This study has been transitioned to CTIS with ID 2024-515466-13-00 check the CTIS register for the current data. The purpose of this study is to assess the safety and tolerability of intravenous 131I-TLX101 administered concomitantly and…
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Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To determine the safety and tolerability of 131I-TLX-101 in combination with
standard of care treatment in newly diagnosed Glioblastoma (GBM)
patients, by determining the Dose Limiting Toxicities (DLT), Maximum Tolerated
Dose (MTD) and Recommended Phase 2 Dose (RP2D). This will be done by assessing
TEAEs type (treatment emergent adverse events) type according to MedDRA,
frequency, severity according to NCI CTCAE V5.0, seriousness, and relationship
of study treatment will be assessed. Laboratory abnormalities will be assessed
according to the NCI CTCAE V5.0.
- Incidence rate and the grade (severity) of DLTs based on the occurrence of
Adverse Events (AEs) reported according to the NCI CTCAE v5.0. DLTs include any
grade >= 3 events considered possibly related to the study drug, but excludes
cerebral oedema, and haematological toxicity.
Secondary outcome
- 1-year overall survival rate of patients treated with 131I-TLX-101 plus
standard of care treatment.
- 2-year overall survival rate of patients treated with 131I-TLX-101 plus
standard of care treatment.
- To determine Progression Free Survival (PFS) from the date of enrolment to
the date of progression or death for any cause, whichever comes first, assessed
up to 51±1 weeks.
- To determine best Objective Response Rate (ORR) in patients with partial
response at weeks 7, 15, 23, 31, 43±1, and 51±1 as defined by modified Response
in Neuro-Oncology (mRANO)* criteria.
- To determine ORR in patients with stable disease at weeks 7, 15, 23, 31,
43±1, and 51±1 as defined by mRANO criteria
- To determine safety throughout study completion for each participant, for a
minimum of 51±1 weeks
- To determine Quality of Life (QoL) as determined using the EORTC QLQ-C30
questionnaire and Quality of Life Questionnaire - Brain Neoplasm (QLQBN20)
questionnaires, and neurocognitive tests: Controlled Oral Word Association Test
(COWA test), Hopkins Verbal Learning Test-Revised (HVLT-R test), and Trail
Making Test (TMT)
Background summary
Glioblastoma is the most aggressive, invasive, and frequently occurring type of
primary astrocytomas. GBM accounts for over 60% of all central nervous system
(CNS) tumours, with extremely poor prognosis. Despite of ideal
multidisciplinary treatment, including maximal surgical resection, followed by
radiotherapy plus concomitant and maintenance TMZ, almost all patients
experience tumor progression. Metabolic reprogramming is vastly identified as a
hallmark of malignancy. The proliferation of cancer cells is highly dependent
on acquisition of exogenous amino acids, where its uptake and metabolism are
aberrantly upregulated in several types of cancer, including GBM. Transmembrane
uptake of amino acids is strictly regulated by Amino Acid Transporters (AAT).
Numerous studies have suggested that LAT-1 expression in cancerous tissues is
higher than that in normal tissues and LAT-1 expression is correlated with the
growth and proliferation of cancer cells, thus making LAT-1 an ideal target for
cancer therapy and radio-imaging.
A combined treatment strategy is suggested to advance GBM treatment efficacy,
in order to address the following challenges:
i) the infiltrative character of the tumour beyond a safety margin makes it
impossible to surgically resect all GBM cells,
ii) systemic chemotherapy reaches the cerebral compartment only to a limited
extent, and
iii) hypoxia and an acidotic milieu of the intratumoral and peritumoral
microenvironment reduce the efficacy of External Beam Radiation Therapy (EBRT)
and chemotherapy.
Currently, Targeted Radiation Therapy (TRT) is considered a potential additive
and potent treatment for primary GBM in combination with standard therapy, or
as an auxiliary treatment when the tumour tissue seems to be radio and/or
chemo-resistant. In the case for EBRT, TRT such as 131I-IPA, causes DNA damage
and is therefore likely to be enhanced by combination with chemotherapeutic
radiosensitisers such as Temozolomide (TMZ).
Upon intravenous administration,131I-IPA actively crosses the BBB and
accumulate specifically in gliomas, presumably via LAT-1 and ASC (Alanine,
Serine and Cystine) amino acid transporters, which are overexpressed in
malignant glioma cells.
Notwithstanding intense preclinical research and clinical trials, standard
therapy has not changed over the past decade. Generally, a combined treatment
strategy is suggested to advance GBM treatment efficacy, and to address the
following challenges: the infiltrative character of the tumour beyond a safety
margin makes it impossible to surgically resect all GBM cells; systemic
chemotherapy reaches the cerebral compartment only to a limited extent and
hypoxia and an acidotic milieu of the intratumoral and peritumoral
microenvironment reduce the efficacy of EBRT and chemotherapy. TRT is
considered a potential additive and potent treatment for primary GBM in
combination with standard therapy. In addition,
131I-IPA has been well tolerated by the patients to whom it was administered.
The present study aims to investigate the safety and efficacy of 131I-IPA in
combination with chemoradiation (consisting of TMZ and EBRT) in newly diagnosed
GBM patients
Study objective
This study has been transitioned to CTIS with ID 2024-515466-13-00 check the CTIS register for the current data.
The purpose of this study is to assess the safety and tolerability of
intravenous 131I-TLX101 administered concomitantly and sequentially with
standard of care in patients newly diagnosed with GBM, to determine the MTD and
the R2PD.
Study design
This is an open label, single arm, parallel-group, multicentre, and dose
finding study to evaluate ascending radioactive dose levels of 4-L-[131I]
iodo-phenylalanine (c.a.131I-IPA) administered intravenously in combination
with best standard of care (SoC) in newly diagnosed Glioblastoma Multiforme
patients.
Approximately 12 participants may be enrolled and treated in cohorts according
to a *3+3* study design with SoC consisting of radiotherapy of 60 Gy/30
fractions for 6 weeks plus 75 mg/m2 TMZ daily (chemoradiotherapy), followed by
4 weeks of treatment break. Participants will receive a
maintenance treatment with 6 maintenance cycles of TMZ 150-200 mg/m2 on Days 1
to 5 q28. 131I-IPA will be administered in 2 fractions corresponding to * full
dose activity, via IV infusion. Participants will be admitted to the hospital
or research facility at Day 0 and receive their first dose of IP prior to the
commencement of chemoradiation therapy and admitted again on Day 56, after
completion of chemoradiation therapy, to receive the second dose of IP, and
discharged at Day 60±3. The first dose of 131I-IPA must be given at least a
week prior to commencement of chemoradiotherapy, and the second dose of
131I-TLX101 must be given 10 days after completion of chemoradiotherapy.
A classic *3+3* study design will be followed to establish DLT, MTD and RP2D.
Initially, 3 participants will be enrolled to a cohort, the occurrence of a
single drug related, grade >=3 DLT in one these 3 patients will prompt the
enrolment of an additional 3 participants to that same cohort. If more than one
grade >=3 DLT occurs in <=6 participants in a dosing cohort, dose escalation will
be stopped, and this dose level will be identified as the non-tolerated dose.
Doses between the non-tolerated dose and the preceding lower dose, where <= 1
grade >=3 DLT occurred, may be explored to more precisely define the MTD.
Intervention
On Day 0 of the study, the patient will receive their first dose of 131-IPA by
intravenous infusion. On Day 7 standard treatment will start with chemotherapy
(temozolomide=TMZ) and radiotherapy and will last for 6 weeks. TMZ will be
administered with a dosage of 75mg/m2 and radiotherapy of 60Gy/30 fractions. On
Day 56, the second dose 131I-IPA will be administered, only after completion of
the standard treatment on that same day.
Four weeks after completing the chemoradiation (TMZ + EBRT), TMZ is
administered for an additional 6 cycles of maintenance treatment. Dosage in
Cycle 1 (maintenance) is 150 mg/m2 once daily for 5 days followed by 23 days
without treatment. After, that another 5 cycles of each 28 days will follow,
during each first 5 days TMZ will be administered. At the start of the 2nd
cycle the dose can be escalated to 200 mg/m2, depending on safety and lab
values.
Study burden and risks
Participation in this study can have some risks and cause some burden for each
participant. The study consists out of 16 study-visits. These visits can cost
extra time compared to regular visits. During the study, 14 times blood samples
will be drawn (in total about 150 ml), 5 times an ECG will be done, and several
scans will be made (18F-FET PET scan, an MRI and a SPECT), which can cause some
discomfort. In addition, during the study each participant will be asked 7
times to complete questionnaires. Also 4 times neurological assessments will be
conducted. Seven times a physical examination will be performed.
After administering 131I-IPA (2 times) each participant will have to stay in an
isolation room in the hospital for up to 6-7 days.
Administering 131I-IPA can also cause some discomfort and risks. This can be:
diarrhea, feeling tired (fatigue), mild allergic reaction (i.e. rash), nausea,
vomiting, stomach pain (abdominal pain), higher chance of getting infections,
low levels of white blood cells, anemia, coagulation disorders and with it
bruising, loss of weight, dizziness, neck pain or stiffness, headache, hiccups,
flushing of the skin.
Suite 401, Flemington Road 55
North Melbourne VIC 3051
AU
Suite 401, Flemington Road 55
North Melbourne VIC 3051
AU
Listed location countries
Age
Inclusion criteria
1. Understand and voluntarily sign the informed consent form prior to any study
relatedprocedure and/or assessments being conducted.
2. Are Male or Female, and aged 18 and older, at the time of signing the
informed consent.
3. Have histologically confirmed intracranial glioblastoma (per WHO 2021
definition) following surgical resection. Tumours primarily localised in the
infratentorial compartment will be excluded.
4. Have had prior surgery for glioblastoma, but no systemic therapy or
radiation therapy for
GBM.
5. Have a Karnofsky Performance Status >=70.
6. Plan to begin chemoradiation therapy 3-6 weeks after surgical resection with
Stupp regimen.
7. Have adequate organ function at Screening:
7.1 Bone marrow:
7.1.1 Leukocytes >=3x10^9/L
7.1.2 Absolute neutrophil count >=1.5x10^9/L
7.1.3 Platelets >=100x10^9/L
7.1.4 Haemoglobin >=9g/dL
7.2 Liver function:
7.2.1 Total bilirubin <=1.5×the upper limit of normal (ULN). For patients with
known Gilbert*s Syndrome <=3×ULN is permitted
7.2.2 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
<=2.5×ULN
7.3 Renal function:
7.3.1 Serum/plasma creatinine <=1.5×ULN or creatinine clearance >=50 mL/min
8. Have at least 6 slides without staining or a tissue block (frozen or
paraffin-embedded) available from a previous biopsy or surgery (tumour sample
previously archived).
9. Have the capacity to understand the study and be able and willing to comply
with all protocol requirements, including compliance with the radiation
protection guidelines (including hospital admissions and isolation) that are
applied by the treating institution to protect their contacts and the public.
10. Agree to practice adequate precautions to prevent pregnancy to avoid
potential problems associated with radiation exposure to the unborn child.
11. Females must have a negative pregnancy test at screening and on dosing day,
must not be lactating.
Exclusion criteria
1. Are unable to provide signed informed consent
2. Have had prior treatment for glioma, excluding surgery.
3. Are unable to undergo contrast-enhanced MRI.
4. Intend to be treated with tumor-treating fields prior to progression.
5. Have a history or evidence of delayed-type hypersensitivity (DTH)-dependent
chronic infection (e.g., tuberculosis, systemic fungal or parasitic infection),
potentially exacerbating under systemic corticoid therapy.
6. Have a known history of allergy TMZ, any excipient in the study medication
or any other intravenously administered human proteins/peptides/antibodies.
7. Have haemostaseologic conditions, precluding catheterisation or invasive
procedures.
8. Have phenylketonuria
9. Have any medical condition that in the opinion of the Investigator may
interfere with the participant*s ability to adhere to the study or may impose a
risk to the participant*s health.
10. Major trauma including major surgery (such as abdominal/cardiac/thoracic
surgery) within 3 weeks of administration of study treatment except surgery on
primary tumour.
11. Pregnant, breastfeeding or planning to get pregnant during the duration of
the study.
12. Requirement of chronic administration of high dose corticosteroids or other
immunosuppressant drugs. Limited or occasional use of corticosteroids to treat
or prevent acute adverse reactions is not considered an exclusion criterion.
13. Have presence of active and uncontrolled infections or other severe
concurrent disease, which, in the opinion of the investigator, would place the
participant at undue risk or unable to comply with study requirements.
HIV-positive participants may be included in the study if they are on a stable
dose of anti-retroviral therapy.
14. Have concurrent malignancies (except: basal cell carcinoma, in situ breast
cancer) unless the patient has been disease-free without intervention for at
least 2 years.
15. Have taken growth factors or immunomodulatory agents within 7 days prior to
the administration of study treatment.
16. Have serious, non-healing wound, ulcer, or bone fracture.
17. Have a requirement of concurrent use of other anti-cancer treatments or
agents other than study medication.
18. Have received any other IMP within 90 days prior to the planned
administration of study drug.
19. Have uncontrolled Hashimoto*s or Grave*s disease
20. Have on-going and unresolved Grade >= 1 AEs following surgical resection
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515466-13-00 |
| EudraCT | EUCTR2022-003038-38-NL |
| ClinicalTrials.gov | NCT0540744/EudraCTnr:2022-003038-38 |
| CCMO | NL82923.041.22 |