SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is, hereby, incorporated by reference in its entirety. Said ASCII copy, created on Mar. 15, 2017, is named P14170DOsequencelistingST25.txt and is 40,960 bytes in size.

BACKGROUND OF THE INVENTION

Field of the Invention

The instant invention provides for a new method of treating colorectal cancer (CRC) and metastases thereof in subjects, and preferably also of other solid cancers and metastases thereof in subjects, wherein said method preferably depends on whether the patient shows certain specific proteins levels in one or more body fluids prior to or during treatment, wherein said treatment comprises the administration of at least one pan αv integrin inhibitor to a patient, a medicament for use in said new methods, and a method of predicting the outcome of a treatment with at least one pan αv integrin inhibitor based on said specific protein levels in one or more body fluids of the patient.

More specifically, the instant invention provides for a new method of treating of solid cancers and/or metastases thereof, and especially of treating colorectal cancer (CRC) and/or metastases thereof, in subjects with at least one pan αv integrin inhibitor, preferably the pan αv integrin inhibitors abituzumab or intetumumab, wherein said subjects show certain specific protein levels in one or more body fluids prior to or during treatment.

Description of Related Art

Colorectal cancer (also known as colon cancer, rectal cancer or bowel cancer) is when cancer develops in the colon or rectum (parts of the large intestine). It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body.

Treatments used for colorectal cancer may include some combination of surgery, radiation therapy, chemotherapy and targeted therapy. Cancers that are confined within the wall of the colon may be curable with surgery while cancer that has spread widely are usually not curable with management focusing on improving quality of life and symptoms. Five year survival rates in the United States are around 65%. This, however, depends on how advanced the cancer is, whether or not all the cancer can be removed with surgery, and the person's overall health. Globally, colorectal cancer is the third most common type of cancer making up about 10% of all cases. In 2012 it resulted in 1.4 million new cases and caused 694,000 deaths. It is more common in developed countries where more than 65% of occur. It is less common in women than men.

In both cancer of the colon and rectum, chemotherapy may be used in addition to surgery in certain cases. In rectal cancer, chemotherapy may be used in the neoadjuvant setting.

If cancer has entered the lymph nodes, adding the chemotherapy agents fluorouracil or capecitabine increases life expectancy. If the lymph nodes do not contain cancer, the benefits of chemotherapy are controversial. If the cancer is widely metastatic or unresectable, treatment is then palliative. Typically in this setting, a number of different chemotherapy medications may be used. Chemotherapy drugs for this condition may include capecitabine, fluorouracil, irinotecan, leucovorin, oxaliplatin and UFT. Another type of agent that is sometimes used are the epidermal growth factor receptor inhibitors.

While a combination of radiation and chemotherapy may be useful for rectal cancer, its use in colon cancer is not routine due to the sensitivity of the bowels to radiation. Just as for chemotherapy, radiotherapy can be used in the neoadjuvant and adjuvant setting for some stages of rectal cancer.

Bone metastases, or metastatic bone disease, is a class of cancer metastases that results from primary tumor invasion to bone. Bone is one of the most common locations for metastasis. [Coleman R E (October 2006). “Clinical features of metastatic bone disease and risk of skeletal morbidity”. Clin. Cancer Res. 12 (20 Pt 2): 6243s-9s.] While any type of cancer is capable of forming metastatic tumors within bone, the microenvironment of the marrow tends to favor particular types of cancer, including prostate, breast, and lung cancers. [Guise T (October 2010). “Examining the metastatic niche: targeting the microenvironment”. Semin. Oncol. 37 (Suppl 2): S2-14.] Particularly in prostate cancer, bone metastases tend to be the only site of metastasis. [Jimenez-Andrade J M, Mantyh W G, Bloom A P, Ferng A S, Geffre C P, Mantyh P W (June 2010). “Bone cancer pain”. Annals of the New York Academy of Sciences 1198: 173-81.]

One of the most common solid tumors is lung cancer, also known as carcinoma of the lung or pulmonary carcinoma, is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung by process of metastasis into nearby tissue or other parts of the body, including the liver, brain and bone. Most cancers that start in the lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. The main primary types are small-cell lung carcinoma (SCLC), and non-small-cell lung carcinoma (NSCLC). Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer other than small cell lung carcinoma (SCLC). As a class, NSCLCs and metastases thereof are relatively insensitive to chemotherapy, compared to small cell carcinoma. A wide variety of chemotherapies are used in metastatic NSCLC, unfortunately with little effect to date. Small-cell carcinoma or small-cell lung cancer (SCLC) is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointesinal tract. SCLC usually metastasizes widely very early on in the natural history of the tumor. Also in this case, the metastasis affects predominantely the bone, liver and brain.

The most common solid cancer in women is breast cancer. Breast cancer develops from breast tissue. It most commonly develops in cells from the lining of milk ducts and the lobules that supply the ducts with milk. Cancers developing from the ducts are known as ductal carcinomas, while those developing from lobules are known as lobular carcinomas. In addition, there are more than 18 other sub-types of breast cancer. The diagnosis of breast cancer is regularily confirmed by taking a biopsy of the concerning lump. Once the diagnosis is made, further tests are done to determine if the cancer has spread beyond the breast and which treatments it may respond to. If the cancer has spread beyond the breast, the breast cancer presents as metastatic disease. The symptoms caused by metastatic breast cancer will depend on the location of metastasis. Common sites of metastasis include bone, liver, lung and brain.

The metastatic process is a multistep event and represents the most dreadful aspect of cancer. At the moment of diagnosis, cancers are frequently far advanced in their natural history, and the presence of metastases is a common event. In fact, approximately 30% of patients have detectable metastases at the moment of clinical diagnosis and a further 30% of patients have occult metastases. Metastases can be disseminated and they can infest different organs at the same time, or localize to a specific organ. In the case of localized disease, surgery is the treatment of choice; however recurrence and prognosis depend on many criteria such as: resectability, patient's clinical situation, and number of metastases.

After resection, recurrence is common, suggesting that micrometastatic foci are present at the moment of diagnosis. Systemic chemotherapy is an ideal setting but only few patients are cured by it, and in the majority systemic chemotherapy fails. Many physiological barriers and pharmacokinetic parameters contribute to decrease its efficacy.

Liver, lungs and lymph nodes are filtration organs and therefore inclined to metastasization. The poor chemosensitivity of metastases, peculiarly those of colorectal origin has forced many researchers to use methods for increasing the time and the concentration of drugs. The need for decreasing or limiting the side effects for this important and delicate organ led to the development of the technique of liver isolation for perfusion of antineoplastic agents. (K. R. Aigner, Isolated liver perfusion. In: Morris D L, McArdle C S, Onik G M, eds. Hepatic Metastases. Oxford: Butterworth Heinemann, 1996. 101-107). Since 1981, modifications and technical improvements have been continuously introduced. Liver metastases may be of different origin and their chemosensitivity may vary according to the histological type and their response in presence of heat.

There still exists a growing need in the art in order to develop new therapeutic strategies for treating cancer, especially metastases, systemically.

SUMMARY OF THE INVENTION

The object of the present invention therefore was to develop such a new strategy. It should be applicable to systemic treatment, and it should lower the dose and/or increase the efficiency of the cancer therapeutical agents to be applied. A further object was to normalize tumor vasculature to increase delivery of systemic therapeutics of tumor, i.e. to reset the tumor vasculature to the functionality of the vasculature of non-tumor tissue.

Thus, it is a preferred objective of the instant invention to provide a more effective, better tolerated treatment for humans, especially human cancer patients suffering from solid cancers and/or metastases thereof, preferably colorectal cancer (CRC) and/or metastases thereof and especially metastatic colorectal cancer (mCRC), preferably independent from the location of the metastases, thus preferably leading to enhanced overal survival (OS), progression-free survival (PFS), quality of life (QOL) and/or increased median survival.

