Re: Targeted Toxins (Immunotoxins) for inoperable or recurrent glioblastomas
- From: J <nexsw@nvalid,anon>
- Date: Sat, 28 Jul 2007 13:49:34 -0400
J wrote:
Targeted Toxins (Immunotoxins) for inoperable or recurrent glioblastoma
http://www.xenova.co.uk/dc_transmid.html
Phase I and Phase II clinical trials for TransMIDTM have been
successfully completed in patients suffering from inoperable, recurrent
high grade gliomas who have failed to respond to all other forms of
treatment. A Phase I dose-escalating study was performed at the NIH in the
US and was followed by a Phase II multi-centre study at nine premier US
medical centres.
In the Phase II study, a reduction in tumour size of 50% or more was noted
in 35% of evaluable patients, with a corresponding increase in life
expectancy in those patients that did respond. In this study, median
survival for patients receiving TransMIDTM was approximately 37 weeks.
This compares to historical average life expectancy of approximately 26
weeks for patients with this condition, currently being treated with best
standard of care.
http://www.medscape.com/viewarticle/540154_3
Targeted Toxins (Immunotoxins) Neurosurg Focus. 2006;20(4):E9
Targeted toxins represent a new class of anticancer agents providing high
specificity for tumor cells that selectively overexpress some surface
proteins.[68,69] Toxins currently in use are recombinant polypeptide molecules
consisting of a tumor-selective ligand coupled with a highly potent peptide
toxin, which is truncated to abolish native toxicity. The most frequently
chosen and best-researched ligands that are in current use bind to
tumor-associated molecules with receptor signaling properties, such as EGFR,
TfR, IL-13R, or IL-4R. The therapeutic part of the molecule in all clinically
used toxins is a polypeptide derived from bacteria (for example,
Corynebacterium diphtheriae or Pseudomonas aeruginosa), which has been
modified by deleting the native targeting and internalization chains of the
polypeptide and replacing them with one of the aforementioned ligands.[36]
The mechanism of action of targeted toxins may have important advantages over
that of radiation and classic chemotherapeutic agents. Toxins are effective
against radiation-resistant hypoxic tumor cells and are far more potent than
any chemotherapy drug; one single molecule of toxin is sufficient to cause
cell death independent of any malignancy-associated genetic alterations and/or
mutations.[29]
Multidrug 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.[27,75,86]
A few targeted toxins have advanced from the laboratory to the stage of Phase
I and II clinical studies, with two of these agents now reaching Phase III
trials.
The IL4-PE (NBI-3001) Studies
This chimeric recombinant fusion protein (proprietary name NBI-3001;
Neurocrine, Inc., San Diego, CA) is composed of circularly permuted IL-4 and a
truncated form of PE.74 The targeted toxin IL4-PE has a 16-fold higher
affinity for binding to GBM cell lines than the native PE toxin, and is three-
to 30-fold more toxic to these cells.[21,73] Whereas normal CNS cells such as
endothelial cells, microglia, or astrocytes express low levels of IL-4R,
malignant glioma cells express high levels of this receptor on their
surface.[75] In a recent study, investigators demonstrated that 15 of 18 GBM
specimens and 12 other brain tumor samples were moderately to intensely
positive for IL-4R. In contrast, no detectable IL-4R was expressed in normal
brain as determined by immunohistochemical evaluation.[74]
Weber, et al.,[103] performed an open-label dose-escalation trial of
intratumoral administration of IL4-PE in patients with recurrent malignant
gliomas.
A total of 31 adult patients were enrolled, 25 with GBM and six with
anaplastic astrocytoma. Patients were assigned to one of four groups receiving
different doses of toxin in different volumes of infusate. The toxin was
administered by CED via an external pump connected to stereotactically placed
catheters.
The overall median duration of survival for the whole group was 8.2 months,
with a median survival of 5.8 months for the patients with GBM.
The 6-month survival rate was 52 and 48%, for these two groups, respectively.
Drug-related Grade 3 or 4 CNS toxicity was seen in a total of 39% of patients
in all groups, and in 22% of patients in the group treated with the MTD of 6
µg/ml in 40 ml.
Treatment-related adverse events were limited to the CNS. No deaths were
attributable to treatment, and no drug-related systemic toxicity was apparent
in any patient. Gadolinium-enhanced MR imaging of the brain in some of the
treated patients demonstrated areas of decreased signal intensity within the
tumor that were consistent with toxin-mediated tumor necrosis.[10]
A Phase II multicenter randomized open-label study of IL4-PE was performed in
patients with recurrent GBM to investigate continuous intratumoral infusion of
the toxin followed by resection of tumor.
The study was designed to evaluate the efficacy of IL4-PE, with a secondary
objective being to evaluate the safety and tolerability of the toxin.[59] In
the toxin-treated group, patients received intratumoral infusion of the agent
at total doses of up to 90 µg and underwent resection of tumor between 2 and 7
days after the completion of toxin infusion.
Patients in the control group underwent tumor resection without prior toxin
treatment. A total of 30 adult patients with unilateral, unifocal tumors with
a volume less than 100 ml and a Karnofsky Performance Scale score of 60 or
lower have been enrolled. Recruitment was completed in 2003, but no final
published results of the study are available yet. There are currently no Phase
III protocols in use for IL4-PE.
The TP-38 Studies
The agent TP-38 (IVAX, Inc., Miami, FL) is a recombinant chimeric protein
composed of transforming growth factor?µ, an EGFR ligand, and the genetically
engineered form of PE described earlier (see The IL4-PE (NBI-3001) Studies).
Human malignant gliomas and many other malignant tumors that metastasize to
the brain express EGFR, and this is commonly associated with amplification
and/or mutation of the EGFR gene during neoplastic transformation.[107]
Amplification and high expression of EGFR in gliomas may drive tumor growth
and proliferation to a significant degree.[35] By contrast, EGFR is expressed
at very low levels or is undetectable on normal human glial cells and neurons,
thus suggesting a potential therapeutic window. The ratio of EGFR expression
in gliomas compared with specimens obtained in normal brains has been shown to
be as high as 300-fold.[51]
Sampson, et al.,[90] investigated TP-38 in a Phase I clinical trial.
The primary objective of the study was to define the MTD and dose-limiting
toxicity of TP-38 infused by CED in patients with recurrent malignant gliomas.
A secondary objective was to detect the efficacy of the toxin.
Twenty patients were enrolled in the study, in which doses were escalated from
25 to 100 ng/ml. A total volume of 40 ml TP-38 was infused by two
stereotactically placed catheters at a flow rate of 0.4 ml/hour for each
catheter. The TP-38 was tolerated well, and an MTD was not established.
Nonspecific toxicity was not found at any of the dose levels. The toxicity
that was encountered was solely neurological and mostly related to infusion
volume, recurrent tumor, or stereotactic catheter placement, but not directly
to TP-38.
Fifteen of the patients in this trial died of progressive disease. When the
study closed, four more patients had no recurrence of tumor and had lived 55,
56, 69, and 116 weeks from the time TP-38 therapy was administered.
The overall median survival for all patients after delivery of TP-38 was 23
weeks, whereas for those without radiographic evidence of residual disease at
the time of therapy the median survival was 31.9 weeks.
Overall, neuroimaging studies in three of 15 patients with residual disease at
the time of therapy have demonstrated a response.[90]
A Phase II multicenter randomized open-label study was conducted in adults
with recurrent GBM.[102] Patients were randomized to two groups treated with
different dose levels of TP-38 (50 or 100 ng/ml), and the toxin was
administered by CED via stereotactically placed catheters. Patients did not
have to undergo tumor resection prior to treatment. The end points of the
study were time to progression, progression-free survival, and overall
survival. Three catheters were stereotactically placed in locations within the
enhancing tumor area that were predetermined by investigators. The infusion
rate was 200 µl/minute per catheter; each catheter delivered 13.4 ml over 67
hours. The total volume infused was approximately 40 ml, and the total dose of
TP-38 was 2 µg (50 ng/ml) or 4 µg (100 ng/ml).
One patient had a complete response 48 weeks after infusion, and in another
patient, a partial response was attained that was stable over 60 weeks.
Twenty-four patients remained stable. Postinfusion MR images obtained in most
patients demonstrated unspecific treatment-related changes such as halo
contrast enhancement around the infusion sites, which made assessment of the
response rather difficult. These changes usually resolved by 20 weeks
posttreatment. There were no Grade 3 and 4 toxicities related to TP-38, and
all adverse effects of the treatment were reversible.[102] A Phase III
clinical protocol using TP-38 is thought to be in development, but no further
details are currently known.
The Cintredekin Besudotox (IL13-PE38) Studies
The agent IL13-PE38 (also known as cintredekin besudotox; NeoPharm, Inc., Lake
Forest, IL) is a recombinant chimeric toxin consisting of human IL-13 fused to
a mutated form of PE. Immune cells, endothelial cells, and normal glia and
neurons generally express no or very small amounts of IL-13R, whereas gliomas
express a large amount of this receptor.[36]
Several Phase I and II studies have been initiated to investigate IL13-PE38 as
an antitumor agent for the treatment of patients with recurrent malignant
gliomas. In a Phase I/II study, IL13-PE38 was infused intratumorally in adult
patients with recurrent malignant gliomas (including anaplastic
oligoastrocytoma) to determine the MDT of the drug.[104] Patients received two
infusions of the agent at a constant infusion rate at 8-week intervals via two
stereotactically placed intratumoral catheters. One aim of the study was to
determine the MTD and toxicity of IL13-PE38 administered by CED through
intratumoral catheters at 200 µl/hr/catheter for 96 hours (total 38.4 ml), in
two courses 8 weeks apart. Dose escalation was planned through nine levels
ranging from 0.125 to 12 µg/ml (total dose 4.8?460.8 µg) in cohorts of three
patients per level. Cohorts of three patients received 0.5, 1, 2, and 4 µg/ml.
Concentrations of up to 2 µg/ml were safe and well tolerated.
Adverse events reported across all dose ranges were mild and mainly
neurological. The incidences of the most frequent drug-related adverse events
were 24% for headache, 24% for hemiparesis, 14% for brain edema, 10% for
aphasia, and 10% for ataxia.
In the Phase I portion of the study, two histopathologically and two
neuroimaging-confirmed responses were observed, with progression-free survival
ranging from 3 to 88 weeks and overall survival duration of up to 147 weeks.
No results have been published yet for the Phase II portion of this
study.[104]
In another Phase I study reported by Kunwar and colleagues,[48,49] IL13-PE38
was investigated in adults with supratentorial malignant gliomas. In this
four-stage study, the primary objectives were to determine the effective dose
of IL13-PE38 either before or after resection of the tumor. In Stage 1, after
biopsy sampling and intratumoral catheter placement on Day 1, IL13-PE38 was
administered for 48 hours at 400 µl/hour on Days 2 to 4 at escalating doses
ranging from 0.25 to 2 µg/ml. The tumor was resected on Day 8 and tissue was
evaluated for necrosis adjacent to the catheter. After resection, two or three
catheters were inserted into the brain adjacent to the tumor resection cavity,
and on Days 10 to 14, IL13-PE38 was given at 750 µl/hour for 96 hours at a
fixed dose of 0.25 µg/ml (total dose 18 µg). In Stage 2, intratumoral infusion
was omitted and patients underwent resection of the lesion followed by a
96-hour peritumoral infusion of IL13-PE38 at 0.5 and 1 µg/ml. In Stage 3, the
duration of peritumoral infusion was increased from 5 to 7 days at a fixed
dose of 0.5 µg/ml. Tumor necrosis up to 2.5 cm from the catheter tip was
demonstrated on neuroimages in at least five patients with preoperative
intratumoral cytotoxin infusion. Tumor specimens obtained in at least two
patients after intratumoral injection of 0.5 µg/ml IL13-PE38 cytotoxin
revealed regional necrosis in an ovoid zone extending 1 to 2 cm from the
catheter tip. The peritumoral postresection MTD was defined as 0.5 µg/ml.
Similar adverse events occurred across all cohorts, with most events being
neurological.
The incidences of the most frequent adverse events were as follows: 53% for
headache, 27% for hemiparesis, 20% for sensory disturbance, 17% for fatigue,
13% for aphasia, facial paresis, and abnormal gait, and 10% for convulsions,
hypesthesia, and lymphopenia. Prolonged individual patient survival has been
observed after peritumoral therapy at concentrations of 0.25 µg/ml (total dose
18 µg) and higher.[10,36,70]
In another Phase I/II multicenter study, the efficacy of IL13-PE38 was
investigated in recurrent supratentorial malignant gliomas in adult patients
with confirmed neuroimaging evidence of recurrent or progressive tumor. The
primary objective of thePhase I portion of the study was to determine the
optimum duration of infusion and drug concentration of IL13-PE38 delivered by
CED via one or two intratumoral catheters prior to resection of tumor.[48,83]
The Phase II objective was to determine the proportion of patients surviving
at 6 months. In Phase I, cohorts of three to six patients received a fixed
drug concentration (0.5 µg/ ml) with an increasing duration of infusion (4?7
days) to determine the MTD based on duration. After determining maximum
duration, the drug concentration was increased from 1 to 4 µg/ml in cohorts of
three to six patients to determine an MTD based on concentration. Tumor
necrosis was assessed 6 to 13 days after the end of infusion, at the time of
resection. There were no severe drug-related adverse events in the 10 treated
patients, although five patients experienced adverse events categorized as
Grades 2 to 3. The most frequent events were headache (70%), hemiparesis,
seizures, and edema (40% each), and aphasia (30%). Progression-free survival
ranged from 6 to 30 weeks, and overall survival ranged from 10 to 30
weeks.[36,48]
In all of the aforementioned studies, intratumoral infusion of IL13-PE38 with
or without tumor resection in patients with recurrent or progressing malignant
gliomas seemed to be well tolerated and did not result in any Grade 3 or 4
adverse event, or in any complication in peripheral organs such as liver,
kidney, and lung.
Neurological adverse events during and after toxin infusion were encountered
in a significant proportion of the treated patients. These included brain
edema, meningitis, seizures, headache, and symptoms of increased intracranial
pressure. All of these complications were temporary and mostly controllable by
administration of steroid drugs. In general, IL13PE38 doses (0.5?2 µg/ml)
showing biological activity in tumors (for example, necrosis on MR imaging
studies) were below the threshold of widespread neurotoxicity (4?12 µg/ml).
Selection of patients without incipient mass effect in the brain due to tumor
size and/or peritumoral edema seemed particularly important in avoiding
serious unwanted side effects.
Some prolonged survival was observed in this selected population of
patients.[10,36,70]
Currently, a Phase III randomized open-label active control parallel
assignment efficacy study (known as the PRECISE study) is being conducted to
determine whether overall duration of survival, safety, and quality of life
are improved in patients treated with IL13-PE38. An enrollment of 200 patients
is planned, and individuals treated with IL13-PE38 are being compared with
patients treated with Gliadel wafers (for whom an enrollment of 100 is
planned) after surgical tumor removal. These two methods are being studied for
the treatment of first recurrence of GBM after initial surgery and
external-beam radiation therapy.[61] The IL13-PE38 is administered over 4 days
by continuous infusion directly into the brain around the cavity where the
tumor has been removed. Catheters are placed stereotactically 2 to 7 days
after the tumor has been surgically removed. Patient enrollment in the study
was started in early 2004, and is ongoing.[36]
The TransMID-107 (Tf-CRM107) Studies
The agent TransMID-107 (TransMID; Xenova Group, Slough, Berkshire, United
Kingdom), also known as TfCRM107 or KSB-311, is a thioether conjugate of human
transferrin with a truncated natural mutant form of diphtheria toxin known as
CRM-107, which lacks receptor binding.[101] The TransMID targets tumor cells
via the TfR, a transmembrane glycoprotein that mediates cellular uptake of
iron. The TfRs are overexpressed on rapidly dividing cells, such as
hematopoietic and neoplastic (including GBM) cells.[85] The TfRs are sparse in
normal brain and their expression is largely restricted to the luminal surface
of brain capillaries.[41] It is this relative difference in the density of
TfRs that TransMID uses to generate differential toxicity to highly
TfR-expressing neoplastic cells, while sparing low-expressing normal brain
cells.[42] Low-density background expression of the respective target
receptors in normal tissue remains a major concern, however, with TransMID and
with all other targeted toxin-based therapies.
Laske, et al.,[50] treated 18 patients with recurrent malignant gliomas with
intratumoral high-flow interstitial microinfusion of TransMID in a
dose-escalating single-arm Phase I clinical trial. The drug was infused at a
maximum flow rate of 4 to 10 µl/minute at a toxin concentration of 0.1 µg/ml.
Based on preclinical data, the rate of infusion was limited to a maximum of 10
µl/minute per catheter to avoid leakage via the catheter track. The drug
concentration at a given infusion volume was escalated by half-log increments
in every three to four patients, unless severe toxicity was detected in one of
the first two or three patients.
Nine of the 15 patients who could be evaluated responded to treatment by at
least a 50% reduction in tumor volume on MR imaging, including two who had
complete responses. Reduction in tumor volume occurred no earlier than 1 month
after completion of the first toxin infusion. In four patients, the response
was not maximal until 6 to 14 months after the first treatment. The tumor
response appeared to be concentration- and dose-dependent. Only two of the
eight patients in the first two treatment groups (0.1?0.32 µg/ml) had partial
responses. In contrast, two of four patients treated with greater than 1 µg/ml
had complete responses and the other two had partial responses. The patients
treated with a total dose of 60 µg or higher all had partial responses;
however, toxicity was noted 1 to 4 weeks posttreatment.
At intermediate toxin concentrations, responses correlated more with total
dose than with the concentration of drug. Although pretreatment tumor volume
seemed to be related to the likelihood of response, this factor did not reach
statistical significance. The median duration of survival after treatment in
the responder group was 74 weeks, with three of the responders still alive at
102 to 142 weeks after the first treatment. Nonresponders survived a median of
36 weeks. Intratumoral infusions of TransMID with total volumes of 5 to 180 ml
were well tolerated. There were no treatment-related deaths or
life-threatening or irreversible toxicity. Transient worsening of a
preexisting neurological deficit during infusion occurred three times in 44
treatments. No symptomatic systemic toxicity occurred.
In this first clinical trial, based on the relationship between dose, drug
concentration, and sustained neurotoxicity, an MTD of 26.8 µg (40 ml at 0.67
µg/ml) was established. The trial results indicated that therapy with TransMID
can reduce the size of malignant brain tumors that are refractory to
conventional therapy without producing severe neurological or systemic
toxicity.[50]
A Phase II multicenter, open-label, single-arm study was performed to
investigate intratumoral CED infusion of TransMID in recurrent or progressive
malignant gliomas in adults.[101] T
he primary study objective was evaluation of the efficacy and safety of
TransMID, and the primary end point was 50% reduction in tumor volume
(measured on MR images) within 12 months after the second treatment.
Inclusion criteria called for unifocal, unilateral, and supratentorial tumors
that were less than 3.5 cm in diameter on contrast-enhanced MR imaging.
Patients received Trans-MID (0.67 µg/ml) at an escalating rate of up to 200
µl/hr/ catheter for 4 to 5 days, until a total volume of 40 ml 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 one.
Forty-four patients were enrolled, and all received at least one TransMID
infusion.
Thirty-one (70%) of the 44 patients completed two treatment cycles.
Of the 34 patients who could be evaluated for the analysis, five experienced a
complete response and seven had a partial one (total of 35% with a response),
which was a statistically significant result.
The median survival time for all 44 patients was 37 weeks.
Infusions of TransMID within this clinical protocol resulted in symptomatic,
progressive brain edema in eight (14%) of the patients who could be evaluated
(some patients were lost to follow up and were not counted in the final
totals). Seizures were seen in three patients, but all of them responded to
anticonvulsant therapy. Patients in whom increased cerebral edema and clinical
neurotoxicity developed demonstrated some changes on MR imaging, such as a
cortical high signal on nonenhanced T1-weighted sequences. These MR imaging
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 or 4 adverse events 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 gliomas (35% of patients who could be evaluated) and
that tumor response as seen on MR images appears to correlate with a
significantly prolonged survival.[101]
A Phase III multicenter, randomized, open-label, active-control, parallel
assignment study of safety and efficacy has been launched to compare TransMID
with the best standard treatment that is currently available for patients with
progressive and/or recurrent nonresectable GBMs.[60] The best standard
treatment involves the chemotherapeutic regimen considered to be the best
standard of care at the institution, and consists of the following agents:
nitrosoureas; platinum compounds; temozolomide; procarbazine; or procarbazine,
CCNU (lomustine), and vincristine. The primary end point of the study is
overall survival time. A planned interim analysis of the primary end point
will be conducted after approximately 50% of the required events have been
observed. In addition, possible differences in efficacy or safety of TransMID
will be associated with the degree of TfR expression in tumor tissue and serum
antidiphtheria toxin antibody titer levels. Adult patients eligible for
enrollment in this trial must have received a diagnosis of histologically
confirmed GBM and must have undergone conventional treatment, including
surgery (biopsy sampling or debulking), and/or radiation therapy, and/or
chemotherapy. Patients must have a recurrent and/or progressive tumor that is
between 1 and 4 cm in diameter.
Patient enrollment began in July 2004, and a total enrollment of 323 patients
is planned. The study is ongoing, with expected closure of data entry by July
2007.[60]
Conclusions and Future Developments
Targeted toxins have shown considerable promise in Phase I and II clinical
trials with recurrent malignant gliomas. There are, however, at least two
major obstacles that need to be overcome before targeted toxins may enter the
mainstream of brain tumor therapies. These are their nonuniform and poorly
predictable distribution in the brain and their nonspecific associated
toxicity to glial and neuronal cells.[13] With the introduction of MR-based
functional imaging and three-dimensional volumetric techniques in routine
clinical practice, it will be possible to determine quantitatively the brain
tumor volumes and volume of infusate in tumor and normal brain.[8,99]
Diffusion tensor imaging is a new MR imaging technique that is sensitive to
directional movements of water molecules induced by tissue barriers.[15]
Because CED makes use of the extracellular space of the brain as a natural
pathway for the widespread distribution of agents infused in an aqueous
solution, therefore the diffusion tensor imaging modality could be used to
demonstrate CED without the need for contrast agents. Further key developments
in MR imaging and MR-related computer software as well as infusion catheter
design and computerized simulation and delivery modeling within the brain may
provide much-needed new resources to be combined with the biologically
targeted toxins.[13]
Current clinical protocols are exploring several points of presumed
significance, such as the use of different numbers of catheters, positioning
of these devices, resection of tumor before or after toxin infusion, and
single compared with repeated infusion, but there is no clear answer to any of
these questions. It remains unknown whether there are benefits from combining
targeted toxins with chemotherapy and/or with fractionated external-beam
radiation. Protocols have been established for investigations in patients with
recurrent or progressing GBMs, and the role of targeted toxin infusion in
primary gliomas remains to be determined. Evidence of prolonged survival and
late local recurrences in treated patients with gliomas has raised the
question of periodically repeated application of toxin for extended control of
local recurrence and progression. Ongoing randomized controlled trials will be
able to provide some answers to questions about the efficacy of the studied
toxins and clinical protocols; however, more clinical research is needed to
address the aforementioned global issues.
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