21-Gene Recurrence Score for prognosis and prediction of taxane benefit after adjuvant chemotherapy plus endocrine therapy: results from NSABP B-28/NRG Oncology.

BACKGROUND: The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node-positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen. METHODS: The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years. RESULTS: In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72-1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69-1.47; p = 0.99), 0.84 (95% CI 0.62-1.14; p = 0.26), and 0.81 (95% CI 0.60-1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints. CONCLUSIONS: RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28).

Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: A multicenter trial.

OBJECTIVE: We hypothesized that the Oncotype Dx® 21-gene Recurrence Score (RS) could guide neoadjuvant systemic therapy (NST) to facilitate breast conserving surgery (BCS) for hormone receptor positive (HR+) breast cancers. METHODS: This study enrolled patients with HR+, HER2-negative, invasive breast cancers not suitable for BCS (size ≥ 2 cm). Core needle biopsy blocks were tested. For tumors with RS < 11, patients received hormonal therapy (NHT); patients with RS > 25 tumors received chemotherapy (NCT); patients with RS 11-25 were randomized to NHT or NCT. Primary endpoint was whether 1/3 or more of randomized patients refused assigned treatment. RESULTS: Sixty-four patients were enrolled. Of 33 patients with RS 11-25, 5 (15%) refused assignment to NCT. This was significantly lower than the 33% target (binomial test, P = 0.0292). Results for clinical outcomes (according to treatment received for 55 subjects) included successful BCS for 75% of tumors with RS < 11 receiving NHT, 72% for RS 11-25 receiving NHT, 64% for RS 11-25 receiving NCT, and 57% for RS > 25 receiving NCT. CONCLUSIONS: Using the RS to guide NST is feasible. These results suggest that for patients with RS < 25 NHT is a potentially effective strategy.

21-Gene Recurrence Score and Locoregional Recurrence in Node-Positive/ER-Positive Breast Cancer Treated With Chemo-Endocrine Therapy.

Background: The 21-gene recurrence score (RS) predicts risk of locoregional recurrence (LRR) in node-negative, estrogen receptor (ER)-positive breast cancer. We evaluated the association between RS and LRR in node-positive, ER-positive patients treated with adjuvant chemotherapy plus tamoxifen in National Surgical Adjuvant Breast and Bowel Project B-28. Methods: B-28 compared doxorubicin/cyclophosphamide (AC X 4) with AC X 4 followed by paclitaxel X 4. Tamoxifen was given to patients age 50 years or older and those younger than age 50 years with ER-positive and/or progesterone receptor-positive tumors. Lumpectomy patients received breast radiotherapy. Mastectomy patients received no radiotherapy. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Cumulative incidence functions and subdistribution hazard regression models were used for LRR to account for competing risks including distant recurrence, second primary cancers, and death from other causes. Median follow-up was 11.2 years. All statistical tests were one-sided. Results: There were 80 LRRs (7.5%) as first events (68% local/32% regional). RS was low: 36.2%; intermediate: 34.2%; and high: 29.6%. RS was a statistically significant predictor of LRR in univariate analyses (10-year cumulative incidence of LRR = 3.3%, 7.2%, and 12.2% for low, intermediate, and high RS, respectively, P < .001). In multivariable regression analysis, RS remained an independent predictor of LRR (hazard ratio [HR] = 2.59, 95% confidence interval [CI] = 1.28 to 5.26, for a 50-point difference, P = .008) along with pathologic nodal status (HR = 1.91, 95% CI = 1.20 to 3.03, for four or more vs one to three positive nodes, P = .006) and tumor size (HR = 1.28, 95% CI = 1.05 to 1.55, for a 1 cm difference, P = .02). Conclusions: RS statistically significantly predicts risk of LRR in node-positive, ER-positive breast cancer patients after adjuvant chemotherapy plus tamoxifen. These findings can help in the selection of appropriate candidates for comprehensive radiotherapy.

Clinical Utility of the 12-Gene DCIS Score Assay: Impact on Radiotherapy Recommendations for Patients with Ductal Carcinoma In Situ.

OBJECTIVE: The aim of this study was to determine the impact of the results of the 12-gene DCIS Score assay on (i) radiotherapy recommendations for patients with pure ductal carcinoma in situ (DCIS) following breast-conserving surgery (BCS), and (ii) patient decisional conflict and state anxiety. METHODS: Thirteen sites across the US enrolled patients (March 2014-August 2015) with pure DCIS undergoing BCS. Prospectively collected data included clinicopathologic factors, physician estimates of local recurrence risk, DCIS Score results, and pre-/post-assay radiotherapy recommendations for each patient made by a surgeon and a radiation oncologist. Patients completed pre-/post-assay decisional conflict scale and state-trait anxiety inventory instruments. RESULTS: The analysis cohort included 127 patients: median age 60 years, 80 % postmenopausal, median size 8 mm (39 % ≤5 mm), 70 % grade 1/2, 88 % estrogen receptor-positive, 75 % progesterone receptor-positive, 54 % with comedo necrosis, and 18 % multifocal. Sixty-six percent of patients had low DCIS Score results, 20 % had intermediate DCIS Score results, and 14 % had high DCIS Score results; the median result was 21 (range 0-84). Pre-assay, surgeons and radiation oncologists recommended radiotherapy for 70.9 and 72.4 % of patients, respectively. Post-assay, 26.4 % of overall recommendations changed, including 30.7 and 22.0 % of recommendations by surgeons and radiation oncologists, respectively. Among patients with confirmed completed questionnaires (n = 32), decision conflict (p = 0.004) and state anxiety (p = 0.042) decreased significantly from pre- to post-assay. CONCLUSIONS: Individualized risk estimates from the DCIS Score assay provide valuable information to physicians and patients. Post-assay, in response to DCIS Score results, surgeons changed treatment recommendations more often than radiation oncologists. Further investigation is needed to better understand how such treatment changes may affect clinical outcomes.

Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor-Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14.

PURPOSE: We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1-expressing groups. PATIENTS AND METHODS: RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) -positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. RESULTS: Median follow-up was 11.2 years for B-28 and 13.9 years for B-14. Of 1,065 B-28 patients, 36% had low (< 18), 34% intermediate (18 to 30), and 30% high (≥ 31) RS. Of 668 B-14 patients, 51% had low, 22% intermediate, and 27% high RS. Median ESR1 expression by reverse transcriptase polymerase chain reaction was: B-28, 9.7 normalized expression cycle threshold units (CT) and B-14, 10.7 CT. In B-28, RS was associated with DR 0 to 5 years (log-rank P < .001) and > 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS ≥ 31, respectively (log-rank P = .01). CONCLUSION: For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis.

Use of Gene Expression Profiling and Chemotherapy in Early-Stage Breast Cancer: A Study of Linked Electronic Medical Records, Cancer Registry Data, and Genomic Data Across Two Health Care Systems.

PURPOSE: The 21-gene recurrence score (RS) identifies patients with breast cancer who derive little benefit from chemotherapy; it may reduce unwarranted variability in the use of chemotherapy. We tested whether the use of RS seems to guide chemotherapy receipt across different cancer care settings. METHODS: We developed a retrospective cohort of patients with breast cancer by using electronic medical record data from Stanford University (hereafter University) and Palo Alto Medical Foundation (hereafter Community) linked with demographic and staging data from the California Cancer Registry and RS results from the testing laboratory (Genomic Health Inc., Redwood City, CA). Multivariable analysis was performed to identify predictors of RS and chemotherapy use. RESULTS: In all, 10,125 patients with breast cancer were diagnosed in the University or Community systems from 2005 to 2011; 2,418 (23.9%) met RS guidelines criteria, of whom 15.6% received RS. RS was less often used for patients with involved lymph nodes, higher tumor grade, and age < 40 or ≥ 65 years. Among RS recipients, chemotherapy receipt was associated with a higher score (intermediate v low: odds ratio, 3.66; 95% CI, 1.94 to 6.91). A total of 293 patients (10.6%) received care in both health care systems (hereafter dual use); although receipt of RS was associated with dual use (v University: odds ratio, 1.73; 95% CI, 1.18 to 2.55), there was no difference in use of chemotherapy after RS by health care setting. CONCLUSION: Although there was greater use of RS for patients who sought care in more than one health care setting, use of chemotherapy followed RS guidance in University and Community health care systems. These results suggest that precision medicine may help optimize cancer treatment across health care settings.

Quantitative Gene Expression by Recurrence Score in ER-Positive Breast Cancer, by Age.

INTRODUCTION: Breast cancer in young women (<50 years) has been associated with an increased risk of recurrence and decreased survival compared with patients older than 50. The objective of this analysis was to determine, from a large database of patients with early-stage breast cancer, if the Recurrence Score(®) result (Oncotype DX(®), Genomic Health, Inc, Redwood City, CA, USA) provided clinically meaningful differences in predicted risk of recurrence in younger-compared with older-patients. METHODS: Tumor samples from patients with estrogen receptor (ER)-positive breast cancers that were successfully processed in the Genomic Health central lab between June 2004 and December 2013 for Recurrence Score and quantitative gene expression of ER, progesterone receptor (PR), and Her/2neu, were included. Descriptive statistics were used to describe the distribution of scores by age group: <40, 40-49, 50-59, 60-69, and ≥70 years, nodal status, and histologic subtype. RESULTS: Specimens from 394,031 patients [3.3% (n = 13,029) aged <40 years; 15.6% (n = 61,643) aged ≥70 years] were included; 81.6% of patients had invasive ductal carcinoma. Nodal status was specified for 362,001 patients (87.0% negative). Median Recurrence Score results were similar across risk groups. Low (<18)- and high (≥31)- risk Recurrence Score results were seen in 58.5% and 8.5% of patients, respectively. A greater proportion of patients aged <40 (14.1%) than ≥70 (8.8%) years had a high-risk score. ER expression increased as a function of age and PR single-gene and invasion gene group expression were similar across age groups. CONCLUSION: These data indicate that in patients with ER-positive breast cancer, age alone does not reflect the underlying individual tumor biology, suggesting that the Recurrence Score result may add potentially useful information for personalized treatment decisions. FUNDING: Genomic Health, Inc.

A Prospective Comparison of the 21-Gene Recurrence Score and the PAM50-Based Prosigna in Estrogen Receptor-Positive Early-Stage Breast Cancer.

INTRODUCTION: The 21-gene Recurrence Score(®) assay (Oncotype DX(®), Genomic Health, Inc.) is a validated predictor of recurrence risk/chemotherapy benefit in patients with estrogen receptor-positive (ER+) early-stage breast cancer treated with endocrine therapy. The Prosigna(®) assay (NanoString Technologies Inc.) is a validated prognosticator in postmenopausal patients with low-risk ER+ early-stage breast cancer treated with endocrine therapy. The assays were analytically/clinically developed and validated differently. This study focused on comparing recurrence risk estimates as determined by these assays and is the first blinded comparison of these assays on matched patient samples. METHODS: Sequential breast cancer specimens from postmenopausal, node-negative, ER+ patients treated at the Marin General Hospital were analyzed: first by the 21-gene assay then by the Prosigna assay in an independent lab blinded to the Recurrence Score results. RESULTS: The final analysis included 52 patients. Correlation between the Recurrence Score and the Prosigna assay results was poor (r = 0.08). Agreement between risk classifications based on these assays was 54%; 4/7 of patients classified as high risk by the Prosigna assay had low Recurrence Score results. Two tumors with high Recurrence Score results had low ER expression (close to positivity threshold); both of which had a low/intermediate Prosigna assay result. The Prosigna assay classified 73.1% and 23.1% of samples as luminal A and luminal B, respectively. A range of Recurrence Score results was observed within the subtypes; 83% of luminal B samples had a low Recurrence Score result. CONCLUSION: Consistent with prior comparisons between the 21-gene and other genomic assays, our study demonstrated substantial differences in the way patients are risk stratified, suggesting that the different assays are not interchangeable. FUNDING: Genomic Health, Inc.

A phase II trial of ixabepilone and cyclophosphamide as neoadjuvant therapy for patients with HER2-negative breast cancer: correlation of pathologic complete response with the 21-gene recurrence score.

Ixabepilone and the taxanes have similar activity in the first-line treatment of metastatic breast cancer, and ixabepilone is sometimes effective in taxane-refractory patients. We conducted a phase 2 trial to evaluate ixabepilone in combination with cyclophosphamide as neoadjuvant treatment for patients with locally advanced HER2-negative breast cancer. Response to neoadjuvant treatment was correlated with the baseline 21-gene Recurrence Score® (Oncotype DX; Genomic Health Inc, Redwood City, CA). Eligible women with HER2-negative locally advanced breast cancer received ixabepilone 40 mg/m(2) plus cyclophosphamide 600 mg/m(2) on day 1 of each 21-day cycle. Following 6 cycles, patients underwent definitive surgery. Primary endpoint was rate of pathologic complete response (pCR). Breast biopsy tumor samples were obtained at pretreatment and at surgery in patients with residual disease. Tumor specimens were analyzed using the 21-gene assay. One hundred sixty-eight patients (median age 52 years; 45 % triple-negative) were enrolled; 161 (96 %) underwent definitive surgery following neoadjuvant ixabepilone/cyclophosphamide. Overall, 27 patients (17 %) achieved pCR, including 19 of 73 (26 %) triple-negative patients. The most frequently occurring grade 3/4 toxicity was neutropenia (98 patients; 58 %). Recurrence Scores were highly correlated with achievement of pCR (0/36 with low or intermediate Recurrence Scores vs. 19/72 with high Recurrence Scores; p = 0.002). There was high concordance between baseline and post-treatment Recurrence Scores in the 72 patients with paired samples. The combination of ixabepilone and cyclophosphamide yielded a pCR rate of 17 %, similar to other neoadjuvant chemotherapy regimens. Pathologic complete responses occurred only in patients with high-risk baseline Recurrence Scores.

The impact of genomic testing on the recommendation for radiation therapy in patients with ductal carcinoma in situ: A prospective clinical utility assessment of the 12-gene DCIS score™ result.

BACKGROUND AND OBJECTIVES: Twenty percent of breast cancers are ductal carcinoma in situ (DCIS), with 15-60% having a local recurrence (LR) after surgery. Radiotherapy reduces LR by 50% but has not impacted survival. The validated Oncotype DX(®) 12-gene assay (DCIS Score) provides individualized 10-year LR estimates. This is the first study to assess whether DCIS Score impacts physicians' recommendations for radiation. METHODS: Ten sites enrolled women (9/2012-2/2014) with DCIS eligible for breast-conserving therapy, excluding patients with invasive carcinoma and planned mastectomy. Prospective data collected included clinicopathologic factors, DCIS Score assay, and treatment recommendation before and after the assay result was known. RESULTS: In 115 patients (median age: 61 years; 74.8% postmenopausal), median DCIS size was 8 mm; 20% were nuclear grade 1, 46.1% grade 2; 64.4% reported necrosis. 86.1% were ER+, 79.1% PR+ (immunohistochemistry assay). Median DCIS Score: 29 (range: 0-85). Pre-assay, 73% (95%CI: 64.0-80.9%) had radiotherapy recommendations vs. 59.1% (95%CI: 49.6-68.2%) post-assay (P= 0.008). Physicians rated DCIS Score as the most impactful factor in planning treatment. CONCLUSIONS: The radiotherapy recommendation changed from pre-assay to post-assay 31.3% (95%CI: 23.0-40.6%) of the time--a clinically significant change. This study supports the clinical utility of the DCIS Score and indicates that the test provides additional, individualized information on LR risk.

A retrospective study of the impact of 21-gene recurrence score assay on treatment choice in node positive micrometastatic breast cancer.

To assess clinical utility of the 21-gene assay (Oncotype DX® Recurrence Score®), we determined whether women with HER2(-)/ER+ pN1mi breast cancer with low (<18) Recurrence Scores results are given adjuvant chemotherapy in a lower proportion than those with high scores (≥31). This was a multicenter chart review of ≥18 year old women with pN1mi breast cancer, HER2(-)/ER+ tumors, ductal/lobular/mixed histology, with the assay ordered on or after 1 January 2007. One hundred and eighty one patients had a mean age of 60.7 years; 82.9% had ECOG performance status 0; 33.7% had hypertension, 22.7% had osteoporosis, 18.8% had osteoarthritis, and 8.8% had type-2 diabetes. Mean Recurrence Score was 17.8 (range: 0-50). 48.6% had a mastectomy; 55.8% had a lumpectomy. 19.8% of low-risk group patients were recommended chemotherapy vs. 57.9% in the intermediate-risk group and 100% in the high-risk group (p < 0.001). A total of 80.2% of the low-risk group were recommended endocrine therapy alone, while 77.8% of the high-risk group were recommended both endocrine and chemotherapy (p < 0.001). The Oncotype DX Recurrence Score result provides actionable information that can be incorporated into treatment planning for women with HER2(-)/ER+ pN1mi breast cancer. The Recurrence Score result has clinical utility in treatment planning for HER2(-)/ER+ pN1mi breast cancer patients.

Clinical outcomes in elderly patients with metastatic colorectal cancer receiving bevacizumab and chemotherapy: results from the BRiTE observational cohort study.

BACKGROUND: Elderly patients are underrepresented in clinical trials and frequently undertreated with standard therapy. The BRiTE observational cohort study assessed the safety and effectiveness of bevacizumab-based first-line therapy for metastatic colorectal cancer among a large cohort of elderly patients (896 patients ≥65 years, among 1,953 total patients). METHODS: Treatment patterns, safety, progression-free survival (PFS), overall survival (OS) and survival beyond first progression (SBP) were analyzed by age cohorts. OS and SBP were further analyzed using Cox proportional hazards regression. RESULTS: Median PFS (months) was similar across age cohorts (<65 years, 9.8; 65 to <75, 9.6; 75 to <80, 10.0; ≥80, 8.6). Median OS (months) decreased with age (<65 years, 26.0; 65 to <75, 21.1; 75 to <80, 20.3; ≥80, 16.2). SBP declined with age; however, a Cox model adjusting for baseline and postbaseline covariates that were imbalanced among age cohorts showed a reduced independent effect of age on SBP (months) (<65 years, 12.0; 65 to <75, 11.4; 75 to <80, 11.3; ≥80, 10.0) compared with unadjusted analyses. Use of bevacizumab in subsequent postprogression regimens decreased with age. Incidence of targeted adverse events did not increase with age, except for arterial thromboembolic events (ATEs), for which Eastern Cooperative Oncology Group performance status, anticoagulation and arterial disease history were stronger prognostic factors than age. CONCLUSIONS: Elderly patients receiving bevacizumab with first-line chemotherapy showed treatment benefit, although there was reduced median survival with increasing age. There was no increased toxicity among elderly patients, except for risk of ATEs.

Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.

PURPOSE: This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. PATIENTS AND METHODS: Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. RESULTS: From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment--Breast were comparable in both treatment groups. CONCLUSION: Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.

A phase I trial of the single-chain immunotoxin SGN-10 (BR96 sFv-PE40) in patients with advanced solid tumors.

PURPOSE: Our purpose in the study was to establish the maximum tolerated dose and toxicity profile of SGN-10 (or BR96 sFv-PE40), a single-chain immunotoxin. SGN-10 is composed of the fused gene products encoding the translocating and ADP-ribosylating domains of Pseudomonas exotoxin (PE40) and the variable heavy (V(H)) and variable light (V(L)) regions of BR96 monoclonal antibody. This antibody is specific for a Lewis(Y) (Le(Y))-related carbohydrate antigen expressed on multiple carcinomas. EXPERIMENTAL DESIGN: A total of 46 patients with Le(Y)-positive metastatic carcinoma were enrolled in a Phase I dose-escalation study in cohorts of three to six patients who received SGN-10 at doses ranging from 0.024 to 0.962 mg/m(2), administered on days 1, 4, 8, and 11, followed by 2 weeks of rest and a second cycle of therapy. Pharmacokinetics and human antibody response to SGN-10 were also determined. RESULTS: The maximum tolerated dose of SGN-10 was 0.641 mg/m(2) with gastrointestinal dose-limiting toxicity. Pharmacokinetic studies performed in eight patients at the 0.641-mg/m(2) dose revealed a t([1/2]) of 2.5 +/- 0.3 h and a C(max) of 389 +/- 112 ng/ml. Pharmacodynamic analyses demonstrated a rapid clearance of the drug by day 11 associated with an antitoxin human antitoxin antibody (HATA) response in most patients. Signs consistent with a modest vascular leak syndrome, specifically, transient hypoalbuminemia, were observed in patients treated with doses of > or =0.384 mg/m(2). No complete or partial tumor responses were observed at an 8-week evaluation, although 31% of patients had stable disease. CONCLUSIONS: The maximal tolerated dose of SGN-10 given twice weekly for 2 weeks is 0.641 mg/m(2) with gastrointestinal dose-limiting toxicity. The immunogenicity of the toxin moiety limits the ability of SGN-10 to circulate by day 11 of therapy. Studies are ongoing to evaluate strategies to ameliorate toxicities and to inhibit the development of the anti-SGN-10 immune response.