1. Background: Brain tumors account for 1.35% of all cancer conditions and cause deaths
in 2.2% of cancer patients (Cancer Facts and Figures 2005). The most common type of
brain tumors are gliomas. Depending on the age group, they account for 40%-90% of
central nervous system tumors. The incidence of malignant gliomas is 0.5-2 per
100,000 people per year. Men are more frequently affected, usually in their 50s and
60s. In the Polish population, approximately 1300 people are diagnosed with gliomas
annually, including about 600 cases of malignant gliomas. The standard treatment
approach includes surgical treatment, radiotherapy, and chemotherapy. Despite the
currently accepted treatment regimen, survival times-depending on the tumor
type-range from 1 to 3 years.
In a typical course, regardless of the therapy used, the extent of surgery, and
other prognostic factors, the progression of the growth process occurs after some
time. The use of chemotherapy extends survival time-depending on the tumor type-by
several to several dozen weeks. This data indicates the need to seek other forms of
treatment. Since brain gliomas are infiltrative in nature, it seems that an
effective drug should exhibit the ability to diffuse freely within the tumor and
specifically bind to cancer cells. Selected peptides exhibit such properties.
One of the mechanisms regulating cell (including cancer cell) function involves
receptor systems located in the cell membrane. These show high specificity of
reaction with specific peptides. The expression of some receptor systems
significantly increases in cells of specific tumor types. This property underlies
the use of radioisotope-labeled peptides in diagnosis and treatment in oncology.
Peptides bind to cancer cells, and ionizing radiation emitted by the attached
radioisotope leads to regression of pathological changes. This method is developed
only in a few centers worldwide and is currently used, among others, in treating
certain types of lymphomas (anti-CD-20 antibody labeled with 90Y or 131I) and
neuroendocrine tumors (somatostatin analogs labeled with 90Y, 177Lu).
The benefit of this method is the ability to treat tumors that exhibit resistance to
conventional chemotherapy and radiotherapy. Based on own experiences and literature
data, it is known that gliomas show increased expression of selected receptor
systems. In grade II-IV gliomas, a significant increase in expression for
neurokinin-1 (NK-1) receptors, for which substance P is the ligand, has been noted.
When administered directly to the tumor, substance P undergoes rapid diffusion and
binding to glioma cells.
At the center in Basel (Institute of Nuclear Medicine, University Hospital Basel), a
derivative of substance P (1,4,7,10-tetraazacyclododecane-1-glutaric
acid-4,7,10-triacetic acid) was developed. It was shown that over 95% of gliomas
exhibit significantly increased expression of the NK-1 receptor system, and that the
proposed peptide has a capacity for specific binding to this type of receptor (out
of 34 glioma tissue samples, 32 samples showed significantly increased NK-1 receptor
system expression).
Substance P can be labeled with various radioisotopes with differing physical
properties, including 90Y and 177Lu-beta radiation emitters. The beta radiation
emitted by 90Y has an energy of 2.1 MeV, with a tissue range of about 12 mm.
Lutetium emits radiation with an energy of 497 keV, with a range of 1 mm. Limiting
factors for the use of beta radiation include its range of action. There is a
potential risk of damage to functionally critical brain centers if the tumor is
located nearby. This was a premise for the use of alpha radiation emitters. One of
the studied radioisotopes is 213Bismuth, which has an energy of 5.8 MeV but a range
limited to only 81 μm.
To date, within the framework of the project "Use of Radioisotope-Labeled Substance
P in Treating Patients with Brain Tumors" (KB/204/A/201), local glioma treatment has
been provided using substance P labeled with alpha emitters 213Bi and 225Ac in the
case of confirmed disease recurrence.
Initially, local treatment was performed using [213Bi]Bi-DOTA-SP at an activity of
up to 11.2 GBq, achieving good treatment tolerance without clinically significant
side effects. The progression-free survival (PFS) was 2.7 months, and the median
overall survival (OS) after disease recurrence was nearly twice as long as expected
in this patient group, amounting to 10.9 months. The median overall survival from
diagnosis was 23.6 months. However, after the start of treatment with
[213Bi]Bi-DOTA-SP, the median survival was 7.5 months.
Considering the difficulties in labeling and quality control with a short half-life
for 213Bi (46 min), the next step involved treatment with the alpha-emitter 225Ac. A
study was conducted evaluating the determination of the maximum tolerated dose of
[225Ac]Ac-DOTA-SP, administering activities of 10 MBq, 20 MBq, and 30 MBq. The
treatment was well tolerated by patients, with predominantly mild and transient
adverse effects such as seizures, aphasia, and hemiparesis. Most adverse effects
occurred in patients treated with the 30 MBq dose of [225Ac]Ac-DOTA-SP; hence, the
maximum tolerated dose was determined to be 20 MBq. Thrombocytopenia of grade 3 was
observed in one study participant, and no grade 3 or 4 toxicity related to the
treatment with [225Ac]Ac-DOTA-SP was reported in the other participants. The median
OS from diagnosis was 35 months, and from recurrence, it was 13.2 months. The PFS
from the start of treatment with [225Ac]Ac-DOTA-SP was 2.4 months.
Studies showed that despite different physical properties (213Bi T1/2 = 46 minutes,
225Ac T1/ 2 = 9.9 days, with 225Ac decaying through alpha particles and 213Bi
decaying only once), the survival data for patients treated with [225Ac]Ac-DOTA-SP
and [213Bi]Bi-DOTA-SP are similar. Theoretically, the significantly longer half-life
of 225Ac should allow for better distribution of [225Ac]Ac-DOTA-SP. The diffusion of
the administered radiopharmaceutical is a critical factor for effective local
therapy and depends on several factors, such as molecular weight, physicochemical
properties, varying extracellular space density, and the post-resection cavity.
Small vectors, such as modified SP (1800 Da), lead to rapid diffusion within
tissues. However, subsequent administrations may increase the density of the
extracellular space due to glioma scarring, leading to heterogeneous diffusion in
subsequent injections of the radiopharmaceutical. A limiting factor for local
treatment is the very slow rate of diffusion into brain tissue. The diffusion rate
in the brain for most substances ranges from 0.15 to 0.6 mm/h. One possible cause
could be increased tissue pressure within the tumor and surrounding tissues, which
reduces the pressure gradient responsible for the diffusion process. It seems that
enhanced diffusion could be achieved by employing forced diffusion via a slow
infusion of 0.5 ml/hour of saline into the cavity immediately after administering
the radiopharmaceutical. Overall results from both treatment arms exhibit a clear
trend for prolonged survival compared to standard therapy.
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2. Main Objective: To evaluate the efficacy of local targeted therapy with the
alpha-emitter labeled neuropeptide [225Ac]Ac-DOTA-SP (TAT) using a forced diffusion
method in cases of recurrence of glioma WHO G3-G4 after first-line treatment.
Secondary Objective: To assess the safety of local targeted therapy with the
alpha-emitter labeled neuropeptide [225Ac]Ac-DOTA-SP (TAT).
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3. Study Design: Interventional study without a control group. The study is initiated
by the investigator, and 225Ac is supplied based on a cooperation agreement between
WUM and the Institute for Transuranium Elements (Karlsruhe).
Sponsoring institution: Medical University of Warsaw (WUM). .
4. Conducting the Study:
1. Qualification visit
- - gathering a medical history, summarizing previous
diagnostics and treatments - necessary documentation from the treatment course
and imaging studies (CT scans and/or MRIs) must be provided.
During the
discussion, the doctor will provide all necessary information regarding the
study and answer any questions.
2. Reoperation with Catheter Placement:
PET/CT scan using [68Ga]Ga-PSMA to indicate the site for biopsy and catheter
placement.
Resection with biopsy or just the biopsy of the tumor. Cathether placement (for
lesions with a diameter >2 cm, up to 3 catheters may be placed). Catheter
placement will take place at the Departments of Neurosurgery of either
University Clinical Centre (UCK) or National Oncology Institute (NIO). This
requires several days of hospitalization.
3. Local Treatment with [225Ac]Ac-DOTA-SP:
Treatment with [225Ac]Ac-DOTA-SP cannot begin earlier than 2 months after the
conclusion of radiotherapy. Chemotherapy may be continued according to the
oncologist's recommendations.
Catheter patency controle about one week before planned treatment. Local
administration of 5 MBq of 68Ga in a volume of 1-3 ml. Imaging of the brain
using PET/CT Siemens Vision 600: 30 minutes after the administration of the
tracer. For the first 3 patients, dual-day imaging with 68Ga and
[68Ga]Ga-DOTA-SP will be performed to assess biodistribution: 5 MBq of 68Ga in
a volume of 1-3 ml; 5 MBq of [68Ga]Ga-DOTA-SP in a volume of 1-3 ml.
4. Conducting the Therapy:
Patients will be treated with a maximum of 6 cycles of [225Ac]Ac-DOTA-SP.
Preparation of the Radiopharmaceutical: The labeling procedure will be carried out
at the Nuclear Medicine Department at WUM. The radioisotope 68Ga is available at the
Nuclear Medicine Department; the department has a registered 68Ge/68Ga generator.
The team of radiopharmacists at the department possess the necessary qualifications
and have been performing radiopharmaceutical labeling using 68Ga for many years.
225Ac will be supplied based on a cooperation agreement between WUM and the
Institute for Transuranium Elements (Karlsruhe). After labeling, the prepared
product will undergo quality control to verify the labeling efficiency and
radiopharmaceutical purity. In any case, if the labeling efficiency is below 90%,
the product will not be administered to the patient.
Therapy: Administered activity of [225Ac]Ac-DOTA-SP
- - 20 MBq in a volume of 10-20%
of the resection cavity volume, maximum amount of SP 200 μg (combined for 68Ga and
225Ac).
- - 20-30 minutes before administering [225Ac]Ac-DOTA-SP, 250 ml of 15% mannitol,
500 ml of 0.9% NaCl, and 8 mg of dexamethasone will be administered
intravenously.
- - Immediately after administering the therapeutic dose of [225Ac]Ac-DOTA-SP along
with 5-10 MBq of [68Ga]Ga-DOTA-SP, brain imaging will be performed; acquisition
time 1-2 minutes.
- - Connection of an infusion pump with saline and administration at a rate of 0.5
ml/hour for 2-4 hours.
- - After the infusion, 2-4 hours after administering [225Ac]Ac-DOTA-SP, brain
imaging will be performed with an acquisition time lasting 4-8 minutes, and a
whole-body scan: acquisition time approx.
10 minutes.
Radioisotope treatment will be carried out in the UCK hospital, during
hospitalization at the Department of Neurosurgery. The length of hospitalization
will depend on the patient's condition; from previous experiences, this has
typically been 3 days.
Previous experiences have shown good tolerance to treatment with [225Ac]Ac-DOTA-SP.
The only noted side effects during therapy were transient facial flushing, and some
patients experienced seizures (all patients had seizures noted before therapy as
well). For this reason, patients will be hospitalized for 24 hours after therapy in
the Department of Neurosurgery (UCK).
However, in the case of poor tolerance to experimental treatment, it will not be
continued. Additionally, steroid therapy will be initiated (if it had not been
previously). In the event of a seizure, standard anticonvulsant treatment will be
applied.
Blood and urine tests will be performed 1, 2, 4, and 24 hours after administering
[225Ac]Ac-DOTA-SP.
Assessment of Distribution of [225Ac]Ac-DOTA-SP via SPECT/CT Imaging:
- - SPECT/CT imaging at two time points: 4 hours after the administration of the
therapeutic radiopharmaceutical (after PET/CT imaging is complete) and 24 hours
after its administration.
- - SPECT/CT imaging will follow a quantitative protocol developed at the Nuclear
Medicine Department (UCK) based on phantom studies, including about 30 minutes
of SPECT imaging using multiple energy windows and approximately 3 minutes of
CT imaging at reduced exposure parameters, performed to locate the accumulation
of the radiopharmaceutical and correct for radiation attenuation.
- - Before each subsequent administration and 2-4 weeks after administering
[225Ac]Ac-DOTA-SP:
Laboratory tests: Hematology, AST, ALT, Na, K, creatinine, urea, CRP, INR, D-dimers.
Assessment of the Karnofsky Performance Status (KPS). Barthel Index assessment.
Assessment of adverse effects. f. Observation: The patient should remain
hospitalized at the Department of Neurosurgery (UCK) for 24 hours after treatment
with [225Ac]Ac-DOTA-SP.
Physical examination, neurological assessment, adverse events. 24 and 48 hours after
the first administration of [225Ac]Ac-DOTA-SP. MRI with contrast will be performed
every 2 months to evaluate treatment efficacy and +/- 2 weeks before each
administration of [225Ac]Ac-DOTA-SP.
Follow-up visits (including telemedicine options) will be conducted according to
Good Clinical Practice and the therapeutic strategy used in the research center,
every 2 months during the first 18 months or depending on the clinical status of the
patient.
After 18 months, scheduled follow-up visits (including telemedicine options) will
take place every 3 months or more frequently if needed.
g. Discontinuation of Therapy: The occurrence of serious adverse events (according
to the definition related to TAT).
Coexisting illness preventing further treatment. Progression of the lesion. In the
case of the appearance of a new symptomatic solitary lesion in the MRI, treatment
may continue at the researcher's discretion, provided that the initially treated
lesion or area is stable or regressing.
Withdrawal of the patient from the study. Changes in the patient's condition that,
in the investigator's opinion, make further treatment impossible.
The investigator may decide to withdraw the patient from the study for unforeseen
reasons, ensuring their safety.
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5. Sample Size: The target sample size is 25 patients. Considering the possibility of
patient dropouts, the group should include up to 35 patients. Patients will be
recruited from those treated at the Departments of Neurosurgery (UCK, NIO).
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6. Study Endpoints:
Primary: overall survival (OS) measured from the date of diagnosis.
Secondary: time to progression (progression-free survival, PFS), defined as:
1. Clinical Progression: Clinical deterioration of performance status according to the
Karnofsky scale or worsening of neurological function. The necessity of using or
increasing the dose of corticosteroids by >50%.
2. Progression on MRI:
Local progression within < 4 cm from the border of the primary lesion after resection or,
A new lesion on MRI or, Progression of the lesion on MRI by > 25% between two consecutive
imaging studies.
In differential diagnostics, radiation necrosis should be included as a treatment-related
effect (MRI perfusion and/or biopsy).
- - Expected Benefits of the Study: The expected outcome of the study is to assess the
efficacy and safety of [225Ac]Ac-DOTA-SP with forced diffusion.
It is anticipated
that the proposed procedure should lead to an extension of survival time and time to
disease progression compared to currently used therapeutic methods.
.
- - Description of Risks and Discomforts for Study Participants: Based on current
experiences with the treatment of [225Ac]Ac-DOTA-SP, no clinically significant side
effects have been observed.
The most frequently reported side effect was seizures
(in all patients previously noted before therapy). No clinically significant side
effects were identified in laboratory tests. There is no conclusive scientific
evidence indicating that the administered local radioactivity poses a risk of
developing cancer or hereditary defects. Current data suggest an extension of PFS
and OS with the use of local treatment with [225Ac]Ac-DOTA-SP.
.
- - Study Duration with Justification: The estimated duration of the study is 3 years.
Patients who remain alive at the end of the study will be monitored until they
report death.
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- - Biological Material: During reoperation and catheter placement, material will be
collected for histopathological and genetic studies as per standard procedure.
.
- - Patient Data Anonymization: No identifiable patient data will be stored alongside
medical data subject to analysis.
Patient medical data will be analyzed anonymously
but will have an individual number corresponding to the anonymization list for each
patient.
