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were conducted in parallel. The primary objective was to
determine the MTD of anatumomab mafenatox as a function
of pretreatment anti-SEA antibody levels [58]. The patients
received a daily, 3 h infusion of anatumomab mafenatox on
four consecutive days (one treatment cycle). Each patient was
treatedwith an individual dose based on the pretreatment anti-
SEA antibody concentration and adjusted for body weight.
Patients were followed for at least 28 days, and additional
cycles were considered in patients with responding or stable
disease. Altogether 78 NSCLC patients received one cycle,
and 26 of these patients received a second cycle. The toxicity
profile was predictable, transient and reversible fever and
hypotension, and easily manageable. A total of eight dose-
limiting toxicities (DLTs) were recorded, consisting of hypo-
tension in four cases, hypotension and dyspnea in two cases,
and hypertension in two cases. A dosing algorithm was
constructed that would allow patients in subsequent clinical
investigations to be treated with a dose of anatumomab
mafenatox that is tailored to their specific tolerance for the
agent, as reflected by their pretreatment anti-SEA concentra-
tions. Blood levels of TNF-
a
were very low, IL-2 levels
increased in some patients and IL-10 levels increased follow-
ing each infusion, but rapidly declined after termination of
therapy. The anti-SEA antibody levels increased rapidly
during the days after a treatment cycle. After the first infusion,
the maximum values were reached by day 28. Thereafter, the
anti-SEA antibody concentration declined slowly. Low levels
of human anti-mouse antibodies (HAMAs) were observed in
some patients after therapy. The results from antitumor
efficacy evaluation using CT scans of anatumomab mafena-
tox treated patients with advanced NSCLC suggested a
treatment effect (disease stabilization or tumor regression),
and a retrospective analysis of survival was performed.
The median overall survival (OS) was 8.3 months, with a
43% 1-year survival and 14% 2-year survival. Interestingly,
there was a significant relationship between exposure and
survival regardless of performance status of the patients.
A noncontrolled Phase IIa study in advanced RCC was
conducted with anatumomab mafenatox in the UK between
2001 and 2003 [38]. A total of 43 RCC patients were treated
and evaluated for antitumor effects. One patient showed a
sustained partial response (PR). After 2 and 4 months of
anatumomab mafenatox treatment, 68% and 40% of the
patients showed stable disease (SD), respectively. Of the
total number of RCC patients included in the study, 72% had
previously received treatment with IL-2, IFN-
a
or chemo-
therapy but had continued to progress before initiating
treatment with anatumomab mafenatox. The high frequency
of patients with SD during treatment in the study indicated
its efficacy, and the safety profile showed that anatumomab
mafenatox was well tolerated. Survival data were collected
for all 43 treated patients and each patient was classified as
high, intermediate, or low risk using the Memorial Sloan-
Kettering Cancer Center
[59,60] for untreated or previously treated patients. Median
OS for the patients was 19.7 months as compared to
simulated control patients having an expectation of 13.7
months (Figure 24.4). Two-year survival for the anatumo-
mab mafenatox treated patients was 42% versus 27% for the
simulated control patients. The 43 patients were divided into
two groups depending on drug exposure (dose/anti-SEA),
that is, high, above or low, below median exposure groups
(Figure 24.4). Patients receiving higher, above median
exposure showed a survival advantage compared to the
low, below median exposure group, 26.6 months versus
12.1 months. Patients who received a high exposure and
showed high-sustained IL-2 response were more likely to
have disease control (SD or PR) and prolonged survival
(Figure 24.4). In conclusion, the recorded prolonged sur-
vival suggested treatment benefit, on the basis of two
independent comparisons. First, the patients had a median
survival of 19.7 months, considerably longer than the 13.7
months survival in matched controls predicted from the
previous extensive analysis [59,60]. Second, there was a
relationship between drug exposure and a reduction in the
rate of tumor growth. Furthermore, a relationship was shown
between drug exposure and survival, where high exposure
patients lived twice as long as low exposure patients. In
addition, sustained IL-2 seemed to be beneficial for anti-
tumor activity induced by anatumomab mafenatox.
24.5.2 Naptumomab Estafenatox
Naptumomab estafenatox was developed in parallel with the
initial clinical studieswithanatumomabmafenatoxandhasbeen
evaluated in Phase I trials with NSCLC, PC, and RCC patients
[39,61]. Altogether 52 patients were investigated in the mono-
therapy (MONO) trial and the combination therapy (COMBO)
trial with docetaxel. The primary aimwas to establish theMTD
of naptumomab estafenatox. The secondary objectives were to
determine safety profile, pharmacokinetic parameters, immu-
nological response, and effects on tumor disease. The MONO
study was carried out in Norway, the United Kingdom, and the
United States. Main inclusion criteria were histologically
or cytologically confirmed disease, which was refractory to
available standard therapies. Patients should have an Eastern
Cooperative Oncology Group (ECOG) performance status of
0 or 1 and life expectancy greater than 3months. Three different
indications were investigated, consisting of 20 cases of
NSCLC, 11 cases of RCC, and 8 cases of PC. The starting
dose was 500 ng/kg/day administrated as a 5-min bolus injec-
tion, and naptumomab estafenatox was given for five consecu-
tive days. Six DLTs were recorded and the highest dose
investigated was 27.4
m
g/kg/day. Patients with SD or response
were considered for treatment with a second five-day cycle,
unless theyhadexperiencedaDLT.Themost notable sideeffects
were fever, nausea, and rigors, and thesewere easilymanaged. It
was concluded that the side effects were not dependant on the
(MSKCC) prognostic criteria
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