In the era of molecular-targeted therapy,
`
`“effective” dose is sometimes measured
`
`through the inhibition of the intended
`
`target, which can prove to be problematic.
`
`Copper Iris_0328. Photograph courtesy of Henry Domke, MD.
`www.henrydomke.com
`
`Risks and Benefits of Phase 1 Clinical Trial Participation
`Amit Mahipal, MD, and Danny Nguyen, MD
`
`Background: The results from phase 1 clinical trials can allow new treatments to progress further in drug
`development or halt that process altogether. At the forefront of phase 1 clinical trials is the safety of every patient
`participant, which is particularly true when testing new oncologic treatments in which patients may risk
`potentially toxic treatments in the hope of slowing the progression of or even curing their disease.
`Methods: We explore the benefits and risks that patients experience when participating in phase 1 clinical trials.
`Results: Rules and regulations have been put into place to protect the safety and interests of patients while
`undergoing clinical trials. Selecting patients with cancer who will survive long enough to accrue data for these
`trials continues to be challenging. New prognostic models have been validated to help health care profession-
`als select those patients who will likely benefit from participation in phase 1 trials. There also are long-lasting
`positive and negative impacts on those patients who choose to participate in phase 1 clinical trials.
`Conclusions: Modern phase 1 clinical trials represent a therapeutic option for many patients who progress
`through frontline therapy for their malignancies. Recent phase 1 clinical trials testing targeted therapies have
`increased responses in many diseases in which other lines of therapy have failed. Patients still face many risks
`and benefits while enrolled in a phase 1 trial, but the likelihood of treatment response in the era of rational,
`targeted therapy is increased when compared with the era of cytotoxic therapy.
`
`Introduction
`Results from clinical trials help to answer questions
`and provide guidance for practicing health care pro-
`fessionals. The regimented clinical trial design was not
`standardized until the twentieth century1; however,
`physicians have been employing concepts of modern
`clinical trials for centuries. An ancient medical text,
`
`From the Clinical Research Unit at the H. Lee Moffitt Cancer Center
`& Research Institute, Tampa, Florida.
`Submitted February 12, 2014; accepted March 6, 2014.
`Address correspondence to Amit Mahipal, MD, Clinical Research
`Unit, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa,
`FL 33647. E-mail: Amit.Mahipal@Moffitt.org
`No significant relationship exists between the authors and the com-
`panies/organizations whose products or services may be referenced
`in this article.
`
`The Canon of Medicine, established guidelines for the
`proper conduct of medical experimentation.2 In this
`text, the principles for testing the efficacy of a new
`medication were laid out, including that the drug must
`be free from any extraneous accidental quality and
`that the experimentation must be performed with the
`human body.2 The essence of these guidelines became
`the scientific method for testing of medications, and,
`for the most part, the medical field regulated itself
`when it came to new medications, elixirs, “cure-alls,”
`panaceas, and the like.
`The turning point in medication development that
`resulted in the rigorous, regimented development of
`clinical trials in the United States occurred in 1937
`when pharmaceutical manufacturer S.E. Massengill
`Company (Bristol, Tennessee) released the first elixir
`
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`formulation of sulfanilamide, an antibiotic that, at the
`time, had been shown to have activity against strep-
`tococcal throat infections.3 The elixir was available
`to consumers without undergoing animal or human
`testing of any kind prior to its release. However, the
`antibiotic was suspended in diethylene glycol, also
`known colloquially as antifreeze. The product was so
`extensively disseminated into US stores that the US
`Food and Drug Administration (FDA) and S.E. Mas-
`sengill could not fully recall the product, which had
`caused the deaths of at least 100 people.1 Even then,
`the FDA was empowered to recall the drug only be-
`cause the label was misleading (ie, it was labeled as
`an “elixir” and, therefore, had to contain alcohol, but
`this “elixir” did not have any). Due in part to this se-
`ries of deaths, the FDA was granted new powers in
`1938 under the Federal Food, Drug, and Cosmetic Act,
`which required drug sponsors to submit safety data
`to the FDA for it to evaluate prior to marketing of the
`drug, thus planting the seed for the modern clinical
`trial structure4; this was later modernized by Hill in
`1948.1 Hill, who was a British statistician, performed
`one of the first randomized controlled studies that
`showed that streptomycin could cure tuberculosis.5
`However, in 1962, thalidomide, a drug popular
`as a hypnotic in Europe and suspected to cause birth
`defects, was supplied to US physicians who subse-
`quently gave the drug to expectant mothers as a rem-
`edy for morning sickness.6 This act resulted in nearly
`a dozen infants being born with birth defects, far less
`than the approximately 10,000 infants worldwide born
`with thalidomide-related defects. The smaller impact
`of thalidomide in the United States was due in part
`to the efforts of the FDA, which denied the thalido-
`mide application on grounds that more evidence of
`
`safety was required.1 The amendments in 1962 that
`followed on the heels of the thalidomide incident
`further strengthened the control of the FDA over new
`investigational drugs, thus requiring pharmaceutical
`companies to demonstrate that their investigational
`drug could be safely given to patients in the preclini-
`cal setting, thereby setting the stage for the formation
`of phase 1 clinical trials (Table 1).1,7
`
`Purpose of Phase 1 Trials
`Historically, the focus of phase 1 clinical trials has
`been to demonstrate that a new drug can be safely
`given to humans at the maximum tolerated dose
`(MTD),8 which is associated with dose-limiting tox-
`icities (DLTs). The MTD, which could be a therapeutic
`dose or the maximum dose that can safely be admin-
`istered, is then carried on to further phases of clinical
`trials. In the era of targeted agents, the biologically
`effective dose is now frequently used rather than the
`MTD. Because the primary purpose is not efficacy,
`maintaining patient population homogeneity and ob-
`taining measurable tumor response is not required;
`however, many investigators include these factors
`in their protocols.9 Understanding the emphasis on
`safety in phase 1 studies requires an understanding of
`the history of drug development in the United States
`and why the FDA is concerned with establishing safety
`followed by efficacy.
`The field of oncology has matured during the
`last 20 years due in part to the understanding of the
`various molecular pathways involved in tumorigen-
`esis. Because of the advent of molecularly targeted
`therapies due to this evolution, the standard dosing
`regimen, which consists of “cycles” of chemotherapy
`at the MTD, may need to be reconsidered.10 In fact, se-
`
`Phase
`
`Preclinical
`
`0
`
`1
`
`2
`
`3
`
`4
`
`Table 1. — Phases of Clinical Trials
`
`Primary Goal
`
`Primary Researcher
`
`Subject Type
`
`Comment
`
`Nonhuman efficacy
`Toxicity
`PK
`
`PhD, MD, PharmD,
`or any researcher
`
`Cell lines (animal)
`
`Determining PK and PD
`
`Clinical researcher
`
`Human
`
`Focuses on determining oral bioavailability
`and half-life
`Often combined with phase 1
`
`Clinical researcher
`
`Human
`
`May be expanded or combined with phase 2
`
`Evaluation of safety and adverse
`events
`
`Examine efficacy and
`dose range
`
`Expanded study to substantiate
`efficacy and safety
`
`Clinical researcher
`
`Human
`
`Clinical researcher
`
`Human (N = large range)
`
`May help in optimizing dose, schedule,
`and select disease types
`
`Generally includes multiple sites
`and investigators
`
`Determines long-term effects
`
`Postmarketing
`surveillance
`
`Primary physician
`
`Human (N = all patients
`taking the drug)
`
`PD = pharmacodynamic, PK = pharmacokinetic.
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`lected molecularly targeted therapies such as tyrosine
`kinase inhibitors (eg, imatinib, ibrutinib, sorafenib)
`are not given in cycles but instead are given orally
`every day.10 The goal in such cases may not be tumor
`regression but rather tumor control. As such, dosing
`at the MTD may not be the dose associated with
`the most effectiveness. As in the case of ibrutinib,
`the MTD was never reached because the drug was
`well-tolerated and the dose selected for further clini-
`cal trials was based on the dose that caused near
`complete occupation of all Bruton tyrosine kinase
`receptors.11 This calls into question whether toxicity
`can continue to be the primary goal for phase 1 trial
`design.10 For a particular agent, its effects on its pur-
`ported molecular target may serve as another marker
`for efficacy. Logistically, this may become a compli-
`cated matter, such as repeatedly obtaining tissue or
`routine blood work. For the patient, this may result
`in more invasive procedures, which carry their own
`inherent risks, or more frequent blood work, which
`
`one may expect to negatively impact patient enroll-
`ment. However, study results indicate that patients
`are willing to undergo multiple biopsies if needed.12
`
`Study Design
`The difficulty in designing a phase 1 clinical trial is
`the decision of whether to escalate the dose of the
`study drug quickly (such that patients develop toxici-
`ties sooner) or whether to escalate the dose slowly
`(such that patients are treated at subtherapeutic doses
`for longer).13 However, study design protocols that at-
`tempt to answer this question are out of the scope of
`this review article, but they may be of interest because
`investigators must consider the impact of the study
`design on patient safety. For instance, one study exam-
`ining phase 1 patients enrolled between 2002 and 2004
`demonstrated that aggressive dose-escalation schemes
`did not have a response advantage for cytotoxic agents
`but were associated with more toxicity when com-
`pared with conservative dose-escalation schemas.14 In
`
`Dose-Escalation Method
`
`Description
`
`Advantages
`
`Disadvantages
`
`Table 2. — Selected Dose Escalation Designs
`
`Rule-Based Designs
`
`3 + 3 (including 2 + 4,
`3 + 3 + 3, and 3 + 1 + 1)
`
`Accelerated titration
`
`Pharmacologic-guided
`dose escalation
`
`Model-Based Designs
`
`Continual reassessment
`
`Dose escalation follows a modified
`Fibonacci sequence (dose escalation
`sequence 100%  67%  50% 
`40%, and so on)
`If 1 patient has a DLT, 3 more patients
`are added (+ 3)
`Escalation continues until 2 patients
`among the same cohort experience
`a DLT
`
`Simple
`Safe
`Adding 3 more patients per
`dose level supplies more
`PK data
`
`Excessive number of escalation
`steps means more patients
`potentially treated at
`subtherapeutic doses
`
`Assignment of patients to dose levels
`follows specific rules according to
`observed toxicities at each dose level
`Allows intrapatient dose escalation
`
`Reduces the amount of patients
`treated at subtherapeutic doses
`Eventual phase 2 dose can be inter-
`preted from data from all patients
`
`May mask cumulative toxic
`effects of treatment if model
`does not fit data
`
`Assumes that DLT is predicted by
`plasma drug concentrations and an
`animal model
`Area under the curve predicted from
`preclinical data
`
`Reduces the amount of patients
`treated at subtherapeutic doses
`(100% dose increment escalation)
`Provides PK data
`
`Logistics behind obtaining
`real-time PK data
`Interpatient variability in drug
`metabolism may affect results
`
`Based on the Bayesian model
`Initial dose based on preclinical data
`All patients treated at predicted
`maximum tolerated dose
`Probability of reaching DLT updated
`for every patient who enters the study
`at every dose level
`Stopping rules vary (eg, when
`6 patients are assigned to the
`same dose level)
`
`Reduces amount of patients treated
`at subtherapeutic doses
`Uses all data gathered from all
`patients
`Phase 2 dose estimated with a
`confidence interval
`Late toxicities are accounted for
`
`Logistics and manpower behind
`calculations for every patient for
`every cohort
`Requires strong support from
`a statistician for dose escalation
`
`DLT = dose-limiting toxicity, PK = pharmacokinetic.
`Adapted from Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101(10):708-720.
`Published in its adapted form by permission of Oxford University Press.
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`trial.18 Because of this, modern phase 1 studies use
`arguably biased stringent inclusion criteria, which
`exclude approximately 33% of participants screened
`for entry.19 Moreover, criteria are so stringent that a
`study published by Seidenfeld et al20 concluded that
`93% of participants of phase 1 trials nearly matched
`the performance status (PS) of the general population.
`Other inclusion criteria, along with Eastern Coopera-
`tive Oncology Group (ECOG) PS, Karnofsky PS, or
`both, generally look at organ function (eg, creatinine,
`liver enzymes), age, lactate dehydrogenase (LDH),
`and other comorbidities.21 In an effort to select which
`patients might reasonably survive long enough to
`accrue safety data for phase 1 studies, many scoring
`systems have been formulated to help select patients
`with the lowest risk of mortality.22,23
`For instance, Wheler et al24 retrospectively deter-
`mined that a history of thromboembolism, the pres-
`ence of liver metastasis, and thrombocytosis predicted
`a shorter survival rate in patients enrolled in phase
`1 clinical trials, with each parameter bearing compa-
`rable risk of death and weighed equally. From these
`data, they developed a risk score with correspond-
`ing risk groups and 6- and 12-month survival rates
`(low risk = 73%, 51%; intermediate risk = 65%, 34%;
`high risk = 35%, 6%, respectively).24 This study was
`the first to report the survival rate of phase 1 par-
`ticipants in the era of biologically and molecularly
`targeted therapy. A median overall survival (OS) rate
`of 9 months was reported in this study,24 which is in
`contrast to the median OS rate of 5 months in the era
`of cytotoxic therapy and ECOG PS and LDH levels.21
`Arkenau et al22 from the Royal Marsden Hospital
`(RMH) developed a prognostic score using retrospec-
`tive data of 212 patients enrolled in their phase 1
`program (Table 3). In this study, 3 variables associ-
`ated with poor outcomes were isolated, including an
`elevated level of LDH (> upper limit of normal), low
`
`Table 3. — Royal Marsden Hospital Prognostic Score
`
`Variable
`
`Score
`
`Hazard Ratio
`
`1.85
`
`1.83
`
`1.54
`
`0 1
`
`0 1
`
`0 1
`
`Lactate Dehydrogenase
`< ULN
`> ULN
`
`Albumin (g/dL)
`> 3.5
`< 3.5
`
`Sites of Metastases
`0–2
`> 2
`
`Scores 0–1 = good prognosis, 2–3 = poor prognosis.
`ULN = upper limit of normal.
`Data from reference 22.
`
`this study, investigators reported a death rate of 1.1%,14
`which, in general, is more than double the typically
`accepted risk of death for phase 1 studies.15
`Innovative, more efficient, and safer designs are
`being developed compared with the traditional 3 +
`3 dose-escalation design,16 which was designed in
`the era of cytotoxic therapy. During this time, higher
`doses were assumed to result in higher efficacy rates,
`but these doses also resulted in higher toxicity rates.
`Another main drawback of the traditional 3 + 3 design
`is that each escalation step may represent a group of
`patients treated with subtherapeutic levels of a par-
`ticular medication. An analysis of 21 trials of cancer
`therapies using the 3 + 3 design between 1992 and
`2008 (therapies eventually approved by the FDA) re-
`vealed that more than one-half of these designs had
`at least 6 dose-escalation levels.17
`Many different dose-escalation schemes exist, al-
`though the predominant scheme used is the 3 + 3
`design. Table 2 lists the advantages and disadvantages
`of selected dose-escalation designs.17 Ultimately, the
`primary goal of newer dose-escalation schemes is to
`maximize the number of patients receiving the most
`efficacious dose.
`In the era of molecular-targeted therapies, new
`questions arise as to what constitutes an “effective”
`dose. Oftentimes, this concept is measured through the
`inhibition of the intended target, which can pose sev-
`eral obstacles, such as access and assessment of tissue
`(eg, tumor, peripheral blood) and the determination
`of the level of inhibition required to obtain a clinical
`response.17 In these situations, dose-escalation designs
`may not be as relevant as during the era of cytotoxic
`therapy. However, generally speaking, toxicity is still
`used as an end point for molecular-targeted thera-
`pies. In addition, emphasis is placed on the preclinical
`setting and the so-called phase 0 trial in which the
`demonstration of a targeted effect is the primary goal.
`Pharmacokinetic and pharmacodynamic data are also
`obtained during phase 0 trials. The advantage of phase
`0 trials is that having data upfront helps expedite new
`drugs through other phases of clinical testing.7
`
`Patient Selection
`From our experience, the largest risk to patients who
`participate in phase 1 trials is death; secondary risks
`include adverse events associated with the study
`drug that may or may not be reversible. Our experi-
`ence also suggests that oncologists generally offer
`patients with progressive, refractory malignancies the
`opportunity to participate in phase 1 studies as a “last
`ditch effort.” Consequently, many patients may be
`frail and will have experienced end-organ dysfunc-
`tion and have short life expectancies. Early reports
`suggested that approximately 20% of patients passed
`away during the first 90 days of entry into a phase 1
`
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`further demonstrate the increased clinical benefit of
`phase 1 clinical trials in the era of targeted therapies.
`
`Phase 1 Trial Participation as a
`Therapeutic Option
`Although the goal of phase 1 studies has primarily
`focused on safety profiles, most patients with can-
`cer participate in these trials with the hope of de-
`riving clinical benefit, and health care professionals
`are beginning to integrate participation in a phase 1
`study as part of a patient’s plan of care.26 Historically,
`health care professionals expected that phase 1 studies
`would yield a response rate of approximately 6% and
`a death rate due to the study drug of approximately
`0.5%.27 With the advent of molecular targets and im-
`munotherapy, this expectation of efficacy has changed.
`Horstmann et al15 updated these findings using data
`from the Cancer Therapy Evaluation Program, which
`consisted of data from 10,402 participants of phase
`1 trials that took place between 1991 and 2002. They
`found an overall response rate of 10.6% and partial
`response and complete response rates of 7.5% and
`3.1%, respectively. They reported that 0.49% of patients
`died while participating in a trial (0.21% of patient
`deaths were attributed to the study drug).
`Italiano et al26 reviewed the efficacy of phase 1
`trials from their own institution between the years
`2003 and 2006. The researchers found an objective
`response rate of 7.2%, a rate of stable disease of 41%,
`a progression-free survival rate of 2.3 months, and a
`median OS rate of 8.7 months.26 In addition, 56.6%
`of participants went on to pursue different treatment
`options after exiting the phase 1 study, demonstrating
`that clinicians at that institution were incorporating
`participation in a phase 1 study as part of treatment
`pathways, particularly for malignancies without a clear,
`preferred treatment option with good effectiveness.26
`Moreover, in some malignancies (eg, progressive head
`and neck cancers), participating in a phase 1 clinical
`trial could potentially mean that patients would have
`progression-free survival rates similar to those seen
`in third-line therapies already approved by the FDA.28
`Considering the evidence of efficacy behind se-
`lected approvals by the FDA,29,30 these results are
`significant. For instance, the addition of cetuximab
`to leucovorin/fluorouracil/irinotecan compared with
`leucovorin/fluorouracil/irinotecan alone in KRAS
`wild-type patients increased the progression-free sur-
`vival rate from 8.7 months to 9.9 months29 and the
`addition of nab-paclitaxel to gemcitabine increased
`the progression-free survival rate from 3.7 months
`to 5.5 months.30
`Further expanding on the benefit of targeted
`therapy, one study found that the risk of death dur-
`ing a phase 1 trial testing a cytotoxic agent was nearly
`quadruple that of a trial testing a targeted agent.31
`
`Cancer Control 197
`
`level of albumin (< 3.5 g/dL), and more than 2 sites
`of metastasis. Patients with a score of 0 to 1 had a
`median OS rate of 74.1 weeks, whereas patients with
`a score of 2 to 3 had a median OS rate of 24.9 weeks
`across all tumor types.22 These data were prospec-
`tively studied at the same institution and validated in
`a follow-up study.25 Using the RMH score, Arkenau et
`al25 demonstrated that nearly 90% of patients who died
`within the first 90 days of entry into a phase 1 trial
`had a prognostic score of 2 to 3. At the time of the
`study, those with a score of 0, 1, 2, or 3 had a median
`OS rate that was not reached: 25.7 weeks, 15.7 weeks,
`and 14.1 weeks, respectively. This scoring system was
`further modified and validated at the phase 1 clinic at
`the University of Texas MD Anderson Cancer Center in
`Houston.23 Wheler et al23 added gastrointestinal tumor
`type and ECOG PS (≥ 1) to the RMH score as factors
`associated with a poor prognosis (Table 4). Using their
`prognostic score, they found that median survival rates
`for the low-risk (0), low-intermediate (1), intermediate-
`risk (2), high-intermediate risk (3), and high-risk (4–5)
`groups were 24.0 months, 15.2 months, 8.4 months,
`6.2 months, and 4.1 months, respectively.23 The rela-
`tive risk of having more than 2 sites of metastasis
`and ECOG PS of at least 1 was lower than the other
`variables, a finding likely due to stringent inclusion
`criteria and clinical judgment. Also of note is the me-
`dian survival rate of 10 months, with 86% patients hav-
`ing received a targeted therapy/biological agent and
`32% having received a cytotoxic agent. These results
`
`Table 4. — MD Anderson Clinical Center Prognostic Score
`
`Variable
`
`Score
`
`Relative Risk for Death
`
`1.74
`
`1.58
`
`1.26
`
`1.32
`
`1.42
`
`0 1
`
`0 1
`
`0 1
`
`0 1
`
`0 1
`
`Lactate Dehydrogenase
`< ULN
`> ULN
`
`Albumin (g/dL)
`> 3.5
`< 3.5
`
`Sites of Metastases
`0–2
`> 2
`
`ECOG PS
`
`0 ≥
`
` 1
`
`Tumor Type
`Non-GI
`GI
`
`Scores: 0 = low risk, 1 = low-intermediate risk, 2 = intermediate risk,
`3 = high-intermediate risk, 4–5 = high risk.
`ECOG PS = Eastern Cooperative Oncology Group performance status,
`GI = gastrointestinal, ULN = upper limit of normal.
`Data from reference 23.
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`Phase 1 studies that include cytotoxic agents that
`have received approval from the FDA also tend to
`have lower risks of death and toxicity than novel
`cytotoxic agents.14
`
`Patient Benefits
`In addition to the possibility of controlling or reduc-
`ing disease burden when other lines of therapy have
`failed, patients derive other benefits from participating
`in phase 1 trials. Per our experience, some research-
`ers view early access to a potentially helpful drug as a
`benefit; however, by the very nature of phase 1 clini-
`cal trials, this early access may also prove to be a risk.
`Dealing with a refractory, recurrent, nonoperable, and/
`or metastatic malignancy can be taxing on patients and
`family members. Most patients are overall satisfied with
`their experiences in phase 1 trials.32,33 The regimented
`routine that patients undergo as part of a phase 1
`trial, which may include routine physical examinations,
`laboratory draws, biopsies, and radiological examina-
`tions, help alleviate some fear about the gravity of
`their disease, and patients were generally satisfied to
`receive more information about their disease as well
`as to supply information themselves.33 Given the very
`nature of toxicity reporting in a phase 1 trial — with
`every symptom scrutinized — patients unexpectedly
`viewed this as being positive. Many of these patients
`developed trust in the trial physician and were content
`knowing that their participation might contribute to
`future patients’ health.11,32 Many also felt empowered
`by attempting to control their disease.13
`
`Patient Risks
`Participation in a phase 1 clinical trial has known
`and unknown risks. The primary risk is death from
`the investigational agent or death from malignancy
`progression or malignancy-related complications. In
`addition to this risk of death, other risks that patients
`may experience include acute toxicities (eg, nausea,
`fatigue, diarrhea) or delayed toxicities, which may not
`be detected until the completion of the phase 1 trial
`and further studies progress. For instance, ponatinib
`was approved by the FDA after study results indicated
`great response rates.34 However, the correlation be-
`tween the risk of thrombotic events was made only
`after ponatinib had been approved by the FDA for
`the treatment of chronic myelogenous leukemia blast
`crisis or those with a T315I mutation.35
`With regard to patient satisfaction, many patients
`do not feel better about their disease once their trial
`participation is completed.32 With the advent of bio-
`marker-driven trials that require the testing of tumor
`tissue, the unavailability of tissue for future trials can
`become an issue. Moreover, many early-phase trials
`require fresh biopsies that subject individual patients
`to risks without any direct benefit to them.
`
`198 Cancer Control
`
`Conclusions
`Study design was originally focused on dosing and
`safety; however, the design of trials is becoming in-
`creasingly sophisticated and includes ways in which
`to maximize clinical benefit through dosing schemes,
`incorporate randomized trial designs36 (including ele-
`ments of phase 2 trial designs), and to use more target-
`ed and biological therapies. During the last 20 years,
`the advent of targeted therapies in phase 1 trials has
`improved clinical benefit in terms of overall survival
`rates and toxicity profiles when compared with the era
`of cytotoxic agents. It is because of the progression
`and refinement of our knowledge of cancer that such
`therapies are available for testing, and it is because of
`better therapeutic targets for drugs that clinical trials
`can often be considered treatment options for patients
`with recurring, relapsed, or refractory malignancies.
`Phase 1 clinical trials should not be viewed as a last
`resort for patients who have failed current therapy.
`Rather, enrollment in clinical trials should be viewed
`as another therapeutic option. The field of oncology
`will continue to accumulate more knowledge and be
`able to rationally target molecular pathways as they
`become elucidated. Indeed, it is an exciting time to
`be in the field of oncology, and phase 1 clinical trials
`are one of the ways that both physicians and patients
`can help reinforce its foundation.
`
`References
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