A total of 84 patients with breast cancer or melanoma were enrolled onto the study from August 2006 to August 2007, of whom 80 were administered 99mTc-tilmanocept. These 80 patients comprised the safety population (for AE compilation) and included 49 patients with primary melanoma and 31 patients with breast cancer (, ). Of the safety population patients, 78 were evaluated for efficacy (evaluable patient population); demographics and clinical staging are listed in .
Analysis of patient populations
Patient inclusion and exclusion criteria
Demographic characteristics and clinical staging for all evaluable patients
The primary objective of this phase 2 clinical study was to determine the pre- and intraoperative tilmanocept localization of 99mTc-tilmanocept in LNs in the lymphatic pathway or pathways draining the primary site of melanoma and breast cancer. Whole-body scans after injection of 99mTc-tilmanocept and before surgery were performed for 55 of the 78 evaluable patients (; ). Of those patients for whom LS was performed, a 99mTc-tilmanocept hot spot was located on the scans of 52 patients (94.5%); in 3 patients, a hot spot did not localize in a preoperative scan.
FIG. 2 Representative dynamic lymphoscintigraphy (LS) after injection of 99mTc-tilmanocept. A melanoma patient underwent LS approximately 5 min after injection of 0.8 mCi-labeled 99mTc-tilmanocept before same-day surgery. One hot spot (right axilla) was located (more ...)
LS and intraoperative localization of 99mTc-tilmanocept in all evaluable patients
Intraoperatively, 99mTc-tilmanocept showed a per-patient localization rate (P), identifying at least one tissue sample in 75 (96.2%) of 78 patients (95% exact binomial confidence interval, 89.2–99.2; P < 0.0001) (, ). The rates were similar across the two diseases: 99mTc-til-manocept localized in 46 (97.9%) of 47 (95% exact binomial confidence interval, 88.7–99.9; P < 0.0004) melanoma patients and 29 (93.5%) of 31 (95% exact binomial confidence interval, 78.6–99.2; P < 0.0374) breast cancer patients. Of those patients with 99mTc-tilmanocept localization, 64.2% had 1–2 gamma-count-positive LNs; 32% of the remaining patients had ≥3 LNs identified by 99mTc-tilmanocept. The average number of 99mTc-tilmanocept-identified LNs per patient over both malignancies was 2.22 (2.30 LNs per melanoma patient; 2.10 LNs per breast cancer patient).
Histology and pathology results in all evaluable patients
In addition to high per-patient localization rates, 99mTc-tilmanocept also exhibited high mapping sensitivity (resected tissues) and tissue specificity (LNs). Of the 182 resected tissues surveyed by histopathology, 173 were 99mTc-tilmanocept identified in vivo (95.1% sensitivity, total LNs removed), and all were subsequently determined to be LNs (100% tissue specificity) (). The secondary efficacy objective was the assessment of the resected LNs to confirm the presence or absence of tumor metastases. Of the 110 tissue specimens received and assessed for disease in tissues from melanoma patients, 18 (16.4%) contained tumor, and specimens were confirmed to be LNs. Of 72 tissue specimens received and assessed for disease in tissues from breast cancer patients, 9 (12.5%) contained tumor, and all specimens were confirmed to be LNs. The overall proportion of 99mTc-tilmanocept-positive LNs containing metastatic disease was 13.7%: 15.5% from melanoma patients and 11.1% from breast cancer patients. One melanoma patient with a disease-positive LN did not have radioactive counts recorded in vivo; therefore, that LN is not included in the 99mTc-tilmanocept-identified LN gamma count where such LNs may be positive for disease. In a single breast cancer patient, one disease-positive LN was not identified by 99mTc-tilmanocept; this patient additionally had two tumor-negative LNs removed that were also not localized by 99mTc-tilmanocept. However, of the 26 disease-positive tissues with intraoperative gamma counts recorded, 25 (96.2%) were effectively identified by 99mTc-tilmanocept (). The remaining 7 of 182 tissue specimens that were removed but not identified by 99mTc-tilmanocept were all negative for metastases.
An exploratory data analysis was conducted to evaluate the effect that time between injection and surgery had on 99mTc-tilmanocept localization. 99mTc-tilmanocept had a 96.8% localization rate (60 of 62) in same-day surgery patients, versus a 93.8% localization rate (15 of 16) in next-day surgery patients (; P > 0.05, not significant). Additional gamma-count-positive specimens were identified for same-day surgery (135 of 141, 95.7%) than next-day surgery (38 of 41, 92.7%) (). In melanoma patients, the injection-to-surgery times had no effect on the performance of 99mTc-tilmanocept, as there was 97.7% (85 of 87) localization rate seen in the same-day group and 100% (23 of 23) in the next-day group (by positive specimens). In breast cancer patients, those who had surgery on the same day had a 92.6% (50 of 54) localization rate; however, those who had surgery the next day showed an 83.3% (15 of 18) localization rate. The rate difference in the breast cancer patients was attributed to the small number of patients in the next-day group (9 of 31).
The study design did not prospectively dictate or exclude the use of VBD, and its use was discretionary. As such, 57 patients (73.1%) were also evaluated with VBD (). An additional exploratory review of available operative and pathology reports was conducted for the concordance (coidentification of a LN by two agents) of 99mTc-tilmanocept hot LNs and VBD blue LNs in these patients. This analysis indicated a concordance rate of 94.4% for 99mTc-tilmanocept hot LNs that also contained blue dye. Conversely, the rate for concordance of VBD with 99mTc-tilmanocept was 86.7%.
As part of the drug safety analysis, AEs were monitored in all patients who received an injection of 99mTc-tilmanocept (n = 80). Overall, 37 patients (46.3%) experienced one or more AEs during the study. No patients experienced AEs that were considered probably or definitely related to study drug. Only 3 patients (3.8%) experienced AEs possibly related to study drug. Adverse events were generally mild to moderate (grade 1–2) in severity. Overall, 5 patients (6.3%) experienced AEs that were considered serious, but all were resolved and were unrelated to the study drug. These procedure-related serious AEs (with cause) included: fever (infection), bladder perforation (surgical, melanoma wide excision), vascular injury (surgical), pneumothorax (surgery reconstruction, infusion port placement), and wound hematoma (surgical). There were no deaths during the study, and no patients were withdrawn from the study as a result of an AE.