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The well-established standard approach to the development of systemic antineoplastic therapy begins with phase 1 trials, when new agents or novel combination drug strategies are initially introduced into the clinical setting.1

Although the primary purpose of phase 1 trials is the determination of safety, these early clinical investigative efforts are also associated with several important secondary endpoints that are essential to future drug development, including: 1) carefully defining the overall toxicity profile and exploring strategies to mitigate serious side effects, 2) establishing both the dose and schedule for subsequent studies, 3) understanding the agent's pharmacokinetic or pharmacodynamic profile, 4) gaining preliminary evidence of efficacy, and 5) learning of the possible relations between proposed biomarkers and response or toxicity. Depending on the specific circumstances, phase 1 trials will be followed by 1 or more phase 2 efficacy and/or phase 3 randomized comparative studies.

Unfortunately, this observer has noted a recent trend in which some oncology investigators have suggested bypassing formal phase 1 testing of presumably theoretically attractive new/novel antineoplastic drug combinations (cytotoxic and noncytotoxic), with the initial evaluation of the regimen being undertaken in the phase 2, or even phase 3, setting.2 This commentary was written to challenge the need for, and wisdom of, this approach and to highlight the potential danger to research subjects participating in later stage trials that are not supported by rigorous phase 1 data.

What follows are several possible justifications for considering early phase studies unnecessary before embarking on phase 2 to 3 efficacy trials, and a brief rebuttal to each suggested rationale for bypassing the conduct of well-designed and conducted phase 1 trials.

The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination

  1. Top of page
  2. The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination
  3. If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination
  4. The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified
  5. The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies
  6. There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies
  7. A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

It is not difficult to document the potential risk of the development of excessively serious side effects associated with new antineoplastic drug combinations or single agents that were not predicted based on pre-existing clinical data.2-, 10 Furthermore, even if the side effect profile was anticipated, it is a highly questionable assertion that a study whose primary focus is efficacy (phases 2 and 3 studies) will serve the equivalent role of defining an optimal dose, schedule, and drug modification strategy as a trial whose specific focus is safety (phase 1 study). This particular point should be noted by all members of Institutional Review Boards (IRBs) who are considering approval of a particular phase 2 or phase 3 trial in which 1 purpose of the study is to “collect the initial toxicity data for a regimen” in the current absence of such information. A specific issue will be the adequacy of the informed consent process and the appropriateness of the document patients/prospective research subjects are asked to read and sign that outlines the risks associated with participation in the “efficacy” trial. How clearly is the lack of information on the safety of the drug regimen explained?

If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination

  1. Top of page
  2. The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination
  3. If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination
  4. The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified
  5. The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies
  6. There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies
  7. A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Because the primary purpose of both phase 2 and phase 3 studies will be to determine efficacy, how will the results of such studies be interpreted if the dose/schedule of a particular experimental regimen is required to be substantially modified during the conduct of the trial because of documentation of excessive toxicity? Is the demonstrated efficacy because of the “higher,” more toxic dose/schedule, or will a similar outcome be observed with the “less” toxic strategy used at a later point in the conduct of the trial? Will the investigators of a study that mandated changes in the dose/schedule because of excessive toxicity simply guess at the answer to this question?

The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified

  1. Top of page
  2. The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination
  3. If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination
  4. The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified
  5. The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies
  6. There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies
  7. A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

In general, the conduct of phase 1 trials requires meticulous monitoring (blood work, patient visits) to ensure patient safety and to be certain that serious but initially more subtle side effects are not overlooked (eg, mild rash in Course 1, but severe rash in Course 2). In fact, most institutions involved in the conduct of phase 1 studies either perform such trials in special units or at least assign patients to be very carefully (and frequently) observed by highly experienced research nurses. In contrast, the conduct of later stage efficacy studies will generally require less frequent patient visits and the research teams may not be as knowledgeable of the requirements associated with detailed evaluations of toxicity, or be appropriately staffed to provide the monitoring or oversight essential to maximize current and future patient/research subject safety. Is this the optimal, or even an acceptable, approach to ensuring safety in the setting of an initial evaluation of a novel drug combination?

The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies

  1. Top of page
  2. The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination
  3. If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination
  4. The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified
  5. The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies
  6. There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies
  7. A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

There is simply no inherent reason 1 or several well-designed and well-conducted phase 1 trials should substantially delay the ultimate conduct of definitive phase 3 studies. In fact, a formal phase 1 trial can include as few as 4 to 6 patients safely treated at a specific dose and on a schedule planned to be used in a future efficacy study. It is only in the setting in which investigators prospectively plan to increase/modify the dose to explore additional regimens or in which unanticipated excessive toxicity is documented and alternative strategies must be examined that a genuine “delay” may be added to the process. However, in the first circumstance, the effort has been designed into the program (often to define the “maximally tolerable dose”) and in the second, the changes are simply essential to ensure patient safety.

There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies

  1. Top of page
  2. The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination
  3. If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination
  4. The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified
  5. The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies
  6. There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies
  7. A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Of course it is an accurate statement that there currently exist a remarkably expanding number of possible drug combinations using both standard cytotoxic agents and a large variety of “targeted therapies” recently introduced into the clinic. However, there is no requirement to test all such combinations in the phase 1 setting. It is appropriate for investigators to select particular combinations for examination in such studies based on either preclinical (eg, evidence of “synergy” observed in experimental model systems) or existing clinical data (eg, known biological activity of the drugs delivered as single agents). It is these specific combinations that are most relevant to examine in the phase 1 setting before embarking on efficacy trials.

A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)

  1. Top of page
  2. The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination
  3. If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination
  4. The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified
  5. The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies
  6. There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies
  7. A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The issue of the acceptability of existing phase 1 study data is most relevant in the case of malignancies in which it is realistically anticipated the patient population will likely receive substantially more cycles of systemic antineoplastic therapy than in other types of cancer that are routinely represented prominently in phase 1 trials (eg, ovarian cancer vs cancers of the lung or pancreas). This observation likely relates to both the inherent sensitivity of these specific diseases to several antineoplastic strategies and to the often relatively indolent (or “chronic”) natural history of the malignancy. The point to be made here is that a clinically relevant side effect may simply not be noted (or noted to be only a minor issue) after 1 or 2 delivered cycles of a particular anticancer agent, but with higher cumulative dosing (using the same dose and schedule), serious side effects may be observed (eg, platinum-associated and paclitaxel-associated peripheral neuropathy; pegylated liposomal doxorubicin-associated hand-foot syndrome).

For unquestionably valid reasons, phase 1 testing of antineoplastic agents and combinations was introduced decades ago into the standard drug development paradigm.1 In the absence of both clinically and ethically acceptable justifications to remove this critical and well-defined component designed to ensure the safety of research subjects, it is difficult to understand the reasons why this effective strategy should be bypassed.

Clearly stated, a desire to “speed up the process” is an inadequate justification for increasing the risk of serious research-related morbidity. It is perhaps time for scientific review committees, IRBs, and regulatory agencies to take a much closer look at proposed antineoplastic drug efficacy studies to be certain that their conduct is based on evidence of safety previously defined in appropriately designed, conducted, and reported phase 1 trials.

REFERENCES

  1. Top of page
  2. The Toxicity of the Individual Drugs is Well-Known and One Can “Anticipate” Their Toxicity When They Are Used in Combination
  3. If Excessive Toxicity is Noted in Phase 2 or Phase 3 Trials, the Study Can Simply Be Modified to Use a Lower Dose of 1 or All Agents in a Drug Combination
  4. The First Group of Patients Participating in a Phase 3 Trial Who Are Receiving the “Experimental” Regimen (the Dose, Schedule, and Toxicity Profile Not Previously Defined in a Phase 1 Trial) Can Be “Carefully Watched” and If Excessive Toxicity Is Observed, the Regimen Can Be Modified
  5. The Performance of Phase 1 Trials Adds Precious Time to Antineoplastic Drug Development and Will Delay the Initiation of Definitive Phase 3 Studies
  6. There Are Currently Too Many Possible Drug Combinations to Evaluate in the Phase 1 Setting. It Is Important to Simply Select a Dose and Schedule and Observe for Toxicity During the Conduct of the Phase 2 Efficacy or Phase 3 Randomized Studies
  7. A Phase 1 Study of a Particular Combination Regimen Has Already Been Completed in a “Typical” Phase 1 Population, With the Median Number of Cycles Delivered Per Patient Being 1 (Range, 1-2)
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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