As described in the preceding chapter (“Therapeutic Targeting of Cancer Cells”) and elsewhere (e.g., Chapter 8, “Vascular and Interstitial Biology of Tumors”), our understanding of the physiology and molecular biology of tumors has provided a wealth of potential targets for anticancer therapy. Although the relative intensity has magnified, the concept of molecular targeting and linkage to diagnostics for selection and monitoring of individual patients has a long history. The selection of hormonal therapies for patients whose tumors express the estrogen receptor was among the first successful uses of molecular targeting. Among several recent successful examples in the current era of targeted cancer pharmacology, two noteworthy cases are the approval and everyday use of imatinib only in patients with chronic myelogenous leukemia (CML) that is Philadelphia chromosome–positive and trastuzumab only in patients with HER2-positive tumors.

In addition to the obvious attraction of matching drugs to the molecular characteristics of the tumor, the therapeutic index can also be improved by examining host tissues. In his last major research publication,¹ Dr. Abeloff was a leader in a large multicenter study of the PG for cyclophosphamide. The goal was to determine if the germline DNA of patients altered the toxicity profile of cyclophosphamide. A subgroup of women was found who had variant GSTP1 alleles that were associated with less susceptibility to adverse hematologic toxicity in regimens containing cyclophosphamide.

Another large cooperative group clinical study examined germline determinants of paclitaxel neurotoxicity.² Wheeler et al.² used genome-wide analyses coupled with well-characterized data from a cell bank to support a polygenic approach to understanding the variation in host tissue sensitivity to the sensory peripheral neuropathy associated with paclitaxel.

Although both studies were only hypothesis-generating, these examples illustrate the possible ways that the therapeutic index for a drug can be improved by examining the host tissues. In the section on Cancer Drug Delivery, the PG of metabolism and cellular membrane transporter cell membranes in host tissues are discussed.

Combinations of Drugs

As described in the various chapters relating to specific malignancies in Part III of this book, it is rare for a drug to be used as a single agent. The development of combinations would be an extensive topic in itself. Box 29-2 provides a set of points to consider for combinations. Within a combination chemotherapy regimen, the drugs are intended to interact at the PD level. Originally, a major strategy was to combine cancer drugs with nonoverlapping toxicities. Increasingly, more detailed knowledge regarding pathways for cancer drugs permits the design and evaluation of combination strategies that target parallel and/or sequential pathways.

Box 29-2 Strategic Factors for Drug Combinations

• Rationale for target-based combinations

• Add-on new drug to established regimen

• Systematic evaluation of all combinations

• Translation of findings into clinical trials

Most combinations are based on a preexisting scientific rationale or by addition of a new agent to an established regimen. However, it would be presumptuous to assume that all possibilities are already understood. One tool to expand the scope of hypothesis generation is the systematic study of all cancer drugs in combination with each other, or in combination with approved agents outside oncology, or testing every investigational agent versus all approved cancer drugs.³ Although this screening approach begins as an empiric exercise, the successful combinations become challenges for explaining the underlying mechanisms of action. The focus on drugs that are already approved provides a potentially fast route to clinical implementation.

Molecular Imaging of Cancer Drug Action

With the widening availability of fluorine-18 fluorodeoxyglucose (¹⁸F-FDG), a consensus was building in the late 1990s that positron emission tomography (PET) would emerge as a complementary tool to anatomic imaging modalities.⁴ Since then, FDG has been highly successful as a general probe in many tumor types, providing additional information to help separate malignant from benign lesions and to monitor response to therapy.

FDG is now an approved drug for imaging. Its success has spurred interest in the development of other probes for PET imaging that are currently in the investigational stage of clinical evaluation, including ¹⁸F-fluorothymidine (FLT). Figure 29-1 shows the results for FLT in a patient with uterine cancer.⁵ At baseline, the FLT image shows major uptake by the tumor, indicative of active proliferation. During treatment with sunitinib, uptake of FLT in the tumor decreased, which was interpreted as reduced proliferation. The image following the withdrawal of treatment exhibited a flare, that is, intensity that rebounded above the baseline value. Anatomic imaging by computed tomography (CT) readily identified the tumor and could monitor regression if that occurred, but FLT provided the ability to follow molecular pathways in real time.

Figure 29-1 Combined positron emission tomography/computed tomography imaging with fluorine-18 fluorothymidine in a patient with uterine cancer treated with sunitinib. (From Liu G, Jeraj R, Vanderhoek M, et al. Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate. Clin Cancer Res 2011;17:7634-44.)

Principles of Cancer Drug Delivery

Once the appropriate drug has been chosen, the most important everyday question in clinical cancer pharmacology is the selection of an appropriate dose. The standard dose is a starting point, but what factors could make this dose too high or too low for individual patients? For many cancer drugs, evidence-based advice is not available. In some cases, guidance for dose adjustment is available based on prior treatment or age, which could be interpreted as PD factors predisposing to greater host tissue sensitivity.

Increasingly, drugs are approved with information about dosage adjustment based on renal function testing, food intake, and use of other drugs concurrently. All of these factors are related to variation in changes in the delivery of drugs. In addition to empiric data from clinical investigations for specific drugs, what are the principles that underlie these decisions based on drug delivery?

Clearance is at the top of the list for drug delivery parameters in Box 29-3 because it is the factor with the greatest impact on dose-adjustment in cancer drug delivery. As stated in Box 29-4, clearance is the summation of all mechanisms for a drug to be removed from the systemic circulation, sometimes called total body clearance. Several specific applications of clearance for dosage adjustment will be covered in the next few sections.

Box 29-3 Drug Delivery Concepts

Clearance (Dose Adjustment)

• Impaired organ function

• Drug-drug interactions

• Metabolic

• Transport

• Pharmacogenetic factors

Bioavailability

• How much drug reaches systemic circulation

• Includes food effects

Half-Life (Dose Interval)

Volume of Distribution, Protein Binding

Box 29-4 Role of Clearance in Dosage Adjustment

Clearance:

Summation of all routes of drug elimination from the body: renal, hepatic, other

Primary Application: Guide Dose Adjustment

Low Clearance → High Exposure (consider reduced dose)

High Clearance → Low Exposure (consider increased dose)

Bioavailability has risen sharply in its utility because of the shift toward oral therapy. This concept will be described in the section on Oral Cancer Drugs. Half-life was previously the most discussed parameter for cancer drug delivery. However, its role is primarily in the development stage, to help guide frequency of dosing. Once a drug is approved for clinical practice, oncologists do not have a frequent need to know this value. Other drug delivery parameters such as volume of distribution or protein binding can have value in specific situations, but only on rare occasions.

Dosage Adjustment Based on Clearance

Compared with other medical areas in which fixed doses are prevalent, dosing in cancer pharmacology has long been titrated on the basis of each patient’s body weight or body surface area. These measurements are intended to serve as first approximations for clearance in the absence of data, but their incremental value compared with a standard dose is unfortunately small, and most current trials have adopted fixed doses, that is, “flat dosing.”⁶

The role of clearance in dosage adjustment is summarized in Box 29-4. The premise is that the standard dose was selected on the basis of the needs of patients with average drug clearance. If a patient has lower clearance than the average, then using the standard dose will lead to higher than average systemic exposure, with the probability of higher than average toxicity. Using a dose reduction to match the lower clearance will normalize the exposure of this patient relative to the average in the population. Similarly, a patient with higher than average clearance will have lower systemic drug exposure than will patients with the average exposure for the population. Although this lower systemic drug exposure will probably reduce the frequency or severity of toxicity, it has the potentially lethal consequence of reducing the response of the tumor.

This overall strategy for dosage adjustment has been elegantly demonstrated for the first scenario in Box 29-3, namely, patients with impaired renal function. The seminal clinical study of carboplatin by Egorin et al.⁷ in patients with variable renal function remains the prototype for dosage adjustment based on impaired organ function. For the other two areas in Box 29-3 (drug-drug interactions and pharmacogenetic factors), many practical cases of dosage adjustment exist. Specific examples will be discussed in the following sections.

Drug-Drug Interactions

Many categories of drug-drug interactions exist. The anticancer drugs in a chemotherapy regimen, which are generally intended to work at the level of mechanisms of drug action, are only the tip of the iceberg for drug-drug interactions. Patients with cancer are simultaneously treated with drugs for various other conditions, including diseases of the heart, gastrointestinal (GI) tract, lungs, infections, depression, and the relief of pain. All of these permutations in polypharmacy can potentially affect the delivery of cancer drugs. As a consequence of these interactions, the standard doses of drugs may need to be either reduced or increased.

Most drug-drug interactions are manifested as safety issues because of increased exposure subsequent to reduced clearance. However, induction (increasing) of clearance can decrease toxicity. Unfortunately, although this type of interaction is “silent” in terms of enhanced toxicity, reduced exposure to drug can also generate the worst toxicity of all: decreases in efficacy.

Drug-drug metabolic interactions are possible for parenteral routes of drug delivery, but they are far more common for the oral route. Because metabolism is the primary determinant of clearance for most drugs, it is the dominant controller for changes in plasma concentrations. Following the paradigm in Box 29-4, inhibition of drug metabolism via a drug-drug interaction will produce lower clearance and thus higher systemic exposure. A reduction in dose may be necessary to avoid increased toxicity. Conversely, drugs such as phenytoin can induce the expression of certain metabolizing enzymes, which would decrease systemic concentrations for the drugs cleared via those enzymes, because the rate of their metabolism would be faster. Decreased exposure increases the probability of inadequate delivery of the cancer drug to the tumor. In the section on Oral Cancer Drugs, Table 29-1 provides some examples of the enzymatic pathways that metabolize cancer drugs.

Table 29-1

Interaction of Drugs with Enzymes and Transporters for Recently Approved Oral Cancer Drugs

Drug	Is This Drug Affected by Inducers/Inhibitors?	Does This Drug Cause Change for Other Drugs?*
Imatinib	3A	3A, 2D6
Lapatinib	3A	3A, 2D6, ABCB1
Pazopanib	3A	3A, 2D6, 2C8
Ruxolitinib	3A	Not reported
Vemurafenib	No data	3A, 1A2, 2D6
Crizotinib	3A	3A
Abiraterone	No data	2D6
Bosutinib	3A	No data
Regorafenib	3A	No data
Enzalutamide	2C8, 3A	3A, 2C9, 2C19

^*The drug metabolism pathways are: 1A2 = CYP1A2; 3A = CYP3A; 2D6 = CYP2D6; and various members of the CYP2C family: 2C8, 2C9, 2C19. For transport, the ABCB1 (MDR1) pathway is cited.

Data retrieved from Food and Drug Administration approved labeling, found at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.

Drug-Drug Transporter Interactions

In cancer pharmacology, the primary focus for transport of drugs has been the flux across the cell membranes of tumors. A major mechanism of drug resistance has been described for tumors with high expression of efflux pumps that reduce the availability of cancer drugs to their targets. Investigations into the influx of cancer drugs into tumors have also been conducted. White et al.⁸ demonstrated that patients with CML had more long-term benefit from imatinib if expression of its influx pump, OCT-1, was higher.

In addition to the interactions of cancer drugs with transporters in the tumor, interactions occur among cancer drugs and cellular transport systems in host tissues that control uptake and elimination of drugs from the GI tract, the liver, and the kidneys. The expression of transporter function can be modulated by other drugs in a manner similar to drug-drug metabolic interactions. Indeed, some of the same inducers of metabolism (phenytoin or rifampin) are also major inducers of transporters. In contrast, ketoconazole, itraconazole, and certain psychopharmacologic agents are inhibitors. This focus on drug transport is important regardless of the route of drug delivery, but similar to metabolic interactions, additional factors exist that are related to control of absorption of cancer drugs from the GI tract. Transporters are also the underpinning of the blood-brain barrier and control the entry of cancer drugs into the brain to treat metastases or primary brain tumors.⁹

Interactions Via Self-Medication

The source of drugs for patients with cancer is not restricted to those prescribed by oncologists, or even medicines prescribed by other medical practitioners. Self-medication with over-the-counter drugs and alternative therapies is prevalent in patients with cancer and includes substances that interact with cancer drugs (see Chapter 33, “Complementary and Alternative Medicine”).

Far less is known about the interactions of cancer drugs with these substances than is known for prescription drugs. Saint John’s wort is a particularly troublesome case. It is marketed over the counter for relief of depression, which is a major issue for patients with cancer. However, this product is a strong inducer of CYP3A enzymes, which inactivate many newer oral cancer drugs. This situation once again reminds us of the potentially serious consequences of reduced delivery of cancer drugs to the tumor.

Interactions of drugs with food have a similar conceptual framework and are discussed in the next section on Oral Cancer Drugs.

Oral Cancer Drugs

Approval of imatinib in 2001 marked a major change in emphasis for cancer drugs. Oral drugs are overwhelmingly used in essentially all other therapeutic areas. In contrast, the intravenous (IV) route of administration was the dominant form for cancer drugs. Exceptions included mercaptopurine, some uses of methotrexate, and a few alkylating agents. In the decade before the approval of imatinib, some attempts were made to convert approved cancer drugs from the IV route to oral delivery. Although those efforts were mostly unsuccessful, capecitabine was approved in 1998 as a prodrug for 5-fluorouracil, which had been used intravenously for four decades.

Parenteral administration will continue to be important, both for the many legacy drugs that remain part of regiments with established therapeutic value and for occasional cases in which an agent cannot be successfully delivered via the oral route. However, based on the up-front goal to achieve oral delivery for most new cancer drugs under development, especially for chronic daily dosing, it is easy to project that the ratio of oral to IV cancer drugs will continue to rise. As shown in Box 29-1, the FDA approved 11 cancer drugs in 2012. Overall, 7 of these 11 drugs are administered orally, including 7 of the 9 small synthetic compounds.

In general, the advantages of oral cancer drugs are overwhelming, and the shift from the prior dominance of parenteral routes is irreversible. Nonetheless, issues regarding oral drugs have now emerged as the aspect of cancer drug delivery that requires the most attention.

As indicated in Box 29-5, adherence to the prescribed regimen is one of the first questions to explore. Although patients with cancer are highly motivated to carefully follow their dosing instructions, it is naïve to expect complete compliance and especially to ignore the problems of persistence over a long period. Marin et al.¹⁰ concluded that poor adherence may be the predominant reason for failure to achieve adequate molecular responses with imatinib. Partridge et al.¹¹ examined the complex scenario of elderly patients with cancer, a population that has a high frequency of polypharmacy and perhaps a fading memory. For adjuvant therapy of early stage breast cancer with tamoxifen, 25% of patients took fewer than 80% of the expected doses, which is problematic. This study included no patients younger than 65 years, but the authors reported that adherence was not dependent on age for persons ranging from 65 to 89 years.

Box 29-5 Issues Unique to Oral Drug Delivery

• Adherence: Does the patient take the drug?

• Variability in absorption due to:

• Degradation in gastrointestinal tract

• Food effect on drug absorption

• Metabolism and transport in liver and intestines

• Drug-drug interactions prior to systemic exposure

• Emesis prior to complete absorption

• Co-morbid difficulties in delivering oral drugs

Switching between oral and parenteral dosage forms needs to be based on evidence from prior clinical studies, but the starting point is an assessment of the concept known as bioavailability, the relative drug delivery to the systemic circulation. Among cancer drugs, imatinib has one of the highest values for oral bioavailability—98%. By definition, the bioavailability of an IV drug is 100%.

Bioavailability

Systemic drug exposure ratio, at equal doses:

SystemicdrugexposurefororaldeliverySystemicdrugexposureforIVdelivery

Although ease of oral cancer drug administration is generally a major advantage, it can become a liability when co-morbid conditions make swallowing drugs a major problem (see Chapter 43, “Oral Complications.” Cancer chemotherapy can produce emesis (see Chapter 42, “Nausea and Vomiting”), which thwarts the reliability of retaining swallowed doses. In addition, the treatment of these complications of cancer therapy can include the use of additional drugs to complicate the drug-drug interaction scenarios.

Some drugs are impractical for oral administration because they degrade at the low pH of the stomach. Large segments of the population are chronic users of a variety of agents that reduce acid in the stomach and raise pH, but this factor only widens the variability among patients.

The most pragmatic question about oral therapy is whether the drug should be taken with food. When patients take medicines for a variety of disorders, it is difficult to keep track of the instructions relating to food, which are often in conflict. Patients cannot simultaneously be fasting and eating a full meal. As each new cancer drug is approved, the quality and quantity of advice regarding the interaction of drugs with food have improved.

For the representative set of 10 cancer drugs described in Table 29-2, the advice for four drugs (ruxolitinib, vemurafenib, crizotinib, and enzalutamide) is that the timing of food intake is not important. The other six drugs are split evenly between recommendations to take while fasting versus taking with a meal. For two of these six drugs, the magnitude of the food effect is provided.

Table 29-2

Impact of Food on Drug Absorption for Recently Approved Oral Oncology Drugs *

Drug	Whether Drugs Should Be Taken with Food	Size of Effect
Imatinib	Yes	??
Lapatinib	No	Fourfold
Pazopanib	No	??
Ruxolitinib	±	NS
Vemurafenib	±	NS
Crizotinib	±	NS
Abiraterone	No	Tenfold
Bosutinib	Yes	??
Regorafenib	Yes	??
Enzalutamide	±	NS

^*If no preference is provided for taking with food or fasting, ± is indicated, and the effect size is not significant (NS). If no advice is provided, ?? is indicated.

Data retrieved from Food and Drug Administration approved labeling, found at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.

If these dosing recommendations are unintentionally or intentionally reversed, potentially serious issues of reduced efficacy or increased toxicity occur, along with potential economic issues. The fourfold increase in absorption of lapatinib with food has been the source of substantial public discussion,¹² which has been extended to cover other oral cancer drugs.¹³ For abiraterone, the tenfold difference in absorption is sufficiently large to capture everyone’s attention. Perhaps abiraterone has a wider therapeutic index than most cancer drugs, but a tenfold difference in exposure seems unlikely to be without consequences.

In addition to the general effects of food on solubility of drugs and passage into the body, a few food substances have highly specific effects on cancer drug metabolism and cancer drug transporters. The most notable example is the interaction of grapefruit juice with metabolism via the CYP3A family and the ABC family of transporters.¹⁴ The specificity of effects with grapefruit and drugs closely resembles the drug-drug interactions described later.

When cancer drugs are administered parenterally, metabolism by the luminal portion of the intestines is bypassed, and metabolism by the liver is diluted because the majority of the drug is distributed systemically before reaching the liver. In contrast, the entire dose of an oral cancer drug is exposed to both intestinal and hepatic metabolism and transporters before any systemic exposure.

For the same set of 10 representative oral cancer drugs described in Table 29-2 for food effects, Table 29-1 provides information from the FDA Web site for drug interactions with enzymes and transporters. The entries in Table 29-1 indicate that all of these drugs have at least some information about enzymatic pathways. The largest category of potential interactions is with the CYP3A family of enzymes, which are present in both intestines and liver and have potential interactions with 9 of the 10 drugs. Scattered information is presented for other members of the CYP superfamily: 1A2, 2C8, 2C9, 2C19, and 2D6. Interest is expanding rapidly in the role of transporters¹⁵ interacting with cancer drugs, but only one drug in this set, lapatinib, has information about the transporter pathways.

Clinical Relevance and Applications

The role of cancer pharmacology for clinical applications is to inform or guide oncologists in therapeutic decision making. Cancer pharmacology is also a major factor in moving drugs from laboratory stages to clinical use, including formulation, animal model validation, toxicology, PK, and PD studies.

A major path forward for advancing our understanding of cancer drug actions includes the search for biomarkers and evaluation of treatment effects. In the long term, the identification and implementation of potential predictive biomarkers for selection and monitoring of therapy is perhaps the most clinically relevant area of cancer pharmacology.

Currently, testing is underway for strategies to select treatment for patients based on molecular profiling of their tumors, including DNA (especially mutations), RNA (expression arrays and real-time polymerase chain reaction), target proteins and their modified states (e.g., phosphorylation, enzyme-linked immunosorbent assays, and Western blots), and functional assays such as enzymatic activity (less frequently). It is too early to draw conclusions about the ultimate roles for such studies. It has become more widely appreciated that each of these end points has various requirements for sample handling that are crucial to interpretation of the results. Further, the issue of interlaboratory validation has moved to the top of the list of requirements for definitive progress in applying these tools.

Cancer drug delivery assists in the selection of feasible doses, schedules, and routes of administration. The most appealing approach to customizing doses for patients would provide advice prior to the first dose to avoid untoward effects and maximize therapeutic delivery. In previous sections on impaired organ function and drug-drug interactions, we discussed some modest advances toward this goal.

Once therapy is underway, adjustments are frequently required. Dosage adjustment based on adverse effects is always the most urgent need. If life-threatening or unbearable toxicity occurs, then the antitumor effects will be moot. Dosage adjustment based on lack of antitumor activity has its attraction, particularly if the toxicity is less than expected, a potential signal of inadequate exposure. However, recognition of the narrow therapeutic index for cancer drugs and many other cautionary clinical factors or concerns about liability tends to discourage escalating a dose higher than the standard. In addition, there is always a sense that if the current treatment is not working, switching to an alternate therapy is urgent before the tumor becomes even more resistant.

Speculation that many shortages could be bypassed by substituting drugs that are “almost as good” was dramatically dashed by the study of Metzger et al.¹⁸ Because of a lack of supply of mechlorethamine, cyclophosphamide was substituted in the multidrug regimen for children with Hodgkin lymphoma. In only 2 years, more than a doubling occurred in the number of patients who no longer had event-free survival.

Approved Indications and Off-Label Use of Drugs

The description of approved indications is included on the drug label. At the beginning of the era of cancer chemotherapy, drugs were approved (indicated) for broad use, for example, “for treatment of cancer.” As we have progressed to a period in which many treatments are already established, the approved indications for new drugs are increasingly narrowed to descriptions such as “the treatment of estrogen-receptor positive breast cancer after second relapse, following at least one regimen containing an anthracycline and one regiment with a taxane.”

On one hand, this narrowness is a precise description of the clinical studies that determined the specific subpopulations that benefit from the drug. On the other hand, with very rare exceptions (e.g., thalidomide restrictive distribution), physicians have the right to prescribe any drug for any situation in which their judgment indicates a benefit for a specific individual patient. In some sense, approval of a drug for marketing in any indication, including nononcologic disease, provides the opportunity to use that agent “for the treatment of cancer.” Of course, in addition to regulatory approvals, powerful pragmatic limits exist. Most patients face reimbursement hurdles for “off-label” use. The prescription can be written (or electronically transmitted), but it cannot be filled unless its cost is reimbursed.

For oncologists, prescribing drugs for uses off-label could create a situation of legal liability in the event of an unsuccessful or adverse outcome. In contrast, the prescribing of drugs for the indications approved by the FDA provides a major shield from liability concerns. Similarly, other evidence-based or generally accepted authoritative compendia also have influence in the areas of both reimbursement and legal liability. Companies are not permitted to advertise a drug for any use except its approved indications.

New Indications and Repurposing (Repositioning)

Terms such as “repurposing” or “repositioning” have become commonplace as researchers and companies seek new uses for approved drugs. Because the safety of the drug has already been established and the supply of clinical-grade drug is readily available, the road to evaluation in patients is accelerated. Initial approval for a drug is not the end of its clinical development.

The simplest version of this concept is to search within the same therapeutic area. Additional uses for cancer drugs are often actively sought. Once again, imatinib sets the standard. In this case, the approved indications were extended from CML to gastrointestinal stromal tumor, and again to various rare cancers.

When therapeutic boundaries are crossed, potential therapies could move from oncology to other diseases or from other diseases into oncology. Methotrexate is used in juvenile and rheumatoid arthritis. Cyclophosphamide is used in both children and adults for nephrotic syndrome. Paclitaxel is used as a coating for cardiac stents. In the other direction, cancer researchers have a recurring interest in evaluation of potential anticancer effects of marketed drugs from outside oncology. Current examples include metformin and simvastatin.

Development and Discovery of Cancer Drugs

Within the context of recent trends for new cancer drugs (Box 29-6), the processes for development and discovery need to be clearly understood. However, the actual research that comprises these phases needs to adapt to the continuous stream of new findings in cancer biology. Further, the optimal approach to information gathering during human evaluation of cancer drugs is continually reevaluated, and the relevance of preclinical models to the clinical realities is continually improved.

Box 29-6 Recent Trends for New Cancer Drugs

1. Rapid pace of approvals

2. Predominantly oral drugs

3. Narrow indications

4. Links to molecular targeting and diagnostic tests

5. Involvement of industry, nonprofit organizations, and government

The lack of consistent definitions of the terms “new drug” and “investigational drug” can be a minor stumbling block in understanding the development process. In the United States, the regulatory definition for a “new drug” is an agent that is regulated under certain portions of the Food, Drug, and Cosmetic Act. All marketed cancer drugs are “new” drugs under this definition, regardless of how long they have been marketed. Outside the regulatory sphere, a compound is described as a “new” drug when it is first marketed, such as the initial approval of imatinib for the indication of treatment of patients with Philadelphia chromosome–positive CML. As discussed earlier, new indications are continually sought for cancer drugs. Thus even though imatinib was already a “new” drug approved for CML, it was simultaneously an “investigational” agent for treatment of gastrointestinal stromal tumors until it was subsequently approved for that indication.

Clinical Phases of Drug Development

As indicated in Box 29-7, the clinical stages of drug development have been divided into phases that are related to the primary goals. These stages have historical and regulatory significance, but the boundaries are always being pushed, and it is not possible to assign every compound into the same bins. For patients with cancer, this view of clinical development is continually challenged by the compelling need to provide therapeutic options when no treatments have been established. The boundaries that are calibrated for less serious diseases may be a bit more flexible in oncology, just as the definition of maximum tolerated dose is a relative term that depends on the medical scenario. Phase 1, phase 2, and phase 3 are long-established terms. Phase 4 was created by a formal change in FDA regulations. Phase 0 is a less-formal term used by some investigators to describe early explorations to seek information before making a decision to launch full-scale development.

Box 29-7 “Historical” Phases of Human Evaluation for Cancer Drugs

• Phase 0: Target-related study and feasibility of delivery

• Phase 1: Safety and early signs of activity

• Phase 2: Is anticancer activity promising?

• Phase 3: Improvement versus current therapy?

• Phase 4: Postmarketing studies

Working backward, phase 3 clinical studies are the largest and most expensive periods of clinical development and have the highest profile in the oncology community. The results of these studies are carefully followed and are prominently featured at large national meetings. These trials are designated as potentially “practice changing” because of their potential for an immediate improvement in the standard of care for the specific stage and type of cancer. The pivotal hallmark of phase 3 trials is a randomized comparison of two or more treatment groups. These trials are undertaken based on preliminary evidence of anticancer activity, and the key question is simply stated: How does the new therapy compare with established therapy?

When phase 3 trials include an investigational agent, the data from these trials are the ordinary basis for the regulatory decision to permit an indication for marketing in the population studied in the trial. Thus these trials are sponsored by the commercial organizations that will be seeking marketing approval. If the phase 3 trial is a comparison of groups for which all of the drugs are off-patent, then the NCI is usually the only organization with the resources and the mission to support such studies. Nonprofit organizations could also serve this role, but they tend to support earlier stages of clinical studies because of the cost of phase 3.

Phase 2 clinical trials are the setting for determining if an agent or combination of agents has sufficient activity in well-defined groups of patients who have no established treatments.¹⁹ In the majority of phase 2 studies, there is only a single treatment group, but randomized designs of two or more groups have been increasingly used. The goal is to determine if the activity of the agent or combination is sufficient to move into much larger phase 3 trials with comparison to standard treatments. Unfortunately, areas within oncology remain for which no standard treatment has been established. In such cases, phase 2 studies can be sufficient for regulatory approval.

Phase 1 clinical studies have historically been the first-in-human studies for new agents or for combinations of investigational or approved drugs. In diseases other than cancer, these safety studies are generally conducted with healthy volunteers. Traditionally, phase 1 clinical studies of cancer drugs were only conducted with patients because of the potential for acute, severe toxicity, as well as longer-term issues such as carcinogenicity or mutagenicity for many classes of older cancer drugs. As the biological properties of cancer drugs have evolved, some investigational agents have adverse effect profiles that are similar to agents outside oncology. For compounds sponsored by the pharmaceutical industry, there has been a trend toward use of healthy volunteers in phase 1 clinical studies for certain classes of cancer drugs.

It is likely that both strategies will co-exist, and the approach will be customized for each investigational agent. Phase 1 studies in healthy volunteers have a track record of lower costs, as well as faster and more reliable recruitment of subjects. On the other hand, the enormous value in determination of molecular effects in tumors via biopsies or imaging is unique to the inclusion of patients in these studies.

Phase 0 clinical studies are an approach to first-in-human studies that extends the preclinical search for specific types of information into the clinic. Frequently, there are concentrations that are considered essential to activity.20,21 For oral therapy, concerns exist about the consistency of absorption.

Phase 4 was added to the process for clinical development to permit approval when sufficient demonstration of safety and efficacy has been established, but before all studies are completed.

For example, during the review of the marketing application, it could be determined that certain subpopulations were not included in the pivotal studies. In return for faster approval, the sponsor of the drug makes a commitment to conduct “postmarketing” studies to fill any gaps defined by the FDA. Situations include clinical studies of patients with impaired organ function, drug-drug interactions, or expanded studies of elderly patients.

The numerical order of the clinical phases provides a logical progression for development but should not be considered as universally linear. As previously noted, a new drug is sometimes approved on the basis of phase 2 studies, and phase 3 trials are not conducted. As another example, an unanticipated problem with dosing during a phase 2 investigation might prompt the return to phase 1 to improve characterization of doses and schedules. Precedents exist for skipping phase 2 studies and moving directly from phase 1 to phase 3. Evidence of activity in phase 1 may seem so compelling that it warrants immediate comparison with standard of care. This strategy has a high risk in terms of the resources invested in a compound without much understanding of the probable activity. Of course, the potential exists for a high reward in terms of bringing new treatments to patients, as well as financially. Of course, this strategy is only feasible if the phase 1 study is conducted in patients with cancer.

Cancer Pharmacology across the Drug Discovery/Development Process

Applications of the principles of cancer pharmacology are embedded in the continuum from early drug discovery through preclinical development, and then bridging to the preapproval stages of clinical development.

During the development phases for a cancer drug, it is essential to monitor the relative drug delivery, as assessed by systemic concentration. When comparing activity studies in murine models, safety studies in various mammals, or early clinical studies, plasma concentrations can be monitored. Variation across animal models might signal important interspecies differences in either PK (e.g., metabolism) or PD (e.g., inherent host cell sensitivity) factors.

In the same manner, when making comparisons between observations of activity in cell culture versus concentrations that can be safely achieved in vivo, it is prudent to consider reasons for any discrepancies. Skepticism is particularly appropriate if “interesting” activity is observed in vitro at concentrations much higher than are achievable in vivo.

What the Future Holds

The fruits of cancer pharmacology are found in the paths that guide drugs into clinical use and in the adjustment of therapy in patients to balance therapeutic and toxic effects. Improving the connections between cancer drug delivery and the quantitative aspects of the activity and toxicity of cancer drugs is essential for further progress. Cancer drug delivery can only provide therapeutic concentrations and avoid toxic concentrations if we have confidence in exploitable differences between tumors and host tissues.

The interrogation of tumor samples to help determine appropriate therapy can be viewed as a direct extension of the historical application of histopathologic classification to guide recommended therapy. In essence, this form of molecular pathology could seamlessly continue the tradition of treatment driven by tumor characteristics.

Realistically, it is not completely clear how quickly the transition will occur. Too few studies have been conducted in which biopsies were obtained from patients before and after treatment and then systematically evaluated using validated methods. Fortunately, many complementary options are also evolving, such as the collection and analysis of circulating tumor cells, as well as molecular imaging probes that can provide real-time confirmation of target engagement in situ.

All models have limitations, but we certainly need improvement in preclinical models of cancer to improve the clinical success rate for new drugs. It is likely that the continued evolution of patient-derived xenografts and genetically engineered mice will provide part of the progress.

With the large and increasing number of drugs available for use (see the Appendix)²², it is not feasible to remember all the details about each one. The widespread availability and use of online resources, including FDA databases, supplements traditional textbooks. Assembling the key pieces of data is only the first step. Professional interpretation and judgment remain as central features.

Appendix *

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Drug Name	Drug Class and/or Mechanism	Pharmacokinetics/Metabolism	Toxicity	Indications	Dosing
Abiraterone acetate (Zytiga)	Inhibits androgen biosynthesis	Do not take with food; inhibits CYP2D6	Joint swelling or discomfort; edema; monitor liver enzymes	Metastatic prostate cancer; castration resistant with prior use of docetaxel	1000 mg once a day orally with 5 mg prednisone BID
Ziv-aflibercept (Zaltrap)	Fusion protein binding VEGF and related ligands	No studies for renal, hepatic, or drug-drug interactions	Hemorrhage, GI perforation, wound healing problems, fistula, hypertension, arterial thrombosis, proteinuria	Metastatic colorectal cancer resistant or progressed while taking oxaliplatin	4 mg/kg via 1-hr IV (not bolus) every 2 wk
Altretamine (Hexalen), hexamethylmelamine, HMM	Alkylating agent	Well absorbed by mouth, metabolized in the liver; half-life 4-13 hr; metabolism may be slowed by cimetidine or enhanced by phenobarbital	Myelosuppression is dose limiting; leukopenia, thrombocytopenia, nausea, and vomiting are common; neurologic toxicity, including confusion, lethargy, weakness, and sensory changes, is common	Refractory ovarian carcinoma	4-12 mg/kg/day in divided doses for 3-6 wk or 150 mg/m²/day for 14 days each cycle; higher doses have been used
Amifostine (Ethyol), WR- 2721, ethiofos	Cytoprotectant; free-radical scavenger	After IV infusion, the drug is metabolized to a thiol metabolite, which is responsible for its beneficial activity	Transient hypotension is dose limiting; nausea, vomiting, and somnolence are common; sneezing, hypocalcemia, and flushing can be seen	Pretreatment with cisplatin; useful as a bone marrow, kidney, and nerve cytoprotectant; useful with other alkylators as well; also FDA approved as a radiation protectant to reduce xerostomia	740 mg/m² IV infusion over 15 min given 15-30 min before the cytotoxic agent or radiation; lower doses and subcutaneous administration have also been used
Anastrazole (Arimidex)	Nonsteroidal aromatase inhibitor; blocks estrogen production selectively	Well absorbed from GI tract, maximum plasma levels within 2 hr; half-life is 50 hr; extensively metabolized in liver; despite hepatic and renal clearance being important, no adjustments needed for abnormal function of these organs because of the wide therapeutic index of this drug	Very well tolerated; asthenia, headache, and hot flashes occur in fewer than 15% of women; diarrhea, abdominal pain, anorexia, nausea, and vomiting occur in 10% or fewer; thrombophlebitis has been reported	Indications: As adjuvant therapy of breast cancer and for treatment of postmenopausal women with breast carcinoma who have progressed while being treated with tamoxifen	1 mg PO every day; higher doses are no more effective
Arsenic trioxide (Trisenox)	Novel arsenical differentiating agent	Half-life of this compound is unknown; it is methylated in the liver and eliminated in the urine	The “differentiation syndrome” is dose limiting and includes leukocytosis, fever, dyspnea, chest pain, tachycardia, hypoxia, and sometimes death; corticosteroids seem to benefit this syndrome; QT prolongation is common; common adverse effects include rash, pruritus, headache, arthralgias, anxiety, bleeding, nausea, and vomiting; liver and renal toxicity are uncommon	Relapsed acute promyelocytic leukemia	0.15 mg/kg/day in 100-250 mL of D5W until remission, not to exceed 60 doses, then up to 25 doses over 5 wk for consolidation starting 3 to 6 wk after achievement of remission
l-Asparaginase (Elspar), colaspase	Naturally occurring enzyme derived from Escherichia coli or Erwinia carotovora that cleaves asparagine, an essential amino acid required by rapidly proliferating cells	After IV or IM injection, the drug is metabolized intravascularly by proteolysis; elimination half-life of 8-30 hr	Hypersensitivity can be life- threatening, requiring anaphylaxis precautions and a 2-unit test dose; coagulopathy is common and requires monitoring; nausea, vomiting, abdominal cramps, anorexia, elevated liver function tests, and transient renal insufficiency are common; lethargy, somnolence, fatigue, depression, and confusion are seen, as are pancreatitis and fever	ALL; also used in AML, late-stage CML, CLL, and non-Hodgkin lymphomas	After a 2-unit intradermal test dose, an IM dose of 6000-10,000 IU/m² every 3 days for 9 doses, or 1000 IU/kg/day IV over 30 min for 10 days, has been used
PEG-Asparaginase (Oncaspar)—pegaspargase	Naturally occurring enzyme, covalently linked to polyethylene glycol to reduce immunogenicity, slow metabolism, and prolong half-life; the enzyme cleaves asparagine, an essential amino acid required by rapidly proliferating cells	When given by IM injection, it has an elimination half-life of approximately 5 days; clearance is not dependent on renal or hepatic function	Although less immunogenic that the non-PEGylated form, hypersensitivity and anaphylaxis can still occur; toxicities similar to those of the non-PEGylated forms are seen, including elevated liver enzymes, coagulopathy, hypercholesterolemia, pancreatitis, hyperglycemia, fever, chills, anorexia, lethargy, confusion, headache, seizures, and azotemia	ALL, and like asparaginase, it is also used for other leukemias and non-Hodgkin lymphomas	2,500 IU/m² IM every 14 days with other chemotherapy agents for induction or maintenance
Asparaginase Erwinia chrysanthemi (Erwinaze)	Substitute for the naturally occurring enzyme	Not characterized	Severe hypersensitivity reactions, including anaphylaxis	ALL	25,000 IU IM 3×/wk for 6 doses per cycle
Axitinib (Inlyta)	Avoid strong CYP3A inhibitors or reduce dose	Decrease dose 50% for CYP3A inhibitors, renal, hepatic impairment	Diarrhea, hypertension, fatigue, nausea	Advanced renal cell carcinoma after one treatment failure	5 mg BID oral
Azacytidine (Vidaza)	Antimetabolite; induces hypomethylation of DNA, either inducing apoptosis or restoring normal function; at higher doses, acts as a cytidine analog	Not orally bioavailable; metabolized by the liver and excreted in urine; elimination half-life of 4 hr	Myelosuppression is dose limiting; leukopenia, thrombocytopenia, and transient elevation of liver function tests are common; nausea and vomiting and abdominal pain are common	Myelodysplastic syndromes	75-100 mg/m² for 7 days; repeated every 4 wk for 4 to 6 cycles
Bacillus Calmette- Guérin (TICE BCG, TheraCys), BCG	Immunostimulant/vaccine; induces a cellular immune response at the site of instillation	BCG is a live, attenuated bacteria culture; it does not enter the body in viable form; it has no detectable pharmacokinetic fate; in rare cases, a clinical infection can result from treatment, indicating invasion of the body at site of administration into systemic circulation	Urinary symptoms predominate, including dysuria, hematuria, hesitancy, urgency, frequency, and secondary infection; other toxicities include fever, chills, malaise, myalgias/arthralgias, anorexia, nausea, vomiting, and anemia; clinical mycobacterial infection is rare and generally seen only in immunocompromised patients	Intravesical instillation for noninvasive bladder cancer after removal of papillary tumors; also used for some experimental vaccine programs as an adjuvant to the vaccine	81 mg per treatment, in 53 mL total volume, instructions as previously given; given once weekly for 6 doses and then at 3, 6, 12, 18, and 24 mo after the induction
Bendamustine (Treanda)	Alkylating agent	Reduce dose for hematologic toxicity	Nausea, pyrexia, vomiting, hematologic abnormalities	CLL and B-cell non-Hodgkin lymphoma	CLL: 100 mg/m² over 60 min, day 1, 2 of 28-day cycle; B-cell: 120 mg/m² over 30 min on day 1, 2 of 21-day cycle
Bevacizumab (Avastin)	Recombinant humanized monoclonal antibody that binds to all forms of VEGF, preventing binding to its receptors	Administered by IV infusion; half-life is 20 days; the fate of parent drug and metabolites is unknown	Asthenia, pain, nausea/vomiting, diarrhea, anorexia, stomatitis, dermatitis, hypertension, proteinuria; infusion-related reactions rare; hemoptysis, hemorrhage, delayed wound healing, GI perforations; increased risk of thromboembolic events can be severe or fatal	Metastatic colorectal cancer and NSCLC; renal cell carcinoma	5-15 mg/m²/day IV every 3 wk
Bexarotene (Targretin)	Synthetic retinoid, differentiating agent

Oncohema Key

Fastest Oncology & Hematology Insight Engine

Cancer Pharmacology

Cancer Pharmacology

Introduction

Fundamental Science

Principles of Cancer Drug Action

Combinations of Drugs

Molecular Imaging of Cancer Drug Action

Principles of Cancer Drug Delivery

Dosage Adjustment Based on Clearance

Drug-Drug Interactions

Drug-Drug Transporter Interactions

Interactions Via Self-Medication

Oral Cancer Drugs

Clinical Relevance and Applications

Alternate Routes of Cancer Drug Delivery

Regional Cancer Drug Delivery

Generics Versus Brand Name

Shortages of Cancer Drugs

Approved Indications and Off-Label Use of Drugs

New Indications and Repurposing (Repositioning)

Development and Discovery of Cancer Drugs

Clinical Phases of Drug Development

Cancer Pharmacology across the Drug Discovery/Development Process

What the Future Holds

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