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.
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
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
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.
- Junod SW. FDA and clinical drug trials: a short history. http://www. fda.gov/AboutFDA/WhatWeDo/History/Overviews/ucm304485.htm. Accessed March 26, 2014.
- Gruner C, transl. A Treatise on the Canon of Medicine of Avicenna. New York: AMS Press; 1973.
- Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995;122(6):456-461.
- US Food and Drug Administration. About FDA: FDA history – part II. The 1938 Food, Drug, and Cosmetic Act. http://www.fda.gov/ aboutFDA/WhatWeDo/History/origin/ucm054826.htm. Accessed April 8, 2014.
- Yoshioka A. Use of randomisation in the Medical Research Council’s clinical trial of streptomycin in pulmonary tuberculosis in the 1940s. BMJ. 1998;317(7167):1220-1223.
- Avorn J. Learning about the safety of drugs–a half-century of evolution. N Engl J Med. 2011;365(23):2151-2153.
- Kummar S, Rubinstein L, Kinders R, et al. Phase 0 clinical trials: conceptions and misconceptions. Cancer J. 2008;14(3):133-137.
- Gad SC. Clinical Trials Handbook. Hoboken, NJ: John Wiley & Sons; 2009.
- Rubinstein LV, Simon RM. Phase I Clinical Trial Design. Bethesda, MD: National Cancer Institute; 2003. http://linus.nci.nih.gov/techreport/phaseIctd.pdf. Accessed March 26, 2014.
- Eisenhauer EA. Phase I and II trials of novel anti-cancer agents: endpoints, efficacy and existentialism. The Michel Clavel Lecture, held at the 10th NCI-EORTC Conference on New Drugs in Cancer Therapy, Amsterdam, 16-19 June 1998. Ann Oncol. 1998;9(10):1047-1052.
- Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.
- Abadie R. The Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects. Durham, NC: Duke University Press; 2010.
- Collins JM, Zaharko DS, Dedrick RL, et al. Potential roles for preclinical pharmacology in phase I clinical trials. Cancer Treat Rep. 1986;70(1):73-80.
- Koyfman SA, Agrawal M, Garrett-Mayer E, et al. Risks and benefits associated with novel phase 1 oncology trial designs. Cancer. 2007;110(5): 1115-1124.
- Horstmann E, McCabe MS, Grochow L, et al. Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med. 2005;352(9): 895-904.
- Ivy SP, Siu LL, Garrett-Mayer E, Rubinstein L. Approaches to phase 1 clinical trial design focused on safety, efficiency, and selected patient populations: a report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee. Clin Cancer Res. 2010;16(6):1726-1736.
- 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.
- Arkenau HT, Olmos D, Ang JE, et al. 90-days mortality rate in patients treated within the context of a phase-I trial: how should we identify patients who should not go on trial? Eur J Cancer. 2008;44(11):1536-1540.
- Karavasilis V, Digue L, Arkenau T, et al. Identification of factors limiting patient recruitment into phase I trials: a study from the Royal Marsden Hospital. Eur J Cancer. 2008;44(7):978-982.
- Seidenfeld J, Horstmann E, Emanuel EJ, Grady C. Participants in phase 1 oncology research trials: are they vulnerable? Arch Intern Med. 2008;168(1):16-20.
- Bachelot T, Ray-Coquard I, Catimel G, et al. Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials. Ann Oncol. 2000;11(2):151-156.
- Arkenau HT, Olmos D, Ang JE, et al. Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience. Br J Cancer. 2008;98(6):1029-1033.
- Wheler J, Tsimberidou AM, Hong D, et al. Survival of 1,181 patients in a phase I clinic: the MD Anderson Clinical Center for targeted therapy experience. Clin Cancer Res. 2012;18(10):2922-2929.
- Wheler J, Tsimberidou AM, Hong D, et al. Survival of patients in a phase 1 clinic: the M. D. Anderson Cancer Center experience [published correction appears in Cancer. 2009;115(7):1588]. Cancer. 2009;115(5):1091-1099.
- Arkenau HT, Barriuso J, Olmos D, et al. Prospective validation of a prognostic score to improve patient selection for oncology phase I trials. J Clin Oncol. 2009;27(16):2692-2696.
- Italiano A, Massard C, Bahleda R, et al. Treatment outcome and survival in participants of phase I oncology trials carried out from 2003 to 2006 at Institut Gustave Roussy. Ann Oncol. 2008;19(4):787-792.
- Smith TL LJ, Kantarjian HM, Legha SS, et al. Design and results of phase I cancer clinical trials: three-year experience at M.D. Anderson Cancer Center. J Clin Oncol. 1996;14(1):287-295.
- Garrido-Laguna I, Janku F, Falchook GS, et al. Patients with advanced head and neck cancers have similar progression-free survival on phase I trials and their last Food and Drug Administration-approved treatment. Clin Cancer Res. 2010;16(15):4031-4037.
- Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408-1417.
- Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691- 1703.
- Roberts TG Jr, Goulart BH, Squitieri L, et al. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA. 2004;292(17):2130-2140.
- Verheggen FW, Nieman FH, Reerink E, et al. Patient satisfaction with clinical trial participation. Int J Qual Health Care. 1998;10(4):319-330.
- Zaric B, Perin B, Ilic A, et al. Clinical trials in advanced stage lung cancer: a survey of patients’ opinion about their treatment. Multidiscip Respir Med. 2011;6(1):20-27.
- Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783-1796.
- Prasad V, Mailankody S. The accelerated approval of oncologic drugs: lessons from ponatinib. JAMA. 2014;311(4):353-354.
- Djulbegovic B, Hozo I, Ioannidis JP. Improving the drug development process: more not less randomized trials. JAMA. 2014;311(4):355-356.
Source: Cancer Control