, which may refer to the relapse of a patient with advanced disease.
  • AHVB is used alone or in combination with one or more other chemotherapeutics in the treatment of advanced disease in a cancer patient.
  • the advanced disease is a solid tumour.
  • the advanced disease is a metastatic disease.
  • the advanced disease is metastatic sarcoma.
  • the advanced disease is . metastatic neuroendocrine cancer or metastatic non-small cell lung carcinoma.
  • a "refractory” cancer or tumour refers to a cancer or tumour that has not responded to treatment.
  • AHVB alone or in combination with one or more other chemotherapeutics can be used to treat a refractory cancer.
  • AHVB is used to treat refractory non-small cell lung carcinoma.
  • AHVB is used to treat refractory colorectal carcinoma.
  • AHVB is used to treat refractory soft tissue sarcoma.
  • AHVB is used to treat refractory pancreatic cancer.
  • AHVB is used to treat refractory breast cancer.
  • AHVB alone or in combination with one or more other chemotherapeutics can be used to treat a patient suspected of having an aggressive cancer, such as a patient has a hormone-resistant cancer.
  • AHVB alone or in combination with one or more other chemotherapeutics is used to treat breast cancer patients with estrogen-receptor negative (ER-) tumours.
  • a phase I trial was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacokinetics of AHNB given as a 1-h intravenous infusion once every 3 weeks in patients with advanced refractory solid tumours.
  • MTD maximum tolerated dose
  • DLT dose-limiting toxicities
  • AHNB pharmacokinetics of AHNB given as a 1-h intravenous infusion once every 3 weeks in patients with advanced refractory solid tumours.
  • Patients and methods Entered into the study were 24 patients with normal bone marrow, hepatic and renal function, and of these 21 were evaluable. There were 12 males and 12 females with a median age of 60 years (range 27 —75 years). Diagnoses were non-small- cell , lung cancer ( ⁇ SCLC) (11), colorectal cancer (5), soft tissue sarcoma (4) and miscellaneous (including pancreatic cancer, breast cancer and metastatic neuroendocrine cancer and renal cell carcinoma: 4). Patients had had a median of three prior chemotherapy regimens (range one to six). A total of 51 courses were administered at doses of 2.5, 5, 10, 16.5, 21, 25 and 30 mg/m 2 in one, three, one, three, six, six and one patient, respectively.
  • Prescient NeuroPharma of Vancouver, Canada supplied the AHVB in single-dose vials.
  • the AHVB was infused intravenously over 1 h in 250 ml 5%dextrose in water within 8 h of dilution.
  • the drug was given every 3 weeks without premedication.
  • the starting dose was 2.5 mg/m 2 (one-seventh of the MTD in the rat, the more sensitive of the species studied).
  • Dose escalation was based on the continual reassessment method (CRM) modified by Faries [J. Biopharm Stat 4:147 (1994)] according to pre-established dose levels [O'Quigley et al, Biometrics, 46:33 (1990)].
  • Toxicity was graded according to the NCI CTC version 2.0.
  • DLT dose-limiting toxicity
  • Plasma sampling and assay AHVB was administered intravenously over 1 h.
  • Blood (7 ml) for pha--macokinetics (PK) was collected before, at 0.25, 0.5 and 1 h during infusion, and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 h following the end of infusion. Samples were immediately centrifuged, and the plasma harvested and stored frozen at -20°C until assayed. Samples were assayed by a validated liquid chromatography/mass spectrometry (LC/MS) assay.
  • LC/MS liquid chromatography/mass spectrometry
  • the instrumental set-up included a Hewlett Packard Series II 1090 HPLC and Insersil column ODS 2, a Fisons VG Quattro IB mass spectrometer no.5763 in atmospheric pressure chemical ionization (APCI) mode, and a Pierce "reacti-Therm” module evaporator.
  • the assay was linear over the range 10 -2000 ng/ml, with a lower limit of quantitation of 10 ng/ml and a minimum RSQ of 0.99987.
  • the interday %RSD of quality control samples ranged from 2.1 % to 10.4%.
  • Vincristine was used as the internal standard and AHVB had a retention time of approximately 10 min. All samples were assayed in duplicate and in random order.
  • Grade 2 toxicities including infusional hypertension, anemia and dizziness were noted.
  • Six patients were entered at 25 mg/m 2 .
  • DLT requiring hospitalization, was noted in two patients and included grade 4 constipation and grade 3 nausea/vomiting. This dose level exceeded the MTD. Since no severe toxicities were seen at 16.5 mg/m 2 and the increment to 25 mg/m 2 represented a 50% increase, six evaluable patients were entered at 21 mg/m 2 ; one of the six had DLT (grade 3 nausea/vomiting) and grade 2 constipation, requiring brief hospitalisation, laxatives and administration of intravenous fluids.
  • grade 3 three patients
  • grade 4 one patient neutropenia
  • the duration of the grade 4 neutropenia was 2 days; this patient also had grade 3 anaemia.
  • the onset of neutropenia was typically delayed; the median time to nadir was 14 days (range 2 -22 days). There were no treatment delays secondary to neutropenia.
  • the nadir neutrophil platelet counts are given in Table 3.
  • Plasma concentration data for AHVB were available in 20 patients.
  • C max ranged from 28.2 ng/ml at 2.5 mg/m to 571 ng/ml at the 30 mg/m 2 .
  • the data fitted a two-compartment PK model, with a median (range) r 2 of 0.89 (0.78 - 0.96).
  • the median t ⁇ /2 ⁇ and t 2 ⁇ were 0.17 and 17.6 h (mean values were: t ⁇ /2 ⁇ 0.19 h; ti ⁇ 20.8 h).
  • the mean clearance (CV%) and volume of distribution (CV%) of AHVB were 26.4 1/h per m 2 (49%) and 45 1/m 2 (34%>), respectively.
  • Figure 2 shows the time-course plots of individual patient AHVB serum concentrations, fit by a 2-compartment linear pharmacokinetic model.
  • Figure 3 shows the clearance of AHVB for each patient at their respective dose level. A minority of subjects demonstrated evidence of a third elimination phase, which could not be characterized.
  • AHVB exhibited linear PK over the range of doses studied, with no significant change in clearance with increasing dose (P >0.05, Kruskal-Wallis) (Figure 8).
  • the AUC increased linearly with dose (r 2 0.82, P ⁇ 0.05 by linear regression) (Figure 4).
  • a similar linear relationship was observed between C max and dose (Figure 5).
  • a goodness of fit plot is shown in Figure 7 demonstrating the model predicted versus measured AHVB concentrations.
  • C max was a better predictor of AHVB toxicity than either dose or AUC.
  • C max was associated with both the occurrence of gastrointestinal toxicity and neutropenia (P ⁇ 0.05).
  • Recursive partitioning identified significant C max breakpoints of approximately 250 ng/ml for both toxicities.
  • Four of the eight patients with AHVB C max >250 ng/ml exhibited significant gastrointestinal toxicity (one grade 2, two grade 3, one grade 4), in contrast to none of 12 patients with C max ⁇ 250 ng/ml (P O.05).
  • four of eight patients with a C max >250 ng/ml had cycle- 1 neutropenia (three grade 3, one grade 4), in contrast to none of 12 patients with a C max ⁇ 250 ng/ml (P ⁇ 0.05).
  • AHVB can safely be a ⁇ ninistered every 3 weeks at a dose of 21 mg/m 2 .
  • the DLT is nausea/vomiting, which could be early or late.
  • the prophylactic use of 5HT3 antagonists should be considered.
  • the prophylactic use of laxatives should be considered in patients on narcotics who receive AHVB.
  • the PK of AHVB are linear at doses of 2.5 to 30 mg/m 2 , and are well described by a two-compartment model.
  • the human PK appear similar to those of vinblastine, which has a terminal elimination half-life of approximately 20 - 25 h [Faries, J.
  • Dose N A AUC B Tie be CL c V ' ss /mg/m 2 /ng/mL al /h /ug/mL*h /ng/mL /h /L/h/m 2 /ng/mL /L/m 2
  • Table 4 Nonhematologic toxicity of AHVB (one cycle only). At doses of 2.5 to 10 mg/m , five patients received 11 courses; one grade 2 nausea/vomiting was seen.

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