**1. Introduction**

144 Advances in Cancer Therapy

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However, changes are difficult. Human beings resist changes.

For many years, chemotherapy has been the gold standard of cancer therapy. The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs (De Vita et al, 2005) and a major break-through in 1965, when James Holland, Emil Freireich, and Emil Frei hypothesized that cancer chemotherapy should follow the strategy of antibiotic therapy for tuberculosis with combinations of drugs, each with different mechanisms of action (Frei et al, 1965). Cytotoxic chemotherapy in fact succeeded in producing major therapeutic effects, including cures, in hematological malignancies and some solid tumors such as testicular and ovarian cancers. However its contribution to the treatment of most solid tumors has been much less. The success history of chemotherapy in leukemia and lymphoma simply did not repeat in most solid tumors.

Chemotherapy has the disadvantage of its high toxicity, because is an unspecific treatment which effect does not distinguish between normal and tumor cells.

The paradigm of selective killing of cancer cells in a way alike to what antibiotics do for infections, created in turn a standardized procedure for stepwise drug development through conventional Phase I, II and III trials, which was soon adopted and translated into regulations by many drug regulatory authorities. The designs of these clinical trials respond to the need of demonstrating the drug efficacy at its maximal tolerable dose (MTD).

However, although retaining the main concept and adapting to the old paradigm malfunctioning, variants have been introduced for cancer drugs approval: i.e. approvals without randomized trials and approvals based in accelerated approval regulations.

From January 1973 through December 2006, 68 new drugs were approved for cancer therapy from which 31 were approved without 2 arms randomized clinical trials including a control arm with different therapy, supportive care or placebo (Tsimberidou, 2009).

Clinical Development Paradigms for Cancer Vaccines: The Case of CIMAvax EGF® 147

excessive toxicity. The effective time of the drug in circulation has to be studied in pharmacokinetics studies, and this has been an additional goal of Phase I clinical trials. Once defined the drug dose, a proof of clinical benefit is the next step. Currently, this is measured as objective response (assessing tumor shrinkage), because cytotoxic drugs are expected to decrease the tumor mass. Phase II trials are designed and conducted to find this kind of anti-tumor activity in some specific patient population. These trials are usually not randomized and evaluate the tumor response according to RECIST criteria (Response Evaluation Criteria in Solid Tumors). They include the minimal patient population required to show statistical significance of a given percentage of tumor response which is different

When the product under study demonstrates to have anti-tumor activity, randomized Phase III trials are then designed to compare the new drug with the currently accepted standard

If a novel chemotherapeutic agent is more efficient and/or has better safety profile than a previous one, it is considered to substitute the previous therapy or to add on it. Usually, a large number of patients are required to achieve statistical power to detect small differences

It is this statistical significance of therapeutic effect in Phase III clinical trials which guarantee the Regulatory Approval. Nevertheless, the limitations of this stepwise process have driven regulatory adaptations such as the concept of AA after an obviously successful Phase II Trial. This concept has had diverse expressions and nuances in different regulatory

**3. A clinical development paradigm shift is needed for cancer vaccines:** 

Therapeutic cancer vaccines are active immunotherapy approaches that provoke an immune response against antigens relevant for tumor cell survival or growth (Talucka, 2011). As their action is very specific towards the cancer associated antigen, cancer vaccines has very low toxicity profiles. That makes possible long lasting use as well as combination with other drugs. In general, not tumor shrinkage is expected, but a prolonged patient´s survival as a consequence of disease control with chronic vaccinations compatible with good quality of

In this very different scenario, the development paradigm used for chemotherapeutics is not

The first trials with cancer vaccines are mainly devoted to demonstrate the proof of the therapeutic principle, i.e. immunogenicity of the vaccine preparation, eliciting an immune response to the antigen they are intended to target; and they are also used for testing different formulations, doses, schemes and, by sure, safety. The novel paradigm of clinical development of cancer vaccines makes then Phase I trials better defined as Proof of Principle

Objective response according to RECIST is not always a good predictor of **SV**.

Combinations can be effective using drugs that are not active as single agents.

In cancer vaccines the MTD is not always the optimal dose.

Cancer vaccines could be active even beyond progression.

Therapeutic benefit could be delayed on time.

from zero.

therapy.

authorities.

**Why?** 

between randomized groups.

life (Lage & Crombet, 2010).

working well (Table 1):

trials (PPT).

Accelerated approval (AA) regulations were established by the US Food and Drug Administration (FDA) designed to shorten development times of drugs for serious medical diseases, i.e. cancer (Dagher et al, 2004; Richey et al, 2009). According these, drugs received AA based in Phase II trials and sponsors must confirm efficacy in post-approval trials. Since the first AA for an oncology indication was granted between 1995 and 2008, 51 new molecular entities have received FDA approval for cancer therapeutic indications: 32 with regular approval and 19 with AA (Richey et al, 2009).

In some way, regulations have moved towards faster access to patients of even the very toxic chemotherapies.

Biotechnology development has provided new therapeutic weapons for cancer therapy. According Pharma 2009 report, there are currently 633 biotechnology medicines under development, from which 254 are for cancer therapy (109 monoclonal antibodies and 63 cancer vaccines). That means, 40% of worldwide biotechnology is cancer therapy.

These Biotechnological products have the characteristics of being highly specific which in turn causes a low toxicity, long-term usability and usability in combinations.

 Biotechnology anticancer drugs are not just more drugs, they are different drugs; and their entrance into cancer therapy high lightened the limitations of the prevalent paradigm for drug development. The enormous differences between the new biotechnological products and chemotherapeutic agents, makes necessary changes in established clinical development paradigms. Specifically, for cancer vaccines, more flexible and focused developmental guidelines are needed to address their unique characteristics (Hoos et al, 2007).

In this report we use the case of CIMAvax-EGF® to illustrate the operation of the emerging paradigms.
