Biomedical Engineering Reference
In-Depth Information
In this first clinical trial, the relationship between dose,
drug concentration, and sustained neurotoxicity established
a MTD of 26.8
m
g (40mL at 0.67
m
g/mL). The trial results
indicated that therapy with TransMID can reduce the size of
malignant brain tumors refractory to conventional therapy
without producing severe neurologic or systemic toxicity
[82].
An open-label, single-arm, multicenter Phase II study
investigated intratumoral CED infusion of TransMID in
recurrent or progressive malignant glioma in adults [83].
The primary study objective was evaluation of efficacy and
safety of TransMID, and the primary endpoint was 50%
reduction in tumor volume (measured by MRI) within 12
months after the second treatment. Inclusion criteria called
for unifocal, unilateral, and supratentorial tumors
of care at the respective institution, and consisting of
nitrosoureas, platinum compounds, temozolomide, procar-
bazine, or PCV (procarbazine, CCNU [lomustine], vincris-
tine). The primary endpoint of the study was overall
survival time. Adult patients eligible for enrolment into
this trial had to be diagnosed with histologically confirmed
GBM and must have had undergone conventional treat-
ment, including surgery (biopsy or debulking) and/or
radiation therapy and/or chemotherapy. Patients were
required to have a recurrent and/or progressive tumor
4.0 cm in diameter [84,85]. The trial was
however prematurely terminated in 2007 after an interim
conditional power analysis showed that it was extremely
unlikely that TransMID would meet the trial criteria for
efficacy [85]. No data from this clinical trial have been
published yet.
1.0 and
3.5 cm
in diameter on contrast-enhanced MRI. Patients received
TransMID (0.67
m
g/mL) at an escalating rate up to 200
m
L/h
per catheter for 4-5 days, until a total volume of 40mL was
delivered. Four to 10 weeks after the initial infusion patients
were due to receive a second round of toxin treatment with
the same parameters as the initial treatment. A total of 44
patients were enrolled in total and all received at least one
TransMID infusion. A total of 31 out of the 44 patients
(70%) completed two treatment cycles. Of the 34 patients
evaluable for analysis, there were a total of five complete
responders and seven partial responders (total of 35%
response), which was a statistically significant result.
Median survival time for all 44 patients was 37 weeks.
Infusions of TransMID within this clinical protocol resulted
in symptomatic progressive brain edema in 8 of 44 patients
(14%). Seizures were seen in three patients, but all of them
responded to anticonvulsant therapy. Patients that developed
increased cerebral edema and clinical neurotoxicity demon-
strated some manifest changes on MRI, such as cortical high
signal on nonenhanced T1 sequences. These MRI changes
were suggestive of venous thrombosis, which may correlate
with the higher expression of TfR on endothelial cells in
normal blood vessels. There were no grade 3 and 4 AE due to
failure of peripheral organs such as liver, kidney, and lung.
The results of this Phase II clinical trial have confirmed the
safety and tumor response data of the Phase I trial. The Phase
II study indicated that tumor response can be obtained in a
significant percentage of recurrent or progressing malignant
glioma (35% of evaluable patients) and that tumor response
as seen on MRI appears to correlate with a significantly
prolonged survival [83].
A multicentric randomized, open label, active control,
parallel assignment, safety, and efficacy Phase III study
(KSB311R/CIII/001 trial) was launched in 2004 in order to
compare TransMID with the best standard treatment avail-
able for patients with progressive and/or recurrent non-
resectable GBM [84,85]. Best standard treatment involved
a chemotherapeutic regimen considered to be best standard
<
20.5 CONCLUSIONS AND FUTURE
DEVELOPMENTS OF TARGETED TOXINS
A number of targeted toxins for tumor specific treatment of
solid and hematological malignancies have been advanced
to the stage of clinical trials in the last decade. Ligands
suchasIL-4,IL-13,EGF,TGF-
a
, and Tf have been used in
conjunction with plant or bacterial toxins. All targeted
toxins have a common principle: the ligand portion defines
the tumor specificity of the construct and directs the toxic
portion to the cell surface; the peptide toxin is then
internalized into the cell, translocates to the cytosol, and
catalytically inactivates protein synthesis leading to cell
death. Targeted toxins are highly potent and able to kill
tumor cells independent of any malignancy-associated
genetic alterations and/or mutations. Multidrug resistance
and apoptosis resistance is therefore not an issue with
toxins—after receptor binding and internalization, no
tumor cell is able to survive the toxin part of the molecule
[24,86,87]. Apart from being tumor selective in cell cul-
ture, targeted toxins retain this selectivity in vivo if used at
an appropriate concentration. The MTD differs with every
type of toxin and with delivery mode and delivery volume.
However, there is currently a strong need for the develop-
ment of improved delivery methods in vivo and for non-
invasive imaging of the intracerebral and intratumoral
distribution of toxin in patients [25]. In animal studies,
SPECT scanning and gamma camera imaging have been
successfully used to study the distribution of TransMID
[80]; however, these studies have not been replicated in
patients.
Targeted toxins have shown considerable promise in
Phase I and II clinical trials with recurrent malignant glio-
mas. There are however at least two major obstacles that
need to be overcome before targeted toxins may enter the
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