Extending the arsenal

Colorectal cancer is one of the most common causes of cancer-related deaths in both men and women across the globe. It is the leading cause of such deaths in Europe and the second leading cause in the US and Canada. The World Health Organisation (WHO) estimates that approximately 639,000 colorectal cancer-related deaths occur each year. A new, potentially first-in-class oral anticancer agent called perifosine (also known as KRX-0401) recently entered phase III registration trials in the US for the treatment of patients with refractory metastatic colorectal cancer — a population for which there are limited, if any, treatment options available.

As colon and rectal cancers arise from the same type of cell and have many similarities, they are often referred to collectively as "colorectal cancer". These cells have the potential to form benign tumours, called polyps, in the large intestine, which — if they are not removed — can become malignant over time. These cells can subsequently invade and damage adjacent tissue, lymph nodes and distant organs, in a process known as metastasis. In colorectal cancer, once metastasis has occurred, a complete cure of the cancer is unlikely.

The past several years have seen unprecedented progress in reducing the incidence of colorectal cancer and subsequent deaths. This has largely been achieved through the increased frequency of screening for colorectal cancer, which has allowed physicians to detect and remove colorectal polyps before they progress to cancer.

Several risk factors for the development of colorectal polyps or colorectal cancer have been identified. These risk factors include, but are not limited to, lifestyle-related factors (including diet, body weight, exercise, smoking and diabetes), age, race, family history of inflammatory bowel disease or colorectal cancer itself, and familial adenomatous polyposis, in which the risk of colorectal cancer increases to almost 100 per cent by the age of 40 if untreated.

Current treatment options
The three standard colorectal cancer treatment options are surgery, chemotherapy (including targeted therapies, such as monoclonal antibodies) and radiation therapy. The optimal treatment plan will depend on the stage of the disease, and may involve only one or a combination of the above-mentioned treatment options. Surgery is often the main treatment recommended for early-stage colorectal cancer.

There are currently seven drugs approved for the treatment of metastatic colorectal cancer: 5-fluorouracil (5-FU), capecitabine (Xeloda; Roche), irinotecan (Camptosar; Pfizer), oxaliplatin (Eloxatin; sanofi-aventis US), bevacizumab (Avastin; Genentech), cetuximab (Erbitux; ImClone Systems, Bristol-Myers Squibb) and panitumumab (Vectibix; Amgen). Depending on the stage of the cancer, two or more of these approved therapies may be combined concurrently, or used sequentially.

Chemotherapy regimens, such as FOLFOX (oxaliplatin + leucovorin + 5-FU) or FOLFIRI (irinotecan + leucovorin + 5-FU), either with or without bevacizumab, have also been shown to increase survival rates in patients with metastatic colorectal cancer.

Introducing perifosine
Perifosine is a small-molecule compound that was originally discovered by Zentaris (now AEterna Zentaris) and has since been licensed to Keryx Biopharmaceuticals in the US, Canada and Mexico, and Handok Pharmaceuticals in South Korea.

The primary mechanism of action of perifosine is to inhibit Akt activation in the phosphoinositide 3-kinase (PI3K) pathway. Akt is a protein in the body that is associated with tumour survival and growth, and high levels of activated Akt, which are seen frequently in many types of cancer, have been correlated with poor prognosis. The effect of perifosine on the Akt/PI3K pathway is of particular interest because of the importance of this pathway in the development of most cancers. Perifosine appears to be the most advanced compound in its class with potential for the treatment of colorectal cancer, which could result in a first-in-class approval for this indication.

In addition, perifosine affects a number of other key signal transduction pathways associated with apoptosis and cellular growth, cellular differentiation and cellular survival, such as the MAPK and JNK pathways.

To date, over 2,000 patients with various cancers have been treated with perifosine in trials conducted in the US, Canada and Europe. Perifosine has demonstrated both safety and clinical efficacy against several tumour types, whether used as a monotherapy or in combination with other chemotherapeutic agents. In phase II trials for metastatic colorectal cancer, perifosine + capecitabine combination therapy more than doubled the time to disease progression (to 28 weeks) in 35 evaluable patients, compared with capecitabine + placebo. Overall response and clinical benefit rates were also higher with perifosine + capecitabine (20 per cent and 74 per cent, respectively), compared with capecitabine + placebo (7 per cent and 40 per cent, respectively).

What to X-PECT
In early April 2010, a phase III registration trial of perifosine for the treatment of refractory metastatic colorectal cancer was initiated under a Special Protocol Assessment from the US Food and Drug Administration (FDA). This randomised, double-blind trial, which is entitled X-PECT (Xeloda + Perifosine Evaluation in Colorectal cancer Treatment), will enrol approximately 430 patients. The trial will evaluate the safety and efficacy of perifosine (one tablet daily) given in combination with capecitabine (twice daily on days 1 to 14 every 21 days), versus placebo given in combination with capecitabine. To be eligible for inclusion, patients must have failed prior treatment with 5-FU, oxaliplatin, irinotecan or bevacizumab and, if patients had wild-type K-ras tumours, failed therapy with prior cetuximab or panitumumab. The primary endpoint of the X-PECT trial is overall survival (OS); the median OS is expected to be approximately 5 months.

In general, perifosine has been well tolerated with dose-related nausea, vomiting, diarrhoea and fatigue being the most commonly observed toxicities. However, it was found that these adverse effects were generally well managed at lower daily doses (either 50mg or 100mg), which have also been shown to induce tumour regression. Perifosine does not appear to cause flu-like symptoms, thrombocytopenia or alopecia (hair loss), all of which occur frequently with many of the chemotherapeutic agents that are currently available.

In April 2010, the FDA also granted perifosine fast track status for the treatment of refractory advanced colorectal cancer.

A separate US-based phase III study is evaluating the efficacy and safety of perifosine when combined with bortezomib and dexamethasone in patients with relapsed multiple myeloma (MM). The FDA has granted perifosine both orphan drug and fast track designation for the treatment of MM.

Also in progress are phase II trials for various other forms of cancer, including chronic lymphocytic leukaemia, gastrointestinal stromal tumours, recurrent glioblastoma multiforme and other malignant gliomas, head and neck cancer, non-small cell lung cancer, renal cancer, sarcoma and Waldenström's macroglobulinaemia. The ability of perifosine to cross the blood-brain barrier has generated much interest in exploring the drug's potential for the treatment of advanced brain tumours.

Phase I trials are also under way in paediatric patients with recurrent solid tumours, either as a monotherapy or in combination with temsirolimus (Torisel; Pfizer), which is an inhibitor of mTOR, a key protein kinase in the PI3K pathway.

Knowledge is power
While perifosine is only one of many different therapies currently being developed for colorectal cancer (including targeted therapies such as vascular endothelial growth factor [VEGF] inhibitors and epidermal growth factor receptor [EGFR] antagonists), it appears to be first in its class to be evaluated for this indication. It is also only one of a handful of therapies — along with aflibercept (Regeneron Pharmaceuticals), brivanib alaninate (Bristol-Myers Squibb) and cediranib (AstraZeneca) — in late-stage clinical trials for this type of cancer.

The results from the phase III X-PECT trial are being eagerly awaited because, if successful, perifosine could provide the therapeutic arsenal needed for this heavily pretreated metastatic colorectal cancer population, for which there are limited, or no, other treatment options available.

Concurrent with this new drug development, improvements in disease screening, greater public health awareness, lifestyle-related changes and application of existing knowledge also hold great potential to prevent this disease, save lives and diminish unnecessary suffering from colorectal cancer.

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The Author
Pipeline was written by Asha Vaidya of Adis International using data derived from Adis R&D Insight and Clinical Trials Insight.
For further information on Adis services, please contact Kuljeet Sohanpal on +44 (0)207 981 0714.

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