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 experience 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 dysfunction 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 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 Cooperative 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 determined that a history of thromboembolism, the presence of liver metastasis, and thrombocytosis predicted a shorter survival rate in patients enrolled in phase 1 clinical trials, with each parameter bearing comparable risk of death and weighed equally. From these data, they developed a risk score with corresponding 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 participants 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 retrospective data of 212 patients enrolled in their phase 1 program (Table 3). In this study, 3 variables associated with poor outcomes were isolated, including an elevated level of LDH (> upper limit of normal), low 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 prospectively 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 relative 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 median survival rate of 10 months, with 86% patients having received a targeted therapy/biological agent and 32% having received a cytotoxic agent. These results further demonstrate the increased clinical benefit of phase 1 clinical trials in the era of targeted therapies.