Between February 2005 and July 2006, 67 patients gave informed consent and were screened for study entry. Three were ineligible based on laboratory measurements. Three discontinued therapy early due to toxicity. One patient discontinued therapy due to need for surgery. Therefore, 60 patients were assessable for response. Thirty-five patients had foregut primary, 16 had midgut primary, three had hindgut primary, one had renal primary, and five had unknown primary. Patient and tumor characteristics are included in .
Tumor and Biochemical Changes
Using intent-to-treat analysis method, overall response rate was 20%. In the per protocol population, we observed 13 confirmed partial responses (PRs; 22%), 42 patients with stable disease (SD; 70%), and five with progressive disease (PD; 8%). Among 30 carcinoid patients, there were five confirmed PRs (17%), 24 SDs (80%), and one PD (3%). Among 30 islet cell patients, there were eight PRs (27%), 18 SDs (60%), and four PDs (13%). Stratified by RAD001 dose, in the 5-mg cohort there were four PRs (13%), 22 SDs (73%), and four PDs (13%); in the 10-mg cohort, there were nine PRs (30%), 20 SDs (67%), and one PD (3%). There were proportionately more carcinoid patients treated at 5 mg and more islet cell patients treated at 10 mg.
Plots of serial tumor measurements over time and a waterfall plot of best response to better characterize antitumor activity show that the majority of patients had some degree of tumor reduction (). Further, response and maximal tumor shrinkage may take time to develop, with some patients experiencing continued tumor shrinkage more than 12 months after initiation of therapy.
Fig 1. Serial tumor measurements. Percentage change in the sum of target lesion diameters by course for (A) all patients and (C) for those in the 5-mg and (D) 10-mg cohorts. (B) The percentage change as the best response in each patient is shown as a waterfall (more ...)
Thirty-seven patients had elevated CGA at study entry. Thirteen were octreotide naïve, and 24 had received prior octreotide. Among these, 26 achieved a CGA response. The response rates among patients who either had prior octreotide or were octreotide-naïve were 67% and 77%, respectively (odds ratio, 1.7; 95% CI, 0.4 to 7.8).
PFS and OS
The overall median PFS of patients treated with octreotide LAR and RAD001 was 60 weeks (95% CI, 54 to 66 weeks; ). Stratified by tumor group (), median PFS of patients with carcinoid and islet cell tumors was 63 weeks (95% CI, 55 to 71 weeks) and 50 weeks (95% CI, 31 to 70 weeks), respectively (HR, 1.2; 95% CI, 0.7 to 2.2). By dose level (), median PFS of patients treated with 5 and 10 mg of RAD001 was 50 weeks (95% CI, 23 to 78 weeks) and 72 weeks (95% CI, 60 to 83 weeks) respectively, (HR, 1.5; 95% CI, 0.8 to 2.6). Prior octreotide therapy had no impact on median PFS (60 weeks in both groups). Disease status at time of study entry (by tumor measurements) did affect PFS (; HR, 2.9; 95% CI, 1.4 to 6.1); median PFS for patients with known SD at entry was 74 weeks (95% CI, 60 to 89 weeks), whereas median PFS for those in progression was 50 weeks (95% CI, 25 to 76 weeks). When tumor type, dose level, prior octreotide use, and disease status at time of study entry were analyzed in a Cox proportional hazard model, RAD001 dose of 10 mg was associated with superior PFS (HR, 0.5; 95% CI, 0.3 to 0.98), and progression at study entry was associated with shorter PFS (HR, 3.3; 95% CI, 1.5 to 7.2). However, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory.
Fig 2. Kaplan-Meier analysis of progression-free survival (PFS). (A) For all 60 patients, 6- and 12-month PFS rates were 80% and 59%. (B) PFS by disease subgroups. Six- and 12-month PFS rates were 86% and 69% for the carcinod (more ...)
Median OS for the study has not been reached. The 1-, 2-, and 3-year survival rates estimated by the Kaplan-Meier method were 83%, 81%, and 78%, respectively. Patients with known progression at entry had inferior median survival (31 months) compared with those known to be stable (not reached; P = .02).
Safety was monitored by patient diary and laboratory measurements. Treatment with the combination of RAD001 at 5 or 10 mg per day and octreotide LAR 30 mg every 4 weeks was feasible and generally well tolerated. Common hematologic adverse events attributed to RAD001 included mild grade 1/2 thrombocytopenia (30%) and leukopenia (48%). Grade 3 thrombocytopenia occurred in 3% in the 5-mg cohort and 6% in the 10-mg cohort. Grade 3/4 leukopenia occurred in 3% treated in the 5-mg cohort and in 6% in the 10-mg cohort. Hematologic toxicities were more likely to occur among patients with pre-existing cytopenia at time of study entry. Other common laboratory abnormalities included grade 1/2 hyperglycemia (61%), hypertriglyceridemia (44%), and hypophosphatemia (21%). Grade 3/4 hyperglycemia (9%), hypertriglyceridemia (3%), and hypophosphatemia (11%) were less common.
The most common nonhematologic adverse event was aphthous ulceration, which is graded under CTCAE as stomatitis. These grade 1/2 events generally appearing as one to two foci of oral ulceration that often resolved without intervention, occurred in 61% of treated patients. Grade 1/2 rash was also common and occurred in 59% of the patients. Grade 3 aphthous ulcerations occurred in 8% of patients, and grade 3 rash occurred in 5% of the patients.
A less common but potentially more serious adverse event associated with mTOR inhibitors is pneumonitis. We did not observe any pneumonitis at the 5-mg dose level. However, at the 10-mg dose level, three patients (9%) experienced grade 2 pneumonitis and one patient experienced grade 3 pneumonitis. A variety of supportive measures were used, including a brief treatment break and steroids. Treatment for the single patient with grade 3 pneumonitis included a treatment break followed by a dose reduction to 5 mg per day.
Grade 3/4 adverse events by dose level are summarized in . In all, eight patients (one from the 5-mg cohort and seven from the 10-mg cohort) required a dose reduction for adverse events. Two each were for aphthous ulceration, leukopenia, and hypophosphatemia, and one each was for thrombocytopenia and pneumonitis. Final doses tolerated were 5 mg per day in five patients and 5 mg every other day in three.
National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 Grade 3 and 4 Adverse Events
There was a consistent rise in plasma lactate dehydrogenase (LDH) after treatment with RAD001, although some of the increase was subtle, for example, rising from low normal to high normal. This was confirmed by paired comparison of serial LDH measurements. The mean pretreatment LDH was 510 U/L and rose to 680, 810, 785, and 738 U/L at weeks 2, 4, 8, and 12, respectively. Compared with baseline, these differences were statistically significant by paired sample t-test (P < .01 in all comparisons), as was the increase from week 2 to week 4 (P < .01); peak LDH increase occurred at week 4.
Comparison of serial LDH measurements by dosing cohort () showed no significant differences in baseline LDH (P = .47), but higher LDH values were observed in the 10-mg cohort at week 2 (P = .1), week 4 (P = .09), week 8 (P = .04), and week 12 (P = .02).
Fig 3. (A) Changes in mean (± standard deviation) plasma lactate dehydrogenase (LDH) levels during treatment for the 5-mg and 10-mg dose groups. (B) Kaplan-Meier analysis of progression-free survival (PFS) for patients in the lowest (< 109 U/L) (more ...)
Changes in LDH values did not correlate with RECIST response but did correlate with PFS. Analyses were performed by separating the patients into four quartiles ranking their absolute LDH changes at week 4. Median PFS by quartiles was 38, 69, 62, and 66 weeks. Those in the lowest quartile (LDH increase < 109 U/L), compared with those in the higher three quartiles as a group (≥ 109 U/L increase), had a significantly shorter PFS (P = .01). All LDH measurements were performed at M. D. Anderson Cancer Center (normal range, 313 to 618 U/L).
Tumor Ki-67 Proliferation
Some patients underwent image-guided core needle biopsy of metastatic tumor before treatment initiation and after 2 weeks of therapy. Sufficient tumor tissue was available in seven patients for Ki-67 analyses in a blinded manner (). Five of seven patients had a decrease in Ki-67 labeling. In two patients, Ki-67 labeling was unchanged. Mean tumor Ki-67 decreased from 6.7% (± 2.6) to 2.1% (± 0.5). The decrease was statistically significant (P = .04) by Wilcoxon signed rank test.
Fig 4. Changes in Ki-67 measurements. Patients consenting to optional biopsy had prospective sampling of metastases by image guided core needle biopsy at baseline and week 2. Mean tumor Ki-67 decreased from 6.7% (± 2.6) to 2.1% (± (more ...)