Patent Publication Number: US-2010112077-A1

Title: Nanoparticles of paclitaxel and albumin in combination with bevacizumab against cancer

Description:
TECHNICAL FIELD 
     The present invention relates to methods and compositions for the treatment of proliferative diseases comprising the administration of a combination of a taxane and at least one other and other therapeutic agents, as well as other treatment modalities useful in the treatment of proliferative diseases. In particular, the invention relates to the use of nanoparticles comprising paclitaxel and albumin (such as Abraxane®) in combination with other chemotherapeutic agents or radiation, which may be used for the treatment of cancer. 
     BACKGROUND 
     The failure of a significant number of tumors to respond to drug and/or radiation therapy is a serious problem in the treatment of cancer. In fact, this is one of the main reasons why many of the most prevalent forms of human cancer still resist effective chemotherapeutic intervention, despite certain advances in the field of chemotherapy. 
     Cancer is now primarily treated with one or a combination of three types of therapies: surgery, radiation, and chemotherapy. Surgery is a traditional approach in which all or part of a tumor is removed from the body. Surgery generally is only effective for treating the earlier stages of cancer. While surgery is sometimes effective in removing tumors located at certain sites, for example, in the breast, colon, and skin, it cannot be used in the treatment of tumors located in other areas, inaccessible to surgeons, nor in the treatment of disseminated neoplastic conditions such as leukemia. For more than 50% of cancer individuals, by the time they are diagnosed they are no longer candidates for effective surgical treatment. Surgical procedures may increase tumor metastases through blood circulation during surgery. Most of cancer individuals do not die from the cancer at the time of diagnosis or surgery, but rather die from the metastasis and the recurrence of the cancer. 
     Other therapies are also often ineffective. Radiation therapy is only effective for individuals who present with clinically localized disease at early and middle stages of cancer, and is not effective for the late stages of cancer with metastasis. Radiation is generally applied to a defined area of the subject&#39;s body which contains abnormal proliferative tissue, in order to maximize the dose absorbed by the abnormal tissue and minimize the dose absorbed by the nearby normal tissue. However, it is difficult (if not impossible) to selectively administer therapeutic radiation to the abnormal tissue. Thus, normal tissue proximate to the abnormal tissue is also exposed to potentially damaging doses of radiation throughout the course of treatment. There are also some treatments that require exposure of the subject&#39;s entire body to the radiation, in a procedure called “total body irradiation”, or “TBI.” The efficacy of radiotherapeutic techniques in destroying abnormal proliferative cells is therefore balanced by associated cytotoxic effects on nearby normal cells. Because of this, radiotherapy techniques have an inherently narrow therapeutic index which results in the inadequate treatment of most tumors. Even the best radiotherapeutic techniques may result in incomplete tumor reduction, tumor recurrence, increasing tumor burden, and induction of radiation resistant tumors. 
     Chemotherapy involves the disruption of cell replication or cell metabolism. Chemotherapy can be effective, but there are severe side effects, e.g., vomiting, low white blood cells (WBC), loss of hair, loss of weight and other toxic effects. Because of the extremely toxic side effects, many cancer individuals cannot successfully finish a complete chemotherapy regime. Chemotherapy-induced side effects significantly impact the quality of life of the individual and may dramatically influence individual compliance with treatment. Additionally, adverse side effects associated with chemotherapeutic agents are generally the major dose-limiting toxicity (DLT) in the administration of these drugs. For example, mucositis is one of the major dose limiting toxicity for several anticancer agents, including the antimetabolite cytotoxic agents 5-FU, methotrexate, and antitumor antibiotics, such as doxorubicin. Many of these chemotherapy-induced side effects if severe may lead to hospitalization, or require treatment with analgesics for the treatment of pain. Some cancer individuals die from the chemotherapy due to poor tolerance to the chemotherapy. The extreme side effects of anticancer drugs are caused by the poor target specificity of such drugs. The drugs circulate through most normal organs of individuals as well as intended target tumors. The poor target specificity that causes side effects also decreases the efficacy of chemotherapy because only a fraction of the drugs is correctly targeted. The efficacy of chemotherapy is further decreased by poor retention of the anti-cancer drugs within the target tumors. 
     Due to the severity and breadth of neoplasm, tumor and cancer, there is a great need for effective treatments of such diseases or disorders that overcome the shortcomings of surgery, chemotherapy, and radiation treatment. 
     Problems of Chemotherapeutic Agents 
     The drug resistance problem is a reason for the added importance of combination chemotherapy, as the therapy both has to avoid the emergence of resistant cells and to kill pre-existing cells which are already drug resistant. 
     Drug resistance is the name given to the circumstance when a disease does not respond to a treatment drug or drugs. Drug resistance can be either intrinsic, which means the disease has never been responsive to the drug or drugs, or it can be acquired, which means the disease ceases responding to a drug or drugs that the disease had previously been responsive to. Multidrug resistance (MDR) is a specific type of drug resistance that is characterized by cross-resistance of a disease to more than one functionally and/or structurally unrelated drugs. Multidrug resistance in the field of cancer is discussed in greater detail in “Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,” by Kuzmich and Tew, particularly section VII “The Multidrug-Resistant Phenotype (MDR),” Medical Research Reviews, Vol. 11, No. 2, 185-217, (Section VII is at pp. 208-213) (1991); and in “Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy,” by Georges, Sharom and Ling, Advances in Pharmacology, Vol. 21, 185-220 (1990). 
     One form of multi-drug resistance (MDR) is mediated by a membrane bound 170-180 kD energy-dependent efflux pump designated as P-glycoprotein (P-gp). P-glycoprotein has been shown to play a major role in the intrinsic and acquired resistance of a number of human tumors against hydrophobic, natural product drugs. Drugs that act as substrates for and are consequently detoxified by P-gp include the vinca alkaloids (vincristine and vinblastine), anthracyclines (Adriamycin), and epipodophyllotoxins (etoposide). While P-gp associated MDR is a major determinant in tumor cell resistance to chemotherapeutic agents, it is clear that the phenomenon of MDR is multifactorial and involves a number of different mechanisms. 
     A major complication of cancer chemotherapy and of antiviral chemotherapy is damage to bone marrow cells or suppression of their function. Specifically, chemotherapy damages or destroys hematopoietic precursor cells, primarily found in the bone marrow and spleen, impairing the production of new blood cells (granulocytes, lymphocytes, erythrocytes, monocytes, platelets, etc.). Treatment of cancer individuals with 5-fluorouracil, for example, reduces the number of leukocytes (lymphocytes and/or granulocytes), and can result in enhanced susceptibility of the individuals to infection. Many cancer individuals die of infection or other consequences of hematopoietic failure subsequent to chemotherapy. Chemotherapeutic agents can also result in subnormal formation of platelets which, produces a propensity toward hemorrhage. Inhibition of erythrocyte production can result in anemia. For some cancer individuals, the risk of damage to the hematopoietic system or other important tissues frequently limits the opportunity for chemotherapy dose escalation of chemotherapy agents high enough to provide good antitumor or antiviral efficacy. Repeated or high dose cycles of chemotherapy may be responsible for severe stem cell depletion leading to serious long-term hematopoietic sequelea and marrow exhaustion. 
     Prevention of, or protection from, the side effects of chemotherapy would be a great benefit to cancer individuals. For life-threatening side effects, efforts have concentrated on altering the dose and schedules of the chemotherapeutic agent to reduce the side effects. Other options are becoming available, such as the use of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), epidermal growth factor (EGF), interleukin 11, erythropoietin, thrombopoietin, megakaryocyte development and growth factor, pixykines, stem cell factor, FLT-ligand, as well as interleukins 1, 3, 6, and 7, to increase the number of normal cells in various tissues before the start of chemotherapy (See Jimenez and Yunis, Cancer Research 52:413-415; 1992). The mechanisms of protection by these factors, while not fully understood, are most likely associated with an increase in the number of normal critical target cells before treatment with cytotoxic agents, and not with increased survival of cells following chemotherapy. 
     Chemotherapeutic Targeting For Tumor Treatment 
     Both the growth and metastasis of solid tumors are angiogenesis-dependent (Folkman, J. Cancer Res., 46, 467-73 (1986); Folkman, J. Nat. Cancer Inst., 82, 4-6 (1989); Folkman et al., “Tumor Angiogenesis,” Chapter 10, pp. 206-32, in The Molecular Basis of Cancer, Mendelsohn et al., eds. (W. B. Saunders, 1995)). It has been shown, for example, that tumors which enlarge to greater than 2 mm in diameter must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. After these new blood vessels become embedded in the tumor, they provide nutrients and growth factors essential for tumor growth as well as a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner, New Eng. J. Med., 324(1), 1-8 (1991)). When used as drugs in tumor-bearing animals, natural inhibitors of angiogenesis can prevent the growth of small tumors (O′Reilly et al., O′Reilly et al., Cell, 79, 315-28 (1994)). Indeed, in some protocols, the application of such inhibitors leads to tumor regression and dormancy even after cessation of treatment (O′Reilly et al., Cell, 88, 277-85 (1997)). Moreover, supplying inhibitors of angiogenesis to certain tumors can potentiate their response to other therapeutic regimes (e.g., chemotherapy) (see, e.g., Teischer et al., Int. J. Cancer, 57, 920-25 (1994)). 
     Protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A. F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-111; S. A. Courtneidge, Dev. Suppl., 1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classified as receptor (e.g. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (e.g. c-src, Ick, Zap70) kinases. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. For example, elevated epidermal growth factor receptor (EGFR) activity has been implicated in non-small cell lung, bladder and head and neck cancers, and increased c-erbB-2 activity in breast, ovarian, gastric and pancreatic cancers. Thus, inhibition of protein tyrosine kinases should be useful as a treatment for tumors such as those outlined above. 
     Growth factors are substances that induce cell proliferation, typically by binding to specific receptors on cell surfaces. Epidermal growth factor (EGF) induces proliferation of a variety of cells in vivo, and is required for the growth of most cultured cells. The EGF receptor is a 170-180 kD membrane-spanning glycoprotein, which is detectable on a wide variety of cell types. The extracellular N-terminal domain of the receptor is highly glycosylated and binds EGF antibodies that selectively bind to EGFR. Agents that competitively bind to EGFR have been used to treat certain types of cancer, since many tumors of mesodermal and ectodermal origin overexpress the EGF receptor. For example, the EGF receptor has been shown to be overexpressed in many gliomas, squamous cell carcinomas, breast carcinomas, melanomas, invasive bladder carcinomas and esophageal cancers. Attempts to exploit the EGFR system for anti-tumor therapy have generally involved the use of monoclonal antibodies against the EGFR. In addition, studies with primary human mammary tumors have shown a correlation between high EGFR expression and the presence of metastases, higher rates of proliferation, and shorter individual survival. 
     Herlyn et al., in U.S. Pat. No. 5,470,571, disclose the use of radiolabeled Mab 425 for treating gliomas that express EGFR. Herlyn et al. report that anti-EGFR antibodies may either stimulate or inhibit cancer cell growth and proliferation. Other monoclonal antibodies having specificity for EGFR, either alone or conjugated to a cytotoxic compound, have been reported as being effective for treating certain types of cancer. Bendig et al, in U.S. Pat. No. 5,558,864, disclose therapeutic anti-EGFR Mab&#39;s for competitively binding to EGFR. Heimbrook et al., in U.S. Pat. No. 5,690,928, disclose the use of EGF fused to a  Pseudomonas  species-derived endotoxin for the treatment of bladder cancer. Brown et al., in U.S. Pat. No. 5,859,018, disclose a method for treating diseases characterized by cellular hyperproliferation mediated by, inter alia, EGF. 
     Chemotherapeutic Modes of Administration 
     People diagnosed as having cancer are frequently treated with single or multiple chemotherapeutic agents to kill cancer cells at the primary tumor site or at distant sites to where cancer has metastasized. Chemotherapy treatment is typically given either in a single or in several large doses or over variable times of weeks to months. However, repeated or high dose cycles of chemotherapy may be responsible for increased toxicities and severe side effects. 
     New studies suggest that metronomic chemotherapy, the low-dose and frequent administration of cytotoxic agents without prolonged drug-free breaks, targets activated endothelial cells in the tumor vasculature. A number of preclinical studies have demonstrated superior anti-tumor efficacy, potent antiangiogenic effects, and reduced toxicity and side effects (e.g., myelosuppression) of metronomic regimes compared to maximum tolerated dose (MTD) counterparts (Bocci, et al., Cancer Res, 62:6938-6943, (2002); Bocci, et al., PNAS, vol, 100(22):12917-12922, (2003); and Bertolini, et al., Cancer Res, 63(15):4342-4346, (2003)). It remains unclear whether all chemotherapeutic drugs exert similar effects or whether some are better suited for such regimes than others. Nevertheless, metronomic chemotherapy appears to be effective in overcoming some of the major shortcomings associated with chemotherapy. 
     Chemotherapeutic Agents 
     Paclitaxel has been shown to have significant antineoplastic and anticancer effects in drug-refractory ovarian cancer and has shown excellent antitumor activity in a wide variety of tumor models, and also inhibits angiogenesis when used at very low doses (Grant et al., Int. J. Cancer, 2003). The poor aqueous solubility of paclitaxel, however, presents a problem for human administration. Indeed, the delivery of drugs that are inherently insoluble or poorly soluble in an aqueous medium can be seriously impaired if oral delivery is not effective. Accordingly, currently used paclitaxel formulations (e.g., Taxol®) require a Cremophor® to solubilize the drug. The presence of Cremophor® in this formulation has been linked to severe hypersensitivity reactions in animals (Lorenz et al.,  Agents Actions  7:63-67 (1987)) and humans (Weiss et al.,  J. Clin. Oncol.  8:1263-68 (1990)) and consequently requires premedication of individuals with corticosteroids (dexamethasone) and antihistamines. It was also reported that clinically relevant concentrations of the formulation vehicle Cremophor® EL in Taxol® nullify the antiangiogenic activity of paclitaxel, suggesting that this agent or other anticancer drugs formulated in Cremophor® EL may need to be used at much higher doses than anticipated to achieve effective metronomic chemotherapy (Ng et al.,  Cancer Res.,  64:821-824 (2004)). As such, the advantage of the lack of undesirable side effects associated with low-dose paclitaxel regimes vs. conventional MTD chemotherapy may be compromised. See also U.S. Patent Pub. No. 2004/0143004; WO00/64437. 
     Abraxane® is a Cremophor® EL-Free Nanoparticle Albumin-Bound Paclitaxel 
     Preclinical models have shown significant improvement in the safety and efficacy of Abraxane® compared with Taxol® (Desai et al., EORTC-NCI-AACR, 2004) and in individuals with metastatic breast cancer (O′Shaughnessy et al., San Antonio Breast Cancer Symposium, Abstract #1122, December 2003). This is possibly due to the absence of surfactants (e.g., Cremophor® or Tween® 80, used in Taxol® and Taxotere®, respectively) in Abraxane®, and/or preferential utilization of an albumin-based transport mechanism utilizing gp60/caveolae on microvascular endothelial cells (Desai et al., EORTC-NCI-AACR, 2004). In addition, both Cremophor® and Tween® 80 have been shown to strongly inhibit the binding of paclitaxel to albumin, possibly affecting albumin based transport (Desai et al., EORTC-NCI-AACR, 2004). 
     IDN5109 (Ortataxel) is a new taxane, currently in phase II, selected for its lack of cross-resistance in tumor cell lines expressing the multidrug resistant phenotype (MDR/Pgp) and inhibition of P-glycoprotein (Pgp) (Minderman;  Cancer Chemother. Pharmacol.  2004; 53:363-9). Due to its hydrophobicity, IDN5109 is currently formulated in the surfactant Tween® 80 (same vehicle as Taxotere®). Removal of surfactants from taxane formulations e.g., in the case of nanoparticle albumin-bound paclitaxel (Abraxane®) showed improvements in safety and efficacy over their surfactant containing counterparts (O′Shaughnessy et al., San Antonio Breast Cancer Symposium, Abstract #1122, December 2003). Tween® 80 also strongly inhibited the binding of the taxane, paclitaxel, to albumin, possibly compromising albumin based drug transport via the gp60 receptor on microvessel endothelial cells (Desai et al., EORTC-NCI-AACR, 2004). 
     The antitumor activity of colchicine, which is the major alkaloid of the autumn crocus,  Colchicum autumnale , and the African climbing lily,  Gloriosa superba , was first reported at the beginning of the 20 th  century. The elucidation of its structure was finally completed from X-ray studies and a number of total syntheses (see Shiau et al.,  J. Pharm. Sci.  1978, 67(3) 394-397). Colchicine is thought to be a mitotic poison, particularly in tyhmic, intestinal, and hermatopoietic cells, which acts as a spindle poison and blocks the kinesis. Its effect on the mitotic spindle is thought to represent a special case of its effects on various organized, labile, fibrillar systems concerned with structure and movement. 
     Thiocolchicine dimer IDN5404 was selected for its activity in human ovarian subline resistant to cisplatin and topotecan A2780-CIS and A2780-TOP. This effect was related to dual mechanisms of action, i.e., microtubule activity as in Vinca alkaloids and a topoisomerase I inhibitory effect different from camptothecin. (Raspaglio,  Biochemical Pharmacology  69:113-121 (2005)). 
     It has been found that nanoparticle compositions of a taxane (such as albumin bound paclitaxel (Abraxane®)) have significantly lower toxicities than other taxanes like Taxol® and Taxotere® with significantly improved outcomes in both safety and efficacy. 
     Combination chemotherapy, e.g., combining one or more chemotherapeutic agents or other modes of treatment, e.g., combining for example, chemotherapy with radiation or surgery and chemotherapy, have been found to be more successful than single agent chemotherapeutics or individual modes of treatment respectively. 
     Other references include U.S. Pub. No. 2006/0013819; U.S. Pub. No. 2006/0003931; WO05/117986; WO05/117978; and WO05/000900. 
     More effective treatments for proliferative diseases, especially cancer, are needed. 
     The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety. In countries where this is appropriate, this application incorporates by reference any application to which this application claims the priority benefit. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention provides methods for the treatment of proliferative diseases such as cancer. The invention provides combination therapy methods of treating proliferative diseases (such as cancer), comprising a) a first therapy comprising administering to an individual an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and a carrier protein (such as albumin) and b) a second therapy, such as chemotherapy, radiation therapy, surgery, or combinations thereof. In another aspect, there are provided methods of administering to an individual a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and a carrier protein (such as albumin) based on a metronomic dosing regime. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of at least one other chemotherapeutic agent. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), and b) an effective amount of at least one other chemotherapeutic agent. In some variations, the chemotherapeutic agent is any of (and in some variations selected from the group consisting of) antimetabolites (including nucleoside analogs), platinum-based agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkloids, proteasome inhibitors, macrolides, and topoisomerase inhibitors. In some variations, the chemotherapeutic agent is a platinum-based agent, such as carboplatin. 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer, for example breast cancer) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising taxane (such as paclitaxel) and a carrier protein, and b) an effective amount of an anti-VEGF antibody (such as bevacizumab, for example Avastin®). In some variations, there is provided a method of inhibiting tumor metastasis (such as breast cancer metastasis) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising taxane (such as paclitaxel) and a carrier protein, and b) an effective amount of an anti-VEGF antibody (such as bevacizumab, for example Avastin®). In some variations, the effective amounts of the nanoparticle composition and the anti-VEGF antibody synergistically inhibit cell proliferation or metastasis. 
     In some variations, the effective amount of taxane in the nanoparticle composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane (e.g., paclitaxel) in the nanoparticle composition is about 100 mg/m 2 . In some variations, the taxane in the nanoparticle composition is administered weekly. In some variations, the effective amount of taxane in the nanoparticle composition is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the taxane in a nanoparticle composition is administered every two weeks. In some variations, the effective amount of taxane in the nanoparticle composition is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane (e.g., paclitaxel) in the nanoparticle composition is about 260 mg/m 2 . In some variations, the taxane in the nanoparticle composition is administered every three weeks. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg. In some variations, the anti-VEGF antibody is administered every two weeks or every three weeks. In some variations of the above dosages and/or administrations, the taxane is paclitaxel. In some variations of the above dosages and/or administrations, the anti-VEGF antibody is bevacizumab) (Avastin®. In some variations of the above dosages and/or administrations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (Avastin®) 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer, for example breast cancer) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of an anti-VEGF antibody (such as bevacizumab, for example Avastin®), wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, there is provided a method of inhibiting tumor metastasis (such as breast cancer metastasis) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising taxane, and b) an effective amount of an anti-VEGF antibody (such as bevacizumab, for example Avastin®), wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, the taxane-mediated induction of VEGF in vivo is taxane-mediated induction of VEGF-A. In some variations, the taxane is paclitaxel. In some variations, the taxane is docetaxel. In some variations, the composition comprising a taxane is a composition comprising nanoparticles comprising a taxane and a carrier protein. In some variations, the nanoparticles comprising a taxane are nanoparticles comprising paclitaxel. In some variations, the nanoparticles comprising a taxane are nanoparticles comprising docetaxel. 
     In some variations, the effective amount of taxane in the composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the composition is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane (e.g., paclitaxel) in the composition is about 100 mg/m 2 . In some variations, the taxane is administered weekly. In some variations, the effective amount of taxane in the composition is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the composition is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the taxane is administered every two weeks. In some variations, the effective amount of taxane (e.g., paclitaxel) in the composition is about 260 mg/m 2 . In some variations, the taxane is administered every three weeks. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of anti-VEGF antibody is between about 5 to about 10 mg/kg. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In some variations, the anti-VEGF antibody is administered every two weeks or every three weeks. In some variations of the above dosages and/or administrations, the taxane is paclitaxel. In some variations of the above dosages and/or administrations, the anti-VEGF antibody is bevacizumab (Avastin®). In some variations of the above dosages and/or administrations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (Avastin®) 
     In some variations, the composition comprising nanoparticles (also referred to as “nanoparticle composition”) and the chemotherapeutic agent are administered simultaneously, either in the same composition or in separate compositions. In some variations, the nanoparticle composition and the chemotherapeutic agent are administered sequentially, i.e., the nanoparticle composition is administered either prior to or after the administration of the chemotherapeutic agent. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent are concurrent, i.e., the administration period of the nanoparticle composition and that of the chemotherapeutic agent overlap with each other. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent are non-concurrent. For example, in some variations, the administration of the nanoparticle composition is terminated before the chemotherapeutic agent is administered. In some variations, the administration of the chemotherapeutic agent is terminated before the nanoparticle composition is administered. 
     In some variations, the first therapy taxane is nano-particle albumin bound paxlitaxel, described, for example, in U.S. Pat. No. 6,566,405, and commercially available under the tradename Abraxane®. In addition, the first therapy taxane is also considered to be nanoparticle albumin bound docetaxel described for example in U.S. Patent Application Publication 2005/0004002A1. In some variations, the anti-VEGF antibody is bevacizumab (i.e., Avastin®). 
     In another aspect, there is provided a method of treating a proliferative disease (such as cancer) in an individual comprising a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) a second therapy comprising radiation therapy, surgery, or combinations thereof. In some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual comprising a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), and b) a second therapy comprising radiation therapy, surgery, or combinations thereof. In some variations, the second therapy is radiation therapy. In some variations, the second therapy is surgery. In some variations, the first therapy is carried out prior to the second therapy. In some variations, the first therapy is carried out after the second therapy. 
     In another aspect, the method comprises administering to a mammal having a proliferative disease (such as cancer) a combination therapy comprising a first therapy comprising a taxane and a second therapy selected from the group consisting of chemotherapeutic agent and radiation or combinations thereof. The combination therapy may be administered in any of a variety of ways such as sequentially or simultaneously, and if sequential, the taxane may be administered before or after the second therapy although it is preferred that the first therapy comprising a taxane is administered first. It will also be understood that the second therapy can include more than one chemotherapeutic agent. 
     The present invention also provides metronomic therapy regimes. In some variations, there is provided a method of administering a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of taxane at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. In some variations, there is provided a method of administering a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of paclitaxel at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. In some variations, the dose of the taxane (such as paclitaxel, for example Abraxane®) per administration is less than about any of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 18%, 20%, 22%, 24%, or 25% of the maximum tolerated dose. In some variations, the nanoparticle composition is administered at least about any of 1×, 2×, 3×, 4×, 5×, 6×, 7× (i.e., daily) a week. In some variations, the intervals between each administration are less than about any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, and 1 day. In some variations, the nanoparticle composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30 and 36 months. 
     In some variations, there is provided a method of administering a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), wherein the taxane is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25 mg/m 2  to about 25 mg/m 2 . In some variations, there is provided a method of administering a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), wherein the paclitaxel is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25 mg/m 2  to about 25 mg/m 2 . In some variations, the dose of the taxane (such as paclitaxel, for example Abraxane®) per administration is less than about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 20, 22, and 25 mg/m 2 . In some variations, the nanoparticle composition is administered at least about any of 1×, 2×, 3×, 4×, 5×, 6×, 7× (i.e., daily) a week. In some variations, the intervals between each administration are less than about any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, and 1 day. In some variations, the nanoparticle composition is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30 and 36 months. 
     The methods of the invention generally comprise administration of a composition comprising nanoparticles comprising a taxane and a carrier protein. In some variations, the nanoparticle composition comprises nanoparticles comprising paclitaxel and an albumin. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm. In some variations, the paclitaxel/albumin nanoparticle composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the weight ratio of the albumin to paclitaxel in the composition is about 18:1 or less, such as about 9:1 or less. In some variations, the paclitaxel is coated with albumin. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel/albumin composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel is coated with albumin. Other combinations of the above characteristics are also contemplated. In some variations, the nanoparticle composition is Abraxane®. Nanoparticle compositions comprising other taxanes (such as docetaxel and ortataxel) may also comprise one or more of the above characteristics. 
     In some variations, there is provided a method of treating a proliferative disease in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising taxane and a carrier protein, and b) an effective amount of an anti-VEGF antibody, wherein the effective amount of taxane in the nanoparticle composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, there is provided a method of treating a proliferative disease in an individual comprising administering to the individual: (1) an effective amount of a composition comprising a taxane, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, the composition comprising the taxane is a composition comprising nanoparticles comprising a taxane and a carrier protein. 
     In some variations, the proliferative disease is cancer. In some variations, the cancer is breast cancer. In some variations, the anti-VEGF antibody is bevacizumab. In some variations, the effective amount of the anti-VEGF antibody is about 6 mg/kg. In some variations, the effective amount of the anti-VEGF antibody is about 8 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is between about 80 mg/m 2  to about 150 mg/m 2  of taxane in the nanoparticle composition. In some variations, the effective amount of taxane in the nanoparticle composition is between about 200 m g/m 2  to about 350 mg/m 2  of taxane in the nanoparticle composition. In some variations, the nanoparticle composition and the anti-VEGF antibody are administered sequentially to the individual. In some variations, the nanoparticle composition is administered for at least one cycles prior to the administration of the anti-VEGF antibody. In some variations, the administration of the nanoparticle composition is followed by the administration of an anti-VEGF antibody for at least about 3 weeks. In some variations, the method comprises administration taxane in a nanoparticle composition concurrent with administration of anti-VEGF antibody. In some variations, the taxane is paclitaxel. In some variations, the average diameter of the nanoparticles in the composition is no greater than about 200 nm. In some variations, the carrier protein is albumin. In some variations, the weight ratio of the albumin and the taxane in the nanoparticle composition is less than about 9:1. In some variations, the nanoparticle composition is free of Cremophor. In some variations, the individual is human. 
     In some variations, there is provided a method of inhibiting tumor metastasis in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising taxane and a carrier protein, and b) an effective amount of an anti-VEGF antibody, wherein the effective amount of taxane in the nanoparticle composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, there is provided a method of inhibiting tumor metastasis in an individual comprising administering to the individual: (1) an effective amount of a composition comprising a taxane, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, the composition comprising the taxane is a composition comprising nanoparticles comprising a taxane and a carrier protein. 
     In some variations, the tumor metastasis is metastasis to lymph node. In some variations, the tumor metastasis is metastasis to the lung. In some variations, the tumor metastasis is metastasis of breast cancer. In some variations, the anti-VEGF antibody is bevacizumab. In some variations, the effective amount of the anti-VEGF antibody is about 6 mg/kg. In some variations, the effective amount of the anti-VEGF antibody is about 8 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is between about 80 mg/m 2  to about 150 mg/m 2  of taxane in the nanoparticle composition. In some variations, the effective amount of taxane in the nanoparticle composition is between about 200 mg/m 2  to about 350 mg/m 2  of taxane in the nanoparticle composition. In some variations, the nanoparticle composition and the anti-VEGF antibody are administered sequentially to the individual. In some variations, the nanoparticle composition is administered for at least one cycles prior to the administration of the anti-VEGF antibody. In some variations, the administration of the nanoparticle composition is followed by the administration of an anti-VEGF antibody for at least about 3 weeks. In some variations, the method comprises administration of taxane in a nanoparticle composition concurrent with administration of anti-VEGF antibody. In some variations, the taxane is paclitaxel. In some variations, the average diameter of the nanoparticles in the composition is no greater than about 200 nm. In some variations, the carrier protein is albumin. In some variations, the weight ratio of the albumin and the taxane in the nanoparticle composition is less than about 9:1. In some variations, the nanoparticle composition is free of Cremophor. In some variations, the individual is human. In some variations, at least about 40% of metastasis is inhibited. In some variations, at least about 80% of metastasis is inhibited. 
     These and other aspects and advantages of the present invention will become apparent from the subsequent detailed description and the appended claims. It is to be understood that one, some, or all of the properties of the various variations described herein may be combined to form other variations of the present invention. 
    
    
     
       BRIEF DESCRIPTION OF FIGURES 
         FIG. 1A  shows the effect of ABI-007 on rat aortic ring angiogenesis. 
         FIG. 1B  shows the effect of ABI-007 on human endothelial cell proliferation. 
         FIG. 1C  shows the effect of ABI-007 on endothelial cell tube formation. 
         FIG. 2  shows the determination of an optimal biological dose of ABI-007 for metronomic dosing. Shown are the levels of viable circulating endothelial progenitors (CEPs) in peripheral blood of Balb/cJ mice in response to escalating doses of ABI-007. Untr&#39;d, untreated control; S/A, saline/albumin vehicle control. Bars, mean±SE. * Significantly (p&lt;0.05) different from the untreated control. 
         FIGS. 3A and 3B  show the effects of ABI-007 and Taxol® used in metronomic or MTD regimes on MDA-MB-231 (A) and PC3 (B) tumor growth tumor-bearing SCID mice.  FIGS. 3C and 3D  show the effects of ABI-007 and Taxol® used in metronomic or MTD regimes on the body weight of MDA-MB-231 (C) and PC3 (D) tumor-bearing SCID mice. 
         FIGS. 4A and 4B  show changes in the levels of viable circulating endothelial progenitors (CEPs) in peripheral blood of MDA-MB-231 ( FIG. 4A ) and PC3 ( FIG. 4B ) tumor-bearing SCID mice after treatment with A, saline/albumin; B, Cremophor EL control; C, metronomic Taxol® 1.3 mg/kg; D, E, and F, metronomic ABI-007 3, 6, and 10 mg/kg, respectively; G, MTD Taxol®; H, MTD ABI-007. Bars, mean±SE.  a  Significantly (p&lt;0.05) different from saline/albumin vehicle control.  b  Significantly (p&lt;0.05) different from Cremophor EL vehicle control. 
         FIG. 5A  shows intratumoral microvessel density of MDA-MB-231 (▪) and PC3 (□) xenografts treated with A, saline/albumin; B, Cremophor EL control; C, metronomic Taxol® 1.3 mg/kg; D, E, and F, metronomic ABI-007 3, 6, and 10 mg/kg, respectively; G, MTD Taxol; H, MTD ABI-007. Bars, mean±SE.  FIGS. 5B and 5C  show the correlation between intratumoral microvessel density and the number of viable CEPs in peripheral blood in MDA-MB-231 ( FIG. 5B ) and PC3 ( FIG. 5C ) tumor-bearing SCID mice. 
         FIG. 6  shows the effects of ABI-007 or Taxol used in metronomic or MTD regimes on basic fibroblast growth factor (bFGF)-induced angiogenesis in matrigel plugs injected subcutaneously into the flanks of Balb/cJ mice. Treatments-A, saline/albumin; B, Cremophor EL control; C, metronomic Taxol 1.3 mg/kg; D, E, and F, metronomic ABI-007 3, 6, and 10 mg/kg, respectively; G, MTD Taxol; H, MTD ABI-007. Matrigel implanted without bFGF (-bFGF) served as negative control. Bars, mean±SE. 
         FIG. 7A  and  FIG. 7B  show the cytotoxic activity of nab-rapamycin in combination with Abraxane® on vascular smooth muscle cells. Cytotoxicity was evaluated by staining with ethidium homodimer-1 ( FIG. 7A ) or by staining with calcein ( FIG. 7B ). 
         FIG. 8  shows the cytotoxic activity of nab-rapamycin in combination with Abraxane® in a HT29 human colon carcinoma xenograft model. 
         FIG. 9  shows the cytotoxic activity of nab-17-AAG in combination with Abraxane® in a H358 human lung carcinoma xenograft model. 
         FIGS. 10A and 10B  show necrosis in MDA-MB-231 tumor cells after treatment with saline control or Abraxane®.  FIGS. 10C and 10D  show hypoxia in MDA-MB-231 cells after treatment with saline control or Abraxane®. Arrows indicate sites of necrosis ( 10 A and  10 B) or sites of hypoxia ( 10 C and  10 D). 
         FIGS. 11A and 11B  show the effect of VEGF-A and Avastin® on Abraxane®-treated cells in cytotoxicity and clonogenic assays. In  FIG. 11A , results are shown as viable cells as a percentage of untreated cells. Dark circles indicate cells treated with Abraxane® alone; open circles indicate cells treated with Abraxane® and VEGF-A; dark triangles indicate cells treated with Abraxane® and Avastin®. In  FIG. 11B , results are shown as the mean number of cell colonies per plate. 
         FIG. 12  shows the effect of Abraxane® and Avastin® Avastin® treatment on the growth of MDA-MB-231 breast tumor xenografts. Dark squares indicate mean tumor volume in saline-treated mice; dark circles indicate mean tumor volume in Abraxane®-treated mice; dark diamonds indicate mean tumor volume in Avastin®-treated mice; open diamonds indicate mean tumor volume in Abraxane®+Avastin® (2 mg/kg)-treated mice; open circles indicate mean tumor volume in Abraxane®+Avastin® (4 mg/kg)-treated mice; triangles indicate mean tumor volume in Abraxane®+Avastin® (8 mg/kg)-treated mice. Two bars labeled ABX indicate the two Abraxane® treatment cycles. 
         FIGS. 13A and 13B  show the effect of Abraxane® and Avastin® treatment on metastasis of luciferase-expressing MDA-MB-231 tumor cells to the lymph nodes and lungs in tumor-bearing mice. Results are shown as levels of luciferase activity in lymph node or lung cellular extracts. 
         FIG. 14  shows the effect of solvent-based (i.e., Taxol®) and solvent-free (i.e., nab-paclitaxel, Abraxane®) formulations of paclitaxel on tumor volume ( FIG. 14A ) and reactionary angiogenesis ( FIG. 14B ) in paclitaxel-sensitive (MX-1 and MES-SA) and paclitaxel-resistant (MES-SA/Dx5) xenografts. 
         FIG. 15  shows that administration of Avastin® in combination with Abraxane® to mice bearing MDA-MS-231 human breast cancer xenografts significantly improves tumor suppression induced by Abraxane® alone. 
         FIG. 16  shows that combination therapy with Abraxane® and Avastin® but not Abraxane® or Avastin® alone resulted in sustainable tumor regressions in all treated mice for at least 95 days after tumor implantation. 
         FIG. 17  shows that combination therapy with Abraxane® and Avastin® but not Abraxane® or Avastin® alone resulted in inhibition of lymphatic ( FIG. 17A ) and pulmonary ( FIG. 17B ) metastasis. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides methods of combination therapy comprising a first therapy comprising administration of nanoparticles comprising a taxane and a carrier protein (such as albumin) in conjunction with a second therapy such as radiation, surgery, administration of at least one other chemotherapeutic agent, or combinations thereof. The invention also provides methods of metronomic therapy. 
     The present invention involves the discovery that Abraxane®, due to its superior anti-tumor activity and reduced toxicity and side effects, can be administered in combination with other therapeutic drugs and/or treatment modalities and can also be used in metronomic chemotherapy. Due to significantly improved safety profiles with compositions comprising drug/carrier protein nanoparticles (such as Abraxane®), we believe that combination chemotherapy with such nanoparticle compositions (such as Abraxane®) is more effective than combination chemotherapy with other drugs. In addition the use of nanoparticle composition (such as Abraxane®) in combination with radiation is also believed to be more effective than combination of other agents with radiation. Thus, the nanoparticle compositions (especially a paclitaxel/albumin nanoparticle composition, such as Abraxane®), when used in combination with other chemotherapeutic agents or when combined with other treatment modalities, should be very effective and overcome the deficiencies of surgery, radiation treatment, and chemotherapy in the treatment of proliferative disease (such as cancer). 
     The present invention in one its variations is the use of a first therapy comprising a taxane, such as Abraxane®, in combination with a second therapy such as another chemotherapeutic agent or agents, radiation, or the like for treating proliferative diseases such as cancer. The first therapy comprising a taxane and second therapy can be administered to a mammal having the proliferative sequentially, or they can be co-administered, and even administered simultaneously in the same pharmaceutical composition. 
     Further, a metronomic dosing regime using Abraxane® has been found to be more effective than the traditional MTD dosing schedule of the same drug composition. Such metronomic dosing regime of Abraxane® has also been found to be more effective than metronomic dosing of Taxol®. 
     The methods described herein are generally useful for treatment of diseases, particularly proliferative diseases. As used herein, “treatment” is an approach for obtaining beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing or delaying spread (e.g., metastasis) of disease, preventing or delaying occurrence or recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, and remission (whether partial or total). Also encompassed by “treatment” is a reduction of pathological consequence of a proliferative disease. The methods of the invention contemplate any one or more of these aspects of treatment. 
     As used herein, a “proliferative disease” is defined as a tumor disease (including benign or cancerous) and/or any metastases, wherever the tumor or the metastasis are located, more especially a tumor selected from the group comprising one or more of (and in some variations selected from the group consisting of) breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, colorectal cancer, head and neck cancer. In a broader sense of the invention, a proliferative disease may furthermore be selected from hyperproliferative conditions such as hyperplasias, fibrosis (especially pulmonary, but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or restenosis following angioplasty. In some variations, the proliferative disease is cancer. In some variations, the proliferative disease is a non-cancerous disease. In some variations, the proliferative disease is a benign or malignant tumor. Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer are mentioned, also metastasis in the original organ or tissue and/or in any other location are implied alternatively or in addition, whatever the location of the tumor and/or metastasis is. 
     The term “effective amount” used herein refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms. In reference to cancers or other unwanted cell proliferation, an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation. In some variations, an effective amount is an amount sufficient to delay development. In some variations, an effective amount is an amount sufficient to prevent or delay occurrence and/or recurrence. An effective amount can be administered in one or more administrations. In the case of cancer, the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; and/or (vii) relieve to some extent one or more of the symptoms associated with the cancer. 
     In some variations, there is provided a method of treating a primary tumor. In some variations, there is provided a method of treating metastatic cancer (that is, cancer that has metastasized from the primary tumor). In some variations, there is provided a method of treating cancer at advanced stage(s). In some variations, there is provided a method of treating breast cancer (which may be HER2 positive or HER2 negative), including, for example, advanced breast cancer, stage 1V breast cancer, locally advanced breast cancer, and metastatic breast cancer. In some variations, there is provided a method of treating lung cancer, including, for example, non-small cell lung cancer (NSCLC, such as advanced NSCLC), small cell lung cancer (SCLC, such as advanced SCLC), and advanced solid tumor malignancy in the lung. In some variations, there is provided a method of treating any of ovarian cancer, head and neck cancer, gastric malignancies, melanoma (including metastatic melanoma), colorectal cancer, pancreatic cancer, and solid tumors (such as advanced solid tumors). In some variations, there is provided a method of reducing cell proliferation and/or cell migration. In some variations, there is provided a method of treating any of the following diseases: restenosis, stenosis, fibrosis, angiogenesis, psoriasis, atherosclerosis, and proliferation of smooth muscle cells. The present invention also provides methods of delaying development of any of the proliferative diseases described herein. 
     The term “individual” is a mammal, including humans. An individual includes, but is not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some variations, the individual is human. The individual (such as human) may have advanced disease or lesser extent of disease, such as low tumor burden. In some variations, the individual is at an early stage of a proliferative disease (such as cancer). In some variations, the individual is at an advanced stage of a proliferative disease (such as an advanced cancer). In some variations, the individual is HER2 positive. In some variations, the individual is HER2 negative. 
     The methods may be practiced in an adjuvant setting. “Adjuvant setting” refers to a clinical setting in which an individual has had a history of a proliferative disease, particularly cancer, and generally (but not necessarily) been responsive to therapy, which includes, but is not limited to, surgery (such as surgical resection), radiotherapy, and chemotherapy. However, because of their history of the proliferative disease (such as cancer), these individuals are considered at risk of development of the disease. Treatment or administration in the “adjuvant setting” refers to a subsequent mode of treatment. The degree of risk (i.e., when an individual in the adjuvant setting is considered as “high risk” or “low risk”) depends upon several factors, most usually the extent of disease when first treated. The methods provided herein may also be practiced in a neoadjuvant setting, i.e., the method may be carried out before the primary/definitive therapy. In some variations, the individual has previously been treated. In some variations, the individual has not previously been treated. In some variations, the treatment is a first line therapy. 
     It is understood that aspect and variations of the invention described herein include “consisting” and/or “consisting essentially of” aspects and variations. 
     As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. 
     Combination Therapy with Chemotherapeutic Agent 
     The present invention provides methods of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin); and b) an effective amount of at least one other chemotherapeutic agent. In some variations, the taxane is any of (and in come variations consisting essentially of) paclitaxel, docetaxel, and ortataxel. In some variations, the nanoparticle composition comprises Abraxane®. In some variations, the chemotherapeutic agent is any of (and in some variations selected from the group consisting of) antimetabolite agents (including nucleoside analogs), platinum-based agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkloids, proteasome inhibitors, macrolides, and topoisomerase inhibitors. 
     In some variations, the method comprises administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin; and b) an effective amount of at least one other chemotherapeutic agent. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm. In some variations, the paclitaxel/albumin nanoparticle composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the weight ratio of the albumin to paclitaxel in the composition is about 18:1 or less, such as about 9:1 or less. In some variations, the paclitaxel is coated with albumin. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel/albumin composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel is coated with albumin. In some variations, the nanoparticle composition is Abraxane®. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual comprising administering to the individual a) an effective amount of Abraxane®, and b) an effective amount of at least one other chemotherapeutic agent. Preferred drug combinations for sequential or co-administration or simultaneous administration with Abraxane® are those which show enhanced antiproliferative activity when compared with the single components alone, especially combinations that that lead to regression of proliferative tissues and/or cure from proliferative diseases. 
     The chemotherapeutic agents described herein can be the agents themselves, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable esters thereof, as well as steroisomers, enantiomers, racemic mixtures, and the like. The chemotherapeutic agent or agents as described can be administered as well as a pharmaceutical composition containing the agent(s), wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier vehicle, or the like. 
     The chemotherapeutic agent may be present in a nanoparticle composition. For example, in some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin); and b) an effective amount of a composition comprising nanoparticles comprising at least one other chemotherapeutic agent and a carrier protein (such as albumin). In some variations, the method comprises administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®); and b) an effective amount of a composition comprising nanoparticles comprising at least one other chemotherapeutic agent and a carrier protein (such as albumin). In some variations, the chemotherapeutic agent is any of (and in some variations selected from the group consisting of) thiocolchicine or its derivatives (such as dimeric thiocolchicine, including for example nab-5404, nab-5800, and nab-5801), rapamycin or its derivatives, and geldanamycin or its derivatives (such as 17-allyl amino geldanamycin (17-AAG)). In some variations, the chemotherapeutic agent is rapamycin. In some variations, the chemotherapeutic agent is 17-AAG. 
     An exemplary and non-limiting list of chemotherapeutic agents contemplated is provided herein. Suitable chemotherapeutic agents include, for example, vinca alkaloids, agents that disrupt microtubule formation (such as colchicines and its derivatives), anti-angiogenic agents, therapeutic antibodies, EGFR targeting agents, tyrosine kinase targeting agent (such as tyrosine kinase inhibitors), transitional metal complexes, proteasome inhibitors, antimetabolites (such as nucleoside analogs), alkylating agents, platinum-based agents, anthracycline antibiotics, topoisomerase inhibitors, macrolides, therapeutic antibodies, retinoids (such as all-trans retinoic acids or a derivatives thereof); geldanamycin or a derivative thereof (such as 17-AAG), and other standard chemotherapeutic agents well recognized in the art. 
     In some variations, the chemotherapeutic agent is any of (and in some variations selected from the group consisting of) adriamycin, colchicine, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, mitoxantrone, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferons, camptothecin and derivatives thereof, phenesterine, taxanes and derivatives thereof (e.g., paclitaxel and derivatives thereof, taxotere and derivatives thereof, and the like), topetecan, vinblastine, vincristine, tamoxifen, piposulfan, nab-5404, nab-5800, nab-5801, Irinotecan, HKP, Ortataxel, gemcitabine, Herceptin®, vinorelbine, Doxil®, capecitabine, Alimta®, Avastin®, Velcade®, Tarceva®, Neulasta®, Lapatinib, Sorafenib, derivatives thereof, chemotherapeutic agents known in the art, and the like. In some variations, the chemotherapeutic agent is a composition comprising nanoparticles comprising a thiocolchicine derivative and a carrier protein (such as albumin). 
     In some variations, the chemotherapeutic agent is a antineoplastic agent including, but is not limited to, carboplatin, Navelbine® (vinorelbine), anthracycline (Doxil®), lapatinib (GW57016), Herceptin®, gemcitabine (Gemzar®), capecitabine (Xeloda®), cisplatin, 5-fluorouracil, epirubicin, cyclophosphamide, Avastin®, Velcade®, etc. 
     In some variations, the chemotherapeutic agent is an antagonist of other factors that are involved in tumor growth, such as EGFR, ErbB2 (also known as Herb), ErbB3, ErbB4, or TNF. Sometimes, it may be beneficial to also administer one or more cytokines to the individual. In some variations, the therapeutic agent is a growth inhibitory agent. Suitable dosages for the growth inhibitory agent are those presently used and may be lowered due to the combined action (synergy) of the growth inhibitory agent and the taxane. 
     In some variations, the chemotherapeutic agent is a chemotherapeutic agent other than an anti-VEGF antibody, a HER2 antibody, interferon, and an HGFβ antagonist. 
     Reference to a chemotherapeutic agent herein applies to the chemotherapeutic agent or its derivatives and accordingly the invention contemplates and includes either of these variations (agent; agent or derivative(s)). “Derivatives” or “analogs” of a chemotherapeutic agent or other chemical moiety include, but are not limited to, compounds that are structurally similar to the chemotherapeutic agent or moiety or are in the same general chemical class as the chemotherapeutic agent or moiety. In some variations, the derivative or analog of the chemotherapeutic agent or moiety retains similar chemical and/or physical property (including, for example, functionality) of the chemotherapeutic agent or moiety. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of a tyrosine kinase inhibitor. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), and b) an effective amount of a tyrosine kinase inhibitor. Suitable tyrosine kinase inhibitors include, for example, imatinib (Gleevec®), gefitinib (Iresse®), Tarceva, Sutent® (sunitinib malate), and Lapatinib. In some variations, the tyrosine kinase inhibitor is lapatinib. In some variations, the tyrosine kinase inhibitor is Tarceva. Tarceva is a small molecule human epidermal growth factor type 1/epidermal growth factor receptor (HER1/EGFR) inhibitor which demonstrated, in a Phase III clinical trial, an increased survival in advanced non-small cell lung cancer (NSCLC) individuals. In some variations, the method is for treatment of breast cancer, including treatment of metastatic breast cancer and treatment of breast cancer in a neoadjuvant setting. In some variations, the method is for treatment of advanced solid tumor. In some variations, there is provided a method to inhibit the proliferation of EGFR expressing tumors in a mammal comprising administering to a mammal infected with such tumors Abraxane® and gefitinib, wherein the gefitinib is administered by pulse-dosing. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of an antimetabolite agent (such as a nucleoside analog, including for example purine analogs and pyrimidine analogs). In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), and b) an effective amount of an antimetabolite agent. An “antimetabolic agent” is an agent which is structurally similar to a metabolite, but cannot be used by the body in a productive manner. Many antimetabolite agents interfere with production of nucleic, acids, RNA and DNA. For example, the antimetabolite can be a nucleoside analog, which includes, but is not limited to, azacitidine, azathioprine, capecitabine (Xeloda®), cytarabine, cladribine, cytosine arabinoside (ara-C, cytosar), doxifluridine, fluorouracil (such as 5-fluorouracil), UFT, hydroxyurea, gemcitabine, mercaptopurine, methotrexate, thioguanine (such as 6-thioguanine). Other anti-metabolites include, for example, L-asparaginase (Elspa), decarbazine (DTIC), 2-deoxy-D-glucose, and procarbazine (matulane). In some variations, the nucleoside analog is any of (and in some variations selected from the group consisting of) gemcitabine, fluorouracil, and capecitabine. In some variations, the method is for treatment of metastatic breast cancer or locally advanced breast cancer. In some variations, the method is for first line treatment of metastatic breast cancer. In some variations, the method is for treatment of breast cancer in a neoadjuvant setting. In some variations, the method is for treatment of any of NSCLC, metastatic colorectal cancer, pancreatic cancer, or advanced solid tumor. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of an alkylating agent. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), and b) an effective amount of an alkylating agent. Suitable alkylating agents include, but are not limited to, cyclophosphamide (Cytoxan), mechlorethamine, chlorambucil, melphalan, carmustine (BCNU), thiotepa, busulfan, alkyl sulphonates, ethylene imines, nitrogen mustard analogs, estramustine sodium phosphate, ifosfamide, nitrosoureas, lomustine, and streptozocin. In some variations, the alkylating agent is cyclophosphamide. In some variations, the cyclophosphamide is administered prior to the administration of the nanoparticle composition. In some variations, the method is for treatment of an early stage breast cancer. In some variations, the method is for treatment of a breast cancer in an adjuvant or a neoadjuvant setting. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of a platinum-based agent. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), and b) an effective amount of a platinum-based agent. Suitable platinum-based agents include, but are not limited to, carboplatin, cisplatin, and oxaliplatin. In some variations, the platinum-based agent is carboplatin. In some variations, the method is for treatment of: breast cancer (HER2 positive or HER2 negative, including metastatic breast cancer and advanced breast cancer); lung cancer (including advanced NSCLC, first line NSCLC, SCLC, and advanced solid tumor malignancies in the lung); ovarian cancer; head and neck cancer; and melanoma (including metastatic melanoma). 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of an anthracycline antibiotic. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), and b) an effective amount of an anthracycline antibiotic. Suitable anthracycline antibiotic include, but are not limited to, Doxil®, actinomycin, dactinomycin, daunorubicin (daunomycin), doxorubicin (adriamycin), epirubicin, idarubicin, mitoxantrone, valrubicin. In some variations, the anthracycline is any of (and in some variations selected from the group consisting of) Doxil®, epirubicin, and doxorubicin. In some variations, the method is for treatment of an early stage breast cancer. In some variations, the method is for treatment of a breast cancer in an adjuvant or a neoadjuvant setting. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of a vinca alkloid. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising palitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), and b) an effective amount of a vinca alkloid. Suitable vinca alkaloids include, for example, vinblastine, vincristine, vindesine, vinorelbine (Navelbine®), and VP-16. In some variations, the vinca alkaloid is vinorelbine (Navelbine®). In some variations, the method is for treatment of stage 1V breast cancer and lung cancer. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of a macrolide. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), and b) an effective amount of a macrolide. Suitable macrolides include, for example, rapamycin, carbomycin, and erythromycin. In some variations, the macrolide is rapamycin or a derivative thereof. In some variations, the method is for treatment of a solid tumor. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of a topoisomerase inhibitor. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), and b) an effective amount of a topoisomerase inhibitor. In some variations, the chemotherapeutic agent is a topoisomerase inhibitor, including, for example, inhibitor of topoisomerase I and topoisomerase II. Exemplary inhibitors of topoisomerase I include, but are not limited to, camptothecin, such as irinotecan and topotecan. Exemplary inhibitors of topoisomerase II include, but are not limited to, amsacrine, etoposide, etoposide phosphate, and teniposide. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of an antiangiogenic agent. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), and b) an effective amount of an antiangiogenic agent. In some variations, the method is for treatment of metastatic breast cancer, breast cancer in an adjuvant setting or a neoadjuvant setting, lung cancer (such as first line advanced NSCLC and NSCLC), ovarian cancer, and melanoma (including metastatic melanoma). 
     Many anti-angiogenic agents have been identified and are known in the art, including those listed by Carmeliet and Jain (2000). The anti-angiogenic agent can be naturally occurring or non-naturally occurring. In some variations, the chemotherapeutic agent is a synthetic antiangiogenic peptide. For example, it has been previously reported that the antiangiogenic activity of small synthetic pro-apoptic peptides comprise two functional domains, one targeting the CD13 receptors (aminopeptidase N) on tumor microvessels and the other disrupting the mitochondrial membrane following internalization. Nat. Med. 1999, 5(9):1032-8. A second generation dimeric peptide, CNGRC-GG-d(KLAKLAK) 2 , named HKP (Hunter Killer Peptide) was found to have improved antitumor activity. Accordingly, in some variations, the antiangiogenic peptide is HKP. In some variations, the antiangiogenic agent is other than an anti-VEGF antibody (such as Avastin®). 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of a proteasome inhibitor, such as bortezomib (Velcade). In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), and b) an effective amount of a proteasome inhibitor such as bortezomib (Velcade®). 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), and b) an effective amount of a therapeutic antibody. In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®) and a carrier protein (such as albumin), and b) an effective amount of a therapeutic antibody. Suitable therapeutic antibodies include, but are not limited to, anti-VEGF antibody (such as Avastin® (bevacizumab)), anti-HER2 antibody (such as Herceptin® (trastuzumab)), Erbitux® (cetuximab), Campath (alemtuzumab), Myelotarg (gemtuzumab), Zevalin (ibritumomab tiuextan, Rituxan (rituximab), and Bexxar (tositumomab). In some variations, the chemotherapeutic agent is Erbitux® (cetuximab). In some variations, the chemotherapeutic agent is a therapeutic antibody other than an antibody against VEGF or HER2. In some variations, the method is for treatment of HER2 positive breast cancer, including treatment of advanced breast cancer, treatment of metastatic cancer, treatment of breast cancer in an adjuvant setting, and treatment of cancer in a neoadjuvant setting. In some variations, the method is for treatment of any of metastatic breast cancer, breast cancer in an adjuvant setting or a neoadjuvant setting, lung cancer (such as first line advanced NSCLC and NSCLC), ovarian cancer, head and neck cancer, and melanoma (including metastatic melanoma). For example, in some variations, there is provided a method for treatment of HER2 positive metastatic breast cancer in an individual, comprising administering to the individual 125 mg/m 2  paclitaxel/albumin nanoparticle composition (such as Abraxane®) weekly for three weeks with the fourth week off, concurrent with the administration of Herceptin®. 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer, for example breast cancer) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising taxane and a carrier protein, and b) an effective amount of an anti-VEGF antibody. In some variations, the effective amounts of the taxane nanoparticle composition and the anti-VEGF antibody synergistically inhibit cell proliferation (such as tumor cell growth). In some variations, at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) cell proliferation is inhibited. In some variations, the taxane is paclitaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane in the nanoparticle in the composition is administered by intravenous administration. In some variations, the anti-VEGF antibody is administered by intravenous administration. In some variations, both the taxane in the nanoparticle composition and the anti-VEGF antibody are administered by intravenous administration. 
     In some variations, there is provided a method of inhibiting tumor metastasis (such as metastasis of breast cancer) in an individual, comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising taxane and a carrier protein, and b) an effective amount of an anti-VEGF antibody. In some variations, the effective amounts of the taxane nanoparticle composition and the anti-VEGF antibody synergistically inhibit tumor metastasis. In some variations, at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) metastasis is inhibited. In some variations, method of inhibiting metastasis to lymph node is provided. In some variations, method of inhibiting metastasis to the lung is provided. In some variations, the taxane is paclitaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane in the nanoparticle in the composition is administered by intravenous administration. In some variations, the anti-VEGF antibody is administered by intravenous administration. In some variations, both the taxane in the nanoparticle composition and the anti-VEGF antibody are administered by intravenous administration. 
     Suitable dosages for anti-VEGF antibody include, for example, about 1 mg/kg to about 20 mg/kg, including for example about 1 mg/kg to about 15 mg/kg (such as about any of 2, 4, 6, 8, 10, or 12 mg/kg). In some variations, the dosage of the anti-VEGF antibody is about 40 mg/m 2  to about 600 mg/m 2 , including for example about 100 mg/m 2  to about 400 mg/m 2  (such as about any of 100, 200, or 300 mg/m 2 ). In some variations, the taxane is paclitaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (such as Avastin®). 
     Suitable combinations of the amounts of taxane in a nanoparticle composition and the anti-VEGF antibody include, for example, about 1 mg/kg to about 20 mg/kg (such as about any of 2, 5, 10, or 15 mg/kg) taxane in a nanoparticle composition and about 1 mg/kg to about 20 mg/kg (such as about any of 2, 4, 6, 8, 10, 12, 14, 16, or 18 mg/kg) anti-VEGF antibody; about 3 mg/m 2  to about 400 mg/m 2  (such as about any of 6, 10, 15, 30, 45, 60, 100, 150, 200, or 300 mg/m 2 ) taxane in a nanoparticle composition and 40 mg/m 2  to about 600 mg/m 2 , including for example about 100 mg/m 2  to about 400 mg/m 2  (such as about any of 100, 200, or 300 mg/m 2 ) anti-VEGF antibody; about 3 mg/m 2  to about 300 mg/m 2  (such as about any of 6, 10, 15, 30, 45, 60, 100, 150, 200, or 300 mg/m 2 ) taxane in a nanoparticle composition and about 1 mg/kg to about 20 mg/kg (such as about any of 2, 4, 6, 8, 10, 12, 14, 16, or 18 mg/kg) anti-VEGF antibody. In some variations, the method comprises administering to an individual at least about 200 mg/m 2  taxane in a nanoparticle composition and at least about any of 2, 4, 8, or 10 mg/kg anti-VEGF antibody. In some variations, the taxane is paclitaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (such as Avastin®). 
     In some variations of the method, the taxane nanoparticle composition and the anti-VEGF antibody are administered simultaneously to the individual. In some variations of the method, the administration of the nanoparticle composition and the chemotherapeutic agent are concurrent. One exemplary dosing regime for the combination therapy of taxane nanoparticle composition includes administration of 100 mg/m 2 -300 mg/m 2  (such as 200 mg/m 2 ) taxane in nanoparticle composition at least weekly (including for example every 1, 2, 3, 4, 5, or 6 days) concurrent with administration of 2 mg/kg -15 mg/kg (such as any of 4, 6, 8, 10 mg/kg or 15 mg/kg) anti-VEGF antibody every two weeks or more frequently (for example every week, twice every week, or three times a week). In some variations, the taxane is paclitaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (such as Avastin®). 
     In some variations, the taxane nanoparticle composition and the anti-VEGF antibody are administered sequentially to the individual. For example, in some variations, the taxane nanoparticle composition is administered for at least one (such as at least any of two, three, four, five, or six) cycles prior to the administration of the anti-VEGF antibody. This is then followed by the administration of an anti-VEGF antibody for at least once (such as twice) a week for at least about 3 (such as 4, 5, or 6) weeks. One exemplary dosing regime for the combination therapy of taxane nanoparticle composition (such as paclitaxel/albumin nanoparticle composition, for example Abraxane®) and anti-VEGF antibody (such as bevacizumab, for example Avastin®) includes administration of 10 mg/kg taxane in a nanoparticle composition daily for 5 days in two cycles separated by one week followed by administration of an anti-VEGF antibody at dosages of 2 mg/kg, 4 mg/kg, or 8 mg/kg twice a week for 6 weeks. In some variations, the taxane is paclitaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the taxane is paclitaxel and the anti-VEGF antibody is bevacizumab (such as Avastin®). 
     In some variations, the effective amount of Abraxane is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of bevacizumab is about 10 mg/kg or about 15 mg/kg. In some variations, the effective amount of Abraxane is about 100 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. 
     In some variations, the effective amount of Abraxane is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is between about 5 mg/kg and about 15 mg/kg. In some variations, the effective amount of Abraxane is about 260 mg/m 2 . In some variations, Abraxane is administered every three weeks. In some variations, the effective amount of bevacizumab is between about 5 mg/kg and about 10 mg/kg. In some variations, the effective amount of bevacizumab is about 15 mg/kg. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer, for example breast cancer) in an individual comprising administering to the individual: (1) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of taxane in the nanoparticle composition is between about 45 m g/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is about 100 mg/m 2 . In some variations, the taxane in a nanoparticle composition is administered weekly. In some variations, the anti-VEGF antibody is administered every 2 weeks or every 3 weeks. In some variations, the effective amount of taxane in the nanoparticle composition is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the taxane in a nanoparticle composition is administered every two weeks. In some variations, the effective amount of taxane in the nanoparticle composition is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is about 260 mg/m 2 . In some variations, the taxane in a nanoparticle composition is administered every three weeks. In some variations, the anti-VEGF antibody is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg. 
     In some variations, the taxane is paclitaxel. In some variations, the carrier protein is albumin. In some variations, the taxane is paclitaxel and the carrier protein is albumin. In some variations, the albumin is human serum albumin. In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane. In some variations, the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane and the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the effective amount of Abraxane is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of Abraxane is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of Abraxane is about 100 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, the bevacizumab is administered every 2 weeks or every 3 weeks. In some variations, the effective amount of Abraxane is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the Abraxane is administered every two weeks. In some variations, the effective amount of Abraxane is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of Abraxane is about 260 mg/m 2 . In some variations, Abraxane is administered every three weeks. In some variations, the bevacizumab is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of bevacizumab is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg. 
     In some variations of any of the above methods, the proliferative disease is cancer. In some variations, the cancer is breast cancer, lung cancer, prostate cancer, ovarian cancer, or melanoma. In some variations, the breast cancer is metastatic breast cancer. In some variations, the metastatic breast cancer is heavily pretreated with anthracylines and/or taxanes. In some variations, the lung cancer is non-small cell lung cancer (NSCLC). In some variations, the NSCLC is stage IIIB and/or stage 1V non-small cell lung cancer. 
     In some variations, there is provided a method of inhibiting tumor metastasis (such as metastasis of breast cancer) in an individual comprising administering to the individual: (1) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of taxane in the nanoparticle composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is about 100 mg/m 2 . In some variations, the taxane in a nanoparticle composition is administered weekly. In some variations, the anti-VEGF antibody is administered every 2 weeks or every 3 weeks. In some variations, the effective amount of taxane in the nanoparticle composition is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the taxane in a nanoparticle composition is administered every two weeks. In some variations, the effective amount of taxane in the nanoparticle composition is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is about 260 mg/m 2 . In some variations, the taxane in a nanoparticle composition is administered every three weeks. In some variations, the anti-VEGF antibody is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg. 
     In some variations, the taxane is paclitaxel. In some variations, the carrier protein is albumin. In some variations, the taxane is paclitaxel and the carrier protein is albumin. In some variations, the albumin is human serum albumin. In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane. In some variations, the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane and the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the effective amount of Abraxane is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of Abraxane is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of Abraxane is about 100 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, the bevacizumab is administered every 2 weeks or every 3 weeks. In some variations, the effective amount of Abraxane is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the Abraxane is administered every two weeks. In some variations, the effective amount of Abraxane is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of Abraxane is about 260 mg/m 2 . In some variations, Abraxane is administered every three weeks. In some variations, the bevacizumab is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of bevacizumab is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg. 
     In some variations of any of the above methods, the tumor metastasis is metastatic breast cancer, metastatic lung cancer, metastatic prostate cancer, metastatic ovarian cancer, or metastatic melanoma. In some variations, tumor metastasis is metastatic breast cancer. In some variations, the metastatic breast cancer is heavily pretreated with anthracylines and/or taxanes. In some variations, the metastatic lung cancer is metastatic non-small cell lung cancer (NSCLC). 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer, for example breast cancer) in an individual comprising administering to the individual: (1) an effective amount of a composition comprising a taxane, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, the taxane-mediated induction of VEGF in vivo is taxane-mediated induction of VEGF-A. In some variations, the taxane is paclitaxel. In some variations, the taxane is docetaxel. In some variations, the composition comprising a taxane is a composition comprising nanoparticles comprising a taxane and a carrier protein. In some variations, the nanoparticles comprising a taxane are nanoparticles comprising paclitaxel. In some variations, the nanoparticles comprising a taxane are nanoparticles comprising docetaxel. In some variations, the carrier protein is albumin. In some variations, the taxane is paclitaxel and the carrier protein is albumin. In some variations, the albumin is human serum albumin. In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane. In some variations, the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane and the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the effective amounts of the taxane and the anti-VEGF antibody synergistically inhibit cell proliferation (such as tumor cell growth). In some variations, at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) cell proliferation is inhibited. In some variations, the taxane is administered by intravenous administration. In some variations, the anti-VEGF antibody is administered by intravenous administration. In some variations, both the taxane and the anti-VEGF antibody are administered by intravenous administration. 
     In some variations, there is provided a method of inhibiting tumor metastasis (such as metastasis of breast cancer) in an individual, comprising administering to the individual: (1) an effective amount of a composition comprising a taxane, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, the taxane-mediated induction of VEGF in vivo is taxane-mediated induction of VEGF-A. In some variations, the taxane is paclitaxel. In some variations, the taxane is docetaxel. In some variations, the composition comprising a taxane is a composition comprising nanoparticles comprising a taxane and a carrier protein. In some variations, the nanoparticles comprising a taxane are nanoparticles comprising paclitaxel. In some variations, the nanoparticles comprising a taxane are nanoparticles comprising docetaxel. In some variations, the carrier protein is albumin. In some variations, the taxane is paclitaxel and the carrier protein is albumin. In some variations, the albumin is human serum albumin. In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane. In some variations, the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane and the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, at least about 10% (including for example at least about any of 20%, 30%, 40%, 60%, 70%, 80%, 90%, or 100%) metastasis is inhibited. In some variations, method of inhibiting metastasis to lymph node is provided. In some variations, method of inhibiting metastasis to the lung is provided. In some variations, the taxane is administered by intravenous administration. In some variations, the anti-VEGF antibody is administered by intravenous administration. In some variations, both the taxane and the anti-VEGF antibody are administered by intravenous administration. 
     Suitable dosages for anti-VEGF antibody include, for example, about 1 mg/kg to about 20 mg/kg, including for example about 1 mg/kg to about 15 mg/kg (such as about any of 2, 4, 6, 8, 10, or 12 mg/kg). In some variations, the dosage of the anti-VEGF antibody is about 40 mg/m 2  to about 600 mg/m 2 , including for example about 100 mg/m 2  to about 400 mg/m 2  (such as about any of 100, 200, or 300 mg/m 2 ). In some variations, the taxane is paclitaxel. In some variations, the taxane is docetaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®) and the taxane is paclitaxel. 
     Suitable combinations of the amounts of taxane and the anti-VEGF antibody include, for example, about 1 mg/kg to about 20 mg/kg (such as about any of 2, 5, 10, or 15 mg/kg) taxane and about 1 mg/kg to about 20 mg/kg (such as about any of 2, 4, 6, 8, 10, 12, 14, 16, or 18 mg/kg) anti-VEGF antibody; about 3 mg/m 2  to about 400 mg/m 2  (such as about any of 6, 10, 15, 30, 45, 60, 100, 150, 200, or 300 mg/m 2 ) taxane and 40 mg/m 2  to about 600 mg/m 2 , including for example about 100 mg/m 2  to about 400 mg/m 2  (such as about any of 100, 200, or 300 mg/m 2 ) anti-VEGF antibody; about 3 mg/m 2  to about 300 mg/m 2  (such as about any of 6, 10, 15, 30, 45, 60, 100, 150, 200, or 300 mg/m 2 ) taxane and about 1 mg/kg to about 20 mg/kg (such as about any of 2, 4, 6, 8, 10, 12, 14, 16, or 18 mg/kg) anti-VEGF antibody. In some variations, the method comprises administering to an individual at least about 200 mg/m 2  taxane and at least about any of 2, 4, 8, or 10 mg/kg anti-VEGF antibody. In some variations, the taxane is paclitaxel. In some variations, the taxane is docetaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®) and the taxane is paclitaxel. 
     In some variations of the methods, the taxane and the anti-VEGF antibody are administered simultaneously to the individual. In some variations of the methods, the administration of the taxane and the anti-VEGF antibody are concurrent. One exemplary dosing regime for the combination therapy of taxane (such as paclitaxel) includes administration of 100 mg/m 2 -300 mg/m 2  (such as 200 mg/m 2 ) taxane at least weekly (including for example every 1, 2, 3, 4, 5, or 6 days) concurrent with administration of 2 mg/kg-15 mg/kg (such as any of 4, 6, 8, 10 mg/kg or 15 mg/kg) anti-VEGF antibody every two weeks or more frequently (for example every week, twice every week, or three times a week). In some variations, the taxane is paclitaxel. 
     In some variations, the taxane is docetaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®) and the taxane is paclitaxel. 
     In some variations, the taxane and the anti-VEGF antibody are administered sequentially to the individual. For example, in some variations, the taxane is administered for at least one (such as at least any of two, three, four, five, or six) cycles prior to the administration of the anti-VEGF antibody. This is then followed by the administration of an anti-VEGF antibody for at least once (such as twice) a week for at least about 3 (such as 4, 5, or 6) weeks. One exemplary dosing regime for the combination therapy of taxane composition (such as paclitaxel/albumin nanoparticle composition, for example Abraxane®) and anti-VEGF antibody (such as bevacizumab, for example Avastin®) includes administration of 10 mg/kg taxane in a nanoparticle composition daily for 5 days in two cycles separated by one week followed by administration of an anti-VEGF antibody at dosages of 2 mg/kg, 4 mg/kg, or 8 mg/kg twice a week for 6 weeks. In some variations, the taxane is paclitaxel. In some variations, the taxane is docetaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®) and the taxane is paclitaxel. 
     In some variations, the effective amount of taxane in the composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the composition is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the composition is about 100 mg/m 2 . In some variations, the taxane is administered weekly. In some variations, the effective amount of taxane in the composition is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the composition is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the taxane is administered every two weeks. In some variations, the effective amount of taxane in the composition is about 260 mg/m 2 . In some variations, the taxane is administered every three weeks. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of anti-VEGF antibody is between about 5 to about 10 mg/kg. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 10 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 15 mg/kg. In some variations, the anti-VEGF antibody is administered every two weeks or every three weeks. In some variations, the taxane is paclitaxel. In some variations, the taxane is docetaxel. In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®). In some variations, the anti-VEGF antibody is bevacizumab (such as Avastin®) and the taxane is paclitaxel. 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer, for example breast cancer) in an individual comprising administering to the individual: (1) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, the taxane-mediated induction of VEGF in vivo is taxane-mediated induction of VEGF-A. In some variations, the effective amount of taxane in the nanoparticle composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective of amount of taxane in the nanoparticle composition is about 100 mg/m 2 . In some variations, the taxane in a nanoparticle composition is administered weekly. In some variations, the effective amount of taxane in the nanoparticle composition is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the taxane in a nanoparticle composition is administered every two weeks. In some variations, the effective amount of taxane in the nanoparticle composition is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is about 260 mg/m 2 . In some variations, taxane in the nanoparticle composition is administered every three weeks. In some variations, the anti-VEGF antibody is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of anti-VEGF antibody is between about 5 mg/kg and about 10 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 10 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 15 mg/kg. 
     In some variations, the taxane is paclitaxel. In some variations, the carrier protein is albumin. In some variations, the taxane is paclitaxel and the carrier protein is albumin. In some variations, the albumin is human serum albumin. In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane. In some variations, the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane and the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the effective amount of Abraxane is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of Abraxane is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective of amount of Abraxane is about 100 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, the effective amount of Abraxane is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, Abraxane is administered every two weeks. In some variations, the effective amount of Abraxane is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of Abraxane is about 260 mg/m 2 . In some variations, Abraxane is administered every three weeks. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of bevacizumab is between about 5 mg/kg and about 10 mg/kg. In some variations, the effective amount of bevacizumab is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In some variations, the effective amount of bevacizumab is about 10 mg/kg. In some variations, the effective amount of bevacizumab is about 15 mg/kg. 
     In some variations, the effective amount of Abraxane is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of bevacizumab is about 10 mg/kg or about 15 mg/kg. In some variations, the effective amount of Abraxane is about 100 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. 
     In some variations, the effective amount of Abraxane is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is between about 5 mg/kg and about 15 mg/kg. In some variations, the effective amount of Abraxane is about 260 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, the effective amount of bevacizumab is between about 5 mg/kg and about 10 mg/kg. In some variations, the effective amount of bevacizumab is about 15 mg/kg. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. 
     In some variations of any of the above methods, the proliferative disease is cancer. In some variations, the cancer is breast cancer, lung cancer, prostate cancer, ovarian cancer, or melanoma. In some variations, the breast cancer is metastatic breast cancer. In some variations, the metastatic breast cancer is heavily pretreated with anthracylines and/or taxanes. In some variations, the lung cancer is non-small cell lung cancer (NSCLC). In some variations, the NSCLC is stage IIIB and/or stage 1V non-small cell lung cancer. 
     In some variations, there is provided a method of inhibiting tumor metastasis (such as metastasis of breast cancer) in an individual comprising administering to the individual: (1) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein, and (2) an effective amount of an anti-VEGF antibody, wherein the effective amount of the anti-VEGF antibody is an amount effective to suppress taxane-mediated induction of VEGF in vivo. In some variations, the taxane-mediated induction of VEGF in vivo is taxane-mediated induction of VEGF-A. In some variations, the effective amount of taxane in the nanoparticle composition is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective of amount of taxane in the nanoparticle composition is about 100 mg/m 2 . In some variations, the taxane in a nanoparticle composition is administered weekly. In some variations, the effective amount of taxane in the nanoparticle composition is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the taxane in a nanoparticle composition is administered every two weeks. In some variations, the effective amount of taxane in the nanoparticle composition is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of anti-VEGF antibody is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of taxane in the nanoparticle composition is about 260 mg/m 2 . In some variations, taxane in the nanoparticle composition is administered every three weeks. In some variations, the anti-VEGF antibody is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of anti-VEGF antibody is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of anti-VEGF antibody is between about 5 mg/kg and about 10 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 10 mg/kg. In some variations, the effective amount of anti-VEGF antibody is about 15 mg/kg. 
     In some variations, the taxane is paclitaxel. In some variations, the carrier protein is albumin. In some variations, the taxane is paclitaxel and the carrier protein is albumin. In some variations, the albumin is human serum albumin. In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane. In some variations, the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the nanoparticles comprising a taxane and a carrier protein is Abraxane and the anti-VEGF antibody is bevacizumab (i.e., Avastin®). In some variations, the effective amount of Abraxane is between about 45 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of Abraxane is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective of amount of Abraxane is about 100 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, the effective amount of Abraxane is between about 170 mg/m 2  to about 200 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, Abraxane is administered every two weeks. In some variations, the effective amount of Abraxane is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is between about 1 mg/kg to about 20 mg/kg. In some variations, the effective amount of Abraxane is about 260 mg/m 2 . In some variations, Abraxane is administered every three weeks. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. In some variations of any of the above methods, the effective amount of bevacizumab is greater than 1 mg/kg to less than 10 mg/kg or greater than 15 mg/kg to less than 20 mg/kg. In some variations, the effective amount of bevacizumab is between about 5 mg/kg and about 10 mg/kg. In some variations, the effective amount of bevacizumab is about 2 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or about 15 mg/kg. In some variations, the effective amount of bevacizumab is about 10 mg/kg. In some variations, the effective amount of bevacizumab is about 15 mg/kg. 
     In some variations, the effective amount of Abraxane is between about 80 mg/m 2  to about 150 mg/m 2  and the effective amount of bevacizumab is about 10 mg/kg or about 15 mg/kg. In some variations, the effective amount of Abraxane is about 100 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. 
     In some variations, the effective amount of Abraxane is between about 200 mg/m 2  to about 350 mg/m 2  and the effective amount of bevacizumab is between about 5 mg/kg and about 15 mg/kg. In some variations, the effective amount of Abraxane is about 260 mg/m 2 . In some variations, Abraxane is administered weekly. In some variations, the effective amount of bevacizumab is between about 5 mg/kg and about 10 mg/kg. In some variations, the effective amount of bevacizumab is about 15 mg/kg. In some variations, bevacizumab is administered every 2 weeks or every 3 weeks. 
     In some variations of any of the above methods, the tumor metastasis is metastatic breast cancer, metastatic lung cancer, metastatic prostate cancer, metastatic ovarian cancer, or metastatic melanoma. In some variations, tumor metastasis is metastatic breast cancer. In some variations, the metastatic breast cancer is heavily pretreated with anthracylines and/or taxanes. In some variations, the metastatic lung cancer is metastatic non-small cell lung cancer (NSCLC). 
     The term “amount effective to suppress taxane-mediated induction of VEGF in vivo,” as used herein, refers to and includes both complete (including substantially complete) and/or partial suppression. Methods indicating such suppression are known in the art and described herein, although it is understood that when administering to an individual patient based on established medical practice on the basis of clinical trials, such measurements need not be given in an individual. In some variations, the term “amount effective to suppress taxane-mediated induction of VEGF,” as used herein, refers to substantially complete prevention of VEGF expression and/or activity or reduction in the amount VEGF (such as VEGF-A) expression and/or activity in cells, tissues or fluids in vivo upon administration of a formulation containing a taxane. In some variations, the reduction in the amount VEGF expression and/or activity in cells, tissues or fluids in vivo upon administration of a formulation containing a taxane is by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. In some variations, the suppression of taxane induction can be observed qualitatively and/or quantitatively by methods known in the art and described herein. 
     In some variations, two or more chemotherapeutic agents are administered in addition to the taxane in the nanoparticle composition. These two or more chemotherapeutic agents may (but not necessarily) belong to different classes of chemotherapeutic agents. Examples of these combinations are provided herein. Other combinations are also contemplated. 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), b) an effective amount of an antimetabolite (such as a nucleoside analog, for example, gemcitabine), and c) an anthracycline antibiotic (such as epirubicin). In some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), b) an effective amount of an antimetabolite (such as a nucleoside analog, for example, gemcitabine), and c) an effective amount of an anthracycline antibiotic (such as epirubicin). In some variations, the method is for treatment of breast cancer in a neoadjuvant setting. For example, in some variations, there is provided a method of treating locally advanced/inflammatory cancer in an individual comprising administering to the individual 220 mg/m 2  paclitaxel/albumin nanoparticle composition (such as Abraxane®) every two weeks; 2000 mg/m 2  gemcitabine, every two weeks; and 50 mg/m 2  epirubicin, every two weeks. In some variations, there is provided a method of treating breast cancer in an individual in an adjuvant setting, comprising administering to the individual 175 mg/m 2  paclitaxel/albumin nanoparticle composition (such as Abraxane®) every two weeks, 2000 mg/m 2  gemcitabine, every two weeks, and 50 mg/m 2  epirubicin, every two weeks. 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), b) an effective amount of a platinum-based agent (such as carboplatin), and c) a therapeutic antibody (such as ant-HER2 antibody (such as Herceptin®) and anti-VEGF antibody (such as Avastin®)). In some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), b) an effective amount of a platinum-based agent (such as carboplatin), and c) a therapeutic antibody (such as ant-HER2 antibody (such as Herceptin®) and anti-VEGF antibody (such as Avastin®)). In some variations, the method is for treatment of any of advanced breast cancer, metastatic breast cancer, breast cancer in an adjuvant setting, and lung cancer (including NSCLC and advanced NSCLC). In some variations, there is provided a method of treating metastatic cancer in an individual, comprising administering to the individual 75 mg/m 2  paclitaxel/albumin nanoparticle composition (such as Abraxane®) and carboplatin, AUC=2, wherein the administration is carried out weekly for three weeks with the fourth week off. In some variations, the method further comprises weekly administering about 2-4 mg/kg of Herceptin®. 
     In some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), b) an effective amount of a platinum-based agent (such as carboplatin), and c) a vinca alkaloid (such as Navelbine®). In some variations, there is provided a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), b) an effective amount of a platinum-based agent (such as carboplatin), and c) a vinca alkaloid (such as Navelbine®). In some variations, the method is for treatment of lung cancer. 
     In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), b) an effective amount of an alkylating agent (such as cyclophosphamide) and c) an anthracycline antibiotic (such as adriamycin). In some variations, the invention provides a method of treating a proliferative disease (such as cancer) in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin, b) an effective amount of an alkylating agent (such as cyclophosphamide) and c) an anthracycline antibiotic (such as adriamycin). In some variations, the method is for treatment of an early stage breast cancer. In some variations, the method is for treatment of a breast cancer in an adjuvant or a neoadjuvant setting. For example, in some variations, there is provided a method of treating an early stage breast cancer in an individual, comprising administering 260 mg/m 2  paclitaxel/albumin nanoparticle composition (such as Abraxane®), 60 mg/m 2  adriamycin, and 600 mg/m 2  cyclophosphamide, wherein the administration is carried out once every two weeks. 
     Other variations are provided in Table 1. For example, in some variations, there is provided a method of treating advanced breast cancer in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising a paclitaxel and an albumin (such as Abraxane®), b) an effective amount of carboplatin. In some variations, the method further comprises administering an effective amount of Herceptin® to the individual. In some variations, there is provided a method of treating metastatic breast cancer in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), b) an effective amount of gemcitabine. In some variations, there is provided a method of treating advanced non-small cell lung cancer in an individual, comprising administering to the individual a) an effective amount of a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), b) an effective amount of carboplatin. 
     In some variations, there is provided a composition comprising nanoparticles comprising a taxane (such as paclitaxel, docetaxel, or ortataxel) and a carrier protein (such as albumin) and at least one other chemotherapeutic agent. The compositions described herein may comprise effective amounts of the taxane and the chemotherapeutic agent for the treatment of a proliferative disease (such as cancer). In some variations, the chemotherapeutic agent and the taxane are present in the composition at a predetermined ratio, such as the weight ratios described herein. In some variations, the invention provides a synergistic composition of an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel, docetaxel, or ortataxel) and an effective amount of at least one other chemotherapeutic agent. In some variations, the other chemotherapeutic agent is an anti-VEGF antibody (such as bevacizumab, for example, Avastin®). 
     In some variations, the invention provides pharmaceutical compositions comprising nanoparticles comprising a taxane and a carrier protein (such as albumin) for use in the treatment of a proliferative disease (such as cancer), wherein said use comprises simultaneous and/or sequential administration of at least one other chemotherapeutic agent. In some variations, the invention provides a pharmaceutical composition comprising a chemotherapeutic agent for use in the treatment of a proliferative disease (such as cancer), wherein said use comprises simultaneous and/or sequential administration of a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin). In some variations, the invention provides taxane-containing nanoparticle compositions and compositions comprising one other chemotherapeutic agent for simultaneous, and/or sequential use for treatment of a proliferative disease (such as cancer). 
     Modes of Administration 
     The composition comprising nanoparticles comprising taxane (also referred to as “nanoparticle composition”) and the chemotherapeutic agent can be administered simultaneously (i.e., simultaneous administration) and/or sequentially (i.e., sequential administration). 
     In some variations, the nanoparticle composition and the chemotherapeutic agent (including the specific chemotherapeutic agents described herein) are administered simultaneously. The term “simultaneous administration,” as used herein, means that the nanoparticle composition and the chemotherapeutic agent are administered with a time separation of no more than about 15 minute(s), such as no more than about any of 10, 5, or 1 minutes. When the drugs are administered simultaneously, the drug in the nanoparticles and the chemotherapeutic agent may be contained in the same composition (e.g., a composition comprising both the nanoparticles and the chemotherapeutic agent) or in separate compositions (e.g., the nanoparticles are contained in one composition and the chemotherapeutic agent is contained in another composition). For example, the taxane and the chemotherapeutic agent may be present in a single composition containing at least two different nanoparticles, wherein some of the nanoparticles in the composition comprise the taxane and a carrier protein, and some of the other nanoparticles in the composition comprise the chemotherapeutic agent and a carrier protein. The invention contemplates and encompasses such compositions. In some variations, only the taxane is contained in nanoparticles. In some variations, simultaneous administration of the drug in the nanoparticle composition and the chemotherapeutic agent can be combined with supplemental doses of the taxane and/or the chemotherapeutic agent. 
     In some variations, the nanoparticle composition and the chemotherapeutic agent are administered sequentially. The term “sequential administration” as used herein means that the drug in the nanoparticle composition and the chemotherapeutic agent are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60 or more minutes. Either the nanoparticle composition or the chemotherapeutic agent may be administered first. The nanoparticle composition and the chemotherapeutic agent are contained in separate compositions, which may be contained in the same or different packages. 
     In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent are concurrent, i.e., the administration period of the nanoparticle composition and that of the chemotherapeutic agent overlap with each other. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent are non-concurrent. For example, in some variations, the administration of the nanoparticle composition is terminated before the chemotherapeutic agent is administered. In some variations, the administration of the chemotherapeutic agent is terminated before the nanoparticle composition is administered. The time period between these two non-concurrent administrations can range from about two to eight weeks, such as about four weeks. 
     The dosing frequency of the drug-containing nanoparticle composition and the chemotherapeutic agent may be adjusted over the course of the treatment, based on the judgment of the administering physician. When administered separately, the drug-containing nanoparticle composition and the chemotherapeutic agent can be administered at different dosing frequency or intervals. For example, the drug-containing nanoparticle composition can be administered weekly, while a chemotherapeutic agent can be administered more or less frequently. In some variations, sustained continuous release formulation of the drug-containing nanoparticle and/or chemotherapeutic agent may be used. Various formulations and devices for achieving sustained release are known in the art. 
     The nanoparticle composition and the chemotherapeutic agent can be administered using the same route of administration or different routes of administration. In some variations (for both simultaneous and sequential administrations), the taxane in the nanoparticle composition and the chemotherapeutic agent are administered at a predetermined ratio. For example, in some variations, the ratio by weight of the taxane in the nanoparticle composition and the chemotherapeutic agent is about 1 to 1. In some variations, the weight ratio may be between about 0.001 to about 1 and about 1000 to about 1, or between about 0.01 to about 1 and 100 to about 1. In some variations, the ratio by weight of the taxane in the nanoparticle composition and the chemotherapeutic agent is less than about any of 100:1, 50:1, 30:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, and 1:1 In some variations, the ratio by weight of the taxane in the nanoparticle composition and the chemotherapeutic agent is more than about any of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 30:1, 50:1, 100:1. Other ratios are contemplated. 
     The doses required for the taxane and/or the chemotherapeutic agent may (but not necessarily) be lower than what is normally required when each agent is administered alone. Thus, in some variations, a subtherapeutic amount of the drug in the nanoparticle composition and/or the chemotherapeutic agent are administered. “Subtherapeutic amount” or “subtherapeutic level” refer to an amount that is less than the therapeutic amount, that is, less than the amount normally used when the drug in the nanoparticle composition and/or the chemotherapeutic agent are administered alone. The reduction may be reflected in terms of the amount administered at a given administration and/or the amount administered over a given period of time (reduced frequency). 
     In some variations, enough chemotherapeutic agent is administered so as to allow reduction of the normal dose of the drug in the nanoparticle composition required to effect the same degree of treatment by at least about any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or more. In some variations, enough drug in the nanoparticle composition is administered so as to allow reduction of the normal dose of the chemotherapeutic agent required to affect the same degree of treatment by at least about any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or more. 
     In some variations, the dose of both the taxane in the nanoparticle composition and the chemotherapeutic agent are reduced as compared to the corresponding normal dose of each when administered alone. In some variations, both the taxane in the nanoparticle composition and the chemotherapeutic agent are administered at a subtherapeutic, i.e., reduced, level. In some variations, the dose of the nanoparticle composition and/or the chemotherapeutic agent is substantially less than the established maximum toxic dose (MTD). For example, the dose of the nanoparticle composition and/or the chemotherapeutic agent is less than about 50%, 40%, 30%, 20%, or 10% of the MTD. 
     A combination of the administration configurations described herein can be used. The combination therapy methods described herein may be performed alone or in conjunction with another therapy, such as surgery, radiation, chemotherapy, immunotherapy, gene therapy, and the like. Additionally, a person having a greater risk of developing the proliferative disease may receive treatments to inhibit or and/or delay the development of the disease. 
     As will be understood by those of ordinary skill in the art, the appropriate doses of chemotherapeutic agents will be approximately those already employed in clinical therapies wherein the chemotherapeutic agent are administered alone or in combination with other chemotherapeutic agents. Variation in dosage will likely occur depending on the condition being treated. As described above, in some variations, the chemotherapeutic agents may be administered at a reduced level. 
     The nanoparticle compositions described herein can be administered to an individual (such as human) via various routes, such as parenterally, including intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, or transdermal. For example, the nanoparticle composition can be administered by inhalation to treat conditions of the respiratory tract. The composition can be used to treat respiratory conditions such as pulmonary fibrosis, broncheolitis obliterans, lung cancer, bronchoalveolar carcinoma, and the like. In some variations, the nanoparticle composition is administrated intravenously. In some variations, the nanoparticle composition is administered orally. 
     The dosing frequency of the administration of the nanoparticle composition depends on the nature of the combination therapy and the particular disease being treated. An exemplary dosing frequency include, but is not limited to, weekly without break; weekly, three out of four weeks; once every three weeks; once every two weeks; weekly, two out of three weeks. See also Table 1. 
     The dose of the taxane in the nanoparticle composition will vary with the nature of the combination therapy and the particular disease being treated. The dose should be sufficient to effect a desirable response, such as a therapeutic or prophylactic response against a particular disease. An exemplary dose of the taxane (in some variations paclitaxel) in the nanoparticle composition include, but is not limited to, about any of 50 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 160 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 260 mg/m 2 , and 300 mg/m 2 . For example, the dosage of paclitaxel in a nanoparticle composition can be in the range of 100-400 mg/m 2  when given on a 3 week schedule, or 50-250 mg/m 2  when given on a weekly schedule. See also Table 1. 
     Other exemplary dosing schedules for the administration of the nanoparticle composition (such as paclitaxel/albumin nanoparticle composition, for example Abraxane®) include, but are not limited to, 100 mg/m 2 , weekly, without break; 75 mg/m 2  weekly, 3 out of four weeks; 100 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 2 out of 3 weeks; 130 mg/m 2 , weekly, without break; 175 m g/m 2 , once every 2 weeks; 260 mg/m 2 , once every 2 weeks; 260 mg/m 2 , once every 3 weeks; 180-300 mg/m 2 , every three weeks; 60-175 mg/m 2 , weekly, without break. In addition, the taxane (alone or in combination therapy) can be administered by following a metronomic dosing regime described herein. 
     Exemplary dosing regimes for the combination therapy of nanoparticle composition (such as paclitaxel/albumin nanoparticle composition, for example Abraxane®) and other agents include, but are not limited to, 125 mg/m 2  weekly, two out of three weeks, plus 825 mg/m 2  Xeloda®, daily; 260 mg/m 2  once every two weeks, plus 60 mg/m 2  adriamycin and 600 mg/m 2  cyclophosphamide, once every two weeks; 220-340 mg/m 2  once every three weeks, plus carboplatin, AUC=6, once every three weeks; 100-150 mg/m 2  weekly, plus carboplatin, AUC=6, once every three weeks; 175 mg/m2 once every two weeks, plus 2000 mg/m 2  gemcitabine and 50 mg/m 2  epirubicin, once every two weeks; and 75 mg/m 2  weekly, three out of four weeks, plus carboplatin, AUC=2, weekly, three out of four weeks. 
     In some variations, the nanoparticle composition of the taxane and the chemotherapeutic agent is administered according to any of the dosing regimes described in Table 1. 
     In some variations, there is provided a method of treating breast cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 1 to 35 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 1 to 35 in Table 1. In some variations, there is provided a method of treating metastatic breast cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 2, 4-8, and 10-15 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 2, 4-8, and 10-15 in Table 1. 
     In some variations, there is provided a method of treating advanced breast cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 1 and 16 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 1 and 16 in Table 1. In some variations, there is provided a method of treating stage 1V breast cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Row 3 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be the dosing regime as indicated in Row 3 in Table 1. 
     In some variations, there is provided a method of treating breast cancer in an individual in an adjuvant setting comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 18 to 24 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 18 to 24 in Table 1. 
     In some variations, there is provided a method of treating breast cancer in an individual in a neoadjuvant setting comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 25 to 35 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 25 to 35 in Table 1. 
     In some variations, there is provided a method of treating lung cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 36 to 48 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 36 to 48 in Table 1. 
     In some variations, there is provided a method of treating NSCLC (including advanced NSCLC and first line NSCLC) in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 36-40 and 42-43 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 36-40 and 42-43 in Table 1. In some variations, there is provided a method of treating advanced solid tumor malignancy in the lung in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Row 41 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be the dosing regimes as indicated in Row 41 in Table 1. In some variations, there is provided a method of treating SCLC in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Row 48 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be the dosing regimes as indicated in Row 48 in Table 1. 
     In some variations, there is provided a method of treating ovarian cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 49 to 52 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 49 to 52 in Table 1. 
     In some variations, there is provided a method of treating head and neck cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 53 to 55 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 53 to 55 in Table 1. 
     In some variations, there is provided a method of treating solid tumor (including advanced solid tumor) in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 56 to 59 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 56 to 59 in Table 1. 
     In some variations, there is provided a method of treating melanoma (including metastatic melanoma) in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 60-63 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 60 to 63 in Table 1. 
     In some variations, there is provided a method of treating metastatic colorectal cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Row 64 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be the dosing regime as indicated in Row 64 in Table 1. 
     In some variations, there is provided a method of treating pancreatic cancer in an individual comprising administering to the individual: a) an effective amount of a composition comprising nanoparticles comprising a taxane (such as paclitaxel) and an albumin, and b) an effective amount of at least one other chemotherapeutic agent as provided in Rows 65 to 66 in Table 1. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 65 to 66 in Table 1. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
               
                 Row 
                   
                   
                 Study therapy 
                   
               
               
                 No. 
                 Combination 
                 Regime/Dosage 
                 type 
                 Protocol title 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1. 
                 ABX + 
                 ABX: 100 mg/m 2  D1, 8, 15 
                 Advanced 
                 A phase II study of 
               
               
                   
                 Carboplatin + 
                 q4wk × 6 
                 HER2+ Breast 
                 weekly dose-dense 
               
               
                   
                 Herceptin ® 
                 Carbo: AUC = 2 D1, 8, 15 q4wk × 6 
                 Cancer 
                 nanoparticle paclitaxel 
               
               
                   
                   
                 Herceptin ®: 4 mg/kg on wk 1, 2 mg/kg 
                   
                 (ABI-007) 
               
               
                   
                   
                 all subsequent weeks 
                   
                 carboplatin ™, with 
               
               
                   
                   
                   
                   
                 Herceptin ® as first or 
               
               
                   
                   
                   
                   
                 second-line therapy of 
               
               
                   
                   
                   
                   
                 advanced HER2+ 
               
               
                   
                   
                   
                   
                 breast cancer 
               
               
                 2. 
                 ABX alone 
                 ABX: 125 mg/m 2   
                 Metastatic 
                 Phase II trial of weekly 
               
               
                   
                 (+Herceptin ®) 
                 qwk × ¾ 
                 Breast Cancer 
                 Abraxane ® 
               
               
                   
                   
                   
                   
                 monotherapy for 1st- 
               
               
                   
                   
                   
                   
                 line MBC (plus 
               
               
                   
                   
                   
                   
                 Herceptin ® in HER2+ 
               
               
                   
                   
                   
                   
                 pts) 
               
               
                 3. 
                 ABX + 
                 L1: ABX: 80 mg/m 
                 Stage IV 
                 Phase I-II study weekly 
               
               
                   
                 Navelbine ® 
                 Nav: 15 mg/m 2   
                 Breast Cancer 
                 ABX + Navelbine ®, 
               
               
                   
                 (±G-CSF) 
                 L2: ABX: 90 mg/m 2   
                   
                 with or without G-CSF, 
               
               
                   
                   
                 Nav: 20 mg/m 2   
                   
                 in stage IV breast 
               
               
                   
                   
                 L3: ABX: 100 mg/m 2   
                   
                 cancer 
               
               
                   
                   
                 Nav: 22.5 mg/m 2   
               
               
                   
                   
                 L4: ABX: 110 mg/m 2   
               
               
                   
                   
                 Nav: 25 mg/m 2   
               
               
                   
                   
                 L5: ABX: 125 mg/m 2   
               
               
                   
                   
                 Nav: 25 mg/m 2   
               
               
                   
                   
                 qwk all levels 
               
               
                 4. 
                 ABX + Xeloda ® 
                 ABX: 125 mg/m 2  qwk × ⅔ 
                 Metastatic 
                 Phase II 1st-line ABX + 
               
               
                   
                   
                 Xeloda ®: 825 mg/m 2  D1-14 
                 Breast Cancer 
                 Xeloda ® MBC trial 
               
               
                   
                   
                 q3wk 
               
               
                 5. 
                 ABX + 
                   
                 Metastatic 
                 Phase I/II trial ABX 
               
               
                   
                 Anthracycline 
                   
                 Breast Cancer 
                 plus Doxil ® for MBC 
               
               
                   
                   
                   
                   
                 plus limited PK 
               
               
                 6. 
                 ABX + 
                 ABX: 125 mg/m 2   
                 Metastatic 
                 Randomized Phase II 
               
               
                   
                 Gemcitabine 
                 Gem: 1000 mg/m2 
                 Breast Cancer 
                 Trial of Weekly nab 
               
               
                   
                   
                 qwk × ⅔ 
                   
                 (nanoparticle albumin 
               
               
                   
                   
                   
                   
                 bound)-Paclitaxel (nab- 
               
               
                   
                   
                   
                   
                 paclitaxel) in 
               
               
                   
                   
                   
                   
                 Combination with 
               
               
                   
                   
                   
                   
                 Gemcitabine in Patients 
               
               
                   
                   
                   
                   
                 with HER2 Negative 
               
               
                   
                   
                   
                   
                 Metastatic Breast 
               
               
                   
                   
                   
                   
                 Cancer 
               
               
                 7. 
                 ABX + 
                   
                 Metastatic 
                 Phase I/II Abraxane ® + 
               
               
                   
                 Lapatinib 
                   
                 Breast Cancer 
                 GW572016 
               
               
                 8. 
                 ABX + 
                 ABX: 100 mg/m 2  qwk × ¾ 
                 Metastatic 
                 Phase I dose escalation 
               
               
                   
                 Lapatinib 
                 Lapatinib: starting at 1000 mg/d × 
                 Breast Cancer 
                 study of a 2 day oral 
               
               
                   
                   
                 2 days 
                   
                 lapatinib 
               
               
                   
                   
                   
                   
                 chemosensitization 
               
               
                   
                   
                   
                   
                 pulse given prior to 
               
               
                   
                   
                   
                   
                 weekly intravenous 
               
               
                   
                   
                   
                   
                 Abraxane ® in patients 
               
               
                   
                   
                   
                   
                 with advanced solid 
               
               
                   
                   
                   
                   
                 tumors 
               
               
                 9. 
                 ABX + FEC 
                 ABX: 220 mg/m 2  q2wk × 6 
                 Breast Cancer 
                 Phase II preoperative 
               
               
                   
                 (+Herceptin ®) 
                 followed by 
                   
                 trial of Abraxane ® 
               
               
                   
                   
                 FEC: 4 cycles (+Herceptin ® for 
                   
                 followed by FEC 
               
               
                   
                   
                 HER2+ pts) 
                   
                 (+Herceptin ® as 
               
               
                   
                   
                   
                   
                 appropriate) in breast 
               
               
                   
                   
                   
                   
                 cancer 
               
               
                 10. 
                 ABX + 
                 ABX: 100 mg/m 2  qwk D1, 8, 15 
                 Metastatic 
                 Phase II safety and 
               
               
                   
                 Carboplatin + 
                 Carbo: AUC = 2 qwk D1, 8, 15 
                 Breast Cancer 
                 tolerability study of 
               
               
                   
                 Avastin ® 
                 Avastin ®: 10 mg/m 2  q2wk 
                 (HER2−, ER−, 
                 Abraxane ®, Avastin ® 
               
               
                   
                   
                   
                 PR−) 
                 and carboplatin in triple 
               
               
                   
                   
                   
                   
                 negative metastatic 
               
               
                   
                   
                   
                   
                 breast cancer patients 
               
               
                 11. 
                 ABX + Avastin ® 
                 ABX: 130 mg/m 2  qwk + 
                 Metastatic 
                 Three arm phase II trial 
               
               
                   
                   
                 Avastin ® 
                 Breast Cancer 
                 in 1 st  line HER2− 
               
               
                   
                   
                 vs 
                   
                 negative MBC patients 
               
               
                   
                   
                 ABX: 260 mg/m 2  q2wk + 
               
               
                   
                   
                 Avastin ® 
               
               
                   
                   
                 vs 
               
               
                   
                   
                 ABX: 260 mg/m 2  q3wk + 
               
               
                   
                   
                 Avastin ® 
               
               
                 12. 
                 ABX + Avastin ® 
                 ABX: 125 mg/m 2  qwk × ¾ + 
                 Metastatic 
                 Single arm study of 
               
               
                   
                   
                 Avastin ® 
                 Breast Cancer 
                 Abraxane ® and 
               
               
                   
                   
                   
                   
                 Avastin ® in 1 st  line 
               
               
                   
                   
                   
                   
                 MBS 
               
               
                 13. 
                 ABX + Avastin ® 
                 ABX + Avastin ® qwk 
                 Metastatic 
                 Randomized Phase III 
               
               
                   
                   
                 vs 
                 Breast Cancer 
                 trial in 1 st  line and 2 nd   
               
               
                   
                   
                 Taxol ® + Avastin ® qwk 
                   
                 line MBC with 
               
               
                   
                   
                   
                   
                 biological correlates 
               
               
                   
                   
                   
                   
                 analysis 
               
               
                 14. 
                 ABX + Xeloda ® + 
                   
                 Metastatic 
                 Phase II Abraxane ® in 
               
               
                   
                 Lapatinib 
                   
                 Breast Cancer 
                 combination with 
               
               
                   
                   
                   
                   
                 Xeloda ® and Lapatinib 
               
               
                   
                   
                   
                   
                 for metastatic breast 
               
               
                   
                   
                   
                   
                 cancer 
               
               
                 15. 
                 ABX + 
                 ABX: 3000 mg/m 2  D1 q3wk 
                 Metastatic 
                 Single arm Phase II 
               
               
                   
                 Gemcitabine 
                 Gem: 1250 mg/m 2  D1, 8 q3wk 
                 Breast Cancer 
                 study of Abraxane ® and 
               
               
                   
                   
                   
                   
                 gemcitabine for 1 st  line 
               
               
                   
                   
                   
                   
                 MBC 
               
               
                 16. 
                 ABX + RAD001 
                   
                 Advanced 
                 Phase I/II study of 
               
               
                   
                   
                   
                 Breast Cancer 
                 Abraxane ® in 
               
               
                   
                   
                   
                   
                 combination with 
               
               
                   
                   
                   
                   
                 RAD001 in patients 
               
               
                   
                   
                   
                   
                 with advanced breast 
               
               
                   
                   
                   
                   
                 cancer 
               
               
                 17. 
                 ABX + Sutent ® 
                   
                 Breast Cancer 
                 Phase I study of 
               
               
                   
                   
                   
                   
                 Abraxane ® in 
               
               
                   
                   
                   
                   
                 combination with 
               
               
                   
                   
                   
                   
                 Sutent ® 
               
               
                 18. 
                 ABX + AC + G- 
                 AC + G-CSF q2wk × 4 
                 Breast Cancer - 
                 Abraxane ® in dose- 
               
               
                   
                 CSF 
                 followed by 
                 Adjuvant 
                 dense adjuvant 
               
               
                   
                 (+Herceptin ®) 
                 ABX: 260 mg/m 2  q2wk × 4 
                   
                 chemotherapy for early 
               
               
                   
                   
                 (+Herceptin ® for HER2+ pts) 
                   
                 stage breast cancer 
               
               
                 19. 
                 ABX + AC + G- 
                 Dose dense AC + G-CSF 
                 Breast Cancer - 
                 Phase II pilot adjuvant 
               
               
                   
                 CSF 
                 followed by ABX 
                 Adjuvant 
                 trial of Abraxane ® in 
               
               
                   
                 (+Herceptin ®) 
                 (+Herceptin ® for HER2+ pts) 
                   
                 breast cancer 
               
               
                   
                   
                 qwk 
               
               
                 20. 
                 ABX + AC 
                 AC followed by ABX: 260 mg/m 2   
                 Breast Cancer - 
                 Adjuvant Dose dense 
               
               
                   
                   
                 vs 
                 Adjuvant 
                 Registrational Trial 
               
               
                   
                   
                 AC followed by Taxol ® 
               
               
                   
                   
                 Rx length 16 wks 
               
               
                 21. 
                 ABX + AC 
                 AC q2wk followed by 
                 Breast Cancer - 
                 Phase II dose dense 
               
               
                   
                 (+G-CSF) 
                 ABX: 260 mg/m 2  + G-CSF q2wk 
                 Adjuvant 
                 pilot adjuvant study of 
               
               
                   
                   
                 Rx length 16 wks 
                   
                 Abraxane ® in breast 
               
               
                   
                   
                   
                   
                 cancer 
               
               
                 22. 
                 ABX + AC 
                 Dose dense AC followed by 
                 Breast Cancer - 
                 Pilot adjuvant breast 
               
               
                   
                 (+Avastin ®) 
                 ABX (+Avastin ® in HER2+ pts) 
                 Adjuvant 
                 cancer study 
               
               
                 23. 
                 ABX + AC 
                 AC 
                 Breast Cancer - 
                 BIG study: Dose dense 
               
               
                   
                   
                 followed by ABX 
                 Adjuvant 
                 vs standard adjuvant 
               
               
                   
                   
                 q2wk or q3wk 
                   
                 chemotherapy 
               
               
                 24. 
                 ABX (ABI-007) + 
                 AC followed by 
                 Breast Cancer - 
                 Phase II - Pilot Study 
               
               
                   
                 AC + 
                 ABX q2wk × 4 
                 Adjuvant 
                 Evaluating the Safety of 
               
               
                   
                 Neulasta ® 
                   
                   
                 a Dose-Dense Regime - 
               
               
                   
                   
                   
                   
                 AC × 4 =&gt; ABI-007 × 4 
               
               
                   
                   
                   
                   
                 Q 2 WEEKS + 
               
               
                   
                   
                   
                   
                 Neulasta ® - Given as 
               
               
                   
                   
                   
                   
                 Adjuvant 
               
               
                   
                   
                   
                   
                 Chemotherapy of High- 
               
               
                   
                   
                   
                   
                 Risk Women with Early 
               
               
                   
                   
                   
                   
                 Breast Cancer 
               
               
                 25. 
                 ABX + FEC 
                 ABX: 100 mg/m 2  qwk × 12 
                 Locally 
                 A Phase II Study of 
               
               
                   
                 (+Herceptin ®) 
                 followed by 
                 Advanced Breast 
                 Neoadjuvant 
               
               
                   
                   
                 5-FU: 500 mg/m 2  q3wk 
                 Cancer - 
                 Chemotherapy with 
               
               
                   
                   
                 Epirubicin: 100 mg/m 2   
                 Neoadjuvant 
                 Sequential Weekly 
               
               
                   
                   
                 (without Herceptin ®) 
                   
                 Nanoparticle Albumin 
               
               
                   
                   
                 or 
                   
                 Bound Paclitaxel 
               
               
                   
                   
                 Epirubicin: 75 mg/m 2   
                   
                 (Abraxane ®) Followed 
               
               
                   
                   
                 (with Herceptin ® for HER2+ 
                   
                 by 5-Fluorouracil, 
               
               
                   
                   
                 pts) 
                   
                 Epirubicin, 
               
               
                   
                   
                 Cyclophosphamide: 500 mg/m 2   
                   
                 Cyclophosphamide 
               
               
                   
                   
                 q3wk 
                   
                 (FEC) in Locally 
               
               
                   
                   
                   
                   
                 Advanced Breast 
               
               
                   
                   
                   
                   
                 Cancer 
               
               
                 26. 
                 ABX + 
                 Arm 1: Neoadjuvant: Gem: 2000 mg/m 2 , 
                 Breast Cancer - 
                 Phase II Trial of Dose 
               
               
                   
                 Gemcitabine + 
                 ABX: 175 mg/m 2 , Epi 
                 Neoadjuvant 
                 Dense Neoadjuvant 
               
               
                   
                 Epirubicin 
                 50 mg/m 2   
                   
                 Gemcitabine, 
               
               
                   
                   
                 q2wk × 6 
                   
                 Epirubicin, ABI-007 
               
               
                   
                   
                 Arm 2: Adjuvant: Gem: 2000 mg/m 2 , 
                   
                 (GEA) in Locally 
               
               
                   
                   
                 ABX: 220 mg/m 2   
                   
                 Advanced or 
               
               
                   
                   
                 q2wk × 4 
                   
                 Inflammatory Breast 
               
               
                   
                   
                   
                   
                 Cance 
               
               
                 27. 
                 ABX + 
                 ABX: 260 mg/m 2  q2wk + 
                 Breast Cancer - 
                 Phase II Multi-center 
               
               
                   
                 Herceptin ® 
                 Herceptin ® 
                 Neoadjuvant 
                 study neoadjuvant. 
               
               
                   
                   
                 followed by 
               
               
                   
                   
                 Navelbine ® + Herceptin ® 
               
               
                 28. 
                 ABX + 
                 TAC 
                 Breast Cancer - 
                 3 arms Randomized 
               
               
                   
                 Carboplatin 
                 vs 
                 Neoadjuvant 
                 dose dense phase II 
               
               
                   
                 (+Herceptin ®) + 
                 AC followed by ABX + carbo 
                   
                 trial of neoadjuvant 
               
               
                   
                 AC 
                 vs 
                   
                 chemotherapy in 
               
               
                   
                   
                 AC followed by ABX + carbo + 
                   
                 patients with breast 
               
               
                   
                   
                 Herceptin ® 
                   
                 cancer 
               
               
                 29. 
                 ABX + 
                 ABX: 260 mg/m 2  q3wk × 4 
                 Breast Cancer - 
                 Phase II neoadjuvant 
               
               
                   
                 Capecitabine 
                 Xeloda ® 850 mg/m 2  D1-14 
                 Neoadjuvant 
                 trial of Abraxane ® and 
               
               
                   
                   
                 q3wk × 4 
                   
                 capecitabine in locally 
               
               
                   
                   
                   
                   
                 advanced breast cancer 
               
               
                 30. 
                 ABX + 
                 ABX qwk 
                 Breast Cancer - 
                 Phase I/II trial of 
               
               
                   
                 Carboplatin 
                 carbo qwk + 
                 Neoadjuvant 
                 neoadjuvant 
               
               
                   
                 (+Avastin ®) 
                 Avastin ® in HER2+ pts 
                   
                 chemotherapy (NCT) 
               
               
                   
                   
                   
                   
                 with weekly 
               
               
                   
                   
                   
                   
                 nanoparticle paclitaxel 
               
               
                   
                   
                   
                   
                 (ABI-007, Abraxane ®) 
               
               
                   
                   
                   
                   
                 in combination with 
               
               
                   
                   
                   
                   
                 carboplatin and 
               
               
                   
                   
                   
                   
                 Avastin ® in clinical 
               
               
                   
                   
                   
                   
                 stage I-III. 
               
               
                 31. 
                 ABX + 
                 ABX: 100 mg/m 2  qwk × ¾ 
                 Breast Cancer - 
                 Phase II study of 
               
               
                   
                 Carboplatin + 
                 Carbo: AUC = 5 + 
                 Neoadjuvant 
                 weekly bevacizumab 
               
               
                   
                 Herceptin ® + 
                 Herceptin ® + 
                   
                 administered with 
               
               
                   
                 Avastin ® 
                 Avastin ® 
                   
                 weekly trastuzumab, 
               
               
                   
                   
                 4 week cycle × 6 
                   
                 ABI-007, and 
               
               
                   
                   
                   
                   
                 carboplatin as 
               
               
                   
                   
                   
                   
                 preoperative therapy in 
               
               
                   
                   
                   
                   
                 HER2-neu gene 
               
               
                   
                   
                   
                   
                 amplified breast cancer 
               
               
                   
                   
                   
                   
                 tumors 
               
               
                 32. 
                 ABX + 
                 ABX: 260 mg/m 2  q3wk 
                 Breast Cancer - 
                 Pilot neoadjuvant trial 
               
               
                   
                 Lapatinib 
                 Lapatinib: 1000 mg/day 
                 Neoadjuvant 
                 with combination of 
               
               
                   
                   
                   
                   
                 ABI-007 (Abraxane ®) 
               
               
                   
                   
                   
                   
                 and GW572016 
               
               
                   
                   
                   
                   
                 (Lapatinib) 
               
               
                 33. 
                 ABX + 
                 ABX: 200 mg/m 2   
                 Breast Cancer - 
                 Phase II neoadjuvant 
               
               
                   
                 Capecitabine 
                 q3wk × 4 
                 Neoadjuvant 
                 trial of Abraxane ® and 
               
               
                   
                   
                 Xeloda ®: 1000 mg/m 2   
                   
                 capecitabine in locally 
               
               
                   
                   
                 D1-14 q3wk × 4 
                   
                 advanced breast cancer 
               
               
                 34. 
                 ABX ± Avastin ® + 
                 ABX qwk ± Avastin ® followed 
                 Breast Cancer - 
                 Phase III trial of 
               
               
                   
                 AC 
                 by A qwk + C daily 
                 Neoadjuvant 
                 paclitaxel vs Abraxane ® 
               
               
                   
                 (+G-CSF) 
                 vs 
                   
                 with or without 
               
               
                   
                   
                 Taxol ® qwk ± Avastin ® followed 
                   
                 Avastin ® in 
               
               
                   
                   
                 by A qwk + C daily 
                   
                 combination with 
               
               
                   
                   
                   
                   
                 doxorubicin and 
               
               
                   
                   
                   
                   
                 cyclophosphamide plus 
               
               
                   
                   
                   
                   
                 G-CSF 
               
               
                 35. 
                 ABX + AC 
                 ABX followed by AC 
                 Breast Cancer - 
                 Phase II neoadjuvant 
               
               
                   
                   
                   
                 Neoadjuvant 
                 trial with gene 
               
               
                   
                   
                   
                   
                 expression analyses 
               
               
                 36. 
                 ABX + 
                 ABX: 300 mg/m 2  q3wk 
                 1 st  line 
                 An open label phase II 
               
               
                   
                 Carboplatin + 
                 Carbo: AUC = 6 q3wk 
                 Advanced 
                 trial of Abraxane ®, 
               
               
                   
                 Avastin ® 
                 Avastin ®: 15 mg/kg 
                 NSCLC 
                 carboplatin and 
               
               
                   
                   
                 4 cycles 
                   
                 Avastin ® in patients 
               
               
                   
                   
                   
                   
                 with advanced non- 
               
               
                   
                   
                   
                   
                 squamous non-small 
               
               
                   
                   
                   
                   
                 cell lung cancer 
               
               
                 37. 
                 ABX + 
                 L1: ABX: 225 mg/m 2   
                 Advanced 
                 Phase II toxicity pilot 
               
               
                   
                 Carboplatin 
                 L2: ABX: 260 mg/m 2   
                 NSCLC 
                 study of Abraxane ® and 
               
               
                   
                   
                 L3: ABX: 300 mg/m 2   
                   
                 carboplatin in advanced 
               
               
                   
                   
                 Cohorts 1-4: ABX q3wk 
                   
                 non-small cell lung 
               
               
                   
                   
                 Cohorts 5-7: ABX weekly 
                   
                 cancer. 
               
               
                   
                   
                 Cohort 8: 75 additional patients 
               
               
                   
                   
                 Carbo fixed at AUC = 6 q3wk 
               
               
                 38. 
                 ABX + 
                 Carbo: AUC = 6 + ABX 
                 1 st  line NSCLC 
                 Phase III Registration - 
               
               
                   
                 Carboplatin 
                 vs 
                   
                 NSCLC 1st line therapy 
               
               
                   
                   
                 Carbo: AUC = 6 + Taxol ®: 225 mg/m 2   
               
               
                 39. 
                 ABX + 
                 ABX: 100 mg/m 2  d1, 8, 15 
                 1 st  line NSCLC 
                 Phase II Trial of weekly 
               
               
                   
                 Carboplatin 
                 Carbo: AUC = 6 q4wk 
                   
                 Abraxane ® plus 
               
               
                   
                   
                 Amendment: ABX: 125 mg/m 2   
                   
                 carboplatin in 1st-line 
               
               
                   
                   
                 D1, 8, 15 
                   
                 NSCLC 
               
               
                 40. 
                 ABX + 
                 Weekly 
                 NSCLC 
               
               
                   
                 Carboplatin + 
               
               
                   
                 Avastin ® 
               
               
                 41. 
                 ABX + 
                 Arm 1: ABX: 100, 125, 150 mg/m 2   
                 Lung Cancer - 
                 Phase I Trial of 
               
               
                   
                 Carboplatin 
                 D1, 8, 15 q4wk 
                 Advanced Solid 
                 carboplatin and 
               
               
                   
                   
                 Arm 2: ABX 220, 260, 300, 340 mg/m 2   
                 Tumor 
                 Abraxane ® on a weekly 
               
               
                   
                   
                 q3wk 
                 Malignancy 
                 and every three week 
               
               
                   
                   
                 Arm 3: ABX 100, 125, 150 mg/m 2   
                   
                 schedule in patients 
               
               
                   
                   
                 D1, 8 
                   
                 with Advanced Solid 
               
               
                   
                   
                 Carbo: AUC = 6 in all arms 
                   
                 Tumor Malignancies 
               
               
                 42. 
                 ABX + 
                   
                 NSCLC 
                 Abraxane ® in 
               
               
                   
                 Gemcitabine or 
                   
                   
                 combination with 
               
               
                   
                 ABX + Avastin ® 
                   
                   
                 gemcitabine or 
               
               
                   
                   
                   
                   
                 Avastin ® 
               
               
                 43. 
                 ABX + 
                   
                 NSCLC 
                 Phase I trial of 
               
               
                   
                 Gemcitabine 
                   
                   
                 Abraxane ® in 
               
               
                   
                   
                   
                   
                 combination with 
               
               
                   
                   
                   
                   
                 gemcitabine 
               
               
                 44. 
                 ABX + 
                 ABX: 225, 260, 300 mg/m 2   
                 Lung Cancer 
                 Phase I/II study of 
               
               
                   
                 Carboplatin + 
                 Carbo: AUC = 6 
                   
                 Abraxane ® and 
               
               
                   
                 Avastin ® 
                 q3wk + 
                   
                 carboplatin AUC 6, 
               
               
                   
                   
                 Avastin ® 
                   
                 plus Avastin ® (Standard 
               
               
                   
                   
                   
                   
                 3 + 3 Phase I design; 
               
               
                   
                   
                   
                   
                 PhII: 40 pts) 
               
               
                 45. 
                 ABX + Alimta ® 
                 ABX: 220, 260, 300 mg/m 2   
                 Lung Cancer 
                 Phase I/II study of 
               
               
                   
                   
                 q3wk 
                   
                 Abraxane ® + Alimta ® 
               
               
                   
                   
                 Pemtrexed: 500 mg q3wk 
                   
                 for 2nd-line NSCLC 
               
               
                 46. 
                 ABX + Cisplatin 
                   
                 Lung Cancer 
                 Phase I/II trial of 
               
               
                   
                   
                   
                   
                 Abraxane ® plus 
               
               
                   
                   
                   
                   
                 cisplatin in advanced 
               
               
                   
                   
                   
                   
                 NSCLC 
               
               
                 47. 
                 ABX + 
                   
                 Lung Cancer 
                 Phase I/II study of 
               
               
                   
                 Navelbine ® + 
                   
                   
                 Abraxane ®, 
               
               
                   
                 Cisplatin 
                   
                   
                 Navelbine ®, and 
               
               
                   
                   
                   
                   
                 Cisplatin for treatment 
               
               
                   
                   
                   
                   
                 of advanced NSCLC 
               
               
                 48. 
                 ABX + 
                 ABX: 300 mg/m 2  q3wk 
                 SCLC 
                 Phase II trial of 
               
               
                   
                 Carboplatin 
                 Carbo: AUC = 6 q3wk 
                   
                 Abraxane ® and 
               
               
                   
                   
                   
                   
                 carboplatin in extensive 
               
               
                   
                   
                   
                   
                 stage small cell lung 
               
               
                   
                   
                   
                   
                 cancer 
               
               
                 49. 
                 ABX + 
                 ABX: 100 mg/m 2  qwk × ¾ 
                 Ovarian Cancer 
                 A phase II trial of 
               
               
                   
                 Carboplatin 
                 Carbo: AUC = 6 
                   
                 Abraxane ® + 
               
               
                   
                   
                   
                   
                 Carboplatin in recurrent 
               
               
                   
                   
                   
                   
                 ovarian cancer 
               
               
                 50. 
                 ABX + 
                 ABX: qwk 
                 Ovarian Cancer 
                 Phase I study of 
               
               
                   
                 Carboplatin 
                 ABX: q3w 
                   
                 Abraxane ® plus carbo 
               
               
                   
                   
                 Carbo: AUC = 6 both arms 
                   
                 for treatment of 
               
               
                   
                   
                   
                   
                 advanced ovarian 
               
               
                   
                   
                   
                   
                 cancer 
               
               
                 51. 
                 ABX + 
                 ABX: TBD by ABI-CA034 
                 Ovarian Cancer 
                 1st line, optimally 
               
               
                   
                 Carboplatin 
                 vs 
                   
                 debulked, registration 
               
               
                   
                   
                 Taxol ® 175 mg/m 2   
                   
                 trial. Carbo AUC 6 + 
               
               
                   
                   
                 Carbo: AUC = 6 in both arms 
                   
                 ABX vs Carbo + 
               
               
                   
                   
                   
                   
                 Taxol ® 175 mg/m 2 . 
               
               
                   
                   
                   
                   
                 Endpoint: relapse free 
               
               
                   
                   
                   
                   
                 survival, survival 
               
               
                 52. 
                 ABX + Avastin ® 
                 ABX: 100 mg/m 2  qwk × ¾ 
                 Ovarian Cancer 
                 Phase II study of 
               
               
                   
                   
                 Avastin ®: 10 mg/m 2  q2wk 
                   
                 bevacizumab with 
               
               
                   
                   
                   
                   
                 Abraxane ® in patients 
               
               
                   
                   
                   
                   
                 with recurrent, 
               
               
                   
                   
                   
                   
                 platinum resistant 
               
               
                   
                   
                   
                   
                 primary epithelial 
               
               
                   
                   
                   
                   
                 ovarian or primary 
               
               
                   
                   
                   
                   
                 peritoneal carcinoma 
               
               
                 53. 
                 ABX + 5-FU + 
                 ABX: D1 
                 Head and Neck 
                 Unresectable localized 
               
               
                   
                 Cisplatin 
                 5-FU: 750 mg/m 2  CIV × 5 
                 Cancer 
                 head and neck cancer 
               
               
                   
                   
                 cisplatin: 75 mg/m 2  D1 
                   
                 Phase II Abraxane ® in 
               
               
                   
                   
                 followed by XRT/surgery 
                   
                 combination with 5-FU 
               
               
                   
                   
                   
                   
                 and cisplatin 
               
               
                 54. 
                 ABX + 5-FU + 
                 5-FU: 750 mg/m 2  CIV × 5 
                 Head and Neck 
                 Unresectable localized 
               
               
                   
                 Cisplatin 
                 cisplatin: 75 mg/m 2  D1 ± 
                 Cancer 
                 head and neck cancer 
               
               
                   
                   
                 ABX D1 
                   
                 Phase III 5-FU and 
               
               
                   
                   
                 followed by XRT/surgery 
                   
                 cisplatin with or without 
               
               
                   
                   
                   
                   
                 Abraxane ® 
               
               
                 55. 
                 ABX + 
                   
                 Head and Neck 
                 Phase II multicenter trial 
               
               
                   
                 Cetuximab 
                   
                 Cancer 
                 of Abraxane ® in 
               
               
                   
                   
                   
                   
                 combination with 
               
               
                   
                   
                   
                   
                 cetuximab in 1 st  line 
               
               
                   
                   
                   
                   
                 treatment of locally 
               
               
                   
                   
                   
                   
                 advanced or metastatic 
               
               
                   
                   
                   
                   
                 head and neck cancer 
               
               
                 56. 
                 ABX + 
                 ABX: 100 mg/m 2  qwk 
                 Solid Tumors 
                 Phase I Study of 
               
               
                   
                 Rapamycin 
                 Rapamycin: 5-40 mg dose 
                   
                 Rapamycin in 
               
               
                   
                   
                 escalation 
                   
                 Combination with 
               
               
                   
                   
                   
                   
                 Abraxane ® in Advanced 
               
               
                   
                   
                   
                   
                 Solid Tumors 
               
               
                 57. 
                 ABX + 
                   
                 Solid Tumors 
                 Phase I trial of Abraxane ® 
               
               
                   
                 Satraplatin 
                   
                   
                 and Satraplatin 
               
               
                 58. 
                 ABX + 
                 ABX: 180, 220, 260, 300, 340 mg/m 2   
                 Advanced Solid 
                 Phase I Trial of Abraxane ® 
               
               
                   
                 Gemcitabine 
                 q3wk 
                 Tumors 
                 in combination with 
               
               
                   
                   
                 Gemcitabine: 1000 mg/m 2  D1 
                   
                 Gemcitabine 
               
               
                   
                   
                 and D8 
               
               
                 59. 
                 ABX + Gefitinib 
                 ABX: 100 mg/m 2  qwk × ¾ 
                 Advanced Solid 
                 Phase I dose escalation 
               
               
                   
                   
                 Gefitinib starting at 1000 mg/d × 2 
                 Tumors 
                 study of gefitinib 
               
               
                   
                   
                   
                   
                 chemosensitization pulse 
               
               
                   
                   
                   
                   
                 given prior to weekly 
               
               
                   
                   
                   
                   
                 Abraxane ® 
               
               
                 60. 
                 ABX + Avastin ® 
                   
                 Metastatic 
                 Phase II study of 
               
               
                   
                   
                   
                 Melanoma 
                 Abraxane ® and 
               
               
                   
                   
                   
                   
                 Avastin ® in metastatic 
               
               
                   
                   
                   
                   
                 melanoma 
               
               
                 61. 
                 ABX + Avastin ® 
                   
                 Melanoma 
                 Abraxane ® and 
               
               
                   
                   
                   
                   
                 Avastin ® as therapy for 
               
               
                   
                   
                   
                   
                 patients with malignant 
               
               
                   
                   
                   
                   
                 melanoma 
               
               
                 62. 
                 ABX + 
                   
                 Metastatic 
                 Phase II study of 
               
               
                   
                 Carboplatin 
                   
                 Melanoma 
                 Abraxane ® and 
               
               
                   
                   
                   
                   
                 carboplatin in 
               
               
                   
                   
                   
                   
                 metastatic melanoma 
               
               
                 63. 
                 ABX + 
                 ABX: qwk 
                 Metastatic 
                 Phase II study of 
               
               
                   
                 Sorafenib + 
                 Sorafenib: D2-19 
                 Melanoma 
                 Abraxane ® in 
               
               
                   
                 Carboplatin 
                 Carbo: AUC = 6 D1 
                   
                 combination with 
               
               
                   
                   
                   
                   
                 carboplatin and 
               
               
                   
                   
                   
                   
                 sorafenib in metastatic 
               
               
                   
                   
                   
                   
                 melanoma 
               
               
                 64. 
                 ABX + 
                   
                 Metastatic 
                 Phase II trial of 
               
               
                   
                 Capecitabine 
                   
                 Colorectal 
                 Abraxane ® in 
               
               
                   
                   
                   
                 Cancer (after 
                 combination with 
               
               
                   
                   
                   
                 failure of 
                 Xeloda ® for previously 
               
               
                   
                   
                   
                 oxaliplatin- 
                 treated patient with 
               
               
                   
                   
                   
                 based therapy 
                 advance or metastatic 
               
               
                   
                   
                   
                 and irinotecan- 
                 colorectal cancer 
               
               
                   
                   
                   
                 based therapy) 
               
               
                 65. 
                 ABX + 
                 Weekly 
                 Pancreatic 
                 Phase I study of 
               
               
                   
                 Gemcitabine 
                   
                 Cancer 
                 Abraxane ® in combination 
               
               
                   
                   
                   
                   
                 with gemcitabine in 
               
               
                   
                   
                   
                   
                 pancreatic cancer 
               
               
                 66. 
                 ABX + 
                 ABX + Gem 
                 Pancreatic 
                 Phase III registration trial 
               
               
                   
                 Gemcitabine 
                 vs 
                 Cancer 
                 in pancreatic cancer 
               
               
                   
                   
                 Gem 
               
               
                 67. 
                 ABX + anti- 
                   
                   
                 Abraxane ® combined 
               
               
                   
                 angiogenic 
                   
                   
                 with anti-angiogenic 
               
               
                   
                 agents 
                   
                   
                 agents, e.g. Avastin ® 
               
               
                 68. 
                 ABX + 
                   
                   
                 Abraxane ® combined 
               
               
                   
                 proteasome 
                   
                   
                 with proteasome 
               
               
                   
                 inhibitors 
                   
                   
                 inhibitors, e.g. 
               
               
                   
                   
                   
                   
                 Velcade ® 
               
               
                 69. 
                 ABX + EGFR 
                   
                   
                 Abraxane ® combined 
               
               
                   
                 inhibitors 
                   
                   
                 with EGFR inhibitors, 
               
               
                   
                   
                   
                   
                 e.g. Tarceva ® 
               
               
                   
               
            
           
         
       
     
     As used in herein (for example in Table 1), ABX refers to Abraxane®; GW572016 refers to lapatinib; Xel refers to capecitabine or Xeloda®; bevacizumab is also known as Avastin®; trastuzumab is also known as Herceptin®; pemtrexed is also known as Alimta®; cetuximab is also known as Erbitux®; gefitinib is also known as Iressa®; FEC refers to a combination of 5-fluorouracil, Epirubicin and Cyclophosphamide; AC refers to a combination of Adriamycin plus Cyclophosphamide; TAC refers to a FDA approved adjuvant breast cancer regime; RAD001 refers to a derivative of rapamycin; NSCLC refers to non-small cell lung cancer; and SCLC refers to small cell lung cancer. 
     As used herein (for example in Table 1), AUC refers to area under curve; q4wk refers to a dose every 4 weeks; q3wk refers to a dose every 3 weeks; q2wk refers to a dose every 2 weeks; qwk refers to a weekly dose; qwk×3/4 refers to a weekly dose for 3 weeks with the 4 th  week off; qwk×2/3 refers to a weekly dose for 2 weeks with the 3 rd  week off. 
     Combination Therapy with Radiation Therapy and Surgery 
     In another aspect, the present invention provides a method of treating proliferative disease (such as cancer) comprising a first therapy comprising administering a taxane (particularly nanoparticles comprising a taxane) and a carrier protein and a second therapy comprising radiation and/or surgery. 
     In some variations, the method comprises: a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising an effective amount of a taxane and a carrier protein (such as albumin) and b) a second therapy comprising radiation therapy, surgery, or combinations thereof. In some variations, the taxane is coated with the carrier protein (such as albumin). In some variations, the second therapy is radiation therapy. In some variations, the second therapy is surgery. 
     In some variations, the method comprises a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising paclitaxel and an albumin; and b) a second therapy comprising radiation therapy, surgery, or combinations thereof. In some variations, the second therapy is radiation therapy. In some variations, the second therapy is surgery. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm. In some variations, the paclitaxel/albumin nanoparticle composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the weight ratio of the albumin to paclitaxel in the composition is about 18:1 or less, such as about 9:1 or less. In some variations, the paclitaxel is coated with albumin. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel/albumin composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel is coated with albumin. In some variations, the nanoparticle composition is Abraxane®. 
     The administration of the nanoparticle composition may be prior to the radiation and/or surgery, after the radiation and/or surgery, or concurrent with the radiation and/or surgery. For example, the administration of the nanoparticle composition may precede or follow the radiation and/or surgery therapy by intervals ranging from minutes to weeks. In some variations, the time period between the first and the second therapy is such that the taxane and the radiation/surgery would still be able to exert an advantageously combined effect on the cell. For example, the taxane (such as paclitaxel) in the nanoparticle composition may be administered less than about any of 1, 3, 6, 9, 12, 18, 24, 48, 60, 72, 84, 96, 108, 120 hours prior to the radiation and/or surgery. In some variations, the nanoparticle composition is administered less than about 9 hours prior to the radiation and/surgery. In some variations, the nanoparticle composition is administered less than about any of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to the radiation/surgery. In some variations, the taxane (such as paclitaxel) in the nanoparticle composition is administered less than about any of 1, 3, 6, 9, 12, 18, 24, 48, 60, 72, 84, 96, 108, or 120 hours after the radiation and/or surgery. In some variations, it may be desirable to extend the time period for treatment significantly, where several days to several weeks lapse between the two therapies. 
     Radiation contemplated herein includes, for example, γ-rays, X-rays (external beam), and the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated such as microwaves and UV irradiation are also contemplated. Radiation may be given in a single dose or in a series of small doses in a dose-fractionated schedule. The amount of radiation contemplated herein ranges from about 1 to about 100 Gy, including, for example, about 5 to about 80, about 10 to about 50 Gy, or about 10 Gy. The total dose may be applied in a fractioned regime. For example, the regime may comprise fractionated individual doses of 2 Gy. Dosage ranges for radioisotopes vary widely, and depends on the half-life of the isotope and the strength and type of radiation emitted. 
     When the radiation comprises use of radioactive isotopes, the isotope may be conjugated to a targeting agent, such as a therapeutic antibody, which carries the radionucleotide to the target tissue. Suitable radioactive isotopes include, but are not limited to, astatine 211 ,  14 carbon,  51  chromium,  36 chlorine,  57 iron,  58 cobalt, copper 67 ,  152 Eu, gallium 67 ,  3 hydrogen, iodine 123 , iodine 131 , indium 111 ,  59 ion,  32 phosphorus, rhenium 186 ,  75 selenium,  35 sulphur, technicium 99m , and/or yttrium 90 . 
     In some variations, enough radiation is applied to the individual so as to allow reduction of the normal dose of the taxane (such as paclitaxel) in the nanoparticle composition required to effect the same degree of treatment by at least about any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or more. In some variations, enough taxane in the nanoparticle composition is administered so as to allow reduction of the normal dose of the radiation required to effect the same degree of treatment by at least about any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or more. In some variations, the dose of both the taxane (such as paclitaxel) in the nanoparticle composition and the radiation are reduced as compared to the corresponding normal dose of each when used alone. 
     In some variations, the combination of administration of the nanoparticle composition and the radiation therapy produce supra-additive effect. In some variations, the taxane (such as paclitaxel) in the nanoparticle composition is administered once at the dose of 90 mg/kg, and the radiation is applied five times at 80 Gy daily. 
     Surgery described herein includes resection in which all or part of cancerous tissue is physically removed, exercised, and/or destroyed. Tumor resection refers to physical removal of at least part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and micropically controlled surgery (Mohs surgery). Removal of superficial surgery, precancers, or normal tissues are also contemplated. 
     The radiation therapy and/or surgery may be carried out in addition to the administration of chemotherapeutic agents. For example, the individual may first be administered with a taxane-containing nanoparticle composition and at least one other chemotherapeutic agent, and subsequently be subject to radiation therapy and/or surgery. Alternatively, the individual may first be treated with radiation therapy and/or surgery, which is then followed by the administration of a nanoparticle composition and at least one other chemotherapeutic agent. Other combinations are also contemplated. 
     Administration of nanoparticle compositions disclosed above in conjunction with administration of chemotherapeutic agent is equally applicable to those in conjunction with radiation therapy and/or surgery. 
     In some variations, the nanoparticle composition of the taxane and/or the chemotherapeutic agent is administered in conjunction with radiation according to any of the dosing regimes described in Table 2. 
     In some variations, there is provided a method of treating NSCLC in an individual comprises a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising taxane (such as paclitaxel) and an albumin; and b) a second therapy comprising radiation as provided in Rows 1 to 5 in Table 2. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 1 to 5 in Table 2. 
     In some variations, there is provided a method of treating head and neck cancer in an individual comprises a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising taxane (such as paclitaxel) and an albumin; and b) a second therapy comprising radiation as provided in Rows 6 to 9 in Table 2. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be any of the dosing regimes as indicated in Rows 6 to 9 in Table 2. 
     In some variations, there is provided a method of treating pancreatic cancer in an individual comprises a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising taxane (such as paclitaxel) and an albumin; and b) a second therapy comprising radiation as provided in Row 10 in Table 2. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be the dosing regimes as indicated in Row 10 in Table 2. 
     In some variations, there is provided a method of treating gastric malignancies in an individual comprises a) a first therapy comprising administering to the individual a composition comprising nanoparticles comprising taxane (such as paclitaxel) and an albumin; and b) a second therapy comprising radiation as provided in Row 11 in Table 2. In some variations, the administration of the nanoparticle composition and the chemotherapeutic agent may be the dosing regimes as indicated in Row 11 in Table 2. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Row 
                   
                   
                 Study therapy 
                   
               
               
                 No. 
                 Combination 
                 Regime/Dosage 
                 type 
                 Protocol title 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1 
                 ABX + 
                   
                 NSCLC 
                 Phase I/II trial of 
               
               
                   
                 Radiation 
                   
                   
                 Abraxane ® combined 
               
               
                   
                   
                   
                   
                 with radiation 
               
               
                 2 
                 ABX + 
                   
                 NSCLC 
                 Phase I/II trial of 
               
               
                   
                 Carboplatin + 
                   
                   
                 Abraxane ® and 
               
               
                   
                 Radiation 
                   
                   
                 carboplatin combined 
               
               
                   
                   
                   
                   
                 with radiation. 
               
               
                 3 
                 ABX + 
                 1 cycle ABX/Carbo induction 
                 NSCLC 
                 Phase II chemoradiation 
               
               
                   
                 Carboplatin + 
                 followed by 
                   
                 in NSCLC 
               
               
                   
                 Radiation 
                 2 or 3 times weekly pulse ABX + 
               
               
                   
                   
                 radiation 
               
               
                 4 
                 ABX + 
                   
                 NSCLC 
                 Abraxane ®/carboplatin 
               
               
                   
                 Carboplatin + 
                   
                   
                 induction followed by 
               
               
                   
                 Radiation 
                   
                   
                 Abraxane ® + radiation 
               
               
                   
                   
                   
                   
                 in stage III A&amp;B PS2 
               
               
                   
                   
                   
                   
                 NSCLC patients 
               
               
                 5 
                 ABX + 
                 ABX qwk + carbo + radiation 
                 NSCLC 
                 Phase II study 
               
               
                   
                 Carboplatin + 
                 followed by 
               
               
                   
                 Radiation 
                 ABX q3wk + carbo 
               
               
                 6 
                 ABX + 
                   
                 Head and 
                 Abraxane ® as a 
               
               
                   
                 Radiation 
                   
                 Neck Cancer 
                 radiosensitizer in head 
               
               
                   
                   
                   
                   
                 and neck cancer 
               
               
                 7 
                 ABX + 
                   
                 Head and 
                 PhaseI/II Abraxane ® in 
               
               
                   
                 Cetuximab + 
                   
                 Neck Cancer 
                 combination with 
               
               
                   
                 Radiation 
                   
                   
                 cetuximab and radiation 
               
               
                 8 
                 ABX + 
                 Induction: ABX 135 mg/m 2   
                 Head and 
                 Phase I/II study of 
               
               
                   
                 Carboplatin + 
                 qwk + carbo: AUC = 2 
                 Neck Cancer 
                 induction chemotherapy 
               
               
                   
                 5-FU + 
                 followed by 
                   
                 with Abraxane ® and 
               
               
                   
                 Hydroxyurea + 
                 Concurrent chemoradiation: 
                   
                 carboplatin followed by 
               
               
                   
                 Radiation 
                 ABX: 100 mg/m 2   
                   
                 concomitant 
               
               
                   
                   
                 5-FU: 600 mg/m 2   
                   
                 fluorouracil, 
               
               
                   
                   
                 hydroxyurea: 5000 mg BID 
                   
                 hydroxyurea, 
               
               
                   
                   
                   
                   
                 Abraxane ® and IMRT 
               
               
                   
                   
                   
                   
                 for locally advanced 
               
               
                   
                   
                   
                   
                 head and neck cancers 
               
               
                 9 
                 ABX + 
                 ABX: 20-50 mg/m 2  qwk × 7 
                 Locally 
                 Phase I trial of 
               
               
                   
                 Carboplatin + 
                 dose escalation 
                 Advanced 
                 Abraxane ® in 
               
               
                   
                 Erbitux ® + 
                 Eribitux ®: 400 mg/m 2  day 7, 
                 Head and 
                 combination with 
               
               
                   
                 Radiation 
                 250 mg/m 2  qwk × 7 
                 Neck Cancer 
                 carboplatin, cetuximab 
               
               
                   
                   
                 Carbo: AUC = 1.5 qwk × 7 
                   
                 and IMRT in locally 
               
               
                   
                   
                 IMRT 
                   
                 advanced squamous cell 
               
               
                   
                   
                   
                   
                 cancer of the head and 
               
               
                   
                   
                   
                   
                 neck 
               
               
                 10 
                 ABX + 
                 qwk 
                 Pancreatic 
                 A randomized phase II 
               
               
                   
                 Gemcitabine + 
                   
                 Cancer 
                 trial of weekly 
               
               
                   
                 Radiation 
                   
                   
                 gemcitabine, 
               
               
                   
                   
                   
                   
                 Abraxane ®, and 
               
               
                   
                   
                   
                   
                 external irradiation for 
               
               
                   
                   
                   
                   
                 locally advanced 
               
               
                   
                   
                   
                   
                 pancreatic cancer 
               
               
                 11 
                 ABX + 
                   
                 Gastric 
                 Phase I/II combination 
               
               
                   
                 Cisplatin + 
                   
                 Malignancies 
                 of Abraxane ®/cisplatin 
               
               
                   
                 Radiation 
                   
                   
                 and radiation for 
               
               
                   
                   
                   
                   
                 patients with resected 
               
               
                   
                   
                   
                   
                 gastric/GEJ 
               
               
                   
                   
                   
                   
                 malignancies. 
               
               
                   
               
            
           
         
       
     
     In some variations, the invention provides pharmaceutical compositions comprising nanoparticles comprising a taxane (such as paclitaxel) and a carrier protein (such as albumin) for use in the treatment of a proliferative disease (such as cancer), wherein said use comprises a second therapy comprising radiation therapy, surgery, or combinations thereof. 
     Metronomic Therapy 
     The invention also provides metronomic therapy regime. There is provided a method of administering to an individual a composition comprising nanoparticles comprising a taxane (such as paclitaxel, docetaxel, or ortataxel) and a carrier protein (such as albumin) based on a metronomic dosing regime. The methods are applicable to methods of treatment, delaying development, and other clinical settings and configurations described herein. For example, in some variations, the methods are useful for treatment of proliferative diseases (such as cancer). 
     “Metronomic dosing regime” used herein refers to frequent administration of a taxane at without prolonged breaks at a dose below the established maximum tolerated dose via a traditional schedule with breaks (hereinafter also referred to as a “standard MTD schedule” or a “standard MTD regime”). In metronomic dosing, the same, lower, or higher cumulative dose over a certain time period as would be administered via a standard MTD schedule may ultimately be administered. In some cases, this is achieved by extending the time frame and/or frequency during which the dosing regime is conducted while decreasing the amount administered at each dose. Generally, the taxane administered via the metronomic dosing regime of the present invention is better tolerated by the individual. Metronomic dosing can also be referred to as maintenance dosing or chronic dosing. 
     In some variations, there is provided a method of administering a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. In some variations, there is provided a method of administering a composition comprising nanoparticles comprising paclitaxel and an albumin, wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. 
     In some variations, the dosing of the taxane (such as paclitaxel) in the nanoparticle composition per administration is less than about any of 1%, 2%, 3&amp;, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 18%, 20%, 22%, 24%, or 25% of the MTD for the same taxane (such as paclitaxel) in the same formulation following a given traditional dosing schedule. Traditional dosing schedule refers to the dosing schedule that is generally established in a clinical setting. For example, the tradition dosing schedule for Abraxane® is a three-weekly schedule, i.e., administering the composition every three weeks. 
     In some variations, the dosing of the taxane (such as paclitaxel) per administration is between about 0.25% to about 25% of the corresponding MTD value, including for example any of about 0.25% to about 20%, about 0.25% to about 15%, about 0.25% to about 10%, about 0.25% to about 20%, and about 0.25% to about 25%, of the corresponding MTD value. The MTD value for a taxane following a traditional dosing schedule is known or can be easily determined by a person skilled in the art. For example, the MTD value when Abraxane® is administered following a traditional three-week dosing schedule is about 300 mg/m 2 . 
     In some variations, there is provided a method of administering a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25 mg/m 2  to about 25 mg/m 2 . In some variations, there is provided a method of administering a composition comprising nanoparticles comprising paclitaxel and an albumin, wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25 mg/m 2  to about 25 mg/m 2 . 
     In some variations, the dose of the taxane (such as paclitaxel) at each administration is less than about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 20, 22, 25, and 30 mg/m 2 . For example, the dose of the taxane (such as paclitaxel) can range from about 0.25 m g/m 2  to about 30 mg/m 2 , about 0.25 mg/m 2  to about 25 mg/m 2 , about 0.25 mg/m 2  to about 15 mg/m 2 , about 0.25 mg/m 2  to about 10 mg/m 2 , and about 0.25 mg/m 2  to about 5 mg/m 2 . 
     Dosing frequency for the taxane (such as paclitaxel) in the nanoparticle composition includes, but is not limited to, at least about any of once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or daily. Typically, the interval between each administration is less than about a week, such as less than about any of 6, 5, 4, 3, 2, or 1 day. In some variations, the interval between each administration is constant. For example, the administration can be carried out daily, every two days, every three days, every four days, every five days, or weekly. In some variations, the administration can be carried out twice daily, three times daily, or more frequent. 
     The metronomic dosing regimes described herein can be extended over an extended period of time, such as from about a month up to about three years. For example, the dosing regime can be extended over a period of any of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, and 36 months. Generally, there are no breaks in the dosing schedule. 
     The cumulative dose of the taxane (such as paclitaxel) administered by the metronomic regime may be higher than that of the taxane administered according to a standard MTD dosing schedule over the same time period. In some variations, the cumulative dose of the taxane administered by the metronomic regime equals to or is lower than that of the taxane administered according to a standard MTD dosing schedule over the same time period. 
     It is understood that the teaching provided herein is for examples only, and that metronomic dosing regime can be routinely designed in accordance with the teachings provided herein and based upon the individual standard MTD schedule, and that the metronomic dosing regime used in these experiments merely serves as one example of possible changes in dosing interval and duration which are made to a standard MTD schedule to arrive at an optimal metronomic dosing regime. 
     The metronomic dosing regime described herein may be used alone as a treatment of a proliferative disease, or carried out in a combination therapy context, such as the combination therapies described herein. In some variations, the metronomic therapy dosing regime may be used in combination or conjunction with other established therapies administered via standard MTD regimes. By “combination or in conjunction with” it is meant that the metronomic dosing regime of the present invention is conducted either at the same time as the standard MTD regime of established therapies, or between courses of induction therapy to sustain the benefit accrued to the individual by the induction therapy, the intent is to continue to inhibit tumor growth while not unduly compromising the individual&#39;s health or the individual&#39;s ability to withstand the next course of induction therapy. For example, a metronomic dosing regime may be adopted after an initial short course of MTD chemotherapy. 
     The nanoparticle compositions administered based on the metronomic dosing regime described herein can be administered to an individual (such as human) via various routes, such as parenterally, including intravenous, intra-arterial, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, or transdermal. For example, the nanoparticle composition can be administered by inhalation to treat conditions of the respiratory tract. The composition can be used to treat respiratory conditions such as pulmonary fibrosis, broncheolitis obliterans, lung cancer, bronchoalveolar carcinoma, and the like. In some variations, the nanoparticle composition is administered orally. 
     Some various exemplary variations are provided below. 
     In some variations, there is provided a method of administering a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. In some variations, the taxane is coated with the carrier protein (such as albumin). In some variations, the dose of the taxane per administration is less than about any of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 18%, 20%, 22%, 24%, or 25% of the maximum tolerated dose. In some variations, the taxane is administered at least about any of 1×, 2×, 3×, 4×, 5×, 6×, 7× (i.e., daily) a week. In some variations, the intervals between each administration are less than about any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, and 1 day. In some variations, the taxane is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30 and 36 months. 
     In some variations, there is provided a method of administering a composition comprising nanoparticles comprising paclitaxel and an albumin, wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25% to about 25% of its maximum tolerated dose following a traditional dosing regime. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm. In some variations, the paclitaxel/albumin nanoparticle composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the weight ratio of the albumin to paclitaxel in the composition is about 18:1 or less, such as about 9:1 or less. In some variations, the paclitaxel is coated with albumin. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel/albumin composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel is coated with albumin. In some variations, the nanoparticle composition is Abraxane®. 
     In some variations, there is provided a method of administering a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25 mg/m 2  to about 25 mg/m 2 . In some variations, the taxane is coated with the carrier protein (such as albumin). In some variations, the dose of the taxane per administration is less than about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, 20, 22, and 25 mg/m 2 . In some variations, the taxane is administered at least about any of 1×, 2×, 3×, 4×, 5×, 6×, 7× (i.e., daily) a week. In some variations, the intervals between each administration are less than about any of 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, and 1 day. In some variations, the taxane is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30 and 36 months. 
     In some variations, there is provided a method of administering a composition comprising nanoparticles comprising paclitaxel and an albumin, wherein the nanoparticle composition is administered over a period of at least one month, wherein the interval between each administration is no more than about a week, and wherein the dose of the taxane at each administration is about 0.25 mg/m 2  to about 25 mg/m 2 . In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm. In some variations, the paclitaxel/albumin nanoparticle composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the weight ratio of the albumin to paclitaxel in the composition is about 18:1 or less, such as about 9:1 or less. In some variations, the paclitaxel is coated with albumin. In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel/albumin composition is substantially free (such as free) of surfactant (such as Cremophor). In some variations, the paclitaxel/albumin nanoparticles have an average diameter of no greater than about 200 nm and the paclitaxel is coated with albumin. In some variations, the nanoparticle composition is Abraxane®. 
     In some variations, the Abraxane® (or other paclitaxel/albumin nanoparticle compositions) is administered at the dose of about 3 mg/kg to about 10 mg/kg daily. In some variations, the Abraxane® is administered at the dose of about 6 mg/kg to about 10 mg/kg daily. In some variations, the Abraxane® is administered at the dose of about 6 mg/kg daily. In some variations, Abraxane® is administered at the dose of about 3 mg/kg daily. 
     The invention also provides compositions for use in the metronomic regime(s) described herein. In some variations, there is provided a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), wherein said composition is administered to an individual via a metronomic dosing regime, such as the dosing regime described herein. 
     Other Aspects of the Invention 
     In another aspects, there are provided methods of treating proliferative diseases comprising administering a composition comprising nanoparticles comprising a taxane (including pacltiaxel, docetaxel, or ortataxel) and a carrier protein (such as albumin). In some variations, there is provided a method of treating cancer comprising administering a composition comprising nanoparticles comprising ortataxel and a carrier protein (such as albumin). 
     In some variations, there is provided methods of treating proliferative diseases comprising administering a composition comprising nanoparticles comprising a thiocolchicine or its derivative (such as dimeric thiocolchicine) and a carrier protein (such as albumin). In some variations, there is provided a method of treating cancer comprising administering a composition comprising nanoparticles comprising dimeric colchicines and a carrier protein (such as albumin). In some variations, the nanoparticle composition is any of (and in some variations selected from the group consisting of) Nab-5404, Nab-5800, and Nab-5801. 
     In some variations, there is provided a method of treating cancer comprising administering a composition comprising nanoparticles comprising paclitaxel, wherein the nanoparticle composition is administered according to any of the dosing regimes described in Table 3. In some variations, the cancer is a Taxane refractory metastatic breast cancer. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                 Row 
                   
                   
                 Study therapy 
                   
               
               
                 No. 
                 Combination 
                 Regimen/Dosage 
                 type 
                 Protocol title 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 1. 
                 ABX alone 
                 ABX: 125 mg/m 2  qwk × ¾ 
                 Metastatic 
                 Phase II study with 
               
               
                   
                   
                   
                 Breast Cancer 
                 weekly Abraxane ® 
               
               
                   
                   
                   
                   
                 treatment in taxane- 
               
               
                   
                   
                   
                   
                 refractory MBC patients 
               
               
                 2. 
                 ABX alone 
                 Arm 1: ABX 130 mg/m 2  qwk 
                 Metastatic 
                 3-arm phase II trial in 1st- 
               
               
                   
                   
                 Arm 2: ABX 260 mg/m 2  q2wk 
                 Breast Cancer 
                 line Her-2- MBC patients. 
               
               
                   
                   
                 Arm 3: ABX 260 mg/m 2  q3wk 
               
               
                 3. 
                 ABX alone 
                 ABX: 260 mg/m 2  q3wk 
                 Metastatic 
                 Phase II Controlled, 
               
               
                   
                 (Capxol) 
                 vs 
                 Breast Cancer 
                 Randomized, Open Label 
               
               
                   
                   
                 Taxol: 175 mg/m 2  q3wk 
                   
                 Study to Evaluate the 
               
               
                   
                   
                   
                   
                 Efficacy and Safety of 
               
               
                   
                   
                   
                   
                 Capxol (a Cremophor- 
               
               
                   
                   
                   
                   
                 Free Nanoparticle 
               
               
                   
                   
                   
                   
                 Paclitaxel) and 
               
               
                   
                   
                   
                   
                 cremophor-formulated 
               
               
                   
                   
                   
                   
                 paclitaxel injection in 
               
               
                   
                   
                   
                   
                 Patient with Metastatic 
               
               
                   
                   
                   
                   
                 Breast Cancer 
               
               
                 4. 
                 ABX alone 
                 Arm 1: ABX weekly 
                 Metastatic 
                 3-arm phase II trial in 1st- 
               
               
                   
                   
                 Arm 2: ABX q3wk 
                 Breast Cancer 
                 line and 2nd-line MBC, 
               
               
                   
                   
                 Arm 3: Taxol weekly 
                   
                 with biological correlates 
               
               
                   
                   
                   
                   
                 analysis 
               
               
                 5. 
                 ABX alone 
                 ABX: 300 mg/m 2  q3wk 
                 Stage IIA, IIB, 
                 Phase II trial of 
               
               
                   
                   
                   
                 IIIA, IIIB and 
                 neoadjuvant 
               
               
                   
                   
                   
                 IV breast cancer 
                 chemotherapy (NCT) with 
               
               
                   
                   
                   
                   
                 nanoparticle paclitaxel 
               
               
                   
                   
                   
                   
                 (ABI-007, Abraxane ®) in 
               
               
                   
                   
                   
                   
                 women with clinical stage 
               
               
                   
                   
                   
                   
                 IIA, IIB, IIIA, IIIB and IV 
               
               
                   
                   
                   
                   
                 (with intact primary) 
               
               
                   
                   
                   
                   
                 breast cancers 
               
               
                 6. 
                 ABX alone 
                 ABX: 125 mg/m 2  qwk × ¾ 
                 1st-line 
                 Phase I/II study of 
               
               
                   
                   
                   
                 advanced 
                 Abraxane ® monotherapy 
               
               
                   
                   
                   
                 NSCLC 
                 in 1st-line advanced 
               
               
                   
                   
                   
                   
                 NSCLC 
               
               
                 7. 
                 ABX alone 
                 ABX 260 mg/m 2   
                 1st-line NSCLC 
                 Phase II ABX mono in 
               
               
                   
                   
                 q3wk 
                   
                 1st-line NSCLC 
               
               
                 8. 
                 ABX alone 
                 Arm 1: ABX q3wk 
                 2 nd  line NSCLC 
                 Phase II study of 
               
               
                   
                   
                 Arm 2: ABX qwk 
                   
                 Abraxane ® monotherapy 
               
               
                   
                   
                 Doses TBD 
                   
                 in 2 nd -line NSCLC 
               
               
                 9. 
                 ABX alone 
                 ABX: 100 mg/m 2  qwk 
                 Prostate Cancer 
                 Randomized phase II 
               
               
                   
                   
                 vs 
                   
                 study Abraxane ® weekly 
               
               
                   
                   
                 ABX: 260 mg/m 2  q3wk 
                   
                 vs every three weeks in 
               
               
                   
                   
                   
                   
                 front line HRP 
               
               
                 10. 
                 ABX alone 
                 ABX qwk 
                 Prostate Cancer 
                 Phase II Abraxane ® in 1st- 
               
               
                   
                   
                   
                   
                 line prostate cancer 
               
               
                 11. 
                 ABX alone 
                 ABX: 150 mg/m 2  qwk × ¾ for 2 
                 Prostate Cancer 
                 Phase II neoadjuvant 
               
               
                   
                   
                 cycles 
                   
                 study 
               
               
                 12. 
                 ABX alone 
                 ABX: 100 mg/m 2  qwk (no break) 
                 Prostate Cancer 
                 Phase II Abraxane ® 100 mg 
               
               
                   
                   
                   
                   
                 weekly no break 
               
               
                 13. 
                 ABX alone 
                 ABX: 100 mg/m 2  (previously 
                 Malignant 
                 Phase II previously treated 
               
               
                   
                   
                 treated) 
                 Melanoma 
                 and untreated metastatic 
               
               
                   
                   
                 ABX: 150 mg/m 2  (untreated) 
                   
                 melanoma patients 
               
               
                   
                   
                 qwk × ¾ 
               
               
                 14. 
                 ABX alone 
                 ABX: 125 mg/m 2   
                 Carcinoma of 
                 Phase II study of 
               
               
                   
                   
                 qwk × ¾ 
                 the cervix 
                 Abraxane ® in treatment of 
               
               
                   
                   
                   
                   
                 persistent or recurrent 
               
               
                   
                   
                   
                   
                 carcinoma of the cervix 
               
               
                 15. 
                 ABX alone 
                   
                 Ovarian Cancer 
                 Phase II study of 
               
               
                   
                   
                   
                   
                 Abraxane ® for treatment 
               
               
                   
                   
                   
                   
                 of advanced ovarian 
               
               
                   
                   
                   
                   
                 cancer (3 rd  line) 
               
               
                 16. 
                 ABX alone 
                   
                 non-hematologic 
                 Phase II single treatment 
               
               
                   
                 (ABI-007) 
                   
                 malignancies 
                 use of ABI-007 
               
               
                   
                   
                   
                   
                 (Abraxane ®) for the 
               
               
                   
                   
                   
                   
                 treatment of non- 
               
               
                   
                   
                   
                   
                 hematologic malignancies. 
               
               
                   
                   
                   
                   
                 Compassionate use 
               
               
                   
               
            
           
         
       
     
     Nanoparticle Compositions 
     The nanoparticle compositions described herein comprise nanoparticles comprising (in various variations consisting essentially of) a taxane (such as paclitaxel) and a carrier protein (such as albumin). Nanoparticles of poorly water soluble drugs (such as taxane) have been disclosed in, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; and 6,537,579 and also in U.S. Pat. Pub. No. 2005/0004002A1. Although the description provided below is specific to taxane, it is understood that the same applies to other drugs, such as rapamycin, 17-AAG, and dimeric thiocolchicine. 
     In some variations, the composition comprises nanoparticles with an average or mean diameter of no greater than about 1000 nanometers (nm), such as no greater than about any of 900, 800, 700, 600, 500, 400, 300, 200, and 100 nm. In some variations, the average or mean diameters of the nanoparticles is no greater than about 200 nm. In some variations, the average or mean diameters of the nanoparticles is no greater than about 150 nm. In some variations, the average or mean diameters of the nanoparticles is no greater than about 100 nm. In some variations, the average or mean diameter of the nanoparticles is about 20 to about 400 nm. In some variations, the average or mean diameter of the nanoparticles is about 40 to about 200 nm. In some variations, the nanoparticles are sterile-filterable. 
     The nanoparticles described herein may be present in a dry formulation (such as lyophilized composition) or suspended in a biocompatible medium. Suitable biocompatible media include, but are not limited to, water, buffered aqueous media, saline, buffered saline, optionally buffered solutions of amino acids, optionally buffered solutions of proteins, optionally buffered solutions of sugars, optionally buffered solutions of vitamins, optionally buffered solutions of synthetic polymers, lipid-containing emulsions, and the like. 
     The term “proteins” refers to polypeptides or polymers of amino acids of any length (including full length or fragments), which may be linear or branched, comprise modified amino acids, and/or be interrupted by non-amino acids. The term also encompasses an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within this term are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. The proteins described herein may be naturally occurring, i.e., obtained or derived from a natural source (such as blood), or synthesized (such as chemically synthesized or by synthesized by recombinant DNA techniques). 
     Examples of suitable carrier proteins include proteins normally found in blood or plasma, which include, but are not limited to, albumin, immunoglobulin including IgA, lipoproteins, apolipoprotein B, alpha-acid glycoprotein, beta-2-macroglobulin, thyroglobulin, transferin, fibronectin, factor VII, factor VIII, factor IX, factor X, and the like. In some variations, the carrier protein is non-blood protein, such as casein, α-lactalbumin, and β-lactoglobulin. The carrier proteins may either be natural in origin or synthetically prepared. In some variations, the pharmaceutically acceptable carrier comprises albumin, such as human serum albumin. Human serum albumin (HSA) is a highly soluble globular protein of M r  65K and consists of 585 amino acids. HSA is the most abundant protein in the plasma and accounts for 70-80% of the colloid osmotic pressure of human plasma. The amino acid sequence of HSA contains a total of 17 disulphide bridges, one free thiol (Cys 34), and a single tryptophan (Trp 214). Intravenous use of HSA solution has been indicated for the prevention and treatment of hypovolumic shock (see, e.g., Tullis,  JAMA,  237, 355-360, 460-463, (1977)) and Houser et al.,  Surgery, Gynecology and Obstetrics,  150, 811-816 (1980)) and in conjunction with exchange transfusion in the treatment of neonatal hyperbilirubinemia (see, e.g., Finlayson,  Seminars in Thrombosis and Hemostasis,  6, 85-120, (1980)). Other albumins are contemplated, such as bovine serum albumin. Use of such non-human albumins could be appropriate, for example, in the context of use of these compositions in non-human mammals, such as the veterinary (including domestic pets and agricultural context). 
     Human serum albumin (HSA) has multiple hydrophobic binding sites (a total of eight for fatty acids, an endogenous ligand of HSA) and binds a diverse set of taxanes, especially neutral and negatively charged hydrophobic compounds (Goodman et al.,  The Pharmacological Basis of Therapeutics,  9 th  ed, McGraw-Hill New York (1996)). Two high affinity binding sites have been proposed in subdomains IIA and IIIA of HSA, which are highly elongated hydrophobic pockets with charged lysine and arginine residues near the surface which function as attachment points for polar ligand features (see, e.g., Fehske et al.,  Biochem. Pharmcol.,  30, 687-92 (198a), Vorum,  Dan. Med. Bull.,  46, 379-99 (1999), Kragh-Hansen,  Dan. Med. Bull.,  1441, 131-40 (1990), Curry et al.,  Nat. Struct. Biol.,  5, 827-35 (1998), Sugio et al.,  Protein. Eng.,  12, 439-46 (1999), He et al.,  Nature,  358, 209-15 (199b), and Carter et al.,  Adv. Protein. Chem.,  45, 153-203 (1994)). Paclitaxel and propofol have been shown to bind HSA (see, e.g., Paal et al.,  Eur. J. Biochem.,  268(7), 2187-91 (200a), Purcell et al.,  Biochim. Biophys. Acta,  1478(a), 61-8 (2000), Altmayer et al.,  Arzneimittelforschung,  45, 1053-6 (1995), and Gamido et al.,  Rev. Esp. Anestestiol. Reanim.,  41, 308-12 (1994)). In addition, docetaxel has been shown to bind to human plasma proteins (see, e.g., Urien et al.,  Invest. New Drugs,  14(b), 147-51 (1996)). 
     The carrier protein (such as albumin) in the composition generally serves as a carrier for the taxane, i.e., the carrier protein in the composition makes the taxane more readily suspendable in an aqueous medium or helps maintain the suspension as compared to compositions not comprising a carrier protein. This can avoid the use of toxic solvents (or surfactants) for solubilizing the taxane, and thereby can reduce one or more side effects of administration of the taxane into an individual (such as a human). Thus, in some variations, the composition described herein is substantially free (such as free) of surfactants, such as Cremophor (including Cremophor EL™ (BASF)). In some variations, the nanoparticle composition is substantially free (such as free) of surfactants. A composition is “substantially free of Cremophor” or “substantially free of surfactant” if the amount of Cremophor or surfactant in the composition is not sufficient to cause one or more side effect(s) in an individual when the nanoparticle composition is administered to the individual. 
     The amount of carrier protein in the composition described herein will vary depending on other components in the composition. In some variations, the composition comprises a carrier protein in an amount that is sufficient to stabilize the taxane in an aqueous suspension, for example, in the form of a stable colloidal suspension (such as a stable suspension of nanoparticles). In some variations, the carrier protein is in an amount that reduces the sedimentation rate of the taxane in an aqueous medium. For particle-containing compositions, the amount of the carrier protein also depends on the size and density of nanoparticles of the taxane. 
     A taxane is “stabilized” in an aqueous suspension if it remains suspended in an aqueous medium (such as without visible precipitation or sedimentation) for an extended period of time, such as for at least about any of 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, 60, or 72 hours. The suspension is generally, but not necessarily, suitable for administration to an individual (such as human). Stability of the suspension is generally (but not necessarily) evaluated at a storage temperature (such as room temperature (such as 20-25° C.) or refrigerated conditions (such as 4° C.)). For example, a suspension is stable at a storage temperature if it exhibits no flocculation or particle agglomeration visible to the naked eye or when viewed under the optical microscope at 1000 times, at about fifteen minutes after preparation of the suspension. Stability can also be evaluated under accelerated testing conditions, such as at a temperature that is higher than about 40° C. 
     In some variations, the carrier protein is present in an amount that is sufficient to stabilize the taxane in an aqueous suspension at a certain concentration. For example, the concentration of the taxane in the composition is about 0.1 to about 100 mg/ml, including for example any of about 0.1 to about 50 mg/ml, about 0.1 to about 20 mg/ml, about 1 to about 10 mg/ml, about 2 mg/ml to about 8 mg/ml, about 4 to about 6 mg/ml, about 5 mg/ml. In some variations, the concentration of the taxane is at least about any of 1.3 mg/ml, 1.5 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 15 mg/ml, 20 mg/ml, 25 mg/ml, 30 mg/ml, 40 mg/ml, and 50 mg/ml. In some variations, the carrier protein is present in an amount that avoids use of surfactants (such as Cremophor), so that the composition is free or substantially free of surfactant (such as Cremophor). 
     In some variations, the composition, in liquid form, comprises from about 0.1% to about 50% (w/v) (e.g. about 0.5% (w/v), about 5% (w/v), about 10% (w/v), about 15% (w/v), about 20% (w/v), about 30% (w/v), about 40% (w/v), or about 50% (w/v)) of carrier protein. In some variations, the composition, in liquid form, comprises about 0.5% to about 5% (w/v) of carrier protein. 
     In some variations, the weight ratio of carrier protein, e.g., albumin, to the taxane in the nanoparticle composition is such that a sufficient amount of taxane binds to, or is transported by, the cell. While the weight ratio of carrier protein to taxane will have to be optimized for different carrier protein and taxane combinations, generally the weight ratio of carrier protein, e.g., albumin, to taxane (w/w) is about 0.01:1 to about 100:1, about 0.02:1 to about 50:1, about 0.05:1 to about 20:1, about 0.1:1 to about 20:1, about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to about 12:1, about 4:1 to about 10:1, about 5:1 to about 9:1, or about 9:1. In some variations, the carrier protein to taxane weight ratio is about any of 18:1 or less, 15:1 or less, 14:1 or less, 13:1 or less, 12:1 or less, 11:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6:1 or less, 5:1 or less, 4:1 or less, and 3:1 or less. 
     In some variations, the carrier protein allows the composition to be administered to an individual (such as human) without significant side effects. In some variations, the carrier protein (such as albumin) is in an amount that is effective to reduce one or more side effects of administration of the taxane to a human. The term “reducing one or more side effects of administration of the taxane” refers to reduction, alleviation, elimination, or avoidance of one or more undesirable effects caused by the taxane, as well as side effects caused by delivery vehicles (such as solvents that render the taxanes suitable for injection) used to deliver the taxane. Such side effects include, for example, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever, anaphylactic reaction, venous thrombosis, extravasation, and combinations thereof. These side effects, however, are merely exemplary and other side effects, or combination of side effects, associated with taxanes can be reduced. 
     In some variations, the composition comprises Abraxane®. Abraxane® is a formulation of paclitaxel stabilized by human albumin USP, which can be dispersed in directly injectable physiological solution. When dispersed in a suitable aqueous medium such as 0.9% sodium chloride injection or 5% dextrose injection, Abraxane® forms a stable colloidal suspension of paclitaxel. The mean particle size of the nanoparticles in the colloidal suspension is about 130 nanometers. Since HSA is freely soluble in water, Abraxane® can be reconstituted in a wide range of concentrations ranging from dilute (0.1 mg/ml paclitaxel) to concentrated (20 mg/ml paclitaxel), including for example about 2 mg/ml to about 8 mg/ml, about 5 mg/ml. 
     Methods of making nanoparticle compositions are known in the art. For example, nanoparticles containing taxanes (such as paclitaxel) and carrier protein (such as albumin) can be prepared under conditions of high shear forces (e.g., sonication, high pressure homogenization, or the like). These methods are disclosed in, for example, U.S. Pat. Nos. 5,916,596; 6,506,405; and 6,537,579 and also in U.S. Pat. Pub. No. 2005/0004002A1. 
     Briefly, the taxane (such as docetaxel) is dissolved in an organic solvent, and the solution can be added to a human serum albumin solution. The mixture is subjected to high pressure homogenization. The organic solvent can then be removed by evaporation. The dispersion obtained can be further lyophilized. Suitable organic solvent include, for example, ketones, esters, ethers, chlorinated solvents, and other solvents known in the art. For example, the organic solvent can be methylene chloride and chloroform/ethanol (for example with a ratio of 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:a). 
     Other Components in the Nanoparticle Compositions 
     The nanoparticles described herein can be present in a composition that include other agents, excipients, or stabilizers. For example, to increase stability by increasing the negative zeta potential of nanoparticles, certain negatively charged components may be added. Such negatively charged components include, but are not limited to bile salts of bile acids consisting of glycocholic acid, cholic acid, chenodeoxycholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, litocholic acid, ursodeoxycholic acid, dehydrocholic acid and others; phospholipids including lecithin (egg yolk) based phospholipids which include the following phosphatidylcholines: palmitoyloleoylphosphatidylcholine, palmitoyllinoleoylphosphatidylcholine, stearoyllinoleoylphosphatidylcholine stearoyloleoylphosphatidylcholine, stearoylarachidoylphosphatidylcholine, and dipalmitoylphosphatidylcholine. Other phospholipids including L-α-dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), distearyolphosphatidylcholine (DSPC), hydrogenated soy phosphatidylcholine (HSPC), and other related compounds. Negatively charged surfactants or emulsifiers are also suitable as additives, e.g., sodium cholesteryl sulfate and the like. 
     In some variations, the composition is suitable for administration to a human. In some variations, the composition is suitable for administration to a mammal such as, in the veterinary context, domestic pets and agricultural animals. There are a wide variety of suitable formulations of the nanoparticle composition (see, e.g., U.S. Pat. Nos. 5,916,596 and 6,096,331). The following formulations and methods are merely exemplary and are in no way limiting. Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions. Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art. 
     Examples of suitable carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline solution, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. 
     Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation compatible with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Injectable formulations are preferred. 
     In some variations, the composition is formulated to have a pH range of about 4.5 to about 9.0, including for example pH ranges of any of about 5.0 to about 8.0, about 6.5 to about 7.5, and about 6.5 to about 7.0. In some variations, the pH of the composition is formulated to no less than about 6, including for example no less than about any of 6.5, 7, or 8 (such as about 8). The composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol. 
     Kits 
     The invention also provides kits for use in the instant methods. Kits of the invention include one or more containers comprising taxane-containing nanoparticle compositions (or unit dosage forms and/or articles of manufacture) and/or a chemotherapeutic agent, and in some variations, further comprise instructions for use in accordance with any of the methods described herein. The kit may further comprise a description of selection an individual suitable or treatment. Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable. 
     In some variations, the kit comprises a) a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), b) an effective amount of at least one other chemotherapeutic agent, and c) instructions for administering the nanoparticles and the chemotherapeutic agents simultaneously and/or sequentially, for treatment of a proliferative disease (such as cancer). In some variations, the taxane is any of paclitaxel, docetaxel, and ortataxel. In some variations, the kit comprises nanoparticles comprising a) a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), b) an effective amount of at least one other chemotherapeutic agent, and c) instructions for administering the nanoparticles and the chemotherapeutic agents simultaneously and/or sequentially, for the effective treatment of a proliferative disease (such as cancer). 
     In some variations, the kit comprises a) a composition comprising nanoparticles comprising a taxane and a carrier protein (such as albumin), b) a composition comprising nanoparticles comprising at least one other chemotherapeutic agent and a carrier protein (such as albumin), and c) instructions for administering the nanoparticle compositions simultaneously and/or sequentially, for treatment of a proliferative disease (such as cancer). In some variations, the kit comprises nanoparticles comprising a) a composition comprising nanoparticles comprising paclitaxel and an albumin (such as Abraxane®), b) a composition comprising nanoparticles comprising at least one other chemotherapeutic agent and a carrier protein (such as albumin), and c) instructions for administering the nanoparticle compositions simultaneously and/or sequentially, for the effective treatment of a proliferative disease (such as cancer). 
     The nanoparticles and the chemotherapeutic agents can be present in separate containers or in a single container. It is understood that the kit may comprise one distinct composition or two or more compositions wherein one composition comprises nanoparticles and one composition comprises a chemotherapeutic agent. 
     The kits of the invention are in suitable packaging. Suitable packaging include, but is not limited to, vials, bottles, jars, flexible packaging (e.g., seled Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information. 
     The instructions relating to the use of the nanoparticle compositions generally include information as to dosage, dosing schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of the taxane (such as taxane) as disclosed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the taxane and pharmaceutical compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies. 
     Those skilled in the art will recognize that several variations are possible within the scope and spirit of this invention. The invention will now be described in greater detail by reference to the following non-limiting examples. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. 
     EXAMPLES 
     Example 1 
     Improved Response and Reduced Toxicities for Abraxane® Compared to Taxol® in a Phase III Study of Abraxane® Given Every Three Weeks 
     Significantly reduced incidence of neutropenia and hypersensitivity, absence of requirement of steroid premedication, shorter duration of neuropathy, shorter infusion time and higher dose. 
     ABI-007 (Abraxane®), the first biologically interactive albumin-bound paclitaxel in a nanoparticle form, free of any solvent, was compared with Cremophor®-based paclitaxel (Taxol®) in individuals with metastatic breast cancer (MBC). This phase III study was performed to confirm the preclinical studies demonstrating superior efficacy and reduced toxicity of ABI-007 when compared with Taxol®. Individuals were randomly assigned to 3-week cycles of either ABI-007 260 mg/m 2  (iv) over 30 minutes without premedication (n=229) or Taxol® 175 mg/m 2  IV over 3 hours with premedication (n=225). ABI-007 demonstrated significantly higher response rates compared with Taxol® (33% vs. 19%; p=0.001) and significantly longer time to tumor progression (23.0 vs. 16.9 weeks; HR=0.75; p=0.006). There was a trend for longer overall survival in individuals who received ABI-007 (65.0 vs. 55.7 weeks; p=0.374). In an unplanned analysis, ABI-007 improved survival in individuals receiving treatment as second- or greater-line therapy (56.4 vs. 46.7 weeks; HR=0.73; p=0.024). The incidence of grade 4 neutropenia was significantly lower in the ABI-007 group (9% vs. 22%; p&lt;0.001) despite a 49% higher paclitaxel dose. Grade 3 sensory neuropathy was more common in the ABI-007 group than in the Taxol® group (10% vs. 2%; p&lt;0.001) but was easily managed and improved more rapidly (median, 22 days) than for Taxol® (median 73 days). No severe (grade 3 or 4) treatment-related hypersensitivity reactions occurred in any of the individuals in the ABI-007 group despite the absence of premedication and shorter administration time. In contrast, grade 3 hypersensitivity reactions occurred in the Taxol® group despite standard premedication (chest pain: 2 individuals; allergic reaction: 3 individuals). Per protocol, corticosteroids and antihistamines were not administered routinely to individuals in the ABI-007 group; however, premedication was administered for emesis, myalgia/arthralgia, or anorexia in 18 individuals (8%) in the ABI-007 group in 2% of the treatment cycles, whereas 224 individuals (&gt;99%) in the Taxol® group received premedication at 95% of the cycles. The only clinical chemistry value that was notably different between the 2 treatment arms was higher serum glucose levels in the Taxol®-treated individuals, who also had a higher incidence of hyperglycemia reported as an AE (adverse effects) (15 [7%] vs. 3 [1%]; p=0.003). Overall, ABI-007 demonstrated greater efficacy and a favorable safety profile compared with Taxol® in this individual population. The improved therapeutic index and elimination of the steroid premedication required for solvent-based taxanes make this nanoparticle albumin-bound paclitaxel an important advance in the treatment of MBC. 
     Example 2 
     Weekly Abraxane® in Taxane-Refractory Metastatic Breast Cancer Individuals 
     A recent Phase II clinical study showed that weekly administration of Abraxane® (nanoparticle albumin-bound paclitaxel) at a dose of 125 mg/m 2  resulted in long-term disease control in individuals with metastatic breast cancer whose disease had progressed while being treated with Taxol® or Taxotere® (that is, individuals who are taxane-refractory). 
     Abraxane® is believed to represent the first biologically interactive composition that exploits the receptor-mediated (gp60) pathway found to be integral to achieving high intracellular tumor concentrations of the active ingredient-paclitaxel. The Phase II study included 75 individuals with taxane-refractory metastatic breast cancer. Abraxane® was administered weekly via a 30-minute infusion at 125 mg/m 2  without steroid/antihistamine premedication or G-CSF prophylaxis. Individuals received three weekly doses followed by one week of rest, repeated every 28 days. Unlike Taxol® or Taxotere®, which contain detergents that may inhibit tumor uptake, the mechanism of action of the albumin-bound nanoparticle paclitaxel may result in improved outcomes, especially in this difficult-to-treat individual population. 
     Specifically, the data showed that despite this high weekly dose of 125 mg/m 2  in this highly pre-treated and prior taxane-exposed individual population, only 3 of 75 individuals (4%) had to discontinue Abraxane® due to peripheral neuropathy. Furthermore, of those who experienced Grade 3 peripheral neuropathy, 80% were typically able to resume treatment after a delay of only 1 or 2 weeks and continued to receive Abraxane® at a reduced dose for an average of 4 additional months. This rapid improvement was consistent with our observation from the Phase III trial—that the peripheral neuropathy induced by paclitaxel alone (i.e., without Cremophor®) improves rapidly as compared to that induced by Taxol®. These Abraxane® clinical trial experiences provide the first clinical opportunity to evaluate the effects of the chemotherapeutic agent itself, paclitaxel, from the effects from those of solvents. Based upon both the Phase II and III experience, the data now suggest that the peripheral neuropathy from Abraxane® is not comparable to the peripheral neuropathy from Taxol® or Taxotere® with respect to duration and impact on the individual. 
     With regard to the clinical experience of peripheral neuropathy following Taxol® or Taxotere®, Abraxis Oncology recently completed a survey of 200 oncologists who were asked how long they thought the peripheral neuropathy induced by Taxol® took to improve and/or resolve: 25% reported “7-12 months” and another 23% reported “never resolved”; for Taxotere®, the respective percentages were 29% and 7%. These data are consistent with the statements in the Taxotere® and Taxol® package inserts. 
     Analysis of the Phase II data demonstrates Abraxane® to be active in this poor-prognosis individual population (87% visceral (lung and liver) disease, 69%&gt;3 metastatic sites, 88% tumor growth while on taxanes), of taxane-refractory individuals with metastatic breast cancer. Observations included a 44% disease control in Taxotere®-refractory individuals and 39% disease control in Taxol®-refractory individuals. Of those individuals whose disease progressed while on Taxotere® alone in the metastatic setting (n=27) a 19% response rate was noted after receiving weekly Abraxane®. Of those individuals whose disease progressed while on Taxol® alone in the metastatic setting (n=23) a 13% response rate was noted after receiving weekly Abraxane®. 
     Abraxane® was found to be well tolerated when administered weekly over 30 minutes without steroids or G-CSF prophylaxis: Grade 4 neutropenia=3% (without G-CSF); Grade 4 anemia=1%; no severe hypersensitivity reactions (despite absence of premedication). In this heavily pretreated individual population, 75% of individuals were treated at the full high dose of 125 mg/m 2  weekly Abraxane®, with no dose reductions due to toxicities/adverse events. Of the individuals who developed grade 3 sensory neuropathy, 77% were able to restart Abraxane® at a reduced dose (75-100 mg/m 2 ) and received a mean of 12.2 (range, 1-28) additional doses of Abraxane®. It was remarkable to note that of these individuals who resumed Abraxane®, 80% (8 of 10) were able to restart the drug within 14 days after improvement of neuropathy to Grade 1 or 2. These results support the observations in the pivotal Phase III trial of 260 mg/m 2  Abraxane® administered every 3 weeks, in which rapid improvement of neuropathy (median of 22 days) was also noted. Taken together these two clinical trials suggest when paclitaxel is given alone, the neuropathy which occurs appears to be short-lived and is easily managed. Abraxane® utilizes the gp60 receptor based pathway on the microvessel endothelial cells to transport the albumin-paclitaxel complex out of the blood vessel and into the tumor interstitium, and it has been shown that Taxol was not transported by this mechanism. Furthermore, an albumin-binding protein, SPARC, was over-expressed in breast tumors and may play a role in the increased intra-tumoral accumulation of Abraxane®. The proposed mechanism suggested that once in the tumor interstitium, the albumin-paclitaxel complex would bind to SPARC that was present on the tumor cell surface and be rapidly internalized into the tumor cell by a non-lysosomal mechanism. 
     In addition, the surfactants/solvents commonly used in current taxane formulations such as Cremophor®, Tween® 80 and TPGS, strongly inhibit the binding of paclitaxel to albumin, thereby limiting transendothelial transport. Additional data presented showed a statistically improved efficacy of Abraxane® over Taxotere® in the MX-1 mammary breast carcinoma xenograft at equal dose. 
     In conclusion, 75% of individuals were treated at full high dose with no dose reductions. Data indicate rapid improvement of peripheral neuropathy when nanoparticle albumin-bound paclitaxel is administered alone, without the solvent Cremophor®. Additional data provide increased evidence that mechanism of action may play important role in enhancing individual outcomes. 
     Example 3 
     Abraxane® (ABI-007) Acts Synergistically with Targeted Antiangiogenic Pro-Apoptotic Peptides (HKP) in MDA-MB-435 Human Tumor Xenografts 
     The antiangiogenic activity of small synthetic pro-apoptotic peptides composed of two functional domains, one targeting the CD13 receptors (aminopeptidase N) on tumor microvessels and the other disrupting the mitochondrial membrane following internalization have previously been reported. See Nat. Med. 1999 September; 5(9):1032-8. A second generation dimeric peptide, CNGRC-GG-d(KLAKLAK) 2 , named HKP (Hunter Killer Peptide) was found to have improved antitumor activity. Since anti-angiogenic agents such as Avastin® exhibit synergism in combination with cytotoxic agents such as 5-fluorouracil, we evaluated the combination of the antiangiogenic HKP with Abraxane® (ABI-007), an albumin nanoparticle paclitaxel that is transported by the gp60 receptor in vascular endothelium (Desai, SABCS 2003), in MDA-MB-435 human breast tumor xenografts. 
     Methods: MDA-MB-435 human tumor xenografts were established at an average tumor volume of 100 mm 3 , mice were randomized into groups of 12-13 animals and treated with HKP, Abraxane®, or HKP and Abraxane®. HKP was delivered i.v. (250 ug), once a week, for 16 weeks. Abraxane® was administered i.v., daily for 5 days at 10 mg/kg/day only for the first week of treatment. The Abraxane® dose used was substantially below its MTD (30 mg/kg/day, qd×5) to prevent the tumor from complete regression so effect of HKP could be noted. 
     Results: At nineteen weeks of treatment, tumor volume was significantly decreased between control group (10,298 mm 3 ±2,570) and HKP (4,372 mm 3 ±2,470; p&lt;0.05 vs control) or ABI-007 (3,909 mm 3 ±506; p&lt;0.01 vs control). The combination of ABI-007 and HKP significantly reduced the tumor volume over either monotherapy (411 mm 3 ±386; p&lt;0.01 vs. Abraxane® monotherapy or HKP monotherapy). The treatments were well tolerated. 
     Conclusion: The combination of Abraxane® (ABI-007), a nanoparticle albumin-bound paclitaxel, with the vascular targeting anti-angiogenic dimeric peptide HKP(CNGRC-GG-d(KLAKLAK) 2 ) against the MDA-MB-435 xenograft breast tumor showed a significant reduction in tumor volume compared to monotherapy of either agent alone. Our results suggest that the combination of Abraxane® with antiangiogenic agents such as HKPs or perhaps Avastin® may be beneficial. 
     Example 4 
     Metronomic ABI-007 Therapy: Antiangiogenic and Antitumor Activity of a Nanoparticle Albumin-bound Paclitaxel 
     Example 4a 
     Methods: The antiangiogenic activity of ABI-007 was assessed by the rat aortic ring, human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. Optimal dose of ABI-007 for metronomic therapy was determined by measuring the levels of circulating endothelial progenitors (CEPS) in peripheral blood of Balb/c non-tumor bearing mice (n=5/group; dosing: 1-30 mg/kg, i.p, qd×7) with flow cytometry (Shaked et al., Cancer Cell, 7:101-111 (2005)). Subsequently, the antitumor effects of metronomic (qd; i.p.) and MTD (qd×5, 1 cycle; i.v.) ABI-007 and Taxol® were evaluated and compared in SCID mice bearing human MDA-MD-231 breast and PC3 prostate cancer xenografts. 
     Results: ABI-007 at 5 nM significantly (p&lt;0.05) inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation and tube formation by 53%, 24%, and 75%, respectively. The optimal dose of ABI-007 for metronomic therapy was observed to be 6-10 mg/kg based on CEP measurements. Metronomic ABI-007 (6 mg/kg) but not Taxol® (1.3 mg/kg) significantly (p&lt;0.05) suppressed tumor growth in both xenograft models. Neither ABI-007 nor Taxol® administered metronomically induced any weight loss. Although MTD ABI-007 (30 mg/kg) inhibited tumor growth more effectively than MTD Taxol® (13 mg/kg), significant weight loss was noted with the former. Interestingly, the antitumor effect of metronomic ABI-007 approximated that of MTD Taxol®. 
     Conclusion: ABI-007 exhibits potent antiangiogenic and antitumor activity when used in a metronomic regime. 
     Example 4b 
     Rat Aortic Ring Assay. Twelve-well tissue culture plates were coated with Matrigel (Collaborative Biomedical Products, Bedford, Mass.) and allowed to gel for 30 min at 37° C. and 5% CO 2 . Thoracic aortas were excised from 8- to 10-week-old male Sprague-Dawley rats, cut into 1-mm-long cross-sections, placed on Matrigel-coated wells and covered with an additional Matrigel. After the second layer of Matrigel had set, the rings were covered with EGM-II and incubated overnight at 37° C. and 5% CO 2 . EGM-II consists of endothelial cell basal medium (EBM-II; Cambrex, Walkersville, Md.) plus endothelial cell growth factors provided as the EGM-II Bulletkit (Cambrex). The culture medium was subsequently changed to EBM-II supplemented with 2% FBS, 0.25 μg/ml amphotericin B and 10 μg/ml gentamycin. Aortic rings were treated with EBM-II containing the vehicle (0.9% saline/albumin), carboxyamidotriazole (CAI; 12 μg/ml), or ABI-007 (0.05-10 nM paclitaxel) for 4 days and photographed on the fifth day. CAI, a known anti-angiogenic agent, was used at a higher than clinically achievable concentration as a positive control. Experiments were repeated four times using aortas from four different rats. The area of angiogenic sprouting, reported in square pixels, was quantified using Adobe Photoshop 6.0. 
     As shown in  FIG. 1A , ABI-007 significantly inhibited rat aortic microvessel outgrowth in a concentration-dependent manner relative to the vehicle control, reaching statistical significance (p&lt;0.05) at 5 nM (53% inhibition) and 10 nM (68% inhibition). The amount of albumin present at each concentration of ABI-007 alone did not inhibit angiogenesis. 
     Endothelial Cell Proliferation Assay. Human umbilical vein endothelial cells (HUVEC; Cambrex) were maintained in EGM-II at 37° C. and 5% CO2. HUVECs were seeded onto 12-well plates at a density of 30,000 cells/well and allowed to attach overnight. The culture medium was then aspirated, and fresh culture medium containing either the vehicle (0.9% saline/albumin), or ABI-007 (0.05-10 nM paclitaxel) was added to each well. After 48 h, cells were trypsinized and counted with a Coulter Z1 counter (Coulter Corp., Hialeah, Fla.). All experiments were repeated three times. 
     As shown in  FIG. 1B , human endothelial cell proliferation was significantly inhibited by ABI-007 at 5 nM and 10 nM by 36% and 41%, respectively. 
     Endothelial Cell Tube Formation Assay. Eight-well slide chambers were coated with Matrigel and allowed to gel at 37° C. and 5% CO 2  for 30 min. HUVECs were then seeded at 30,000 cells/well in EGM-II containing either the vehicle (0.9% saline/albumin) or ABI-007 (0.05-10 nM paclitaxel) and incubated at 37° C. and 5% CO 2  for 16 h. After incubation, slides were washed in PBS, fixed in 100% methanol for 10 s, and stained with DiffQuick solution II (Dade Behring Inc., Newark, Del.) for 2 min. To analyze tube formation, each well was digitally photographed using a 2.5× objective. A threshold level was set to mask the stained tubes. The corresponding area was measured as the number of pixels using MetaMorph software (Universal Imaging, Downingtown, Pa.). Experiments were repeated three times. 
     As shown in  FIG. 1C , ABI-007 blocked tube formation by 75% at both 5 nM and 10 nM. 
     Determination of the In Vivo Optimal Biologic Dose of ABI-007 by Measuring Circulating Endothelial Cells (CECs) and Circulating Endothelial Progenitors (CEPs). Six- to eight-week-old female Balb/cJ mice were randomized into the following eight groups (n=5 each): untreated, treated with i.p. bolus injections of either the drug vehicle (0.9% saline/albumin), or ABI-007 at 1, 3, 6, 10, 15 or 30 mg/kg paclitaxel daily for 7 days. At the end of the treatment period, blood samples were drawn by cardiac puncture and collected in EDTA-containing vacutainer tubes (Becton Dickinson, Franklin Lakes, N.J.). CECs and CEPs were enumerated using four-color flow cytometry. Monoclonal antibodies specific for CD45 were used to exclude CD45+ hematopoietic cells. CECs and their CEP subset were depicted using the murine endothelial markers fetal liver kinase 1/VEGF receptor 2 (flk-1/VEGFR2), CD13, and CD117 (BD Pharmingen, San Diego, Calif.). Nuclear staining (Procount; BD Biosciences, San Jose, Calif.) was performed to exclude the possibility of platelets or cellular debris interfering with the accuracy of CEC and CEP enumeration. After red cell lysis, cell suspensions were evaluated by a FACSCalibur (BD Biosciences) using analysis gates designed to exclude dead cells, platelets, and debris. At least 100,000 events/sample were obtained in order to analyze the percentage of CECs and CEPs. The absolute number of CECs and CEPs was then calculated as the percentage of the events collected in the CEC and CEP enumeration gates multiplied by the total white cell count. Percentages of stained cells were determined and compared to the appropriate negative controls. Positive staining was defined as being greater than non-specific background staining. 7-aminoactinomycin D (7AAD) was used to enumerate viable versus apoptotic and dead cells. 
       FIG. 2  shows that ABI-007 administered i.p. daily for 7 days at 3, 10-30 mg/kg significantly decreased CEP levels in non-tumor bearing Balb/cJ mice. However, ABI-007 at 10-30 mg/kg was associated with a significant reduction of white blood cell count indicative of toxicity. Although the reduction of CEP levels by ABI-007 at 6 mg/kg did not reach statistical significance, decrease in white blood cell count was not evident. Therefore it was concluded that the in vivo optimal biologic dose for metronomic ABI-007 was between 3-10 mg/kg. In one study, metronomic Taxol® at 1.3, 3, 6, or 13 mg/kg given i.p. daily for 7 days did not significantly reduce viable CEP levels, whereas metronomic Taxol® at 30 mg/kg or higher resulted in severe toxicity and eventually mortality in mice. It was previously reported that the i.p. administration of Taxol® at doses commonly used in the clinic resulted in entrapment of paclitaxel in Cremophor® EL micelles in the peritoneal cavity and consequently, insignificant plasma paclitaxel concentration (Gelderblom et al.,  Clin. Cancer Res.  8:1237-41 (2002)). This would explain why doses of metronomic Taxol® (1.3, 3, 6, and 13 mg/kg) that did not cause death failed to change viable CEP levels. In this case, the i.p. administration of metronomic Taxol® at 1.3 mg/kg would not be any different from that at 13 mg/kg. Therefore the lower dose, 1.3 mg/kg, was selected to minimize the amount of Cremophor® EL per paclitaxel administration for subsequent experiments. 
     Antitumor effects of metronomic and MTD ABI-007 compared with metronomic and MTD Taxol®. Human prostate cancer cell line PC3 and human breast cancer cell line MDA-MD-231 were obtained from the American Type Culture Collection (Manassas, Va.). PC3 cells (5×10 6 ) were injected s.c. into 6- to 8-week-old male SCID mice, whereas MDA-MB-231 cells (2×10 6 ) were implanted orthotopically into the mammary fat pad of female SCID mice. When the primary tumor volume reached approximately 150-200 mm 3 , animals were randomized into eight groups (n=5-10/group). Each group was treated with either 0.9% saline/albumin vehicle control, Cremophor® EL vehicle control, metronomic Taxol® (1.3 mg/kg, i.p., qd), metronomic ABI-007 (3, 6, or 10 mg/kg paclitaxel, i.p., qd), MTD Taxol® (13 mg/kg, i.p., qd×5, 1 cycle), or MTD ABI-007 (30 mg/kg paclitaxel, i.v., qd×5, 1 cycle). Perpendicular tumor diameters were measured with a caliper once a week and their volumes were calculated. At the end of the treatment period, blood samples were drawn by cardiac puncture from mice in all groups. CECs and CEPs were enumerated as described herein. 
     Metronomic ABI-007 (3, 6 and 10 mg/kg) but not Taxol® (1.3 mg/kg) administered i.p. daily for 4 weeks significantly (p&lt;0.05) inhibited growth of both MDA-MB-231 and PC3 tumors ( FIG. 3A  and  FIG. 3B ). Neither ABI-007 nor Taxol® administered metronomically induced any weight loss ( FIG. 3C  and  FIG. 3D ). Although MTD ABI-007 (30 mg/kg) inhibited tumor growth more effectively than MTD Taxol® (13 mg/kg), significant weight loss was noted with the former, indicating toxicity. In addition, two out of five mice treated with MTD ABI-007 displayed signs of paralysis in one limb 6 days after the last dose of drug. The paralysis was transient and resolved within 24-48 hours. Interestingly, the antitumor effect of metronomic ABI-007 at 6 mg/kg approximated that of MTD Taxol® in the MDA-MB-231 xenograft model ( FIG. 3A ). Increasing the dose of metronomic ABI-007 to 10 mg/kg did not seem to confer more pronounced tumor growth inhibition. In contrast, metronomic ABI-007 elicited greater antitumor response at 10 mg/kg than at 3 and 6 mg/kg in the PC3 xenografts ( FIG. 3B ). 
     Metronomic ABI-007 significantly decreased the levels of viable CEPs in a dose-dependent manner in MDA-MB-231 tumor-bearing mice ( FIG. 4A ). Viable CEP levels also exhibited a dose-dependent reduction in response to metronomic ABI-007 in PC3 tumor-bearing mice, but reached statistical significance only at 10 mg/kg ( FIG. 4B ). The levels of CEPs were not altered by metronomic Taxol® in both xenograft models ( FIGS. 4A and 4B ). 
     Effects of metronomic and MTD ABI-007 and metronomic and MTD Taxol® on intratumoral microvessel density were studied. Five-um thick sections obtained from frozen MDA-MB-231 and PC3 tumors were stained with H&amp;E for histological examination by standard methods known to one skilled in the art. For detection of microvessels, sections were stained with a rat anti-mouse CD31/PECAM-1 antibody (1:1000, BD Pharmingen) followed by a Texas Red-conjugated goat anti-rat secondary antibody (1:200, Jackson ImmunoResearch Laboratories, Inc., West Grove, Pa.). A single microvessel was defined as a discrete cluster or single cell stained positive for CD31/PECAM-1d, and the presence of a lumen was not required for scoring as a microvessel. The MVD for each tumor was expressed as the average count of the three most densely stained fields identified with a 20× objective on a Zeiss AxioVision 3.0 fluorescence microscopic imaging system. Four to five different tumors per each vehicle control or treatment group were analyzed. 
     In MDA-MB-231 tumors, metronomic ABI-007 at 6 and 10 mg/kg as well as MTD ABI-007 seemed to reduce microvessel density (MVD) slightly although statistical significance was not reached ( FIG. 5A ). In PC3 tumors, metronomic ABI-007 at 3 and 10 mg/kg appeared to decrease MVD but without reaching statistical significance ( FIG. 5A ). Interestingly, a significant correlation existed between MVD and the level of viable CEPs in the MDA-MB-231 ( FIG. 5B ; r=0.76, P-0.04) but not in the PC3 ( FIG. 5C ; r=−0.071, P-0.88) model. 
     In vivo angiogenesis evaluation were carried out. A Matrigel plug perfusion assay was performed with minor modifications to methods known by one skilled in the art. Briefly, 0.5 ml Matrigel supplemented with 500 ng/ml of basic fibroblast growth factor (bFGF; R&amp;D Systems Inc., Minneapolis, Minn.) was injected s.c. on day 0 into the flanks of 10-week-old female Balb/cJ mice. On day 3, animals were randomly assigned to eight groups (n=5 each). Each group was treated with either 0.9% saline/albumin vehicle control, Cremophor® EL vehicle control, metronomic Taxol® (1.3 mg/kg, i.p., qd), metronomic ABI-007 (3, 6, or 10 mg/kg paclitaxel, i.p., qd), MTD Taxol® (13 mg/kg, i.v., qd×5), or MTD ABI-007 (30 mg/kg paclitaxel, i.v, qd×5). As a negative control, five additional female Balb/cJ mice of similar age were injected with Matrigel alone. On day 10, all animals were injected i.v. with 0.2 ml of 25 mg/ml FITC-dextran (Sigma, St. Louis, Mo.). Plasma samples were subsequently collected. Matrigel plugs were removed, incubated with Dispase (Collaborative Biomedical Products, Bedford, Mass.) overnight at 37° C., and then homogenized. Fluorescence readings were obtained using a FL600 fluorescence plate reader (Biotech Instruments, Winooski, Vt.). Angiogenic response was expressed as the ratio of Matrigel plug fluorescence to plasma fluorescence. 
     Metronomic ABI-007 at 6 and 10 mg/kg appeared to decrease angiogenesis although the inhibition did not reach statistical significance ( FIG. 6 ). Angiogenesis seemed to be unaltered by metronomic ABI-007 at 3 mg/kg, MTD ABI-007, MTD and metronomic Taxol® relative to the respective vehicle controls ( FIG. 6 ). These observations were similar to the intratumoral MVD results described herein. 
     Example 5 
     Nab-5109, a Nanoparticle Albumin-Bound IDN5109 (Nab-5109) Shows Improved Efficacy and Lower Toxicity over the Tween® Formulation (Tween®-5109, Ortataxel) 
     Methods: Nanoparticle nab-5109 was prepared using nab technology and characterized by laser light scattering. Nab-5109 and Tween-5109 were tested against Pgp+DLD-1 (known to be resistant against paclitaxel and docetaxel-Vredenburg et al,  JNCI  93: 1234-1245, 2001) human colon carcinoma xenograft in nude mice (n=5/group) at doses of 50 mg/kg (Tween®-5109, previously shown as MTD) and 75 mg/kg (nab-5109) given q3d×4, i.v. Control groups of PBS and human serum albumin (HSA) were also used. 
     Results: Nab-5109 yielded nanoparticles with mean size, Z Ave =119 nm and Zeta potential=−32.7 mV. Nab-5109 was lyophilized to a dry powder that easily dispersed in saline. In vivo, there was significantly more weight loss (ANOVA, p&lt;0.001) in the tumor bearing animals with Tween®-5109 (50 mg/kg, 8.8% wt loss) than with nab-5109 (75 mg/kg, 3.4% wt loss) indicating substantially lower toxicity of nab-5109 despite the 50% higher dose. There was significant tumor suppression by nab-5109 and Tween®-5109 (ANOVA, p&lt;0.0001 vs. controls) with tumor growth delays of 36 and 28 days respectively for nab-5109 (75 mg/kg) and Tween®-5109 (50 mg/kg). Nab-5109 was more effective than Tween®-5109 (ANOVA, p=0.0001) in suppressing tumor growth. There were no differences between the PBS and HSA control group in term of toxicity and efficacy. 
     Conclusion: Nanoparticle albumin-bound, nab-5109 was successfully prepared and could be given at 50% higher dose than Tween®-5109 with lower toxicity despite higher dose. At this higher dose, 75 mg/kg (q3d×4), nab-5109 showed significantly improved efficacy in the Pgp+DLD-1 human colon xenograft compared with Tween®-5109. 
     Example 6 
     Nanoparticle Albumin Bound (nab) Dimeric Thiocolchicines nab-5404, nab-5800, and nab-5801: A Comparative Evaluation of Antitumor Activity vs Abraxane® and Irinotecan 
     Methods: Nanoparticle colchicines were prepared using nab technology. Cytotoxicity was evaluated in vitro using human MX-1 breast carcinoma cultures. In vivo anti-tumor activity (human HT29 colon tumor xenograft) in nude mice was compared against Irinotecan and Abraxane®. Dose levels for the nab-colchicines and Irinotecan were 20 mg/kg, 30 mg/kg, and 40 mg/kg, given q3d×4, i.v. Abraxane® was dosed at its MTD, 30 mg/kg, given qd×5. 
     Results: The hydrophobic thiocolchicine dimers yielded nanoparticles with average size Z Ave  (nm) of 119, 93, and 84 for nab-5404, nab-5800, and nab-5801, respectively. The nanoparticle suspensions were sterilized through 0.22 um filters and lyophilized. In vitro, nab-5404 was the most potent of the three analogs against MX-1 (p≦0.0005, ANOVA), (IC 50  (ug/ml): 18, 36 and 77 for nab-5404, nab-5800 and nab-5801 respectively) as well as against the HT29 xenograft in vivo (p≦0.0001, ANOVA). Tumor volume was suppressed by 93%, 79%, and 48% with nab-5404 at doses 40 mg/kg, 30 mg/kg, and 20 mg/kg, respectively. In contrast, tumor volume was only suppressed by 31%, 16%, and 21% with nab-5800; and 17%, 30%, and 23% with nab-5801 at 40 mg/kg, 30 mg/kg, and 20 mg/kg, respectively. Nab-5404 was more effective than Irinotecan at all dose levels (p≦0.008, ANOVA) with tumor volumes for Irinotecan suppressed by only 48%, 34%, and 29% at dose levels of 40 mg/kg, 30 mg/kg, and 20 mg/kg, respectively. In comparison to Abraxane®, nab-5404 was more active at equitoxic dose (ETD) based on equal weight loss (p&lt;0.0001, ANOVA). Tumor volume was suppressed 93% by nab-5404 (40 mg/kg, q4d×3) and 80% by Abraxane® (30 mg/kg, qd×5) at their respective ETDs. 
     Conclusions: Nab technology was utilized to convert 3 hydrophobic dimeric thiocolchicines (IDN5404, IDN5800, IDN5801) to nanoparticles suitable for I.V. administration. Nab-5404 had superior antitumor activity in vitro and in vivo compared to nab-5800 and nab-5801. Nab-5404 was more potent than Irinotecan at equal dose. At equitoxic dose, defined by weight loss, nab-5404 was more potent than Abraxane®. These data warrant further investigation of nab-5404. 
     Example 7 
     Abraxane® vs Taxotere®: A Preclinical Comparison of Toxicity and Efficacy 
     Methods: Toxicity of Abraxane® and Taxotere® was compared in a dose-ranging study in nude mice given the drugs on a q4d×3 schedule. The dose levels were Taxotere® 7, 15, 22, 33, and 50 mg/kg and ABX 15, 30, 60, 120, and 240 mg/kg. Antitumor activity of Abraxane® and Taxotere® was compared in nude mice with human MX-1 mammary xenografts at a dose of 15 mg/kg weekly for 3 weeks. 
     Results: In the dose-escalation study in mice, the Taxotere® maximum tolerated dose (MTD) was 15 mg/kg and lethal dose (LD 100 ) was 50 mg/kg. In contrast, the Abraxane® MTD was between 120 and 240 mg/kg and LD 100  was 240 mg/kg. In the tumor study Abraxane® was more effective than equal doses of Taxotere® in tumor growth inhibition (79.8% vs 29.1%, p&lt;0.0001, ANOVA). 
     Conclusion: Nanoparticle abumin-bound paclitaxel (Abraxane®) was superior to Taxotere® in the MX-1 tumor model when tested at equal doses. Furthermore, the toxicity of Abraxane® was significantly lower than that of Taxotere®, which would allow dosing of Abraxane® at substantially higher levels. These results are similar to the enhanced therapeutic index seen with Abraxane® compared to Taxol® and suggest that the presence of surfactants may impair the transport, antitumor activity and increase the toxicity of taxanes. Studies in additional tumor models comparing Abraxane® and Taxotere® are ongoing. 
     Example 8 
     A Nanoparticle Albumin Bound Thiocolchicine Dimer (nab-5404) with Dual Mechanisms of Action on Tubulin and Topoisomerase-1: Evaluation of In vitro and In vivo Activity 
     Methods: IDN5404 was tested for cytotoxic activity using the MCF7-S breast carcinoma and its multidrug resistant variant, MCF7-R (pgp+). Its cytotoxicity was also assessed against the NCI-60 human tumor cell line panel. The nanoparticle albumin bound nab-5404 was administered IV using various schedules, to SCID mice implanted s.c. with a human A121 ovarian tumor xenograft. 
     Results: Against MCF7 cell lines, the parent compound, colchicine, demonstrated tumor growth inhibition with the IC50 value (50% growth inhibitory concentration) for MCF7-S cells at 3.9±0.2 nM. The resistant variant MCF7-R demonstrated an IC50 of 66±8.6 nM, approximately a 17-fold increase due to drug resistance. IDN5404, demonstrated increased activity against both cell lines, displaying IC50 values of 1.7±0.1 and 40±3.8 nM, respectively. These results were confirmed within the NCI 60 human tumor cell line panel with IDN5404 having a mean IC50 of &lt;10 −8 M and &gt;10 fold resistance between the MCF7-S and the MCF7-R cell lines. The COMPARE algorithm identified IDN5404 as a tubulin binder similar to vinca alkaloids, confirming the previous results. In vivo against the A121 ovarian tumor xenograft, efficacy and toxicity of nab-5404 was dose and schedule dependent. Nanoparticle nab-5404 was well tolerated and capable of inducing complete regressions and cures: at 24 mg/kg administered IV qd×5, 5 of 5 mice were long-term survivors (LTS) with no evidence of tumor. However, increasing the dosage to 30 mg/kg resulted in 5 of 5 toxic deaths. On a q3d×4 schedule, 30 mg/kg resulted in 4 of 5 mice LTS and at 50 mg/kg, 5 of 5 toxic deaths. Using a q7d×3 schedule, 40 mg/kg resulted in 3 of 5 mice LTS and at 50 mg/kg, 4 of 4 LTS were noted. 
     Conclusions: IDN5404, a new thiocolchicine dimer with dual mechanism of action showed activity in pgp-expressing, cisplatin and topotecan resistant cell lines. In vivo, nanoparticle albumin bound nab-5404 was active against A121 ovarian xenografts. 
     Example 9 
     Combination Studies of Abraxane® and Other Agents 
     Due to the advantageous properties of Abraxane® (ABX, the nanoparticle albumin-bound paclitaxel) noted above, it was used and being used in a number of studies with different modes of administration and schedules and in combination with other oncology drugs as well as radiation treatment. These are listed below: 
     In metastatic breast cancer, these studies include: 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 Randomized Phase II Trial of 
                 ABX 125, Gem 1000 mg/m 2 , 
                 To evaluate the combination of ABX 
               
               
                 Weekly Abraxane ® in Combination 
                 D1, 8; q 3wk 
                 and Gemcitabine in 1st-line MBC. 
               
               
                 with Gemcitabine in Individuals 
               
               
                 with HER2 Negative Metastatic 
               
               
                 Breast Cancer 
               
               
                 A phase II study of weekly 
                 ABX 100 mg/m 2 , Carbo AUC 
                 Data will be important for using 
               
               
                 dose-dense nanoparticle paclitaxel 
                 2, both D1, 8, 15; Her 2 mg/kg 
                 ABX in combination with carbo 
               
               
                 (ABI-007) carboplatin, with 
                 (4 mg/kg on wk a) q4wk × 6 
                 and/or Herceptin ®. Also helpful for 
               
               
                 Herceptin ® as first or second-line 
                   
                 other combinations. 
               
               
                 therapy of advanced HER2 positive 
               
               
                 breast cancer 
               
               
                 Weekly Vinorelbine and Abraxane ®, 
                 L1: ABX 80, Nav 15; L2: 
                 Multi-center study of ABX in 
               
               
                 with or without G-CSF, in stage IV 
                 ABX 90, Nav 20; L3: ABX 
                 combination with Navelbine ® in 
               
               
                 breast cancer: a phase I-II study 
                 100, Nav 22.5; L4: ABX 110, 
                 1st-line MBC. 
               
               
                   
                 Nav 25; L5: ABX 125, Nav 25 qwk 
               
               
                 Phase II trial of weekly Abraxane ® 
                 ABX 125 mg/m 2  Q3/4wk 
                 A relatively large phase II of weekly 
               
               
                 monotherapy for 1st-line MBC (plus 
                   
                 ABX monotherapy at 125 mg/m 2  in 
               
               
                 Herceptin ® in Her2+ pts) 
                   
                 1st-line MBC. 
               
               
                 Phase I/II trial Abraxane ® plus 
                 ABX + Anthracycline 
               
               
                 Doxil ® for MBC plus limited PK 
               
               
                 3-arm phase II trial in 1st-line MBC 
                 ABX weekly (130 mg/m 2 ) vs. 
                 To optimize ABX monotherapy 
               
               
                   
                 q2wk (260 mg/m 2 ) vs. q3wk 
                 regime for MBC 
               
               
                   
                 (260 mg/m 2 ) 
               
               
                 3-arm phase II trial in 1st-line and 
                 ABX weekly vs. ABX q3wk 
                 randomized ABX MBC trial to 
               
               
                 2nd-line MBC, with biological 
                 vs. Taxol ® weekly 
                 obtain important data: weekly ABX 
               
               
                 correlates analyses 
                   
                 vs. weekly Taxol ®; weekly ABX vs. 
               
               
                   
                   
                 3-weekly ABX; plus biomarker 
               
               
                   
                   
                 study (caveolin-1 and SPARC). 
               
               
                 Phase I/II Abraxane ® + GW572016 
                 TBD 
                 combination of ABX and 
               
               
                   
                   
                 GW572016 (a dual EGFR inhibitor 
               
               
                   
                   
                 and one of the most promising new 
               
               
                   
                   
                 biological agents for BC). 
               
               
                 A phase I dose escalation study of a 
                 Abraxane ® 100 mg/m 2  weekly, 
                 This phase I trial is to determine the 
               
               
                 2 day oral gefitinib 
                 3 out of 4 weeks; Gefitinib 
                 safety and tolerability of a 2 day 
               
               
                 chemosensitization pulse given prior 
                 starting at 1000 mg/d × 2 days 
                 gefitinib pulse given prior to 
               
               
                 to weekly Abraxane ® in individuals 
                   
                 Abraxane ® administration. 
               
               
                 with advanced solid tumors 
               
               
                 Phase II 1 st  line MBC trial 
                 weekly ABX (125 mg/m 2 , 2 
                 To evaluate the combination of ABX 
               
               
                   
                 wk on and 1 wk off) + Xeloda ® 
                 and Xeloda ® in 1st-line MBC, using 
               
               
                   
                 825 mg/m 2  d 1-14 q3wk 
                 2 weekly on and 1 weekly off ABX 
               
               
                   
                   
                 regime. 
               
               
                 Phase II pilot adjuvant trial of 
                 Dose dense AC + G CSF --&gt; 
                 A pilot adjuvant study of a “super 
               
               
                 Abraxane ® in breast cancer 
                 weekly ABX --&gt; Avastin ® 
                 dose dense” 
               
               
                 Abraxane ® in dose-dense adjuvant 
                 AC q2w × 4 + G CSF --&gt; ABX 
                 A pilot adjuvant study of dose dense 
               
               
                 chemotherapy for early stage breast 
                 q2wk × 4 
                 ABX regime - an alternate of a 
               
               
                 cancer 
                   
                 standard adjuvant regime 
               
               
                 Phase II pilot adjuvant trial of 
                 AC Q2wk --&gt; ABX q2wk + 
                 A pilot adjuvant study in preparation 
               
               
                 Abraxane ® in breast cancer 
                 G-CSF 
                 for phase III adjuvant trial 
               
               
                   
               
            
           
         
       
     
     In Breast cancer neoadjuvant setting studies include: 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 Phase II Trial of Dose Dense 
                 Neoadjuvant: Gem 2000, 
                 This neoadjuvant study is based on the 
               
               
                 Neoadjuvant Gemcitabine, Epirubicin, 
                 Epi 60, ABX 175 mg/m 2 , 
                 GET data from Europe which showed 
               
               
                 ABI-007 (GEA) in Locally Advanced 
                 Neul 6 mg SC, all D1 q2wk × 
                 high activity. In the current regime, 
               
               
                 or Inflammatory Breast Cancer 
                 6 Adjuvant: Gem 
                 ABX will replace T, or Taxol ®. 
               
               
                   
                 2000, ABX 220, Neul 6 mg 
               
               
                   
                 D1 q2wk × 4 
               
               
                 Phase II preoperative trial of 
                 ABX 220 mg/m 2  q2wk × 
               
               
                 Abraxane ® followed by FEC (+ 
                 6 followed by FEC × 4 
               
               
                 Herceptin ® as appropriate) in breast 
                 (+Herceptin ® for Her2+ 
               
               
                 cancer 
                 pts) 
               
               
                 Pre-clinical study of drug-drug 
                 ABX + other agents 
               
               
                 interaction 
               
               
                 Phase II neoadjuvant 
                 (ABX + Herceptin ®) 
               
               
                   
                 followed by (Navelbine ® + 
               
               
                   
                 Herceptin ®) 
               
               
                 Randomized phase II trial of 
                 TAC vs. AC followed 
                 To evaluate AC followed by 
               
               
                 neoadjuvant chemotherapy in 
                 ABX + carbo vs. AC 
                 ABX/carbo or ABX/carbo/Herceptin ® 
               
               
                 individuals with breast cancer 
                 followed 
                 combinations vs TAC (a FDA 
               
               
                   
                 ABX + carbo + Herceptin ® 
                 approved adjuvant BC regime) in 
               
               
                   
                   
                 neoadjuvant setting. 
               
               
                 Phase II neoadjuvant trial of 
                 ABX: 200 mg/m 2  D1; 
               
               
                 Abraxane ® and capecitabine in locally 
                 Xel: 1000 mg/m 2  D1-14; 
               
               
                 advanced breast cancer 
                 q3wk × 4 
               
               
                 Phase II trial of neoadjuvant 
                 ABX: 300 mg/m 2  q3wk 
               
               
                 chemotherapy (NCT) with 
               
               
                 nanoparticle paclitaxel (ABI-007, 
               
               
                 Abraxane ®) in women with clinical 
               
               
                 stage IIA, IIB, IIIA, IIIB, and IV (with 
               
               
                 intact primary) breast cancers 
               
               
                   
               
            
           
         
       
     
     In lung cancer the studies include: 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 Phase I/II study of Abraxane ® 
                 ABX weekly 
                 The first phase II trial of ABX 
               
               
                 monotherapy in 1st-line advanced 
                   
                 combo with carbo in NSCLC. 
               
               
                 NSCLC 
               
               
                 Phase II Trial of weekly Abraxane ® 
                 ABX: 125 mg/m 2   
               
               
                 plus carboplatin in 1st-line NSCLC 
                 D1, 8, 15; Carbo: AUC 
               
               
                   
                 6 D1; q4 wk 
               
               
                 A Phase I Trial of Carboplatin and 
                 Arm 1: ABX 100, 125, 
                 This 2-arm phase I study will 
               
               
                 Abraxane ® on a weekly and every 
                 150 mg/m 2  D1, 8, 15 
                 generate important data on 
               
               
                 three week schedule in individuals 
                 q4wk; Arm 2: ABX 
                 ABX/carbo combination for 
               
               
                 with Advanced Solid Tumor 
                 220, 260, 300 mg/m 2   
                 further studies of this combo 
               
               
                 Malignancies 
                 D1 q3wk. Carbo AUC6 
                 in multiple diseases. 
               
               
                   
                 in both arms 
               
               
                 Phase II study of ABI 007 
                 ABX Level(a): 225 mg/m 2 ; 
                 This phase II NSCLC study 
               
               
                 (Abraxane ®) and carboplatin in 
                 Level(b): 260 mg/m 2 ; 
                 will generate data for a future 
               
               
                 advanced non-small cell lung cancer. 
                 Level(3): 300 mg/m 2 ; 
                 phase III registration trial in 
               
               
                   
                 q3wk Carbo 
                 lung cancer 
               
               
                   
                 fixed at AUC6 q3wk 
               
               
                 Phase I study of ABI 007 (Abraxane ®) 
                 ABX q3wk 
               
               
                 and carboplatin 
               
               
                 Phase I/II study of Abraxane ® + 
                 TBD 
                 ABX and Alimta ® can be a 
               
               
                 Alimta ® for 2nd-line NSCLC 
                   
                 promising combination due to 
               
               
                   
                   
                 the non-overlapping toxicity 
               
               
                   
                   
                 profiles. 
               
               
                 Phase I/II trial of Abraxane ® plus 
               
               
                 cisplatin in advanced NSCLC 
               
               
                 Phase I/II study of Abraxane ®, 
               
               
                 Navelbine ®, and Cisplatin for 
               
               
                 treatment of advanced NSCLC 
               
               
                 Phase II ABX mono in 1st-line 
                 ABX 260 mg/m 2  q3wk 
                 The 1st ABX trial in NSCLC. 
               
               
                 NSCLC 
               
               
                 Phase II study of Abraxane ® 
                 Cohort 1: ABX q3wk; 
               
               
                 monotherapy in 2nd-line NSCLC 
                 Cohort 2: ABX 
               
               
                   
                 weekly. Doses TBD 
               
               
                 Phase I/II trial of weekly Abraxane ® 
                 1st line 
               
               
                 and carboplatin in advanced NSCLC 
               
               
                   
               
            
           
         
       
     
     Studies in Prostate include: 
     
       
         
           
               
               
               
             
               
                   
               
             
            
               
                 Randomized phase II ABX 
                 100 mg/m 2   
                   
               
               
                 weekly vs Q3W in front line 
                 weekly vs 
               
               
                 HRP 
                 260 mg/m 2   
               
               
                   
                 q3wk 
               
               
                 Phase II ABX in 1st-line 
                 weekly ABX 
                 Phase II study of weekly 
               
               
                 prostate cancer 
                   
                 ABX in 1st-line HRPC 
               
               
                 Phase II neoadjuvant study 
                 TBD 
                 A multi-center 
               
               
                   
                   
                 neoadjuvant trial of 
               
               
                   
                   
                 ABX in prostate cancer 
               
               
                   
                   
                 plus biomarker study. 
               
               
                 Phase II ABX 100 mg weekly 
               
               
                 no break 
               
               
                   
               
            
           
         
       
     
     Studies in ovarian cancer include: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Phase II study of Abraxane ® for 
                 TBD 
               
               
                   
                 treatment of advanced ovarian 
               
               
                   
                 cancer (3rd-line) 
               
               
                   
                 Phase I study of Abraxane ® plus 
                 ABX weekly + Carbo 
               
               
                   
                 carbo for treatment of advanced 
                 AUC 6 
               
               
                   
                 ovarian cancer 
               
               
                   
                 A phase II trial of 
               
               
                   
                 Abraxane ®/Carboplatin in 
               
               
                   
                 recurrent ovarian cancer 
               
               
                   
                   
               
            
           
         
       
     
     Studies in Chemoradiation include: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Phase I/II trial of Abraxane ® 
                   
               
               
                   
                 combined with radiation in 
               
               
                   
                 NSCLC 
               
               
                   
                 Abraxane ® Combined With 
                 animal model 
               
               
                   
                 Radiation 
               
               
                   
                 H&amp;N (Head and Neck Cancer) 
                 TBD 
               
               
                   
                   
               
            
           
         
       
     
     Other studies include: 
     
       
         
           
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Phase II study of ABX in treatment of 
                 125 mg/m 2  d1, 8, 15 
               
               
                   
                 persistent or recurrent carcinoma of the 
                 q28 days 
               
               
                   
                 cervix 
               
               
                   
                 PhII in preciously treated (100 ABX) 
                 26--&gt;70 
               
               
                   
                 and untreated (150 ABX) metastatic 
               
               
                   
                 melanoma 
               
               
                   
                 Ph II single treatment use of ABI-007 
               
               
                   
                 for the treatment of non-hematologic 
               
               
                   
                 malignancies 
               
               
                   
                 Abraxane ® Combined With 
               
               
                   
                 antiangiogenic agents, e.g., Avastin ®. 
               
               
                   
                 Abraxane ® Combined With proteasome 
               
               
                   
                 inhibitors e.g., Velcade ®. 
               
               
                   
                 Abraxane ® Combined With EGFR 
               
               
                   
                 inhibitors e.g., Tarceva ®. 
               
               
                   
                 A randomized phase II trial of weekly 
               
               
                   
                 gemcitabine, Abraxane ®, and external 
               
               
                   
                 irradiation for locally advanced 
               
               
                   
                 pancreatic cancer 
               
               
                   
                   
               
            
           
         
       
     
     Example 10 
     Combination of Nanoparticle Invention Drugs with Other Agents and Modes of Therapy 
     Lower toxicity of nanoparticle invention drugs described herein allow combination with other oncology drugs and other modes of treatment with more advantageous outcome. These include nanoparticle forms of paclitaxel, docetaxel, other taxanes and analogs, geldanamycins, colchicines and analogs, combretastatins and analogs, hydrophobic pyrimidine compounds, lomaiviticins and analogs including compounds with the lomaiviticin core structures, epothilones and analogs, discodermolide and analogs and the like. The invention drugs may be combined with paclitaxel, docetaxel, carboplatin, cisplatin, other platins, doxorubicin, epirubicin, cyclophosphamide, iphosphamide, gemcitabine, capecitabine, vinorelbine, topotecan, irinotecan, tamoxifen, camptothecins, 5-FU, EMP, etoposide, methotraxate and the like. 
     Example 11 
     Combination of Abraxane® with Carboplatin and Herceptin® 
     The combination of Taxol® and carboplatin has shown significant efficacy against metastatic breast cancer. On a weekly schedule, in this combination, Taxol® can only be dosed at up to 80 mg/m 2 . Higher doses cannot be tolerated due to toxicity. In addition, HER-2-positive individuals derive greater benefit when Herceptin® is included in their therapeutic regime. This open-label Phase II study was conducted to determine the synergistic therapeutic effect of ABI-007 (Abraxane®) with these agents. The current study was initiated to evaluate the safety and antitumor activity of ABI-007/carboplatin with Herceptin® for individuals with HER-2 positive disease. ABI-007 was given in combination with carboplatin and Herceptin® administered intravenously weekly to individuals with HER-2 positive advanced breast cancer. A cohort of 3 individuals received ABI-007 at a dose of 75 mg/m 2  IV followed by carboplatin at target AUC=2 weekly and Herceptin® infusion (4 mg/kg at week 1, and 2 mg/kg on all subsequent weeks) for 1 cycle. These individuals tolerated the drug very well so for all subsequent cycles and individuals the dose of ABI-007 was escalated to 100 mg/m 2 . Six individuals were treated to date. Of the 4 individuals that were evaluated for response, all 4 (100%) showed a response to the therapy. It should be noted that due to lower toxicity of Abraxane®, a higher total paclitaxel dose could be given compared to Taxol® with resulting benefits to the individuals. 
     Example 12 
     Combination of Abraxane® with Carboplatin 
     The combination of Taxol® and carboplatin has shown significant efficacy in lung cancer. Another study with Abraxane® in combination with carboplatin on a 3 weekly schedule in individuals with lung cancer is ongoing. 
     Example 13 
     Use of Abraxane® in Combination with Radiation 
     Example 13a 
     Abraxane®, combined with clinical radiotherapy, enhances therapeutic efficacy and reduces normal tissue toxicity. Abraxane® is used to increase the therapeutic gain of radiotherapy for tumors; to enhance tumor response to single and fractionated irradiation; to enhance normal tissue response to radiation and to increase therapeutic ratio of radiotherapy. 
     A murine ovarian carcinoma, designated OCa-I, which has been investigated extensively is used. First, optimal timing of Abraxane® administration relative to local tumor radiation is timed to produce maximum antitumor efficacy. Tumors are generated in the right hind leg of mice by i.m. injection of tumor cells and treatment is initiated when the tumors reach 8 mm in size. Mice are treated with 10 Gy single dose irradiation, a single dose of Abraxane® or with combination therapy of Abraxane® given at different times 5 days before to 1 day after irradiation. A dose of Abraxane® equal to about 1½ times more than the maximum tolerated dose of paclitaxel is used, a dose of 90 mg/kg. The endpoint of efficacy is tumor growth delay. The groups consist of 8 mice each. Tumors are generated and treated as described in Aim 1. The endpoint of efficacy is tumor growth delay. Tumors are irradiated with 5, 7.5 or 10 Gy delivered either in a single dose or in fractionated doses of 1, 1.5 or 2 Gy radiation daily for five consecutive days. Since Abraxane® is retained in the tumor for several days and exerts its enhancing effect on each of the five daily fractions, Abraxane® is given once at the beginning of the radiation regime. Since the ultimate goal in clinical radiotherapy is to achieve tumor cure, the potential for Abraxane® to enhance tumor radiocurability is determined. The same scheme as described for the fractionated tumor growth delay study is used, except that a range of doses from 2 to 16 Gy is given daily for five consecutive days (total radiation dose 10 to 80 Gy). Tumors are followed for regression and regrowth for up to 120 days after irradiation, when TCD50 (the dose of radiation needed to yield local tumor cure in 50 percent of animals) is determined. There are two TCD50 assays: radiation only and Abraxane® plus radiation, and each assay consists of 10 radiation dose groups containing 15 mice each. To provide therapeutic gain, any radioenhancing agent, including Abraxane®, must increase tumor radioresponse more than increase normal tissue damage by radiation. Damage to jejunal mucosa, a highly proliferative tissue affected by taxanes is assessed. The jejunal microcolony assay is used to determine the survival of crypt epithelial cells in the jejunum of mice exposed to radiation. Mice are exposed to whole body irradiation (WBI) with daily doses of X-rays ranging from 3 to 7 Gy for five consecutive days. The mice are treated with Abraxane®, at an equivalent paclitaxel dose of 80 mg/kg, administered i.v. 24 h before the first dose of WBI and killed 3.5 days after the last dose of WBI. The jejunum is prepared for histological examination, and the number of regenerating crypts in the jejunal cross-section is counted. To construct radiation survival curves, the number of regenerating crypts is converted to the number of surviving cells. 
     Example 13b 
     The objective of this study was to assess whether ABI-007 (a) as a single agent has antitumor activity against the syngeneic murine ovarian carcinoma OCa-1 and (b) enhances the radiation response of OCa-1 tumors in a combined treatment regime as described in the previous example with the following modifications. 
     OCa-1 tumor cells were injected i.m. into the hind leg of C3H mice. When tumors grew to a mean diameter of 7 mm, single treatment with local radiation (10 Gy) to the tumor-bearing leg, ABI-007 90 mg/kg i.v., or both, was initiated. To determine the optimal treatment scheduling, ABI-007 was given from 5 days to 9 hours before radiation as well as 24 hours after radiation. Treatment endpoint was absolute tumor growth delay (AGD), defined as the difference in days to grow from 7-12 mm in diameter between treated and untreated tumors. For groups treated with the combination of ABI-007 and radiation, an enhancement factor (EF) was calculated as the ratio of the difference in days to grow from 7 to 12 mm between the tumors treated with the combination and those treated with ABI-007 alone to the AGD of tumors treated with radiation only. To assess the radiation-enhancing effect of ABI-007 for a fractionated radiation regime on the endpoint tumor cure, a TCD50 assay was performed and analyzed 140 days post treatment. Total doses of 5 to 80 Gy in 5 daily fractions were administered either alone or combined with ABI-007 24 hours before the first radiation dose. 
     As a single agent, ABI-007 significantly prolonged the growth delay of the OCa-1 tumor (37 days) compared to 16 days for untreated tumors. ABI-007 as a single agent was more effective than a single dose of 10 Gy, which resulted in a delay of 29 days. For combined treatment regimes, ABI-007 given at any time up to 5 days before radiation, produced a supra-additive antitumor effect. EF was 1.3, 1.4, 2.4, 2.3, 1.9, and 1.6 at intertreatment intervals of 9h, 24 h and 2, 3, 4, and 5 days, respectively. When ABI-007 was given after radiation, the combined antitumor treatment effect was less than additive. Combined treatment with ABI-007 and radiation also had a significant effect on tumor cure by shifting the TCD50 of 55.3 Gy for tumors treated with radiation only to 43.9 Gy for those treated with the combination (EF 1.3). 
     This experiment demonstrated that ABI-007 possesses single-agent antitumor activity against OCa-1 and enhances the effect of radiotherapy when given several days prior. As previously demonstrated for paclitaxel and docetaxel, the radiation enhancement is likely a result of multiple mechanisms, with a cell cycle arrest in G2/M being dominant at short treatment intervals and tumor reoxygenation at longer intervals. 
     Example 14 
     Combination of Abraxane® and Tyrosine Kinase Inhibitors 
     Pulse-dosing of gefitinib in combination with the use of Abraxane® is useful to inhibit the proliferation of EGFr expressing tumors. 120 nude mice are inoculated with BT474 tumor cells to obtain at least 90 mice bearing BT474 xenograft tumors and split into 18 experimental arms (5 mice each). Arm 1 mice receive control i.v. injections. All other mice receive weekly i.v. injections of Abraxane® at 50 mg/kg for 3 weeks. Arm 2 receives Abraxane® alone. Arms 3, 4, 5, 6, 7, 8 receive weekly Abraxane® preceded by 2 days of a gefitinib pulse at increasing doses. Arms 9, 10, 11, 12, 13 receive weekly Abraxane® preceded by one day of a gefitinib pulse at increasing doses. Arms 14, 15, 16, 17, 18 receive weekly Abraxane® along with everyday administration of gefitinib at increasing doses. The maximum tolerated dose of gefitinib that can be given in a 1 or 2 day pulse preceding weekly Abraxane® or in continuous administration with Abraxane® is established. In addition, measurement of anti-tumor responses will determine whether a dose-response relationship exists and whether 2 day pulsing or 1 day pulsing is superior. These data are used to select the optimal dose of pulse gefitinib and that of continuous daily gefitinib given with Abraxane®. 
     120 nude mice are inoculated with BT474 tumor cells to obtain 90 mice bearing tumors. These mice are split into 6 groups (15 each). Arm 1 receive control i.v. injections. Arm 2 receives Abraxane® 50 mg/kg i.v. weekly for 3 weeks. Arm 3 receive oral gefitinib at 150 mg/kg/day. Arm 4 receive Abraxane® 50 mg/kg along with daily gefitinib at the previously established dose. Arm 5 receive Abraxane® 50 mg/kg preceded by a gefitinib pulse at the previously established dose and duration. Arm 6 receive only a weekly gefitinib pulse at the previously established dose. After three weeks of therapy, mice are followed until controls reach maximum allowed tumor sizes. 
     Example 15 
     Phase II Study of Weekly, Dose-dense nab®-Paclitaxel)(Abraxane®, Carboplatin With Trastuzumab® As First-Line Therapy of Advanced HER-2 Positive Breast Cancer 
     This study aimed to evaluate (1) the safety and tolerability and (2) the objective response rate of weekly dose-dense trastuzumab/Abraxane®/carboplatin as first-line cytotoxic therapy for patients with advanced/metastatic (Stage 1V adenocarcinoma) HER-2-overexpressing breast cancer. Trastuzumab is a monoclonal antibody, also known as Herceptin®, which binds to the extracellular segment of the erbB2 receptor. 
     Briefly, patients without recent cytotoxic or radiotherapy were included. Doses of Abraxane® were escalated from 75 mg/m 2  as 30-min i.v. infusions on days 1, 8, 15 up to 100 mg/m 2  for subsequent cycles according to the standard 3+3 rule. Carboplatin AUC=2 was given as 30-60 min i.v. infusions on days 1, 8, 15 and for an initial 29 day cycle. Trastuzumab was given as i.v. 30-90 min infusion on days 1, 8, 15, 22 at a dose of 4 mg/kg at week 1 and 2 mg/kg on all subsequent weeks. 
     Of 8 out of 9 patients evaluable for response the response rate (confirmed plus unconfirmed) was 63% with 38% stable disease. The most common toxicities were neutropenia (grade 3:44%; grade 4:11%) and leukocytopenia (33%). 
     These results suggest that trastuzumab plus Abraxane® plus carboplatin demonstrated a high degree of antitumor activity with acceptable tolerability as a first-line therapy for MBC. 
     Example 16 
     Phase II Trial of Capecitabine Plus nab®-Paclitaxel)(Abraxane® in the First Line Treatment of Metastatic Breast Cancer 
     The purpose of this phase II study was to evaluate the safety, efficacy (time to progression and overall survival), and quality of life of patients with MBC who received capecitabine in combination with Abraxane®. Capecitabine is a fluoropyrimidine carbamate also known as Xeloda® which has been shown to have substantial efficacy alone and in combination with taxanes in the treatment of MBC. 
     In this open-label, single-arm study, Abraxane® 125 mg/m 2  was given by i.v. infusion on day 1 and day 8 every 3 weeks plus capecitabine 825 mg/m 2  given orally twice daily on days 1 to 14 every 3 weeks. Patients were HER-2/neu negative with a life expectancy of greater than 3 months. Patients had no prior chemotherapy for metastatic disease, no prior capecitabine therapy, and no prior fluoropyrimidine therapy and paclitaxel chemotherapy given in an adjuvant setting. 
     12 patients have been enrolled with safety analysis completed on the first 6 patients and the response rate evaluable after 2 cycles in the first 8 patients. There were no unique or unexpected toxicities with no grade 4 toxicities or neuropathy greater than grade 1. Response data were confirmed on only the first 2 cycles of therapy (first evaluation point) in 6 patients. Two patients have completed 6 cycles with 1 partial response and 1 stable disease. Of the first 8 patients after 2 cycles, there were 2 partial responses and 4 with stable disease. 
     These results show that combination of capecitabine and weekly Abraxane® at effective doses is feasible with no novel toxicities to date. Abraxane® related toxicity was mainly neutropenia without clinical consequences, and hand foot syndrome was the major toxicity of capecitabine. 
     Example 17 
     Pilot Study of Dose-Dense Doxorubicin plus Cyclophosphamide Followed by nab-paclitaxel (Abraxane®) in Patients with Early-Stage Breast Cancer 
     The objective of this study was to evaluate the toxicity of doxorubicin (adriamycin) plus cyclophosphamide followed by Abraxane® in early stage breast cancer. 
     Patients had operable, histologically confirmed breast adenocarcinoma of an early stage. The patients received doxorubicin (adriamycin) 60 mg/m 2  plus cyclophosphamide 600 mg/m 2  (AC) every 2 weeks for 4 cycles followed by Abraxane® 260 mg/m 2  every two weeks for 4 cycles. 
     30 patients received 4 cycles of AC, and 27 of 29 patients received 4 cycles of Abraxane®; 33% of patients received pegfilgrastim (Neulasta®) for lack of recovery of ANC (absolute neutrophil count) during Abraxane®. Nine patients (31%) had Abraxane® dose reductions due to non-hematologic toxicity. A total of 9 patients had grade 2 and 4 patients had grade 3 peripheral neuropathy (PN); PN improved by &gt;1 grade within a median of 28 days. 
     These results indicate that dose-dense therapy with doxorubicin (60 mg/m 2 ) plus cyclophosphamide (600 mg/m 2 ) every 2 weeks for 4 cycles followed by dose-dense Abraxane® (260 mg/m 2 ) every 2 weeks for 4 cycles was well tolerated in patients with early-stage breast cancer. 
     Example 18 
     Weekly nab-Paclitaxel (Abraxane®) as First Line Treatment of Metastatic Breast Cancer with Trastuzumab Add On for HER-2/neu-Positive Patients 
     The purpose of the current study was to move weekly Abraxane® to a front-line setting and add trastuzumab for HER2/neu-positive patients. 
     This phase II, open-label study included 20 HER2-positive and 50 HER2-negative patients with locally advanced or metastatic breast cancer. Abraxane® Abraxane was given at 125 mg/m 2  by 30 minute i.v. infusion on days 1, 8, and 15 followed by a week of rest. Trastuzumab was given concurrently with study treatment for patients who were HER2-positive. The primary endpoint was response rate and the secondary endpoints were time to progression (TTP), overall survival (OS), and toxicity. 
     In the safety population, 23 patients received a median of 3 cycles of Abraxane® to date. The most common treatment-related adverse event was grade 3 neutropenia (8.7%) with no grade 4 adverse events. One out of 4 evaluable patients responded to therapy. 
     Example 19 
     Phase I Trial of nab-Paclitaxel (Abraxane®) and Carboplatin 
     The aim of the current study was to determine the maximum tolerated dose of Abraxane® (both weekly and every 3 weeks) with carboplatin AUC=6 and to compare the effects of sequence of administration on pharmacokinetics (PK). 
     Patients with histologically or cytologically documented malignancy that progressed after “standard therapy” were included. Arm 1 received Abraxane® every 3 weeks in a dose escalation format based on cycle 1 toxicities (220, 260, 300, 340 mg/m 2 ) every 3 weeks followed by carboplatin AUC=6. Arm 2 received weekly (days 1, 8, 15 followed by 1 week off) Abraxane® (100, 125, 150 mg/m 2 ) followed by carboplatin AUC=6. For the PK portion of the study, Abraxane® was followed by carboplatin in cycle 1 and the order of administration reversed in cycle 2 with PK levels determined at initial 6, 24, 48 and 72 hours. 
     On the every 3 weeks schedule, neutropenia, thrombocytopenia and neuropathy were the most common grade 3/4 toxicities (3/17 each). On the weekly schedule, neutropenia 5/13 was the most common grade 3/4 toxicity. The best responses to weekly administration at the highest dose of 125 mg/m 2  (n=6) were 2 partial responses (pancreatic cancer, melanoma) and 2 stable disease (NSCLC). The best responses to the every three week administration at the highest dose of 340 mg/m 2  (n=5) were 1 stable disease (NSCLC) and 2 partial responses (SCLC, esophageal). 
     These data indicate activity of combination of Abraxane® and carboplatin. The MTD for the weekly administration was 300 mg/m 2 , and for the once every 3 week administration was 100 mg/m 2 . 
     Example 20 
     Phase II Trial of Dose-Dense Gemcitabine, Epirubicin, and nab-Paclitaxel (Abraxane®) (GEA) in Locally Advanced/Inflammatory Breast Cancer 
     In an open-label, phase II study an induction/neoadjuvant therapy regime was instituted prior to local intervention. The therapy regime was gemcitabine 2000 mg/m 2  i.v. every 2 weeks for 6 cycles, epirubicin 50 mg/m 2  every 2 weeks for 6 cycles, Abraxane® 175 mg/m 2  every 2 weeks for 6 cycles, with pegfilgrastim 6 mg s.c. on day 2 every 2 weeks. The postoperative/adjuvant therapy regime after local intervention was gemcitabine 2000 mg/m 2  every 2 weeks for 4 cycles, Abraxane® 220 mg/m 2  every 2 weeks for 4 cycles and pegfilgrastim 6 mg s.c. day every 2 weeks. Patients included females with histologically confirmed locally advanced/inflammatory adenocarcinoma of the breast. 
     Example 21 
     Cytotoxic Activity of nab-Rapamycin in Combination with Abraxane® on Vascular Smooth Muscle Cells 
     Vascular smooth muscle cells (VSMC) were seeded onto 96 wells plates in the presence of increasing concentrations of nab-rapamycin and 0 μM, 1 μM, 10 μM, or 100 μM of Abraxane® (ABI-007). To evaluate the cytotoxic effect of nab-rapamycin and Abraxane®, treated VSMCs were stained with ethidium homodimer-1 (Invitrogen, Carlsbad Calif.) and analyzed for red fluorescence. Ethidium homodimer-1 is a high-affinity, fluorescent nucleic acid stain that is only able to pass through compromised membranes of dead cells to stain nucleic acids. As shown in  FIG. 7A , nab-rapamycin, by itself, exhibited dose-dependent cell killing as demonstrated by increasing fluorescence. Cell killing by nab-rapamycin was not enhanced by Abraxane® at 1 μM or 10 μM; however, it was greatly enhanced by Abraxane® at 100 μM (ANOVA, p&lt;0.0001). Cells stained with ethidium homodimer-1 as shown in  FIG. 7A  were also exposed to calcein. Calcein AM (Invitrogen) is a non-fluorescent molecule that is hydrolyzed into fluorescent calcein by nonspecific cytosolic esterases. Live cells exposed to calcein AM exhibit bright green fluorescence as they are able to generate the fluorescent product and retain it. As shown in  FIG. 7B , nab-rapamycin exhibited dose dependent cytotoxic activity as shown by a reduced amount of fluorescent staining by calcein. This reduction in fluorescence was enhanced by coincubation with Abraxane® in a dose dependent manner. ANOVA statistic gave p&lt;0.0001 at all drug concentrations of Abraxane®. 
     Example 22 
     Cytotoxic Activity of nab-Rapamycin in Combination with Abraxane® Against HT29 (Human Colon Carcinoma) Tumor Xenograft 
     Nude mice were implanted with 10 6  HT29 cells on their right flanks. Treatment was initiated once the tumor were palpable and were greater than 100-200 mm 3 . The mice were randomly sorted into 4 groups (n=8 per group). Group 1 received saline 3 times weekly for 4 weeks, i.v.; Group 2 received Abraxane® at 10 mg/kg, daily for 5 days, i.p.; Group 3 received nab-rapamycin at 40 mg/kg, 3 times weekly for 4 weeks, i.v.; and Group 4 received both nab-rapamycin (40 mg/kg, 3 times weekly for 4 weeks, i.v.) and Abraxane® (10 mg/kg, daily for 5 days, i.p.). As shown in  FIG. 8 , the tumor suppression was greater for the Abraxane® plus nab-rapamycin combination therapy than for either single therapy group. 
     Example 23 
     Cytotoxic Activity of nab-17-AAG in Combination with Abraxane® Against 11358 (Human Lung Carcinoma) Tumor Xenograft 
     Nude mice were implanted with 10 7 H358 cells on their right flanks. Treatment was initiated once the tumors were palpable and were greater than 100-200 mm 3 . The mice were randomly sorted into 4 groups (n=8 per group). Group 1 received saline 3 times weekly for 4 weeks, i.v.; Group 2 received Abraxane® at 10 mg/kg, daily for 5 days, i.p.; Group 3 received nab-17-AAG at 80 mg/kg, 3 times weekly for 4 weeks, i.v.; and Group 4 received both nab-17-AAG (80 mg/kg, 3 times weekly for 4 weeks, i.v.) and Abraxane® (10 mg/kg, daily for 5 days, i.p.). As shown in  FIG. 9 , the tumor suppression was greater for the nab-17-AAG plus Abraxane® combination therapy than for either single therapy group. 
     Example 24 
     Abraxane® (ABI-007) Reduces Tumor Growth in MDA-MB-231 Human Tumor Xenografts and Induces Necrosis, Hypoxia and VEGF-A Expression 
     MDA-MB-231 human breast cancer xenografts were orthotopically implanted in the mammary fat pads of female nude (nu/nu) mice. When the average tumor volume was 230 mm 3 , mice were randomized into groups of five animals and treated with saline, Taxol®, Abraxane® or doxorubicin. Taxol® was administered at 10 mg/kg/day, Abraxane® Abraxane was administered at 15 mg/kg/day, and doxorubicin was administered at 10 mg/kg/day. All drugs and control saline were administered i.v. in a volume of 100 μl daily for 5 days. Mice were sacrificed, tumors were harvested and tumor cellular extracts were prepared. VEGF-A protein levels in tumor extracts were determined by ELISA. In some cases, tumors from mice treated with Abraxane® were analyzed by histology. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                 Mean 
                   
                 VEGF-A 
               
               
                   
                 Dose 
                 Tumor Volume 
                   
                 (pg/mg 
               
               
                 Treatment 
                 Schedule 
                 (mm 3 ) 
                 % TGI 
                 protein) 
               
               
                   
               
             
            
               
                 Saline control 
                 100 μl 
                 523 ± 79 
                   
                 337 ± 51 
               
               
                   
                 qd × 5 
               
               
                 Taxol ® 
                 10 mg/kg/day 
                 231 ± 32 
                 56 
                 664 ± 66 
               
               
                   
                 qd × 5 
               
               
                 Abraxane ® 
                 15 mg/kg/day 
                 187 ± 29 
                 64 
                 890 ± 82 
               
               
                   
                 qd × 5 
               
               
                 Doxorubicin 
                 10 mg/kg/day 
                 287 ± 56 
                 45 
                 754 ± 49 
               
               
                   
                 qd × 5 
               
               
                   
               
            
           
         
       
     
     As shown in Table 4, Taxol, Abraxane and doxorubicin all inhibited tumor growth as represented by a reduction in tumor volume when compared to saline-treated control animals. Tumor growth inhibition (TGI) was calculated by comparing mean tumor volume of test groups to that of the control group at the last measurement of the control group. Tumor growth inhibition was greatest in mice treated with Abraxane® (64% inhibition). Taxol® and doxorubicin showed tumor growth inhibition of 56% and 45%, respectively. 
     Levels of VEGF-A protein in tumor cellular extracts were measured by ELISA and shown to be increased in tumors from mice treated with Taxol®, Abraxane® and doxorubicin. VEGF-A protein levels were highest in tumors from mice treated with Abraxane® (164% increase), followed by doxorubicin (124%) and Taxol® (97%). 
     Tumors were harvested from saline-treated control mice and Abraxane®-treated mice one week after the last injection of Abraxane®. The tumors were evaluated for sites of necrosis and for the presence of hypoxic cells. Hypoxic cells were identified by immunohistochemical detection of pimonidazole-protein conjugates. As shown in  FIG. 10 , inhibition of tumor growth in Abraxane®-treated mice was accompanied by necrosis ( FIG. 10B ) and hypoxia ( FIG. 10D ) in the tumor tissue. Necrosis and hypoxia was not observed in tumor tissue from saline-treated control mice ( FIG. 10A  and  FIG. 10C ). 
     Example 25 
     VEGF-A and Avastin® effects on Abraxane®-Induced In Vitro Cytotoxicity 
     In addition to the stimulation of tumor angiogenesis by acting on vascular&#39; endothelial cells, it is possible that the secreted VEGF-A could also act on tumor cells exhibiting VEGF-A receptors (VEGF-R). MDA-MB-231 cells expressed VEGF-R2, whereas HepG2 cells expressed VEGF-R1 and PC3 prostate tumor cells expressed both VEGF-R1 and VEGF-R2 (data not shown). 
     The effect of VEGF-A or an anti-VEGF antibody (Avastin®) on Abraxane®-induced cytotoxicity was assessed in an in vitro cellular cytotoxicity assay. Cells were treated with Abraxane® in a range of concentrations (1 to 24 nM). Cells were also treated with VEGF-A or Avastin® and cytotoxicity was compared to cells treated with Abraxane® alone. As shown in  FIG. 11A , addition of VEGF-A reduced the in vitro cytotoxicity of Abraxane®. In contrast, the addition of Avastin® increased the in vitro cytotoxicity of Abraxane® ( FIG. 11A ). 
     Similar results were observed in an in vitro clonogenic assay. Cells were treated with saline control, Abraxane® alone, VEGF-A alone, Avastin® alone, Abraxane®+VEGF-A or Abraxane®+Avastin®. As shown in  FIG. 11B , Abraxane® reduced the mean number of colonies formed as compared to saline control. Treatment with VEGF-2 alone increased the number of colonies formed, while treatment with Avastin® alone resulted in a slight reduction in the number of colonies formed. The addition of VEGF-A to Abraxane®-treated cells reduced the cytotoxic effect which resulted in a higher number of colonies formed as compared to Abraxane® alone. The addition of Avastin® to Abraxane®-treated cells appeared to have a synergistic effect demonstrating an increase in cytotoxicity (as demonstrated by a sharp decrease in number of colonies formed) over the level observed with Abraxane® or Avastin® alone. 
     Example 26 
     Abraxane® (ABI-007) in Combination with Avastin® Reduces Tumor Growth in MDA-MB-231 Tumor Xenografts 
     Luciferase-expressing MDA-MB-231 human breast cancer xenografts were orthotopically implanted in the mammary fat pads of female nude (nu/nu) mice. When the average tumor volume reached 230 mm 3 , mice were randomized into groups of five animals and treated with saline, Abraxane®, Avastin®, or a combination of Abraxane® plus Avastin®. Abraxane®, either alone or in combination, was administered at 10 mg/kg/day daily for 5 days in two cycles separated by 1 week. Avastin® was administered following the two cycles of Abraxane® at dosages of 2 mg/kg, 4 mg/kg or 8 mg/kg twice a week for 6 weeks. Avastin® alone was administered at a dosage of 4 mg/kg at the same time as mice in combination therapy. Mice were monitored for tumor growth and drug toxicity. Mice were sacrificed when the mean tumor volume in the saline-treated control group reached 2000 mm 3 . 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 5 
               
               
                   
               
               
                   
                   
                 Mean 
                   
                   
               
               
                   
                 Avastin ® 
                 Tumor Volume 
                   
                 % Complete 
               
               
                 Treatment 
                  Dose 
                 (mm 3 ) 
                 % TGI 
                 Regression 3   
               
               
                   
               
             
            
               
                 Saline control 
                   
                 2391 ± 432 
                   
                 0 
               
               
                 Abraxane ® 
                   
                 117 ± 38 
                 95.11 
                 0 
               
               
                 (ABX) 
               
               
                 Avastin ® 
                 4 mg/kg 
                 2089 ± 251 
                 12.56 
                 0 
               
               
                 ABX + 
                 2 mg/kg 
                 138 ± 42 
                 94.23 
                 20 (1/5) 
               
               
                 Avastin ® 
               
               
                 ABX + 
                 4 mg/kg 
                  60 ± 17 
                 97.49 
                 40 (2/5) 
               
               
                 Avastin ® 
               
               
                 ABX + 
                 8 mg/kg 
                  36 ± 16 
                 98.49 
                 40 (2/5) 
               
               
                 Avastin ® 
               
               
                   
               
            
           
         
       
     
     No toxicity was observed in any treatment group. Tumor growth inhibition (TGI) was calculated by comparing mean tumor volume of test groups to that of the control group at the last measurement of the control group. As shown in Table 5 and in  FIG. 12 , Avastin® at a dose of 4 mg/kg did not significantly inhibit growth of primary tumors (12.56% inhibition). Abraxane® and Avastin® combination therapy yielded a significantly better outcome than Avastin® alone, with tumor inhibition ranging from 94.23% to 98.49%. Abraxane® in combination with Avastin® at the two highest doses, yielded a better outcome that Abraxane® alone (97.49 or 98.49% compared to 95.11% inhibition). Abraxane® and Avastin® in combination resulted in regression of tumors in treated mice wherein complete regression referred to mice with no measurable tumors at day 65. Five of fifteen (30%) mice treated with a combination of Abraxane® and 
     Avastin® showed complete tumor regression; tumors in the remaining mice were reduced by 90% compared with controls. 
     Example 27 
     Abraxane® (ABI-007) in combination with Avastin® reduces tumor metastasis in MDA-MB-231 tumor xenografts 
     As described in Example 25, luciferase-expressing MDA-MB-231 human breast cancer xenografts were orthotopically implanted in the mammary fat pads of female nude (nu/nu) mice. When the average tumor volume reached 230 mm 3 , mice were randomized into groups and treated with saline (n=10), Abraxane® (n=5), Avastin® (n=5), or a combination of Abraxane® plus Avastin® (n=5). Abraxane®, either alone or in combination, was administered at 10 mg/kg/day daily for 5 days in two cycles separated by 1 week. Avastin® was administered following the two cycles of Abraxane® at dosages of 2 mg/kg, 4 mg/kg or 8 mg/kg twice a week for 6 weeks. Avastin® alone was administered at a dosage of 4 mg/kg at the same time as mice in combination therapy. Mice were sacrificed when the mean tumor volume in the saline-treated control group reached 2000 mm 3 . Axillary lymph nodes and both lobes of the lungs were removed from each mouse and cellular extracts were prepared. The presence of MDA-MB-231 cells in these tissues was evaluated by analysis of luciferase activity and was an indicator of metastasis from the primary tumor. Luciferase activity was measured in extracts from 10 lymph nodes and both lobes of the lungs on the day of sacrifice (day 65 after tumor implantation). A value greater than 500 light units per 20 μl lysate was rated as positive for presence of MDA-MB-231 cells and for incidence of metastasis. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 6 
               
             
            
               
                   
                   
               
               
                   
                 Lymph Node 
                 Pulmonary 
               
               
                   
                 Metastasis 
                 Metastasis 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Avastin ® 
                   
                 P 
                   
                 P 
               
               
                 Treatment 
                 Dose 
                 Incidence 
                 Value 
                 Incidence 
                 Value 
               
               
                   
               
               
                 Saline 
                   
                 10/10 (100%)  
                   
                  7/10 (70%)  
                   
               
               
                 control 
               
               
                 Abraxane ® 
                   
                  5/5 (100%) 
                 — 
                 ⅘ (80%) 
                 — 
               
               
                 (ABX) 
               
               
                 Avastin ® 
                 4 mg/kg 
                  5/5 (100%) 
                 — 
                 ⅗ (60%) 
                 NS 
               
               
                 ABX + 
                 2 mg/kg 
                  5/5 (100%) 
                 — 
                 ⅕ (20%) 
                 0.045 
               
               
                 Avastin ® 
               
               
                 ABX + 
                 4 mg/kg 
                 2/5 (40%) 
                 0.022 
                 ⅖ (40%) 
                 NS 
               
               
                 Avastin ® 
               
               
                 ABX + 
                 8 mg/kg 
                 2/5 (40%) 
                 0.022 
                  0/5 (0%)  
                 0.025 
               
               
                 Avastin ® 
               
               
                   
               
            
           
         
       
     
     As shown in Table 6, treatment with Abraxane® or Avastin® alone appeared to have no effect on the incidence of tumor metastasis to the lymph nodes as analyzed by luciferase activity in cellular extracts. As used herein, incidence refers to the presence of luciferase activity in tissue from each mouse. Abraxane® in combination with Avastin® did demonstrate a significant effect on tumor metastasis. Incidence of metastases fell to 40% in groups treated with Abraxane® and Avastin® at the two highest dosages of 4 mg/kg and 8 mg/kg. (P value=0.022; wherein the P value was generated by the analysis of difference between test and control groups with Fisher&#39;s exact test; NS refers to non-significant.) Abraxane® or Avastin® alone appeared to have little effect on incidence of tumor metastasis to the lungs as shown in Table 6. Abraxane® in combination with Avastin® demonstrated an effect on the incidence of lung metastases. Incidence of metastases fell to 20%, 40% and 0% with combinations of Abraxane® and Avastin® at dosages of 2 mg/kg, 4 mg/kg and 8 mg/kg, respectively. 
     Tumor metastasis to the lymph nodes and lungs as evaluated by luciferase activity in tissue extracts is shown in  FIG. 13 . The combination of Abraxane® and Avastin® had a synergistic effect on reducing lymph node metastases ( FIG. 13A ) and lung metastases ( FIG. 13B ) of the MDA-MB-231 tumor cells. 
     Example 28 
     Paclitaxel Chemotherapy Increases Microvessel Density in Tumors 
     Solvent-based (i.e., Taxol®) and solvent-free (i.e., nab-paclitaxel, Abraxane®) formulations of paclitaxel were assayed for their ability to reduce tumor volume and to increase microvessel density (“MVD”) in tumors. Parallel experiments each containing four groups of five mice bearing either paclitaxel-sensitive MX-1 xenografts, paclitaxel-sensitive MES-SA xenografts, or paclitaxel-resistant MES-SA/D×5 xenografts were treated with: (1) Taxol® at 13.4 mg/kg administered once daily for five consecutive days (“qd×5”); (2) Abraxane® Abraxane at 13.4 mg/kg qd×5; (3) Abraxane® at 30 mg/kg qd×5; or (4) a comparable volume of phosphate-buffered saline (“PBS”) qd×5. In one experiment, tumor volume was assessed twice weekly starting at day 17. In the second experiment, MVD was quantified by CD31 staining at day 11, the last day of the experiment. MVD was reported as percent of CD31-positive structures in each tissue relative to tumor volume. 
     As shown in  FIG. 14A , tumor growth inhibition confirmed that MES-SA/D×5 is paclitaxel-resistant and that MX-1 and MES-SA are paclitaxel-sensitive. As shown in  FIG. 14B , the MVD increased with tumor shrinkage. For MX-1, MVD increased from 1.08+0.65% (PBS) to 4.93+3.22% (Taxol® at 13.4 mg/kg), 9.03+13.0% (Abraxane® at 13.4 mg/kg), and 9.18+11.19% (Abraxane® at 30 mg/kg). For MES-SA, MVD increased from 3.96+3.68% (PBS), to 7.33+1.30 (Taxol® at 13.4 mg/kg), 3.33+1.03% (Abraxane® at 13.4 mg/kg), and 11.69+7.51% (Abraxane® at 30 mg/kg). For MES-SA/D×5, MVD remained stable at 4.16+2.39%, 4.11+0.55% (Taxol® at 13.4 mg/kg), 4.13+2.30% (Abraxane® at 13.4 mg/kg), and 2.52+1.08% (Abraxane® at 30 mg/kg). In both paclitaxel-sensitive MX-1 and MES-SA, there was a positive correlation between decreasing tumor volume and increasing MVD (compare MX-1 panels in  FIGS. 14A and 14B  and MES-SA panels in  FIGS. 14A and 14B ). There was no observable change in tumor volume and MVD in paclitaxel-resistant MES-SA/D×5 after treatment with Taxol® at 13.4 mg/kg, with either concentration of Abraxane®, or with PBS. The fourth panel of  FIG. 14B  shows the MVD data for all three tumor types plotted together. That data indicated that tumors undergoing paclitaxel-induced regression exhibited increased MVD, reflecting increased angiogenesis in response to chemotherapy, and that the relationship was log linear. 
     Example 29 
     Administration of Avastin® in Combination with Abraxane® (ABI-007) Significantly Improves Tumor Suppression Induced by Abraxane® (ABI-007) Alone 
     The anti-tumor activity of Abraxane® alone and in combination with bevacizumab (Avastin®) was assayed in vivo. MDA-MB-231-Luc+ human breast cancer xenografts were orthotopically implanted in the mammary fat pads (“MFP”) of 4 to 6 week old female nude (nu/nu) mice (Harlan Sprague-Delaney, Indianapolis, Ind.), according to standard methods. Mice bearing MDA-MB-231 tumors of 200-250 mm 3  in volume were randomized into 6 groups of 10 animals each and treated with: (1) PBS; (2) Abraxane® alone (10 mg/kg, administered intravenously (“i.v.”) qd×5); (3) Avastin® alone (4 mg/kg, administered by intraperitoneal (“i.p.”) injection three times weekly (“q3× wkly”)); or (4) Abraxane® followed by Avastin®. Avastin® treatment began 24 hours after the end of one cycle of Abraxane®, at a dose of 2 mg/kg, 4 mg/kg or 8 mg/kg of Avastin® dissolved in 0.1 mL of sterile saline and injected intraperitoneally q3×wkly for 5 weeks. One or two cycles of Abraxane® were administered. In two-cycle Abraxane® treatment, a second cycle of Abraxane® (10 mg/kg, i.v. qd×5) was administered one week after conclusion of the first cycle. The control group received saline administered in the same volume by the same method (i.e., 0.1 ml injected i.v. or i.p.) on the same days as Abraxane® and Avastin® treatments, respectively. 
     Two rounds of experiments were performed on mice bearing luciferase-expressing MDA-MS-231-derived tumors to compare the efficacy of one or two qd×5 cycles of Abraxane® chemotherapy combined with Avastin®. No signs of toxicity as judged by weight loss or behavioral changes were observed in any of the treated mice. A comparative analysis of both experiments presented in  FIG. 15  and Table 7 showed that two cycles of Abraxane® (10 mg/kg) were significantly more effective in suppressing tumor growth than one cycle (p&lt;0.05).  FIG. 15  presents data from combination therapy with Abraxane® at 10 mg/kg and Avastin® at 4 mg/kg. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                   
                   
                 Mean 
                   
                   
                   
               
               
                   
                   
                 Tumor Volume 
                   
                   
                 % Complete 
               
               
                 Treatment 
                 Avastin ® Dose 
                 (mm 3 ) 1   
                 % TGI 2   
                 % TGD 3   
                 Regression 4   
               
               
                   
               
             
            
               
                   
               
            
           
           
               
            
               
                 Experiment No. 1: One cycle of Abraxane ® (10 mg/kg) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Saline control 
                   
                 2079 ± 287 
                   
                   
                 0 
               
               
                 Abraxane ® (ABX) 
                   
                 596 ± 98 
                 71.33 
                 20 
                 0 
               
               
                 Avastin ® 
                 2 mg/kg 
                  953 ± 127 
                 54.16 
                 13 
                 0 
               
               
                 ABX + Avastin ® 
                 2 mg/kg 
                 255 ± 46 
                 87.73 
                 33 
                 0 
               
            
           
           
               
            
               
                 Experiment No. 2: Two cycles of Abraxane ® (10 mg/kg) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Saline control 
                   
                 2391 ± 432 
                   
                   
                 0 
               
               
                 Abraxane ® (ABX) 
                   
                 117 ± 38 
                 95.11 
                 &gt;65 5    
                 0 
               
               
                 Avastin ® 
                 4 mg/kg 
                 2089 ± 251 
                 12.56 
                  7 
                 0 
               
               
                 ABX + Avastin ® 
                 2 mg/kg 
                 138 ± 42 
                 94.23 
                 &gt;65 e    
                 20 (⅕) 
               
               
                 ABX + Avastin ® 
                 4 mg/kg 
                  60 ± 17 
                 97.49 
                 &gt;65 e    
                 40 (⅖) 
               
               
                 ABX + Avastin ® 
                 8 mg/kg 
                  36 ± 16 
                 98.49 
                 &gt;65 e    
                 40 (⅖) 
               
               
                   
               
               
                   1 The mean tumor volume per group (n = 5) ± SE at day of sacrifice of PBS-treated control group because their tumors reached a 2000 mm 3  limit. 
               
               
                   2 Percent reduction in the mean tumor volume in drug-treated groups as compared with that in PBS-treated group at the last day of measurement of control mice. 
               
               
                   3 Tumor growth delay (“TGD”) indicates the number of additional days required for averaged tumor volume in experimental groups to reach 1000 mm 3  compared to that in PBS-treated control group. The control group reached 1000 mm 3  at day 25 post tumor implantation. 
               
               
                   4 Percent of mice with no measurable tumors at day 65 post tumor implantation. Numbers in parentheses indicate a number of mice with complete regressed tumors in each group. 
               
               
                   5 TGD could not be accurately determined because the mean tumor volume did not reach 1000 mm 3  by the end of the experiment (day 65 post tumor implantation). 
               
            
           
         
       
     
     As shown in Table 7, the mean tumor volume after one cycle of Abraxane® was 596±98 mm 3 , corresponding to 71% TGI compared to the average tumor volume in the control group, while the mean tumor volume after two cycles of Abraxane® was 117±38 mm 3 , corresponding to 95% TGI compared with the average tumor volume in the control group. One cycle of Abraxane® delayed the time point at which tumor volume reached 1000 mm 3  by 20 days relative to control animals. In contrast, the mean tumor volume in the group receiving two cycles of Abraxane® did not reach 1000 mm 3  over the entire duration of the experiment, thus prolonging tumor growth delay (“TGD”) for a minimum of 65 days. Avastin® alone (4 mg/kg) produced minor ( FIG. 15A ) to no significant effect ( FIG. 15B ) on tumor growth, since the experiments were performed in mice with well-established tumors (100-150 mm 3  at the first day of treatment). 
     Furthermore, the results demonstrated that combination therapy with Abraxane® and Avastin® delivered a synergistic suppression of tumor growth compared with the either drug administered alone. Even though Abraxane® alone potently inhibited tumor growth, particularly with two cycle therapy, tumor growth resumed in all mice regardless of the extent of tumor suppression and tumor growth delay, and no complete regressions were observed in any of the mice treated with either Abraxane® or Avastin® alone. In contrast, mice receiving combination therapy had smaller tumors on average compared with those in any other experimental group (p&lt;0.05). In addition, several mice displayed no measurable or visually detectable tumors at all ( FIG. 15B  and Table 7) after receiving two cycles of Abraxane® in combination with 2, 4 or 8 mg/kg of Avastin®. Although the relatively small number of mice per group did not allow a direct dose dependency to be established with regard to Avastin® concentrations, there was a trend showing that higher doses of Avastin® appeared to be associated with a higher number of mice with completely regressed tumors (Table 7). 
     Example 30 
     Combination Therapy with Abraxane (ABI-007) and Avastin® but not Abraxane® (ABI-007) or Avastin® Alone Resulted in Complete, Sustainable Tumor Regressions in all Treated Mice 
     Mice bearing MDA-MB-231-derived tumors were generated as described in Example 29. Mice bearing tumors of 200-250 mm 3  in volume were randomized into 6 groups of 10 animals each and treated with: (1) PBS; (2) Avastin® alone (4 mg/kg, administered by intraperitoneal (“i.p.”) injection twice weekly (“q2×wkly”)); (3) Abraxane® alone (30 mg/kg, administered intravenously (“i.v.”) qd×5); or (4) Abraxane® followed by Avastin®. Avastin® treatment began 24 hours after the first injection of Abraxane® and continued until the end of the experiment at a dose of 4 mg/kg of Avastin® dissolved in 0.1 mL of sterile saline, injected intraperitoneally q2×wkly for 5 weeks. Two cycles of Abraxane® were administered (both at 10 mg/kg, i.v. qd×5), separated by one week. The control group received saline administered in the same volume by the same method (i.e., 0.1 ml injected i.v. or i.p.) on the same days as Abraxane® and Avastin® treatments, respectively. 
     Tumor volume was assessed three times a week until completion of the study. A summary of the data is shown in  FIG. 16 . Notably, while two cycles of Abraxane® (30 mg/kg) alone effectively suppressed tumor growth, the tumors began to regrow approximately two weeks after the end of the second cycle of Abraxane®, though somewhat more slowly than in mice treated with Avastin® (4 mg/kg) alone or the PBS-injected control animals. In contrast, two cycles of Abraxane (30 mg/kg) administered in combination with Avastin® (4 mg/kg) not only effectively suppressed tumor growth, but resulted in nearly complete regression of tumors through the end of the experiment, 95 days after tumor implantation. 
     Example 31 
     Combination Therapy with Abraxane® (ABI-007) and Avastin® Inhibits Tumor Growth, Lymphatic and Pulmonary Metastasis in Mice with MDA-MB-435-Luc+-Derived Tumors 
     The luciferase-tagged MDA-MB-435 cell line (“MDA-MB-435-Luc+”) was a generous gift of Dr. Sierra (Universitaria de Bellvitge, Barcelona, Spain), and has been characterized elsewhere. Rubio, N., et al. (2001), “Metastatic behavior of human breast carcinomas overexpression the Bc1-x(L) gene: a role in dormancy and organospecificity,” Lab. Invest. 8:725-34. The MDA-MB-435-Luc+ cell line has high metastatic potential, predominantly to the lungs and, to a lesser degree, to lymph nodes. The culture medium for all tumor lines consisted of Dulbecco&#39;s Modified Eagle Medium supplemented with 5% fetal bovine serum, 2 mM glutamine, 1 mM sodium pyruvate and nonessential amino acids. Tumor cells were harvested for passage by washing the cell monolayer with PBS, followed by 3-4 minutes exposure to 0.5 mM EDTA diluted in PBS. Cells were sub-cultured twice weekly and routinely tested for mycoplasma using an immunodetection kit from Roche Diagnostics GmbH (Penzberg, Germany). 
     MDA-MB-435-Luc+(“435-Luc+”) cells were implanted subcutaneously into the mammary fat pad of 4 to 6 week old female ICR SCID mice (Taconic, Hudson, N.Y.). Every 2-3 days, perpendicular tumor diameters were measured by digital caliper and used to calculate tumor volume according to the formula: volume=Dd 2 π7/6, where D=larger diameter and d=smaller diameter. The 435-Luc +  tumors had an identical proliferation rate to their non-transfected counterpart (mice bearing 435-MBA-MS-derived orthotopic tumors). Animal care was in accordance with institutional guidelines. 
     Mice bearing 435-Luc k  tumors of 200-250 mm 3  in volume were randomized into 6 groups of 5 animals each, and treated with PBS, Abraxane® (“ABX”) alone (10 mg/kg, i.v., qd×5), Avastin® alone (4 mg/kg, i.p., twice a week) or Abraxane® followed by Avastin®. Two cycles of Abraxane® treatment were administered, each for 5 consecutive days with one week of rest between cycles. Avastin® treatment began 24 hours after the end of one cycle of Abraxane®, with a dose of 4 mg/kg dissolved in 0.1 ml of sterile, endotoxin-free PBS and injected i.p., twice a week, for total of 5 weeks. The control group received PBS injected i.v. or i.p. (0.1 ml) on the same days as Abraxane® and Avastin® treatments, respectively. To allow maximal development of metastatic foci, mice were sacrificed when the average tumor volume in the control group reached 2000 mm 3 . Table 8 shows the effect of Abraxane®, Avastin®, and combination therapy with Abraxane® and Avastin® on tumor growth in the MDA-MB-435-Luc+ tumor model. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 MDA-MB-435-Luc+ 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Tumor 
                   
                   
               
               
                   
                 Avastin ® 
                 Volume 
                   
                 % Complete 
               
               
                 Treatment 
                 (mg/kg) 
                 (mm 3 ) 6   
                 % TGI 7   
                 Regressions 8   
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Control 
                   
                 2020 
                   
                 0 
               
               
                 ABX alone 
                   
                 369 
                 81.73 
                 0 
               
               
                 Avastin alone 
                 4 
                 792 
                 60.79 
                 0 
               
               
                 ABX + 
                 4 
                 167 
                 91.73 
                 0 
               
               
                 Avastin ® 
               
               
                   
               
               
                   6 Tumor volume represents the mean tumor volume per group, expressed in cubic millimeters (“mm 3 ”). 
               
               
                   7 Tumor growth inhibition (“TGI”) is presented as percent reduction in the mean tumor volume in experimental groups compared with that in PBS-treated control groups. 
               
               
                   8 Complete regression was defined as the absence of either measurable or palpable tumor at the original tumor injection site for the entire length of the experiment, which was 92 days. 
               
            
           
         
       
     
     Tumor metastasis was determined by measuring luciferase activity in tissue extracts derived from 10 axillary lymph nodes (“LN”) and both lobes of the lungs. Lymph nodes and lungs were excised, washed in PBS, and homogenized in 0.35 ml of cold CCLR buffer (Promega, Madison, Wis.) containing a protease inhibitor cocktail and PMSF (Sigma, Mo.). Cell debris was removed by centrifugation. Protein concentrations of cleared lysates were determined by Bradford assay (Bio-Rad, Hercules, Calif.). Fifty μl of Luciferase Assay Reagent (Promega, Madison, Wis.) was mixed with 10 μl of cleared lysate and a 10 second average of luminescence was detected using a single tube luminometer (Berthold, Germany). CCLR buffer without tissue homogenates, and lymph nodes or lungs of non-tumor bearing mice were assayed for background signal and subtracted from the results. The net results were expressed as relative light units (“RLU”) normalized per mg of total lysate protein. To assess incidence of metastasis, extracts that had a luminescence signal of 800 light units above background (approximately 100 light units) were rated positive. This value was chosen because it was the minimal signal reproducibly detected above background in metastatic tissues, independently confirmed by immunohistochemical detection (data not shown). Differences in lymph node and lung metastases were assessed for statistical significance by Fisher&#39;s exact test using GraphPad InStat (GraphPad Inc., San Diego, Calif.) or SPSS14.0 (SPSS, Inc., Chicago, Ill.). 
     The metastases of MDS-MB-435-Luc+tumor cells were identified by measuring luciferase activity in tissue extracts from lymph nodes and lungs. Incidence of metastasis is presented in Table 9. In combination therapy groups, 435-Luc k  tumor-bearing mice received a 4 mg/kg dose of Avastin®. As expected, 100% of control 435-Luc +  tumor-bearing mice had pulmonary metastases, while only 50% of controls had lymph node metastases (Table 9). 
     
       
         
           
               
             
               
                 TABLE 9 
               
               
                   
               
               
                 MDA-MB-435-Luc+ 
               
               
                   
               
             
            
               
                 Lymph node metastasis 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Avastin ® 
                 Incidence 9   
                 % Inhibition 
                   
               
               
                 Treatment 
                 (mg/kg) 
                 N/total (%) 
                 vs. Control 
                 P value 
               
               
                   
               
               
                 Control 
                   
                 4/8 (50) 
               
               
                 ABX alone 
                   
                 0/6 (0)  
                 100 
                 0.01 
               
               
                 Avastin alone 
                 4 
                 0/6 (0)  
                 100 
                 0.01 
               
               
                 ABX + 
                 4 
                 0/6 (0)  
                 100 
                 0.01 
               
               
                 Avastin ® 
               
               
                   
               
            
           
           
               
            
               
                 Pulmonary metastasis 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Avastin ® 
                 Incidence 
                 % Inhibition 
                   
               
               
                 Treatment 
                 (mg/kg) 
                 N/total (%) 
                 vs. Control 
                 P value 
               
               
                   
               
               
                 Control 
                   
                  7/7 (100) 
               
               
                 ABX alone 
                   
                 5/6 (83) 
                  17 
                 NS 10   
               
               
                 Avastin alone 
                 4 
                 4/8 (50) 
                  50 
                 0.01 
               
               
                 ABX + 
                 4 
                 2/8 (25) 
                  75 
                  0.001 
               
               
                 Avastin ® 
               
               
                   
               
               
                   9 Luciferase activity was measured in extracts from 10 lymph nodes and both lobes of the lungs from each mouse. Samples containing a minimum of 500 light units per 20 μl lysate were rated positive. Lysates from tissues of non-tumor bearing mice produced a luminescence signal of 100 light units, which was considered background and subtracted from positive values. Results are presented as number of mice with lymph node or lung metastasis per total number of mice with tumors in each experimental group. Percentage of mice with metastases is shown in parentheses. 
               
               
                   10 NS = non-significant. The difference between the experimental and control groups does not reach statistical significance when analyzed by the Fisher&#39;s exact test. 
               
            
           
         
       
     
     Although neither Abraxane® (10 mg/kg) nor Avastin® (4 mg/kg) effectively suppressed pulmonary metastasis in 435-Luc+tumor-bearing mice, remarkably, the Abraxane®/Avastin® combination significantly suppressed pulmonary metastasis, and reduced the number of mice with lung tumors by 75% compared to the PBS-injected control. (Table 9). In contrast, Abraxane® (10 mg/kg) alone, Avastin® (4 mg/kg) alone, and the Abraxane®/Avastin® combination therapy all suppressed lymph node metastasis. These results indicate that combination therapy with Abraxane® and Avastin® could be particularly beneficial for suppression of both lymph node and pulmonary metastasis. 
     Example 32 
     Combination Therapy with Abraxane® (ABI-007) and Avastin® Eradicated Lymphatic and Pulmonary Metastasis in Mice with MDA-MB-231- or MDA-MB-231-Luc+-Derived Tumors 
     MDA-MB-231 or 231-Luc +  cells were implanted into the MFP of 4 to 6 week old female nu/nu mice (Harlan Sprague-Delaney, Indianapolis, Ind.) by standard methods. Briefly, mice were anesthetized and 100 μl of cell suspension containing 4×10 6  cells and 50% Matrigel (Sigma, Mo.) were injected into the MFP. Every 2-3 days, perpendicular tumor diameters were measured by digital caliper and used to calculate tumor volume according to the formula: Volume=Dd 2 π/6, where D=larger diameter and d=smaller diameter. The 231-Luc +  tumors had an identical proliferation rate to their non-transfected counterpart. Animal care was in accordance with institutional guidelines. 
     Luciferase-expressing orthotopic MDA-MB-231 (231-Luc+) xenografts were grown to well-established tumors (˜460 mm 3 ) and randomized to four groups of N=5, 6 or 7. Groups were treated with: (1) Abraxane® (30 mg/kg, qd×5) alone; (2) Avastin® (4 mg/kg, q2×wkly for the duration of the experiment) alone; (3) two cycles of Abraxane® (30 mg/kg, qd×5) in combination with Avastin® (4 mg/kg, q2×wkly for the duration); or (4) with an identical volume of PBS. 
     Metastases of MDA-MB-231-Luc+tumor cells were identified by measuring luciferase activity in tissue extracts from lymph nodes and lungs, as described in Example 31 above. To assess incidence of metastasis, extracts that had a luminescence signal of 500 light units above background (approximately 100 light units) were rated positive. This value was chosen because it represented the minimal signal which could be reproducibly detected above background in tissues in which metastases were independently confirmed by immunohistochemical detection of human cells. The net results were expressed as relative light units (RLU) normalized per mg of total lysate protein, and are presented in  FIG. 17A  (lymphatic metastasis) and  FIG. 17B  (pulmonary metastasis). 
     Consistent with the significantly enhanced antitumor effect, the antimetastatic effect was also dramatically improved by nab-paclitaxel/bevacizumab combination in well-established large tumors. While either bevacizumab or nab-paclitaxel alone failed to prevent metastasis to proximal and contralateral lymph nodes and lungs, the lymphatic and pulmonary metastases were completely eliminated by the combination therapy ( FIG. 6  and Table 3), measured by both metastatic burden and incidence. 
     These results indicate that combination therapy with Abraxane® (30 mg/kg) and Avastin® (4 mg/kg) effectively suppressed both lymphatic and pulmonary metastasis in MDA-MB-231-Luc+-derived tumor-bearing mice, remarkably, the Abraxane®/Avastin® combination significantly suppressed pulmonary metastasis, in contrast to treatment with Abraxane® (30 mg/kg) or Avastin® (4 mg/kg) alone. Thus, combination therapy with Abraxane® and Avastin® could be particularly beneficial for prevention of tumor rebound resulting from reactionary angiogenesis, and for suppression of both lymph node and pulmonary metastasis. Furthermore, the improved antitumor efficacy and better safety profile of Abraxane® (nab-paclitaxel) over conventional solvent-based paclitaxel (Taxol®) make it a more promising candidate for combination therapy. Most surprisingly and encouragingly, the Abraxane®/Avastin® combination was even highly effective against well-established large tumors to the extent of total elimination of both primary tumors and metastasis. 
     Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention. 
     All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. 
     Preferred variations of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred variations may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.