Analysis was performed by intention to treat.
The mean age of patients was 57.83 years. Some patients had compensated concomitant cardiovascular and respiratory diseases. Most patients were diagnosed in an early phase but as having metastatic evolutive disease (85.7%) or locally advanced disease (8.5%). The remaining patients had visceral disease located primarily in lung and liver. 65.7% of patients had non visceral metastases (skin, lymphatic nodes and bone). The rest of them had visceral disease mostly in lung and liver. Only 2 patients were diagnosed with an advanced stage of the disease and both had metastases at non visceral sites. The number of metastatic lesions was variable but the majority of patients had one or two metastic sites. (68.6% and 20.0% respectively).
The most frequent histological type was infiltrating ductal carcinoma (69.7%). Also lobular, papillary, colloid and comedocarcinoma were present.
Every patient received treatment after initial diagnosis and metastatic diagnosis. First case treatment includes surgery, chemotherapy, radiotherapy and hormonal therapy, and the majority of treatments include a combination of therapies. Metastatic disease treatment consists of chemotherapy alone (82.9%) and chemo-radiotherapy or radiotherapy alone at 14.3% and 2.8% respectively.
All patients included had good performance status (0–2) according to WHO criteria.
The distribution of all parameters was similar in all dose levels.
Demographic characteristics, previous therapies, site of metastases and total vaccination dose are show in .
A total of 371 immunizations were administered. Every patient included was treated with the vaccine. The 34.2% of patients received complete treatment (15 immunizations) while the rest of patients received more than 5 doses, except of two of whom received three doses and one who received four. Seventeen patients received tamoxifen as hormonotherapy concomitant with vaccine (48.6%).
Twenty-four patients discontinued treatment during the study (68.5%) but in no case was the discontinuation caused by vaccine complications. Principal causes of discontinuation were treatment schedule noncompliance, patient decision, worsening of performance status or death. Treatment interruptions were distributed in all dose levels.
All safety results were analyzed. Every patient developed grade I – II vaccine-related adverse events. Only six severe adverse events were described as vaccine-related in three patients. In one patient episode, these events included fatigue, lipothymy, and sweating. In two separate patient episodes, hypotension and chills were experienced respectively. In no event was treatment interrupted, and all were successfully controlled without harm to the patient.
The most frequent adverse events observed were site-injection reactions: pain and erythema. Patients also presented systemic events but the majority was related to ‘flu-like’ symptoms consisting of fever, chills, nauseas, vomiting, headache, myalgias and asthenia.
Serious adverse events were not present during the trial.
All adverse effects appeared subsequently to the first immunizations. Behavior of adverse events was similar in all dose levels. Toxicity profile is shown in and .
More frequent adverse events vaccination related.
Intensity of adverse events.
Antibody titers against NeuGcGM3 ganglioside were obtained after vaccination in 24 of the 29 patients evaluated. Both IgM and IgG antibodies were present in patients (). The IgM titer range was within 1/160 and 1/6400. Higher titers were obtained independently of dose levels, although the best median was obtained in the group treated with 900 μg of vaccine. Behavior of IgG titers was similar in all dose levels and its titers were lower than IgM’s.
Median of inverse of maximum anti-NGcGM3 gangliosides antibodies titers.
These results demonstrate that the formulation is immunogenic in all dose levels evaluated. The most immunogenic dose was 900 μg.
In twenty-two patients Antitumor response was evaluated in twenty two patients. 72.7% of patients achieved control disease; five of them achieved objective response either complete (CR) or partial (PR) and eleven patients achieved stable disease (SD) ().
Antitumor response by dose level.
Best responses were obtained at the 900μg dose level. Of the patients treated with this dose, one in three achieved CR, one in three achieved PR, and eight of eleven achieved stable disease control. In these level had not patients with progressive disease. Despite this success, no difference in antitumor responses was observed between levels. In order to antitumor responses.
Overall survival was evaluated in all patients. Median global overall survival was 15.9 months (). The best value of survival was obtained at the 900μg dose level and was 28.5 months. much superior to others levels. Also, in this level were included Additionally, five of the eleven patients treated with this dose are currently still alive. Significant differences between doses levels were not observed.
Optimal biological dose
It was determined that the optimal biological dose was 900μg as better results for safety, immunogenicity, and efficacy were obtained. The volume of injection also was also analyzed to select the optimal dose as higher dose levels require higher volume of administration and hence greater patient discomfort. The determined optimal dose allows for formulation of the vaccine in a concentration which requires only one site of injection thereby reducing patient discomfort.