Phase 1 Trial Participation as a Therapeutic Option

Although the goal of phase 1 studies has primarily focused on safety profiles, most patients with can­cer participate in these trials with the hope of de­riving 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 im­munotherapy, 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.

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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 se­lected 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 sur­vival 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 dur­ing a phase 1 trial testing a cytotoxic agent was nearly quadruple that of a trial testing a targeted agent.31

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 reduc­ing disease burden when other lines of therapy have failed, patients derive other benefits from participating in phase 1 trials. Per our experience, some research­ers view early access to a potentially helpful drug as a benefit; however, by the very nature of phase 1 clini­cal 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 examina­tions, 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 be­tween 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 bio­marker-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.


Study design was originally focused on dosing and safety; however, the design of trials is becoming in­creasingly sophisticated and includes ways in which to maximize clinical benefit through dosing schemes, incorporate randomized trial designs36 (including ele­ments of phase 2 trial designs), and to use more target­ed 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.

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: [email protected]

No significant relationship exists between the authors and the com­panies/organizations whose products or services may be referenced in this article. 


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Source: Cancer Control