Palmieri, FM

Abstract Abstract #6149 Background: Internal Review Boards and Data and Safety Monitoring Boards often require protocol-specified adverse event (AE) stopping rules for safety monitoring. However, availability of safety data for investigational agent(s) may be limited at the time of protocol development in the phase II setting. This meta-analysis was undertaken to quantify the variability of AE rates in North Central Cancer Treatment Group (NCCTG) phase II metastatic breast cancer (MBC) clinical trials and to investigate whether study factors are associated with AE rates for the development of AE stopping rules in future phase II clinical trials.
 Methods: All closed NCCTG phase II MBC clinical trials using CTC v2.0 or CTCAE v3.0 for AE monitoring were selected. Rates of G3/4 AEs (overall, hematologic [H], and non-hematologic [NH]) and of study discontinuation [SD] due to AEs were calculated for each trial. Associations between study factors [number of agents (single vs combination); line of therapy (first-line only vs other); and type of therapy (chemotherapy vs other)] and AE rates were assessed via Wilcoxon rank sum tests.
 Results: 15 trials met inclusion criteria. 7 used CTCAE v3.0; 6 investigated single agents; 5 investigated first-line therapy; and 11 investigated chemotherapy regimens. 694 pts were evaluable for AE analysis. The G3/4 AE rate across trials was 68% (16-98%) overall, 45% (0-96%) H, and 51% (16-78%) NH. The overall rate of SD due to AEs was 13% (0-40%). The overall rate of G3/4 AEs was significantly lower in single agents vs combination regimens (30% vs 86%, p=0.004). This association held for H (2% vs 66%, p<0.0001) and NH (27% vs 57%, p=0.03) Aes. The rate of SD due to AEs was also significantly lower in single agents vs combination regimens (0.5% vs 15%, p=0.04). The rate of G3/4 AEs was significantly higher in first-line only trials vs other trials (overall: 90% vs 47%, p=0.04; H: 73% vs 5%, p=0.02; NH: 66% vs 41%, p=0.08). The rate of SD due to AEs was also significantly higher in first-line only trials (18% vs 4%, p=0.008). The only significant association with chemotherapy vs other therapy was G3/4 H AE rates (51% vs 2%, p=0.02).
 Discussion: High variability in G3/4 AE rates overall and in H and NH AEs was noted in these 15 trials. There is also high variability in the rates of SD due to AEs. The data suggest that clinical trials with single agent regimens have lower AE rates than combination regimens and, surprisingly, trials of first-line therapy only have higher AE rates than other trials. This may be due to more aggressive therapy being tested in the first-line setting. Although data from previous trials with the investigational agent(s) should be used for developing AE stopping rules when available, this study suggests that study factors such as number of agents and line of therapy can be useful when previous data are limited. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6149.

Abstract Abstract #6147 Background: Phase II metastatic breast cancer (MBC) clinical trials evaluating efficacy of cancer treatments are often designed using a binary primary endpoint (i.e., each evaluable patient [pt] is classified as a “success” or “failure”). In the era of novel agents in cancer research, endpoints such as 6-month progression-free survival [PFS6] for measuring efficacy of cytostatic agents are more commonly being used. This meta-analysis was undertaken to compare two binary classifications of PFS6 and to compare these binary endpoints with other efficacy endpoints in the phase II setting.
 Material and Methods: All closed North Central Cancer Treatment Group (NCCTG) phase II MBC clinical trials using Response Evaluation Criteria in Solid Tumors (RECIST) with at least 1 year of follow-up since last pt accrued were selected. All eligible pts initiating treatment were included. Two binary classifications of PFS6 were computed for each trial. Success for PFS6-1 is defined as on study treatment 6 months from registration without documentation of disease progression. Success for PFS6-2 does not require a pt to be on study treatment at 6 months. Also computed for each trial are Kaplan-Meier (KM) estimates of PFS6 (PFS6-KM) and 1-year overall survival (OS1-KM). Trial-level endpoints were summarized using descriptive statistics and compared using weighted (by trial sample sizes) Pearson correlations. Lastly, the concordance rate of PFS6-1 and PFS6-2 status with OS status at 1 year at the pt level was computed across all pts (pts censored for OS prior to one year were excluded [n=10]).
 Results: 11 trials met inclusion criteria. All trials required measurable disease and had a single arm. 485 evaluable pts were accrued (median 48 pts per trial [range 19-77]). Median PFS6-1 was 27% (range 10-44%) and median PFS6-2 was 34% (range 10-73%). The median trial-level difference between PFS6-1 and PFS6-2 was 5% (range 0-43%). The correlation between PFS6-1 and PFS6-2 was 0.81 (p<0.01). Among the endpoints, PFS6-2 and PFS6-KM had the highest correlation (>0.99, p<0.01) due to only 2 pts being censored for PFS prior to 6 months. Among the PFS endpoints, OS1-KM was most highly correlated with PFS6-1 (0.79, p<0.01) with the correlations with PFS6-2 and PFS6-KM not being statistically different from zero (both 0.59 with p>0.05). However, overall patient-level concordance between PFS6 status and OS status at 1 year was higher using PFS6-2 (68%) than PFS6-1 (59%).
 Discussion: Differences were observed between the two binary classifications of PFS6. PFS6 with (as compared to without) the requirement that a pt be on study treatment at 6 months appears to have higher correlation with OS at 1 year at the trial level but lower concordance with OS status at 1 year at the pt level. Selection of the historical control should take into consideration the definition of PFS6 being used. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6147.