Internet for Pharmaceutical and Biotech Communities
| Newsletter | Advertising |
 
 
 

  

Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 
   

 

  Pharmaceutical Patents  

 

Title:  Antitumoral treatments
United States Patent: 
7,576,188
Issued: 
August 18, 2009

Inventors: 
Bertino; Joseph R. (New Brunswick, NJ), Barnejee; Debabrata (New Brunswick, NJ), Guray; Saydam (New Brunswick, NJ), Jimeno; Jose (Madrid, ES), Faircloth; Glynn Thomas (Cambridge, MA)
Assignee:  Pharma Mar, S.A.U. (Madrid, ES)
Appl. No.: 
10/546,750
Filed:
 March 12, 2004
PCT Filed: 
March 12, 2004
PCT No.:
 PCT/US2004/007606
371(c)(1),(2),(4) Date:
 November 04, 2005
PCT Pub. No.:
 WO2004/080421
PCT Pub. Date:
 September 23, 2004


 

Training Courses -- Pharm/Biotech/etc.


Abstract

Aplidine and aplidine analogues are of use for the treatment of cancer, in particular in the treatment of leukemias and lymphomas, especially in combination therapies.

Description of the Invention

FIELD OF THE INVENTION

The present invention relates to combinations of aplidine or aplidine analogues with other antitumoral agents, and the use of these combinations in the treatment of cancer, in particular in the treatment of leukemias and lymphomas.

BACKGROUND OF THE INVENTION

Aplidine (Dehydrodidemnin B) is a cyclic depsipeptide that was isolated from a Mediterranean marine tunicate, Aplidium albicans, and it is the subject of WO 9109485. It is related to compounds known as didemnins, and has the following structure -- see Original Patent.

More information on aplidine, aplidine analogues, their uses, formulations and synthesis can be found in patent applications WO 98 1352, WO 99 42125, WO 01 76616, WO 01 35974, WO 02 30441 and WO 02 02596. We incorporate by specific reference the content of each of these PCT texts.

In both animal and human preclinical studies and in clinical Phase I studies this agent has been shown to have cytotoxic potential against a broad spectrum of tumor types including leukemia and lymphoma. See for example: Faircloth, G. et al.: "Dehydrodidemnin B (DDB) a new marine derived anticancer agent with activity against experimental tumour models", 9th NCI-EORTC Symp New Drugs Cancer Ther (March 12-15, Amsterdam) 1996, Abst 111; Faircloth, G. et al.: "Preclinical characterization of aplidine, a new marine anticancer depsipeptide", Proc Amer Assoc Cancer Res 1997, 38: Abst 692; Depenbrock H, Peter R, Faircloth G T, Manzanares I, Jimeno J, Hanauske A R.: "In vitro activity of Aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells" Br. J. Cancer, 1998; 78: 739-744; Faircloth G, Grant W, Nam S, Jimeno J, Manzanares I, Rinehart K.: "Schedule-dependency of Aplidine, a marine depsipeptide with antitumor activity"', Proc. Am. Assoc. Cancer Res. 1999; 40: 394; Broggini M, Marchini S, D'Incalci M, Taraboletti G, Giavazzi R, Faircloth G, Jimeno J.: "Aplidine blocks VEGF secretion and VEGF/VEGF-R1 autocrine loop in a human leukemic cell line", Clin Cancer Res 2000; 6 (suppl): 4509; Erba E, Bassano L, Di Liberti G, Muradore I, Chiorino G, Ubezio P, Vignati S, Codegoni A, Desiderio M A, Faircloth G, Jimeno J and D'Incalci M.: "Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine", Br J Cancer 2002; 86: 1510-1517; Paz-Ares L, Anthony A, Pronk L, Twelves C, Alonso S, Cortes-Funes H, Celli N, Gomez C, Lopez-Lazaro L, Guzman C, Jimeno J, Kaye S.: "Phase I clinical and pharmacokinetic study of aplidine, a new marine didemnin, administered as 24-hour infusion weekly" Clin. Cancer Res. 2000; 6 (suppl): 4509; Raymond E, Ady-Vago N, Baudin E, Ribrag V, Faivre S, Lecot F, Wright T, Lopez Lazaro L, Guzman C, Jimeno J, Ducreux M, Le Chevalier T, Armand J P.: "A phase I and pharmacokinetic study of aplidine given as a 24-hour continuous infusion every other week in patients with solid tumor and lymphoma", Clin. Cancer Res. 2000; 6 (suppl): 4510; Maroun J, Belanger K, Seymour L, Soulieres D, Charpentier D, Goel R, Stewart D, Tomiak E, Jimeno J, Matthews S.:"Phase I study of aplidine in a 5 day bolus q 3 weeks in patients with solid tumors and lymphomas", Clin. Cancer Res. 2000; 6 (suppl): 4509; Izquierdo M A, Bowman A, Martinez M, Cicchella B, Jimeno J, Guzman C, Germa J, Smyth J.: "Phase I trial of Aplidine given as a 1 hour intravenous weekly infusion in patients with advanced solid tumors and lymphoma", Clin. Cancer Res. 2000; 6 (suppl): 4509.

Mechanistic studies indicate that aplidine can block VEGF secretion in ALL-MOLT4 cells and in vitro cytotoxic activity at low concentrations (5nM) has been observed in AML and ALL samples from pediatric patients with de novo or relapsed ALL and AML. Aplidine appears to induce both a G1, and a G2 arrest in drug treated leukemia cells in vitro. Apart from down regulation of the VEGF receptor, little else is known about the mode(s) of action of aplidine.

In phase I clinical studies with aplidine, L-carnitine was given as a 24 hour pretreatment or co-administered to prevent myelotoxicity, see for example WO 02 30441. Co-administration of L-carnitine was proven to be able to improve the recovery of the drug induced muscular toxicity and has allowed for dose escalation of aplidine.

Thus in clinical Phase I studies aplidine was not myelotoxic at maximum tolerated doses, except for mild lymphopenia. These characteristics make aplidine a potentially useful agent for the treatment of leukemia. Adding aplidine to the current chemotherapy for leukemia could improve efficacy without the necessity of dose reductions of drugs with proven antileukemic activity, because of increased myelotoxicity. This seems especially relevant for the treatment of relapsed ALL and newly diagnosed and relapsed AML, since these are diseases with a relatively poor prognosis, which are currently being treated with myelotoxic drug combinations.

SUMMARY OF THE INVENTION

We have for the first time established that aplidine and aplidine analogues potentiate other anticancer agents and therefore can be successfully used in combination therapy for the treatment of cancer. This invention is directed to pharmaceutical compositions, pharmaceutical dosage forms, kits and methods for the treatment of cancer using these combination therapies.

In accordance with one aspect of this invention, we provide effective combination therapies based on aplidine and aplidine analogues, using other drugs which are effective in the treatment of cancer. Preferably the other drug is effective in the treatment of leukemia and/or lymphoma. Most preferably the other drug is selected from the group consisting of methotrexate, cytosine arabinoside, mitoxantrone, vinblastine, methylprednisolone and doxorubicin.

In another embodiment the invention encompasses a method of treating primary and/or metastatic cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of aplidine or an aplidine analogue, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, and a therapeutically effective amount of another drug which is effective in the treatment of cancer or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, administered prior, during, or after administering aplidine or aplidine analogue.

Preferably the other drug is effective in the treatment of leukemia and/or lymphoma. Most preferably the other drug is selected from the group consisting of methotrexate, cytosine arabinoside, mitoxantrone, vinblastine, methylprednisolone and doxorubicin. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at a different time.

The cancer to be treated is preferably a leukemia or a lymphoma, most preferably ALL, AML, CML, MML or CLL.

In another aspect the invention encompasses a method of increasing the therapeutic efficacy of a drug effective in the treament of cancer, preferably a drug effective in the treatment of leukemia and/or lymphoma, most preferably a drug selected from the group consisting of methotrexate, cytosine arabinoside, mitoxantrone, vinblastine, methylprednisolone and doxorubicin, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, which comprises administering to a patient in need thereof an amount of aplidine or an aplidine analogue, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof. Aplidine or the aplidine analogue is administered prior, during, or after administering the other drug.

Aplidine or an aplidine analogue is able to increase the therapeutic efficacy of some cancer drugs. In one aspect, the result is synergism, rather than additive. Such synergistic combinations represent a preferred aspect of the present invention. Synergism may be indicated by use of the Chou-Talalay method, or other methods. In other instances, antagonism may be found.

In a further aspect the invention encompasses a pharmaceutical composition comprising aplidine or an aplidine analogue, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, and another drug effective in the treatment of cancer. Preferably the other drug is effective in the treatment of leukemia and/or lymphoma. Most preferably the other drug is selected from the group consisting of methotrexate, cytosine arabinoside, mitoxantrone, vinblastine, methylprednisolone and doxorubicin.

The invention also encompasses a kit for use in the treatment or prevention of cancer which comprises a dosage form of aplidine or an aplidine analogue, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, a dosage form of another drug effective in the treatment of cancer, or a pharmaceutically acceptable prodrug, salt, solvate or hydrate thereof, and instructions for the use of each actor in combination for the treatment or prevention of cancer. Preferably the other drug is effective in the treatment of leukemia and/or lymphoma. Most preferably the other drug is selected from the group consisting of methotrexate, cytosine arabinoside, mitoxantrone, vinblastine, methylprednisolone and doxorubicin.

In a further aspect, the invention is directed to the use of aplidine for the treatment of chronic lymphocytic leukemia.

DETAILED DESCRIPTION OF THE INVENTION

By cancer it is meant to include tumors, neoplasias, and any other malignant tissue or cells. The present invention is directed to the use of aplidine or an aplidine analogue in combination for the treatments of cancer in general, but more preferably for the treatment of different leukemias and lymphomas.

In order to study the possible potentiation of other anticancer agents with aplidine we have initiated a systematic study of drug combinations for possible use in leukemias and lymphomas. Aplidine was found to be an effective in vitro cytotoxic agent against primary cells from a patient with preB-ALL (DM4) as well as against fresh cells obtained from six chronic lymphocytic leukemia (CLL) patients. The IC.sub.50 value was 10 nM for 3 day exposure with the DM4 line and after a 11 day exposure with the primary CLL samples.

Drug combination studies were carried out on established cell lines rather than primary cells. We studied three cell lines viz. K562, CCRF-CEM and SKI-DLCL representing acute myeloid leukemia, lymphoblastic lymphoma and diffuse B cell large cell lymphoma respectively. The data in the examples show that Aplidine potentiates the effect of methotrexate, cytosine arabino side, mitoxantrone, vinblastine, methylprednisolone as well as doxorubicin in K562, CCRF-CEM and SKI-DLCL cells by lowering the IC.sub.50s for the drugs.

Thus we have found that aplidine is a potent cytotoxic agent against cells of several hematologic mailgnancies. Significantly, we have established for the first time that aplidine inhibits growth of CLL cells in culture. We also found that aplidine enhances the cytotoxicity of agents used in the treatment of leukemias, such as methotrexate (MTX), cytosine arabonoside (AraC), mitoxantrone (Mitox), vinblastine (Vinb), methylprednisolone (Metpred) and doxorubicin (DOX).

Leukemia is classified by how quickly it progresses. Acute leukemia is fast-growing and can overrun the body within a few weeks or months. By contrast, chronic leukemia is slow-growing and progressively worsens over years.

The blood-forming (hematopoietic) cells of acute leukemia remain in an immature state, so they reproduce and accumulate very rapidly. Therefore, acute leukemia needs to be treated immediately, otherwise the disease may be fatal within a few months. Fortunately, some subtypes of acute leukemia respond to available therapies and they are curable. Children often develop acute forms of leukemia, which are managed differently from leukemia in adults.

In chronic leukemia, the blood-forming cells eventually mature, or differentiate, but they are not "normal". They remain in the bloodstream much longer than normal white blood cells, and they are unable to combat infection well.

Leukemia also is classified according to the type of white blood cell that is multiplying--that is, lymphocytes (immune system cells), granulocytes (bacteria-destroying cells), or monocytes (macrophage-forming cells). If the abnormal white blood cells are primarily granulocytes or monocytes, the leukemia is categorized as myelogenous, or myeloid, leukemia. On the other hand, if the abnormal blood cells arise from bone marrow lymphocytes, the cancer is called lymphocytic leukemia.

Other cancers, known as lymphomas, develop from lymphocytes within the lymph nodes, spleen, and other organs. Such cancers do not originate in the bone marrow and have a biological behavior that is different from lymphocytic leukemia.

There are over a dozen different types of leukemia, but four types occur most frequently. These classifications are based upon whether the leukemia is acute versus chronic and myelogenous versus lymphocytic, that is:

Acute myelogenous leukemia (AML): also known as acute nonlymphocytic leukemia (ANLL)--is the most common form of adult leukemia. Most patients are of retirement age (average age at diagnosis=65 years), and more men are affected than women. Fortunately, because of recent advances in treatment, AML can be kept in remission (lessening of the disease) in approximately 60% to 70% of adults who undergo appropriate therapy. Initial response rates are approximately 65-75% but the overall cure rates are more on the order of 40-50%.

Chronic myelogenous leukemia (CML) is known as a myeloproliferative disorder--that is, it is a disease in which bone marrow cells proliferate (multiply) outside of the bone marrow tissue. CML is easy to diagnose, since it has a genetic peculiarity, or marker, that is readily identifiable under a microscope. About 95% of CML patients have a genetic translocation between chromosomes 9 and 22 in their leukemic cells. The Philadelphia chromosome causes uncontrolled reproduction and proliferation of all types of white blood cells and platelets (blood clotting factors). CML is not yet curable by standard methods of chemotherapy or immunotherapy.

Acute lymphocytic leukemia (ALL)--also known as acute lymphoblastic leukemia--is a malignant disease caused by the abnormal growth and development of early nongranular white blood cells, or lymphocytes. The leukemia originates in the blast cells of the bone marrow (B-cells), thymus (T-cells), and lymph nodes. ALL occurs predominantly in children, peaking at 4 years of age.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in North America and in Europe. It is a disease of older adults and is very rare among people who are younger than 50 years of age. Men with CLL outnumber women by a 2-to-1 average. CLL is thought to result from the gradual accumulation of mature, long-lived lymphocytes. Therefore, this cancer is caused not so much by overgrowth as it is by the extreme longevity and build-up of malignant cells. Although the rate of accumulation varies among individuals, the extensive tumor burden eventually causes complications in all CLL patients.

The compositions of the present invention may comprise both components (drugs) in a single pharmaceutically acceptable formulation. Alternatively, the components may be formulated separately and administered in combination with one another. Various pharmaceutically acceptable formulations well known to those of skill in the art can be used in the present invention. Selection of an appropriate formulation for use in the present invention can be performed routinely by those skilled in the art based upon the mode of administration and the solubility characteristics of the components of the composition.

Examples of pharmaceutical compositions containing Aplidine or an aplidine analogue 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. Solubilised aplidine shows substantial degradation under heat and light stress testing conditions, and a lyophilised dosage form was developed, see WO99/42125 incorporated herein by reference.

Administration of aplidine or compositions of the present invention is based on a Dosing Protocol preferably by intravenous infusion. We prefer that infusion times of up to 72 hours are used, more preferably 1 to 24 hours, with about 1, about 3 or about 24 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. Infusion may be carried out at suitable intervals with varying patterns, illustratively once a week, twice a week, or more frequently per week, repeated each week optionally with gaps of typically one week.

The correct dosage of the compounds of the combination 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. Further guidance for the administration of aplidine is given in WO 0135974 which is incorporated herein by reference in its entirety.

For the present invention, analogues of aplidine can be used in place of APL, aplidine itself. Typically such compounds are as defined in WO 0202596. Examples of compounds for the present invention include the preferred compounds given in WO 0202596, and in particular we import into this patent specification the discussion of preferred compounds and related aspects given in WO 0202596. More preferably, the analogues are structurally close to aplidine, and usually differ from aplidine in respect of one amino acid or the terminal sidechain. The different amino acid can be in the cyclic part of the molecule or in the sidechain. Many examples of such compounds are given in WO 0202596, and they are candidates for use in the present invention.
 

Claim 1 of 14 Claims

1. A method of treating leukemia or lymphoma comprising administering to a patient in need of such treatment a synergistic amount of aplidine and a drug, wherein said drug is selected from the group consisting of methotrexate, cytosine arabinoside, mitoxantrone and methylprednisolone.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.
 

 

     
[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]