CA2301665A1 - Methods and compositions for treatment of aids-associated kaposi's sarcoma - Google Patents

Methods and compositions for treatment of aids-associated kaposi's sarcoma Download PDF

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CA2301665A1
CA2301665A1 CA002301665A CA2301665A CA2301665A1 CA 2301665 A1 CA2301665 A1 CA 2301665A1 CA 002301665 A CA002301665 A CA 002301665A CA 2301665 A CA2301665 A CA 2301665A CA 2301665 A1 CA2301665 A1 CA 2301665A1
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paclitaxel
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aids
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Gregory R. Harriman
Susan Griffing
Kenneth Duchin
Karl L. Mettinger
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • AHUMAN NECESSITIES
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    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
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    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The present invention comprises methods and compositions for treating a human with AIDS-associated Kaposi's sarcoma. More specifically, the method comprises administration of a taxane composition over a 3 hour infusion schedule. Importantly, the compositions and methods of administration allows for reduction of side effects and reduces the symptoms of Kaposi's sarcoma.

Description

, i FOR TREATMENT OF '.
AIDS-ASSOCIATED KAPOSI'S SARCOMA
Cross-Reference to Related Applications ~ i This application claims priority to U.S. Provisional i Application No. 601041,651, filed March 27, 1997. i i Technical Field The present invention relates to methods and compositions for treating AIDS-associated Kaposi's sarcoma in humans. More particularly, the present invention relates to j methods for treatitng AIDS-associated Kaposi's sarcoma using a i taxane composition.
Background of the Invention i Kaposi's sarcoma (KS) was initially described in 1872 attd, as originally described, is a rare tumor with an indolent clinical course occurring mainly in elderly males of Mediterranean or Ashkenazi Jewish descent. This form of KS is characterized by lower extremity skin nodules caused by blood vessel proliferation. The usually benign skin lesions in these patients rarely caused any problems or required any treatm~:nt.

..
With the advent of the AIDS era, a virulent form of KS has been expressed in individuals made immunodeficient by HIV (Human Imntunodeficiency Virus). AIDS (Acquired j Immunodeficiency Syndrome) and HIV infection cause worldwide healthcare problems, including a worldwide. increase in the incidence of Kaposi's sarcoma. In the United States in 1996, AIDS-associated Kaposi's sarcoma occurred in approximately 17% of gay men with AIDS and 1-5% of others infected with HIV. As the most common AIDS-related tumor, the treatment of KS has become an important facet of the treatment of AIDS. In association with AIDS (Acquired Immunodeficiency Syndrome), KS commonly presents as an aggressive widely disseminated neoplasm. The KS neoplasms arise in multiple foci from vascular endothelium or lymphatic tissue in skin, mucosal surfaces, lymph I S nodes and visceral organs, including liver, spleen, gastrointestinal tract and lung.
In some HIV positive patients, KS is confined to the skin and may not require intensive therapy. In contrast, other ' patients have an aggressive form of KS where lesions commonly progress from macules to plaques and nodules, which often coalesce and ultimately develop into fungating or ulcerated masses_ At the initial clinical presentation, many patients with AIDS-associated Kaposi's sarcoma present with multiple organ involvement. The most common, and also the most life-thxeatening, organs involved are the gastrointestinal tract and the lung. Gastrointestinal lesions are frequently associated with enteropathic and hemorrhagic symptoms. Pulmonary involvement may be particularly ominous and is often mistaken for opportunistic infections on clinical grounds.
Krown and colleagues developed a system for uniform staging and evaluation of clinical trial outcomes for AIDS-associated Kaposi's sarcoma patients based on three broad stratification criteria: a) Extent of tumor involvement; b) Immunologic status: c) Systemic illness. See Krown et al_, t "Kaposi's sarcoma and the Acquired Immunodeficiency Syndrome: A Proposal foz~ Uniform Evaluation, Response and Staging Criteria." J. Clin_ Onc. 7:1201 (1989). They divided patients into good zisk or poor risk based on the extent of tumor, the number of CD-4 positive cells, and whether or not associated systemic illness was present. This staging system, slightly modified, has been shown in a retrospective analysis to be predictive of survival.
. Cure or long-term complete remission of AIDS
associated Kaposi's sarcoma is unlikely with currently available treatment. Prior to the present invention, the major goal of treatment fox AIDS patients with KS was alleviation of symptoms, shrinkage of the tumors to relieve edema, organ compromise or psychological stress, and prevention of disease progression. Such treatments include local therapies that have been useful for palliation of localized cutaneous and mucosal lesions: Local therapies include radiation therapy, laser therapy, and whole lung irradiation. Surgery as a means of controlling KS has been found to be of minimal benefit.
Intra-lesional drug administration utiliziztg vinblastine, bleomycin, interferon, or TNF (tumor necrosis factor) has induced tumor regression. Other experimental biomodulatory agents have also been used iuntralesionally. These treatments generally require multiple injections and cause local inflammation that may result in ulceration, pain and secondary infections.
Photodynamic therapies have also been used to treat AIDS-associated Kaposi's sarcoma. Phototherapeutic drugs such as dihematoporphyrin were administered followed by laser treatment. Patients undergoing this therapy have to avoid direct su~alight, bright incandescent light or radiant heat for 30 days after treatment. This inconvenience for the patient and the need for special laser equipment makes this treatment plan unwieldy for most KS patients.

< t While these local approaches may temporarily alleviate symptonns, AIDS-associated Kaposi's sarcoma usually requires systemic therapy. Such systemic treatment has evolved from early trials of single cytotoxic or antiviral agents to combinations of cytotoxic and antivixal drug therapy. Prior to the present invention, none of the currently available treatments, single or corntbination administration, have proved to be successful over the Long terra without significant side effects.
Several cytotoxic agents, including the vinca alkaloids, vineristine, anthracyclines, platinum, and bleomycin have demonstrated anti-tumor activity in up to 40-50%a of patients. Combinations of these agents may induce responses in up to 85% of patients and a combination of adriamycin, bleonayein, and vincristine (ABV) induced a complete response in nearly 40% of patients_ In a prospectively randomized fashion, Gill et al. compared ABV with doxorubicin alone and demonstrated a disease-free survival of nine months with the combination vs. 3.5 months with the single agent. Overall survival was not significantly impacted_ See Gill, P.S. et al., "Systemic Treatment of AIDS-related Kaposi s Sarcoma: Results of a Randomized T~nial", Am_ J. Med. 90;427 (1991).
Recently, taxanes, such as paclitaxel, have been shown to have antitumor activity in a variety of tumors.
Paclitaxel is a novel microtubule stabilizing antitumor agent, originally isolated from the stem bark of Taurus bTevifolia, the western (Pacific) yew tree_ Paclitaxel acts by promoting the formation of unusually stable microtubules, and inhibits the normal dynamic reorganization of the microtubule network required for mitosis and cell proliferation. (See Schiff, P. B., et al. (1979) Nature 277, 665; Schiff, P. B., er al. (1981) Biochemistry 20, 3247). In the presence of paclitaxel, the concentration of tubulin required for polymerization is significantly lowered. Mierotubule assembly occurs without GTP
and at low temperatures, and the microtubules formed are more stable to depolymerization by dilution, calcium, cold, and r inhibitory drugs. Paclitaxel reversibly binds to polymerized tubulin, and other tubulin-binding drugs will bind to tubulin in the presence of paclitaxel.
A proposed mechanism for paclitaxel is that S paclitaxel interacts with the microtubule system of many types of organisms_ For example, in mammalian cells a 50 nM paclitaxel concentration usually causes a significant increase in microtubule number, with changes in' cell shape and mitotic arrest in actively dividing cells_ (Parness, J., et al. (1982) Biochem. Biophys. Res.
Commun. 105, 1082). These perturbations of microtubule function caused by paclitaxel have a critical impact on the cell because of the role played by microtubules in cell motility, secretion, and cell division.
Other mechanisms of paclitaxel have been recently demonstrated_ Paclitaxel induces apoptosis in cells by bcl-2 phosphorylation which is triggered by cRaf-1 activation. See M.V. Blagosklonny et al., (1996),Cancex Research, 56(8):1851 1854. Paclitaxel has also been shown to inhibit angiogenesis, a mechanism that is of particular interest in RS. See Klauber et al., Cancer Research (1997) 57:81-86. The tumors of KS are characterized by aberrant and enhanced proliferation of vascular structures.
Paclitaxel has been studied for its effect in combating growth of various tumors in numerous clinical trials using a variety of doses and administration schedules. Severe allergic reactions have been observed following administration of paclitaxel_ I~owever, it has been demonstrated that the incidence and severity of allergic reactions is affected by the rate of paclitaxel infusion and premedication with corticosteroids and antihistamines. (Weiss, R B., et al. (1990) r. Clin. Oncol. 8, 1263). Subsequently, paclitaxel has been approved as a second-line tt'eatment of ovarian and breast cancer in the US and other countries_ The success rate for tumor treatment with paclitaxel has been shown to be very dependent upon dose and administration regimen_ AIDS-associated Kaposi's sarcoma has previously been successfully treated with paclitaxel. These patients were not undergoing concurrent treatment with viral protease inhibitors.
Saville et al, in a phase II study using Taxolt~ (a Bristol-Meyers Squibb formulation of paclitaxel), at a dose . 135 tng/m2, administered intravenously over a three hours ~ period every Z1 days, have demonstrated a response rate of 65% (13/20 patients) in patients with AIDS-associated Kaposi's sareoma_ These thirteen patients had partial response, as defined by the modified Krown's method used. See Sa~ville, et al., "Treatment of HIV-Assocxated Kaposi's Sarcoma with paclitaxel (Taxol C8~)". Lancet 346:2b-28, 1995. Each of the five patients with pulmonary involvement responded. Neutropenia was the most frequent dose limiting toxicity. There were also some novel paclitaxel toxicities obsezved including fevers, rash and eosinophilia_ In another study, Grill et al., in a phase II~'study of paclitaxel at a dose of 100 mg/m2, administered over 3 hours every 14 days, fox patients with advanced or refractory AIDS-associated Kaposi's sarcoma, reported a 59% (16/27) response rate. The remaining 41°~ (11/27) of the evaluable patients had stable disease. Improvement in symptomatic lyrnphedema was noted in 19 of 20 patients. Thirty-seven percent of the patients experienced Grade 3-4 neutropenia. See Gill, P.S., et al.
submitted to 1995 ASH annual meeting December, 1-5, 1995, and Gxll, P_S_, et al., Paclitaxel (Taxol) in the Treatment of Relapsed or Refractory Advanced AIDS-related KS, ASCO, May 2996.
. Paclitaxel, like other chemotherapy agents, has been shown to create drug resistance in tumor cells. Drug resistance by tumor cells is a common response to chemotherapy agents.
Two mechanisms of paclitaxel resistance have been identified in vitro. In one cell type, resistance is due to drug efflux, which is the result of increased levels of membrane P-glycoproteins causing increased drug efhux. (Gupta, R. S. (1985) Cancer Treat. Rep. 69, 515)_ These cells are also resistant to the vines allcaloids, doxorubi.cin, and other natural products, and resistance r.

is reversible with calcium channel blockers such as verapamil (lZacker, E., et al. (1986) Cancer Treat. Rep. 70, 275). Another mechanism of resistance found in other paclitaxel resistant cells involves mutations xn the alpha- or beta-tubulin subunits.
(Schibler, M. J_, et al. (1986) J. Cell Biol. 102, 1522).
An added consideration when treating AIDS-associated Kaposi's sarcoma is the treatment that the patient is undergoing for the underlying HIV infection. Though treatment of HIV infection with AZT (zidovudine) first appeared to be effective, it has been found that many patients cannot tolerate AZT for very long or that AZT had little effect on the progression of their disease. Combintational therapies, including AZT combined with other nucleoside analogs such as ddI or ddC, have been shown to be somewhat effective in overcoming problems associated with AZ'Z' administration alone.
Combinational therapies have also included the'' reverse transcriptase inhibitors such as lamivudine, nevirapine, and stavudine.
Qne of the more recent treatments for AIDS/HTV that shows promise is the administration of viral protease inhibitors to block the replication of the virus itself. An example of such a viral protease inhibitor is l~lorvirTM, a product of Abbott Laboratories, con~only known as ritonavir_ Other known protease inhibittors include indinavir, nelfinavir, and saquinavir.
Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag pol polypeptide precursor which leads to production of non-infectious immature HIV particles.
Like other AIDS therapies, ritonavir-resistant HIV-1 isolates have been found in vitro. _ At the present time, ritonavir is indicated in combination with nucleoside analogs or as monotherapy for the tateatment of HIV-infection when therapy is warranted. The combination of ritonavir with certain other therapeutic agents is contraindicated because rittonavir changes the pharmaeokinetics of c , g many other drugs. Ritonavir is metabolized by cytochrome p450 enzymes and thus it may i.nb,ibit the metabolism of other drugs.
Therapy with ritonaviur is expected to produce a large increase in plasma concentrations of many drugs including bepridil, buprvpion, piroxicam, cisapride, quinidine and rifabutin. Use of protease inhibitors with sedatives such as alprazolam, diazepam and zolpidem has the potential for extreme sedation and respiratory distress and thus coadministratxon is contraindicated.
. Use of chemotherapeutic agents with protease inhibitors must be monitored closely because of the potential large increase in the plasma concentration-time curve, a measure of drug exposure.
Such cheznotherapeutic agents include paclitaxel. See package insert for Norvir or other protease inhibitors for a complete list of agents.
protease inhibitors do not provide a cure for HIV
~-f infection and thus the HIV-associated pathologies of AIDS, including KS, will continue to be a significant health concern.
With the advent of protease inhibitors for treatment of AIDS, there is new Mope for treatment of AIDS and its associated syndromes such as KS. What is needed therefore are new methods and compositions for AIDS-associated Kaposi's sarcoma that can be used in AIDS patients who are undergoing new treatments for the AIDS virus, such as viral protease inhibitors.
Particularly what is needed are methods and compositions for patients who have refractory AIDS-associated Kaposi's sarcoma who are undergoing HfV treatment with viral protease inhibitors.
Furthermore, prior to the present invention, no one has been able to demonstrate an effective regimen for treatment of patients undergoing antiviral treatment with viral protease inhibitors, who have AIDS-associated Kaposi's sarcoma, that provides long-term cessation of KS tumor growth and alleviation of associated problems of pain or organ involvement.
What is also needed are methods and compositions for treatment of AIDS-associated Kapvsi's sarcoma in patients ~ who have undergone liposomal anthracycline therapy that was unsuccessful. Thus, methods and compositions are needed that are capable of treating AIDS-associated Kaposi's sarcoma that is resistant or refractory, and that are safely and effectively combined with HIV therapeutics such as viral protease inhibitors.
Moreover, an infusion treatment regimen that would be efficacious in this treatment would be beneficial. Additionally, methods and compositions that are easily administered are needed.
In addition to infusion methods, a simple and efficacious method of treatment would be through the oral route.
Summary of the Invention Iz~ accordance with the present invention, compositions and methods are provided for treating Kaposi's sarcoma (KS) associated with IiIV (human immunodeflcientcy virus) infection or AIDS (Acquired Immunodeficiency .-f Syndrome). In particular, the compositions and methods are effective for persons who arc undergoing treatment for HIV
infection that includes administration of protease inhibitors. Also, the compositions and nnethods of the present invention are effective for persons with AIDS-associated Kaposi's sarcoma who have failed liposoznal anthracycline treatment for TES. These eompQSitions are easily administered and can be given in dosages that are safe at~d provide for manageable side effects.
The present invention comprises methods and compositions for treating Kaposi's sarcoma. Such methods and compositions comprise initial induction treatments and long-term maintenance treatments with taxanes such as paclitaxel_ Such an initial induction treatment method comprises infusion times of at least approximately 3 hours every two weeks, for approximately ten cycles of treatment. Lang term rnaintenanee treatment methods are effective to maintain clinical level tumor response and stabilization of disease. Such long-term schedules may enhance the activity of taxanes, such as paclitaxel. Thus a preferred embodiment of the long term maintenance method of the present invention is to administer a taxane such as paclitaxel as t.
a 3 hour infusion treatment, every two to four weeks, for more than 10 cycles, in patients with AIDS-associated Kaposi's sarcoma, to effectively treat the KS tumors and to alleviate the symptoms associated with KS.
5 The present invention also includes KS treatment compositions that comprise paclitaxel for treatment of HL'V' infected patients who are undergoing ueatrnent for viral infection t by administration of viral protease inhibitors or other new i treatz~nents that are metabolized by the liver. These patients may 10 ox may not have previously been treated unsuccessfully with liposomal anthracycline treatment for KS. Such compositions may be administered to humans with AIDS-associated Kaposi's sarcoma who are also taking vital protease inhibitors at paclitaxel doses of approximately 20 mg/mz to 200 mg/m2, more preferably at doses of SO rng/m2 to J.50 mg/m2, most preferably 100 mglm2, the dose level being dependent on the efficacy and toxicity of paclitaxel in tht patient.
The present invention also includes conrxpositions and methods for treatment of tumors with taxanes. Such co~nnpositions and methods rnay use various administrative routes for treatments of tumors. AIDS-associated Kaposi's sarcoma is a tumor that has been found by the present inventors to be treatable by administration of taxane compositions, and other tumor types are also treatable with the compositions and methods of the present invention.
Accordingly, it is an object of the present invention to provide methods and compositions to treat AIDS-associated Kaposi's sarcoma.
Another object of the present invention is to provide compositions comp_ rising taxanes for the treatment of AIDS
associated Kaposi's sarcoma.
It is yet another object of the present invention to provide methods of treatment of AIDS-associated Kaposi's sarcoma comprising long-term treatment with at least 10 cycles of taxane treatment.

It is another object of the present invention to provide methods of treatment for patients with AIDS-associated Kaposi's sarcoma that have had tumor progression or no remission of disease after treatment with other chemotherapy 5 regimens_ It is yet another object of the present invention to provide a treatment for patients with AIDS-associated Kaposi's sarcoma who were refractory to treatment with liposomal anthracycline treatments.
10 A further object of the present invention is to provide methods and compositions for treatment of AIDS-associated Kaposi's sarcoma in patients who are also concurrently undergoing treatment for viral infection by administration of viral protease inhibitors.
15 An abject of this invention is to provide methods and compositions for treatment of AIDS-associated Kaposi's sarcoma in patients who are currently undergoing treatment for viral infection by administration of nucleoside or other antiviral compositions.
20 It is another object of the present invention to provide methods and compositions for paclitaxel administration that reduce or alleviate the symptoms of AIDS-associated Kaposi's sarcoma in persons infected with ~'V.
A further object of the present invention is to 25 provide methods and compositions for treatment of AIDS
associated Kaposi's sarcoma in patients who are also concurrently undergoing treatment for viral infection by administration of combination therapy including viral protease inhibitors and nucleoside analogs or reverse transcriptase inhibitors.
30 These and other objects, features and advantages of the present invention will become apparent after a review of the following detailed description of the disclosed embodiments and the appended claims.

Detailed Descritption The present invention comprises compositions and methods for the treatment of AIDS-associated Kaposi's sarcoma.
5 One embodiment of the present invention is the use of taxanes, such as paclitaxel or taxotere, via long-term schedules of at least cycles, to treat patients with AIDS-associated Kaposi's sarcoma who are also undergoing antiviral treatment, such as viral . protease inhibitors. The present invention also comprises shorter 10 term schedules of patients. The present invention also contemplates co~tnpositions and methods for treatment for patients undergoing antiretroviral therapy that has been recognized by governmental agencies such as those recommended by guidelines provided by the Department of Health and Human Services, U.S.
15 Government. The present invention also comprises treatment of patients with AIDS-associated Kaposi's sarcoma who have failed liposomal anthracycline treatments for Kaposi's sarcoma. As used herein, taxane treatment includes treatment with paclitaxel, Taxol~ (BMS), and Taxotere~, docetaxel, or combinations of 20 taxanes, and where paclitaxel is used herein, the other taxanes could be substituted therefor.
A known proposed ~,eehanism for paclitaxel is that paclitaxel interacts with the microtubule system of many types of organisms. Other mechanisms of paclitaxel activity include 25 induction of apoptosis in cells by bc1-2 phosphorylation, triggered by cRaf-1 activation and inhibition of angiogenesis. Though not wishing to be bound by any theory, it is hypothesized that these latter two mechanisms of activity may be accomplished by lower plasma concentrations of paclitaxel than the amount necessary to 30 induce microtubule disruption. Thus, treatment methods, heretofor unknown, using paclitaxel at lower plasma concezttrations xnay be possible to treat diseases or pathologies.
The present invention also comprises compositions and mettaods of treatment of AIDS-associated Kaposi's sarcoma iti 35 patients who have not ~tesponded to or v~ho have been intolerant of previous systemic chemotherapy. Such systemic chemotherapy may include, but is not limited to, treatments involving Doxil~ or DaunoXome~. Doxil~ is an approved therapy for use in patients who have failed prior chemotherapy, whereas DaunoXozne~ is not. These drugs are broadly classified as liposomal.
anthracylines. Thus, the present invention contemplates compositions and methods comprising paclitaxel treatments for patients with AIDS-associated Kaposi's sarcoma who have failed . at least one systemic chemotherapy treatment.
An aspect of the present invention is to provide paclitaxel compositions and methods that are commensurate with, and complexn,entary with, antirctroviral therapy treatnrrent for HIV patients according to approved therapies provided by governmental agencies such as the guidelines provided by the Depamnent of Health and Human Services. Examples of such guidelines are the 1997 drafts of the Report of the NIH Panel to Define Principles of Therapy of HIV Infection, and Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Such guidelines are both announced in the Federal Register and are available from the National AIDS Clearinghouse (http://www.cdcnac.org) and from the HIV/AIDS Treatment Information Service (http://www.hivatis.org). Guidelines are also available at http://www.nih.gov/pr/jun'97,niaid-19 htm. Such documents are herein incorporated in their entirety_ Final forms of the documents are published in the Center for Disease Control and Prevention Morbidity and Mortality Weekly Report.
The Guidelines recommend starting treatment with three drugs and changing at least two drugs when there are indications that treatment is failing, such as when HIV levels in the blood increase. Treatment with only two drugs, in general, is considered less than optimal. Treatment with only one drug is not recommended. However, monotherapy of zidovudine (AZT) is recomumended prophylaxis to prevent HIV transmission to a baby and should be given to relatively healthy HIV-infected pregnant 35. women.
_ . ~._~._._ nnin nin Lni urt1Tn11Y. nW~nn trtT"ln.f nnn~'I"1'Tnn The Guidelines recommend that all patients with AIDS, as defined by the 1.993 CDC Classification System, or those with symptomatic HIV infection, should be placed on andretroviral therapy regardless of viral load. Asymptomatic patients with CD+4 T cell count of less than 500 or with HIV
RNA levels greater than 10,000 copies (by bDhTA test) or greater than 20,000 copies (by RT-PCR test) should be offered therapy. .
However, othez considerations, such as drug toxicity and willingness of the patient to start therapy and comply, will affect IO the strength of the recommendation for therapy.
A regimen suggested by the Guidelines is for treatment of HT'V infected patients with two nucleoside reverse txanscriptase inhibitors and one protease inhibitor to achieve maximum viral suppression. An alternative suggested regimen is to substitute nevirapine fox the protease inhibitor. For acute infection with HIV, the combination of two nucleoside inhibitors and o:ne protease inhibitor is recommended. It is also suggested that if antiviral therapy is halted for an extended time, that treatment with all of the antiyiral drugs cease, rather than continuing treatment with one ox two drugs, to minimize the potential for encouraging resistant viral strains.
There are also suggested considerati,Q~ns for changing treatments in view of a failing regimen. Considerations include distinguishing between drug failure and drug toxicity. Arug toxicity requires the substitution of a different drug for the suspected toxicity causing agent, whereas in drug failure, at least two of the drugs must be changed.
Preferred embodiments of the present invention include the treatment of patients with AIDS-associated Kaposi's sarcoma at dosages of a taxane at 20 mg/m2 to 200 m~g/m2, more preferably at doses of 50 mg/m2 to 150 mg/m2, most preferably 100 mg/na2, the dose level being dependent on the efficacy and toxicity of paclitaxel on the patient. It is contemplated in the present invention that treatment dosages may change, especially from an initial induction ~ period dosage to a Iong-term __ ,_ _,__ ..._ nrr.~ ri.r i.ni. untrnv n nwrn. nrfrr~T CCCT '17'1(' maintenance period dosage_ A preferred embodiment of the method of administration for initial induction period is a dosage of approximately 100 mg/m2 of a taxane and a dosage of 20 mg/m2 to 80 mg/m2, more preferably 25 to 50 mg/m2.
5 The infusion schedule for such methods include duration of at least 3 hours every two weeks, for more than at least 10 cycles of treatment As used herein one cycle means ozte infusion treatment with a taxane, which in a preferred embodiment, one cycle equals a two to four week period.
10 Administaration of taxanes within this range, at doses lower than 100 mg/m2 is also contemplated within the present invention. Treatments comprising lower than 100 mg/m2 for patients who cannot tolerate the 100 mg/m2 dosage level confers successful outcomes for these patients. Additionally, the present 15 invention is not limited by the length of time between the administration of the taxane compositions. The time ~ between cycles, the period of taxane administration may be less than 10 days, or greater than 14 days such as at least 30 days. The length of time between taxane administrations may be dependent on the immune status of the patient or other medical considerations.
Such considerations are well known to those skilled iz~ the art and do not provide a limitation to the practice of the present invention.
Compositions included in the present invention include taxanes, preferably paclitaxel or taxotere, most preferably paclitaxel. Such compositions also comprise mixtures of taxanes.
In a most preferred embodiment, the present invention comprises compositions and methods of treatment of patients with AIDS-associated Kaposi's sarcoma who undergo intravenous infusion of paclitaxel in a 3 hour infusion rate with a dose of 100 mg/m2 paclitaxel every 14 days and who are also undergoing antiviral treatment with a viral protease inhibitor. Another preferred embodiment comprises oral paclitaxel compositions and methods of treatment that provide a treatment similar to the intravenous infusion in patients who axe undergoing antiviral treatment with a .,., .. _".., ."_ nrs.n nxr i.ns. nnwnv » n~~rnr nrlCC'T CCCt 'i'7 'r!7n viral protease inhibitor. Other preferred embodiments comprise compositions and methods of treatment of patients with AIDS, i associated Kaposi's sarcoma who undergo intravenous infusion of ,I
paclitaxel in a 3 hour infusion rate with a dose of 100 mg/m2 paclitaxel every 14 days and who have previously failed treatment by systemic chemotherapy. Another preferred embodiment comprises oral paclitaxel compositions and methods of treatment j that provide a treatment similar to the intravenous infusion in . patients who have previously failed treatment by systemic j chemotherapy. Prefented embodiments of the present invention include treatments with paclitaxel, administered in any available ;
foam, and may be used for AIDS-associated Kaposi's sarcoma patients who have both failed previous systemic chemotherapy .;
treatments and who are uztdergoing antiretroviral therapy, such as that recommended by the U.S. Department of ~iealth and ~Iuman Services, and therapies that include a protease inhibitor. ~'~
As used herein, paclitaxel (USAN generic name) is 513, 20-epoxy-l,2oc,4,7B,10f3,13oc-hexahydroxytax-11-en-9-one 4, 10-diacetate 2-benzoate 12-ester with (2R,3S)-Nbenzoyl-3- i phenylisoserine.
The patients to be treated by the present invention , i include humans with AIDS-associated Kaposi's sarcoma who are undergoing antiviral therapy with viral protease inhibitors an;d other antiviral agents. The present invention also contemplates ;
treatment of AIDS patients who are undergoing antiviral :I
treatments that axe metabolized by the liver and that are also ,' known to effect the pharznacokinetics of concomitantly used drugs. Integrase treatments are also contemplated with the compositions and methods of the present invention. In one embodiment of the present invention, the methods and compositions are useful for patients who have previously undergone liposomal anthracycline treatment for Kaposi's sarcoma wherein such treatment was unsuccessful.
Kaposi's sarcoma (KS) as used herein refers to the 3S ~aposi's sarcoma associated with infection with a virus that causes .,. .. .."" ._,. rrs.n rs.r x.ns. uwrnv n nn.,n" n"xr ~ r rrrt W 7 'tan AIDS (Acquired Immunodeficiency Disease Syndrome). Prior to the advent of AIDS, Kaposi's sarcoma ~uvas described as a rare tumor occurring mainly in elderly men of Mediterranean or Ashkenazi Jewish desccnt. The KS of these elderly men was characterized by lower extremity skin nodules caused by blood vesscl proliferation. AIDS-associated Kaposi's sarcoma has a very different clinical course and patient population. The AIDS-associaLed Kaposi's sarcoma is an aggressive and widely . disseminated neoplasm that can be found in any structure in ~ the body of the pexson with AIDS. The AIDS-associated Kaposi's sarcoma can be life threatening and highly disabling.
Sevcral cytotoxic treatments have been used to treat the aggressive AIDS-associated Kaposi's sarcoma, including vinca alkaloids, vincristinc, platinum, bleomycin and anthracyclines.
Combinations of these agents, such as AB V therapy, a combination of doxorubicin (adriamycin), bleomycin and vincristine, have induced responses in as much as 40% of the treatcd patients. Liposomal DaunoXome~ and Doxil~ are gaining rapid acceptance for treatment of advanced AIDS-associated Kaposi's sarcozzta because the response rates are comparable to AB V but show a better toxicity profile. however, for patients who have failed DaunoXome~ or Doxi1~ and ABV, few therapeutic options rcmain. The compositions and methods of the present invention have been shown to be safe and effective in such patients.
With most AIDS treatment regimens, the ovezxi.ding determinants of clinical response and survival are the extent of CD4+ cell destruction and history of opportunistic infection.
Alpha interferon has also induced responses, most commonly in patients with CD4+ counts above 150/mm3, and whcn used in combination with AZT thexe is some cvidence of synergy. See Fischl, M.A. "Antiviral Therapy in combination with Interferon for AIDS-related Kaposi's Sarcoma," Am. J. Med. 902S. (1991).
The advent of new treatments for the underlying viral infection of patients with AIDS-associated Kaposi's sarcoma .". . ~, "., .... nnz~7 ri.r s.ni, unttnv n nrrvTnn nr rLr ~ r CCC t '~ 7 't!Tn Il li L . L 1 . 1 J J J 1 . a T s ata a v Lt W a I 1 a a 1 L m i a -a w ~ .. a v v .. . ~ . . .. _ . .. .-has affected the possible treatments for KS. Several of the new viral therapies, such as viral protease inhibitors, can modify the pharmacokinetics of drugs used to treat AIDS-associated Kaposi's sarcoma. The viral proteases inhibitors are metabolized by the liver and thus, effect the metabolism of many other drugs. For example, paclitaxel is cautioned for use with one viral protease inhibitor, ritonavir, because of the potential large increase in the plasma concentration-time curve of paclitaxel. Other viral treatments may also effect paclitaxel pharmaeokineties and are thus contemplated by the present invention.
In most countries, paclitaxel has been registered for both platinum pretreated ovarian cancer and for anthraeycline-resistant breast cancer in a dosage of 175 mg/m2 administered as a three-hour i~nfusion_ Most phaxmacokix~etic data of paclitaxel have been gathered during phase I clinical trials in which the drug was given as a one-hour infusiozt daily for five days (15-30 mg/m2); as a six-hour infusion (15-275 mg/m2 ); as a 24-hour a.: infusion (100-390 mg/m2); or as a 96-hour infusion (120-160 mg/m2). Evidence frotz~. a sensitive assay of the metabolism of paclitaxel indicates that the drug circulates for a prolonged period of time. See Huizing, M.T. and Beijnen, r.H., "Bioanalysis and Clinical Pharmacology of Paclitaxel," Taxane 'Journal, Vol. II, No. 1 May, 1996.
Early studies indicated a linear pharmacokinetic behavior of paclitaxel with the clearance independent of dose and schedule. Other schedules and doses however, have shown that the pharrnacokinetic behavior is non-linear. When paclitaxel is given during a 24-hour infusion there are linear kinetics. When paclitaxel is administered in six hours or less as an intravenous infusion, non-linear pharmacokinetics become apparent. When paclitaxel is administered as a 3-hour infusion at dosages above 135 mg/m2, the paclitaxel clearance decreases within increasing dose, indicating non-linear saturation pharmacokinetics. This phenomenon appears with the maximal plasma concentration values which increase exponentially with dose_ These findings J1:1. Ll. 1JJJ 1~JJaau ~~atLiU tF llUalLf1 'ZV'f JTJ LTJJ

were thought to be consistent with saturable processes of elimination with paelitaxel, occurring when the plasma concentrations of the drug are above the level of saturation. The occurrence of non-linear pharmacokinetic behavior may have clinically important conseduences, as this kinetic behavior may lead to dramatic changes in drug exposure when changing dose and or schedule. See Huizing, M.T. and Beijnen, J.H., "Bioanalysis and Clinical Pharmacology of Paclitaxel," Taxane Journal, Vol. YI, No. 1 May, 1996.
Prior to the present invention, there was great uncertainty in the connbination of taxane treatments, which are known to be highly sensitive to dose or schedule administration, with viral protease inhibitor treatments, which are known to effect the metabolism of taxanes. Thus prior teachings of use of paclitaxel, or other taxanes, for treatment of AIDS-associated Kaposi's sarcoma provide no teaching or suggestion for the combination of taxanes with viral protease inhibitors for AIDS-_~. associated Kaposi's sarcoma. Paclitaxel has been used to treat KS, but until the present invention, there has been no treatment of KS
in patients undergoing viral protease inhibitor treatment. It has been the present inventors surprising discovery that treatment of AIDS-associated Kaposi's sarcoma in patients undergoing AIDS
treatment with viral protease inhibitors such as Norvir, with paclitaxel, adxnitnistered in multiple cycles has provided a safe and effective treatment for AIDS-associated Kaposi's sarcoma. The plasma levels of paclitaxel obtained during and after a 1.00 mg/m2 infusion were surprisingly lower than those obtained at doses of 135 mg/m2, the dose which was the lowest one available from the published literature. ,Additionally, in two other patients treated 3Q with paclitaxel alone, and after two weeks of indinavir therapy, the surprising result was found that the patients did not show an appreciable difference in plasma paclitaxel concentration over time _ The following description teaches the administration of a composition comprising paclitaxel. Use of other taxanes in v7 r.. G 1. 1.77.7 1 ~ JJaiu ova Jiu Ui 11U111iti 'tU't J'iJ LYJ.u ""~ ~ ~ ~
~~ '~ ""
place of the paclitaxel is considered part of the present invention.
Use of other medical dtvices such as containers and infusion equipment is also contemplated by the present invention.
Paclitaxel BMP (Baker Morton Pharmaceutical) is 5 .generally supplied as a concentrated sterile solution, 6 mg/mL in 5 anapules (30 mg/ampule). Each mL of sterile solution contains 527 mg polyoxyethylated castor oil (Cremophor~ EL) and 49_79'0 (w/v) absolute alcohol BP. The contents of the ampules must be diluted prior to clinical use. The unused portions of any opened 10 ampules should be disposed of using 4SHA approved guidelines.
'Vials are stored either room temperature (approximately 25° C) or under refrigeration (2-8° C). Each paclitaxel infusion solution should be administered within 24 hours after preparation. Paclitaxel infusion solutions may exhibit 15 a slight haziness directly proportional to the concentration of dyrug and time elapsed after preparation. When prepared, paclitaxel infusion solutions are stable at ambient temperature _, (approximately 25° C) and normal lighting conditions for up to 48 hours. Formation of a small number of fibers in the paclitaxel 20 infusion solution (within acceptable limits established by the USP
Particulate Matter Test for LVP's) has been observed after preparation of paclitaxel infusion solutions. 'VSThile particulate formation does not indicate loss of drug potency, solutions exhibiting excessive particulate matter formation should not be used. ln-line filtration may be necessary and can be accomplished by incorporating a hydrophilic, microporous filter with a pore size no greater than 0.22 microns (IVEX-HP In Line Filter Set-SL, 15", Abbott model #4525 or equivalent) into the fluid pathway distal to the infusion pump.
Paclitaxel must be prepared in nonplasticized solution containers (e.g., glass, polyolefin, or polypropylene) due to leaching of diethylhexylphthlalate (DEHP) plasticizes from polyvinyl chloride (PVC) bags and intravenous tubing. Paclitaxel must not be administered through PVC intravenous sets.
Therefore, polyolefin- or polyethylene-line sets, such as IV

Jlil. L f. 1 JJJ 1 . JJllu ~vml,u uc I1u111itt ~tV~k J~tJ L'~JJ ~~ ~ "~ ~ ~' -~ ""

nitroglycerin sets (or equivalent) should be used to connect the container of the paclitaxel infusion solution to the IV
puutp, a 0.22 micron filter is then attached to the IV set, and then may be directly attached to the patient's central access device.
If necessary, a polyolefinline extension set (PolyfinTi"~
- Extension Set, MiniMed technologies, Model #126) can be used to provide additional distance between the IV pump and the patient's central access de'vice_ .

To practice one embodiment of the invention, the final paclitaxel infusion solution may be prepared by diluting the total paclitaxel dose {x.e., a 3 hour supply) in 250 yr 500 mL of 5% Dextrose Injection, USP ox 0.9% Sodium Chloride Injection, USP in either a glass, polyolefln or polypropylene container, The paclitaxel infusion solution will be infused over 3 hours through i 15 any methods known to those skilled in the art. Should a pump be used, a polyolefin- or polyethylene-line set should be used to connect the bag/bottle to the IV pump, followed by the in-line . filter_ The patient may or may not have a central access device which can be used for the infusion_ An embodiment of the present invention comprises administration of a paclitaxel infusion solution as a 3 hour continuous intravenous infusion_ The paclitaxel infusion solution can be delivered using any methods known in the art, with cycles i repeated every 14 days. Alternatively, oral administration of taxanes that provide pharmacolcinetic benefit, such as plasma levels of paclitaxel in therapeutic ranges, could be administered without requiring the patient to have a venous access_ Because of the possibility of anaphylactic reactions, a physician should be available during the first 30 minutes of each infusion, and intravenous epinephrine, hydrocortisone, and diphenhydramine should also be Dept available.

A preferred embodiment of the present invention is a method of treatment of patients with AIDS-associated Kaposi's sarcoma who have had disease progression after prior treatment with liposoznal anthracyclines_ A most preferred embodiment of the present invention is a method of treatment of humans with AIDS-associated Kaposi's sarcoma who have refractory KS and who are concurrently undergoing antiviral therapy such as treatment with viral protease xnhibitors_ This invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope thereof_ On the contrary, it is to be clearly understood that resort may be had to various other exnbodixnents, modifications, and equivalents thereof which, after reading the description herein, rztay suggest themselves to those skihed in the art without departing from the spit of the present invention and/or the scope of the appended claims.
. Example I
Treatment of AIDS-associated Kaposi's sarcoma s, consisted of a 3-hour infusion of paclitaxel at 100 mg/zn2 administered every 14 days for the first 10 cycles. The paclitaxel, 513, 20-epoxy-l,2oc,4,7B,lOLi,l3a-hexahydroxytax-11-en-9-one 4, 10-diacetate 2-benzoate I2-ester with (2R,3S)-Nbenzoyl-3 phenylisoserine, was supplied as a concentrated sterile solution, 6 mg/mL in 5 mL arrtpules (30 mg/ampule). Each mL of sterile solution contains 527 mg polyoxyethylated castor oil (Cremophore~ EL) and 49.7% (w/v) absolute alcohol BP. The contents of the vials must be diluted prior to clinical use. The unused portions of any opened vials should be disposed of using OSHA approved guidelines, and/or institutional policy, Vials should be stored either at room temperature (approximately 25°
C) or under refrigeration (2-8° C). Each bag/bottle should be administered within 24 hours after preparation, Solutions of paclitaxel may exhitbit a slight haziness directly proportional to the concentrarion of drug and time elapsed after preparation. Solutions of paclitaxel for infusion (0.3 uul. L1. iJJV/ 1.VV..u _~...,.. u, mvyyn yVT vZW ..aver ._ __ n - 1.2 mgJmL) axe stable at ambient temperature (approximately 25°C) and normal lighting conditions for up to 48 hours.
All of the patients treated had AIDS-associated Kaposi s sarcoma with measurable disease and had received at least one prior chemotherapy regimen. The patients had microscopically confirmed diagnosis of KS associated with ITV
infection for which systemic therapy is medically indicated by the presence of at least one of the following: greater than 25 mucocutaneous (mouth or skin) lesions; vitsceral involvement;
symptomatic lymphedema (pain); by physical exam or measurable disease by X-ray, CT or MRI; and had at least one systemic chemotherapy regimen which failed to maintain significant benefit. Intralesional chemotherapy regimens was not considercd as prior chemotherapy.
All patients undorwen,t a 3 hour paclitaxel infusion of 100 mg/m2 every two weeks. The following medications were administered prior to infusion to minimize the risk of ,,, hypersensitivity reactions: Dexaxnethasone 10-20 mg p.o. at 12 hours and again at 6 hours prior to beginning paclitaxel infusion.
Dexamethasone 20 mg IV, 60 min. prior to paclitaxel infusion, may be substituted fox the p.o. dose. The intravenous dose was reduced to 8-10 mg in subsequent cycles if no hypersensitivity reaction was noted xzt cycles one and two; cimetidine 300 mg or ranitidine 50 mg IV (intravenously) and diphenhydramine 50 ~aa.g IV (or p.o.) one hour before the beginning of paclitaxel infusion.
All tumor response classifications were made by comparing current lesion characteristics (i.e., size, number appearance and sitcs of involvement) to the patients' baseline tumor evaluations. If the patient had numerous cutaneous lesions, 5 discrete marker lesions were followed with bidimensional tumor measurements. Total body cutaneous lesions (up to 50) were counted every cycle with an indication as to the number of flat and raised lesions.
patient response was measured as follows.

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Complete response (CR): the absence of any detectable disease, including tumor-associated edema, lasting at least 4 weeks. _ Partial Response (PR) No new lesions (skin or oral), no new visceral sites of involvement or the appearance or worsening of tumor-associated edema or effusions and a 50% or greater decrease in the number of all previously existing lesions, (the decrease in the count must last at least 4 weeks); or a 50%
decrease in the sum of the products of the diameters of all a0 measurable visceral lesions lasting for at least 4 weeks; or complete flattening of at least 50% of all previously raised lesions (i.e., 50% of all previously nodular ox plaque-like lesions become macules); or 50% decrease in the sum of the products of the largest perpendicular diameters of the flue marker lesions.
Stable disease (SD): patients who do not qualify for response nor progressive disease_ Progressive disease (PD): new visceral sites of a. involvement or progression of visceral disease (i.e., increase in lesions or effusion on chest x-ray, increase in size or number of gastrointestinal lesions by endoscopy); or the development of new or increasing tumor-associated edema lasting at least one week and which interferes with the patient's normal activities; or a 25°70 increase in the number of lesions; or a Change in the character of 25% or more of all previously "flat" lesions to "raised" (i.e., 25%
of all previously macular lesions become nodular ox plaque-like);
oz~ a 25% increase in the sum of the products of the largest perpendicular diameters of the marker lesions.
Paclitaxel was given as a 3-hour infusion every 14 days for the first 10 cycles. After 10 cycles, the interval between cycles was 14-28 days. The dose of 100 mg/m2 was diluted in 5%
dextrose for injection, USP, or 0.9% sodium chloride fox injection, USP to a concentration of 0.3 to 1.2 mglmL. Paclitaxel was administered through a free-flowing intravenous line via a pump using non-PYC tubing and connectors, such as the TV
administration sets (polyethylene or polyolefin) used to infuse parenteral nitroglycerin. No other agent was infused concomitantly through the line used to administer paclitaxel.
Paclitaxel was administered through an in-line filter with a microporous membrane not greater than 0.22 microns 5 (e.g. IVEX 2). Solutions with excessive particulate formulation were discarded. After dilution, each bag/bottle was admizii~stered within 24 hours. A central line was not required for patients receiving a 3-hour infusion.
Eighty-nine patients were treated with paclitaxei for 10 AIDS-associated Kaposi's sarcoma. All patients had advanced KS
and all had been previously treated with systemic chemotherapy.
Sixty of the 89 patients had starting CD4 counts <200 while 49 of these patients had CD4 counts <50. Twenty-semen patients had disfiguring facial lesions, 37 had lymphedema and 28 had visceral 15 disease involving the lungs and/or the gastrointestinal tract.
All of the patients had previously undergone at least one systemic chemotherapy treatment for KS. Forty-three .}_ patients had previously received either vincristine or vinblastine (V); bleomycin and vincristine (BV) or Adriarnycin~, bleomycin 20 and vincristine (ABV). Forty-one patients had previously received liposomal DaunoXome~. Twenty-seven patients had previously received Doxil~. A total of 51 of the patients had received one or both of the systemic liposomal anthracycline drugs which had been unsuccessful in treating the ArDS-associated 25 Kaposi's sarcoma_ Of these 51 patients, 33 patients responded to treatment with paclitaxel, for a 65% response rate.
Among the $9 patients, there was an overall 52%
response rate. Patients previously receiving V, B V, or AB V had a 659'o response rate (28/43) while patients who previously received DaunoXome~ had a 51% (21/41) response rate. Patients who had previously received Doxil~ had a 41% (11/27) response rate.
Of these 89 patients, two patients had a complete response and 44 had partial responses (PR). A majority of the patients ~uvere taking viral pxotease inhibitors at some time during uaaa. c.i. 1JJ./ l.vv.... -....-... .n ........... -avx ..av ..ate... . _._ .
__ the paclitaxel treatment. The 89 patients were treated with paclitaxel with from one to 27 cycles of treatment (median of 8 i - cycles). Thirty-four patients have been treated with, more than 10 cycles of treatment. Such therapy represents maintenance treatment beyond the first 10 cycles of induction the~tapy.
Pharmacokinetic studies were performed in 9 0~ the patients during cycle G to I1. Peak concentration, area under the plasma concentration curve, volume of distribution and body clearance are presented in the following table. A comparison is made to data obtained from 135 mg/m2 and 175 mg/m2 tzeatz~t~ent j in patients with solid tumors.
Table I-_ Pharmacokinetic comparisons I Tumvr Dose N Cm~ AUCt~t CL V~ tl/2 ~~ (iy.~8~m2) (ng/mL) (nghr/mL)(~Jtu~/m2)m2 Type I
AIDS- 100 9 1118 3551 27.4 402 24.8 i KS

I 26.8 25.1 25.2 37.7 5.0 Lung 135 3 5687 14446 10.8 14.4 1.6 canr.~r 47.6 61.4 53.8 38.8 9.2 Luag 175 6 7852 22457 8.7* 22.1* 8_8'"

44 43_6 54.1 51.1 9.0 Bre~sd175 8 4214 12604 20.4 136.1 8.9 Ovarian (46.2) (52.2) (84.9) (118_0)(46.1) c~ip~x Example II
Treatment of ,A,IAS-associated Kaposi's sarcoma consisted of a 3-hour infusion of paclitaxel at I00 mg/m2 administered every 14 days as in the manner described in Example 1. This patient was a 32-year-old white male who was diagnosed HIV-positive in July 1993 and has had Kaposi's JIil, (.1, 1JJJ 1~JUaua .va.aau a a1u11Ln YVY JYJ LYJJ " ' ""- -' '-sarcoma since April 1994. ~S involvement included the skin, mouth, and inguinal nodes. By staging, he was a poor risk for tumor and systemic involvement and a good risk for immune status. Previous chemotherapy prior to entering the protocol included VP16, vincristine-vinblastine, and alpha-interferon, to which his best response was progressive disease. The patient was j treated with anti-retrovirai therapy starting at cycle 2 which consisted of the protease inhibitor indinavir and tvvo reverse transcriptase inhibitors, zidovudine and lamivudine. Triple anti retroviral drug therapy was continued throughout his treatment, which continued to cycle 19, although indinavir was switched to ritonavir after cycle 11 _ The patient tolerated treatment well, i with only two episodes of adverse events of grade 3 or greater.
One episode was a grade 3 fever and the other episode was a grade 3 heartburn. The fever was not considered by the j investigator to be attributable to paclitaxel, however the heartburn was.
w This patient showed a partial response to paclitaxel treatment. The Karnofsky performance scale showed an improvement from 70 at baseline to 80 during the study and the Symptom Distrcss Scale showed an improvement from 38 at baseline to 32 at cycle 10. Since the patient had greater than 50 lesions, 28 lesions on the arms and back were followed, of which a maximum of 21 resolved during treatment and only three remained raised. Also, at baseline the patient had extensive scrotal edema along with darkened lesions and edema of the right i leg. By cycle 4, the scrotal, edema markedly decreased and this improvement persisted through cycle 19. A marked decrease in the circumference of the right upper leg occurred during j 30 treatment from about 65 cm at baseline to <58 cm through cycle 19. The upper left leg also showed a decrease from about 60 cm at baseline to about 57 cm through cycle 19.

. . ., .... . .. ... .,. ~ .,....., ~ ..".... ., . ., . .. . .. _ . ., .. _.
_. ., . , .. _ . . _ I

Exatxrpl,e III
Initial treatment of AIDS~associated Kaposi's sarcoma consisted of a 3-hour infusion of paclitaxel at 100 mg/m2 administered every 14 days as in the ~rrianner described in Example 1, followed by treatment at 75 mglm2. This patient was a 33-year.-old black male who was diagnosed HIV.-positive in December 1994 and has had Kaposi's sarcoma since February 1995. KS involvement included the skin, face, mouth, and GI
tract. By staging, he was a poor risk defined by tumor and immune status and a good risk defined by systemic involvement_ Previous chemotherapy prior to entering the protocol included DaunoXomeC9 to which he showed stable disease but had toxicity, and Adriamycin0, bleoznycizt and vincristine, (.A B V) to which he responded partially, but subsequently failed. The patient was on antiretroviral therapy at the time he entered the protocol which consisted of the protease inhibitoz indinavir and two reverse ~transcriptase inhibitors, stavudine and lamivudine_ He continued on these medications throughout his treatment which went to cycle 17. Because the patient experienced a grade 4 neutropenia after the first cycle of paclitaxel, his dose was reduced to 75 mg/xn2 and he was treated with this dose through 17 cycles of treatment.
The patient also experienced a grade 3 urinary tract infection and a grade 3 infection of a scrotal ulcer which were considered by the investigator to be due to paclitaxel treatment. He also had grade 3 and grade 4 increased alkaline phosphatase and grade 3 pneumonia which were not felt to be attributable to paclitaxel.
During treatment with the reduced dose of paclitaxel (75 mg/m2) after the fi~cst cycle of treatment, this patient showed a partial response to paclitaxel. The Karnofsky performance i score improved from 60 at baseline to 90 at cycle 1.0 and the Symptom Distress Scale score improved from 3S at baseline to 18 I at cycle 10. Since the patient had greater than 50 lesions, eight lesions on the left forearm were followed, of which two cleared i and four flattened_ The patient had extensive facial lesions and extensive facial edema. A marked decrease in edema and the prominence of facial lesions was seen by cycle 7.
Example IV
Treatment of AIDS-associated Kaposi's sarcoma consisted of a 3..hour infusion of paclitaxel at 100 mg/m2 administered every 14 days as in the manner described in Example 1. This patient was a 41 year-old black male who was diagnosed HIV-positive in 1990 and had Kaposi's sarcoma since May x 996. KS involvement included the skin, face, and inguinal nodes, with equivocal involvement of the mouth and lung. By staging, he was a poor risk for tumor and imaxiune and a good risk for systemic involvement. Previous chemotherapy prior to entering this protocol veras DaunoXome~, to ~xrhich his best response was progressive disease. When the patient entered the protocol, he was on antiretroviral therapy, which consisted of the .protease inhibitors saquinavir and ritonavir and three reverse transcriptase inhibitors, didanosine, stavudine and lamivudine. He continued on these medications throughout his treatment which has gone to cycle 10. The patient tolerated treatment with paclitaxel well with the only serious adverse events experienced being a grade 3 and grade 4 neutropenia which the investigator attributed to paclitaxel.
The patient had a best response to paclitaxel of stable disease through 10 cycles of treatment. His Karnofsky performance score showed a decrease from 90 at baseline to 80 during cycles 3-10, whereas the Symptom Distress Scale, measured at baseline and cycle 4 showed no change_ Since the patient had greater than 50 lesions, 22 lesions on his fact and upper left thigh were examined, of which one flattened and none cleared. At baseline, numerous lesions were apparent on both legs and the right leg was edematous, with a larger size than the left and marked ankle swelling. The left lcg remained larger than the right throughout treatment, although it had appeared to ___. .... .___ _ __ .__._.. ._. ___ ____ I
decrease in size by cycle 4. The lesions appeared less prominent as a result of treatment. Measurement of the circumference of the lower legs showed no change from baseline in either leg (both 30 cm). However, the right upper leg showed a decrease from 59 5 cm to 57 cm during the study az~d the left leg a sznali decrease from 52.8 cm to 51.5 cm.
Example 'V
10 Treatment of AIDS-associated Kaposi's sarcoma consistcd of a 3-hour infusion of paclitaxcl at 100 mg/m2 administered every 14 days as in the manner described in Example 1. This patient was a 41 year old white male who was HIV-positive since 1985 and has had Kaposi's sarcoma since 15 March 1995. He had pulmonary and skin involvement of KS
lesions. By staging, he was a poor risk by tumor, immune and systemic involvement. Prcvious chemotherapy pxior to entering .>this protocol included both liposomal daunorubicin {[DaunoXome~) to which his best response was a partial response 20 and liposomal doxorubicin (Doxil~) to which his best response was tumor progression. Upon beginning treatment with paclitaxel, he had a partial responsc beginning at cycle 4. He had significant improvement in his pulmonary KS which was seen as early as cycle 4, with significant improvement persisting out to 25 cycle 19. His brcathing, cough and mobility scores improved with paclitaxel treatment_ Of note, the patient was on oxygen prior to treatment with paclitaxel, but was able to discontinue this after starting treatment with paclitaxel.
30 Exa~cnple VI
Treatment of AIDS-associated ~aposi's sarcoma consisted of a 3-hour infusion of paclitaxel at 100 mg/m2 admiu.istered every 14 days as in the manner described in Example I was begun with the following patients but due to medical considerations, their schedules were altered as described.
Patient #687 had his dose of paclitaxel reduced to 75 mg/m2 following the second cycle because of grade 3 hyperbilirubinemia. He continued on this reduced dose from cycles 2 through 7_ The patient had a partial responsc beginning at cycle 6.
Patient #688 had his dose of paclitaxel reduced to 75 mg/m2 following the fourth cycle after the patient experienced grade 3 diarrhea. He continued on this reduced dose from cycles 5 through 9. The patient had a partial response beginning at cycle 6.
Patient # 692 had his dose of paclitaxel reduced to 75 mg/m2 following the first cycle because of grade 4 neutropenia.
He continued on this reduced dose from cycles 2 through 11. 'The patient had a best response of stable disease.
Patient #630 had his dose of paclitaxel reduced to 75 s-mg/m2 following the 12th cycle after the patient experienced grade 4 neuuopenia. 1-ie continued on this reduced dose from cycles 13 through 27. The patient had a partial response which persists out to cycle 27> at the reduced dosc of paclitaxel.
Example VII
Treatment of .AIDS-associated Kaposi's sarcoma consisted of a 3-hour infusion of paclitaxel at 100 mg/m2 administered every 14 days as in the manner described in Example I was begun with the following patient but due to medical considerations, his schedulc was altered as described.
Patient # 637 had the interval of time between cycles increased to between 15-28 days (generally 21-28 days) after his 10th cycle. The patient has received -17 cycles of treatment.
Despite this increased interval between treatments (giving a dose intensity of 25-33 mg/m2 per week) the patient had a partial response maintained between cycles 11 and 17.

Table III shows the antiretroviral medications used by patients in the study detailed in Examples I-'VIII. Patients may have received more than one of each class at any time prior to, oz' during study.
Table II: Usage of Antiretroviral Medications , Number (%) of Patientsl (N
= 89) Started Prior Started During Treatment to first 10 c cles Date Stud Unknown N %) N (%) N (%

Protease 33 (37.1) 35 (39.3) 2 (2.2) Inhibitors Indinavir 21 23.6 21 23_6 2 2.2) Nelfinavir 0 0.0 6 6.7 0 0.0) Ritoriavxr 3 (3.4) 6 6.7) 0 (0.0) Sa uinavir 1.1 (12_4 8 9.0 0 (0.0 Reverse Transcriptase 59 (66_3) 40 (44.9) 6 (6.7) Inhibitors Didanosine 5 (5.6 4 4.5 0 (0.0 Lamivudine 43 (48.3 18 (20.2 5 (5_6 Nevira ine 1 (1.I) 4 (4.5 0 (0.0) Stavudine 31 34_8) 21 23.6) 2 (2.2) ~al.citabine 2 2.2) 1 ( 1 _ 1 0 (0.0) Zidovudine 24 (27.0) 8 (9.0) 2 (2.2) Patients may have received more than one of each class at any time prior to or during study.
lDoes not add across columns.

Table III: Best Response By Dse of Protease inhibitors (Evaluable I ~_a __.... wr--r~~
_.
Best t 10 Res C cles ozlse in Firs Total Success CompletePartial Stable Progression No. (CR or (CR) (PR) (S) (P) of PR) Patients# ('J~ # ~ # ~ # '~ # ~

No Protease 24 19 (79.2.)2 (8.3) 17 (70.8)4 (16.7)1 (4.2) Inhibitors Used During Study or >?dor tv Stud Protcasc Inhibitors53 27 (50-9)0 (0.0) 27 (50.9)26 (49.1)0 (0.0) Used Prior to or During Study Table IV: Tumor Response to Paclitaxel by Previous Systemic Chexx~,otherapy Treatment No. of PatientsBest Response ~' N to Paclitaxel in Fxrst 10 Cycles Success Complete Partial N' % N % N %) Previous Chemothera imezl eutic Re ABV 43 28 (65% 2 (59'0 26 60%

DaunoXome 41 21 51% 1 (2% 20 49%

Doxil 27 11 41 %) 0 0% 11 41 %) Qther 13 12 (92%) 0 0% 12 92%

Number of Previous Chemothera Treatments i 1 Prior 45 24 (539'0 1 2~) 23 5I%) 2 Prior 25 I7 68%) 1 4% 16 64%

> 2 Prior 7 5 (719'0) 0 09'0 5 (71 %) Exannple VIII
Pharmacokinetic Studies Patients were enrolled in a clinical study of paelitaxel , - in AIDS-KS as described in Example I. During one cycle of paclitaxel administration, ranging froze cycle 6 to 11 of therapy, patients who volunteered to participate in this study, remained at the clinic for serial plasma samplings. Relative to the 3-hr paclitaxel infusion, 7 mL of blood were obtained using a hepaz~i.nxzed Vacutainer~ tube for the determination of plasma paclitaxel concentrations at: 0 (prc-infusion), 0.5, 1, 2, 2,5 hr during infusion, 0 (end of infusion), 0.08 (5 minutes), 0.25 ( 15 minutes), 0.5 (30 minutes), 1, 1.5, 2, 3, 6, 8, 10, 18, 24, 30, and 48 hr post infusion. Each blood sample was centrifuged at 3500 rpm for 10 minutes. The separated plasma was transferred into labeled plastic vials (polypropylene) and then stored at -20°C until assayed.
w- Plasma coneentration,s of paclitaxel were determined using a validated LC/MS-MS method. Acetonitrile was added to a 0.8 mL plasma sample to precipitate plasma proteins, After centrifugation, the acetonitrile layer was evaporated to dryness.
An aliquot of the reconstituted extract was injected onto a SCIEX
AP III plus LCIMS-MS with a HPLC column. The lower limit of quantitation of paclitaxel was 50 pg/rnL. Plasma paclitaxel levels were subject to a noncompartmental analysis.
The nine patients from whom this data was obtained were IiIV-positive males with advanced AIDS-associated Kaposi's sarcoma (AIDS-KS). The patients (8 white, 1 black) who participated in this pharmacokinetics study had a mean age of 363 years (range: 27.7 to 48.5), mean weight of 154.5 kg (range 116 to 180), and mean height of 67.9 in. (range 64 to 72). AlI
patients, with the exception of Patient No. 651, were taking reverse transcriptase nucleoside analogs for their HIV disease.
The mean CD4 count at baseline inn these patients was 210.8 cells/mm3 (range. 17 to 640).

Pharmacokinetics: The mean (CV) values for various pharrnacokinetic parameters are shown in Table VI.
Tq~,lo 'V
C~~ AUCI~t AUCm CL ' ~d~ ud~s tl/2 n mL n ht/mL n -hr/mL/m2 m2 m2 1118 3551 3868 27.4* 9$0* 402* 24.B*

26.8 25.1 27.1 25.2 33.7 37.7 25.0 * n= 8 The pharmacokinetic evaluations occurred during cycles 6 to 11, but there was no relationship between the number of cycles of treatment the patients received and the pharnclacokinetic values obtained.
10 It is noteworthy that the CV for each of these parameters is lower than has been reported for higher doses of paclitaxel given over 3 hr. This suggests that lower doses may 'exhibit less intersubject variability compared to higher doses.
Although this was not a formal drug-drug interaction study, 15 patients also received numerous agents to treat the underlying HIV
infection and intercurrent illnesses. AIDS-KS patients typically receive concomitant antifungal agents, so the pharmacokinetics of paclitaxel were compared in the six patients receiving these concomitant imidazole antifungals and the three patients who were not. There were no 20 differences between these groups. Similarly, comparison of the pharmacokinetics in five patients receiving concomitant indinavir, a protease inhibitor, with those in four patients not receiving this agent showed no significaat differences. The mean percent changes in pharmaeol~netie values of paclitaxel after 2 weeks of indinavir (800 mg 25 tid) are noted in the following table.
Table VI
Mean Chan a Cmax AUCI~t A'UC~ CI. VdB

-16 +19 +26 -15 -2 r A number of analyses were done to determine whether demographic or economical status influenced the pharmacokinetic samples obtained. There were no significant relationships between the patient's age and various pharmacokinetic parameters (Cmax (r2= 0.26), AUCI~t (r2 = 0.14), CL (r2 = 0.11), and Vdss (r2 = 0.14)].
From an examination of the few patients with moderate elevations of liner function tests, it was concluded that impaired hepatic function may be associated with a modest reduction in the eliznxnation rate of paclitaxel from the systemic circulation.
Previous studies suggested that drug levels maintained above certain levels were associated with a higher incidence of decreases in white blood cell (WB C) and absolute neutrophil counts (ANC). No correlation could be determined between the datum of time paclitaxel levels were above 0.1 or y. 0.05 ~.~.M and changes in 'WBC and ANC, Five patients had Grade 3 non--hematological toxicities (alopecia (N =3), heartburn (N =
1), and elevated ALT (N = 1)] while participating in this study, although both xeports of alopeci.a occurred prior to the pharmacokinetic study day. There were no appreciable differences in AUC values from patients who developed these adverse events (3650 ng-hr/mL) compared to those who did not (3426 ng-hr/mLng-hr/mL).
There was no apparent di.~ference in the pharmacokinetacs of the five patients who were partial responders to paclitaxel administration and the four who were not at the time of the pharrnacokinetics study. Three of the remaining patients went on to become partial responders during the study.
The results of this study demonstrate that the exposure to paclitaxel after 100 mg/xn2 dose administered over 3 hours is considerably less than has been reported with conventional doses of 13S mg/m2 and higher given over this same interval in cancer patients with solid tumors. Body clearance and volume of distribution of paclitaxel were about 2 to 6 times higher with this lower dose of paclitaxel compared to the previously studied higher doses. As with the higher doses, the pharmacokinetics of paclitaxel appear to be nonlinear.
Interpat~ient variability is lower at this dose than noted in previous studies.
No significant drug-drug or drug level and efficacy or toxicity interactions were ztoted.
. It should be understood, of course, that the foregoing relates only to preferred embodiments of the present invention and that numerous modifications ox alterations may be made therein without departing from the spirit and the scope of the invention as set forth in the appended claims_

Claims (13)

What is claimed is:
1. A method for treatment of AIDS associated Kaposi's sarcoma comprising, concomitantly administering an effective dose of a taxane with one or more protease inhibitors to a human.
2. The method of Claim 1, further comprising concomitantly administering one or more reverse transcriptase inhibitors.
3. The method of Claim 1, wherein the dose of taxane is 30 to 200 mg/m2 every 2 weeks.
4. The method of Claim 1, wherein the dose of taxane is 50 to 155 mg/m2 every 2 weeks.
5. The method of Claim 1, wherein the dose of taxane is 100 mg/m2 every 2 weeks.
6. The method of Claim 1, wherein the human has failed therapy with liposomal anthracyclines.
7. The method of Claim 1, wherein the human has failed therapy with liposomal doxorubicin.
8. The method of Claim 1, wherein the human has failed therapy with combinations of adriamycin, bleomycin or vincristane.
9. The method of Claim 1, wherein the human has failed therapy with liposomal anthracyclines and combinations of adriamycin, bleomycin or vincristine.
10. The method of Claim 1, wherein the human has failed two or more prior cytotoxic chemotherapies.
11. The method of Claim 1, wherein the human receives an induction therapy of about 10 weeks.
12. A method of maintenance therapy for Kaposi's sarcoma patients who have responded to induction therapy of about 10 weeks comprising administering an effective dose of a taxane every 8 to 30 days.
13. The method of Claim 12, wherein the dose of taxane is between 50 to 100 mg/m2.
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