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TKI concurrent with cerebral radiation therapy Dutch: TKI tegelijkertijd met bestraling van de hersenen


- candidate number27920
- NTR NumberNTR6707
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR15-sep-2017
- Secondary IDsMETC METC number will follow
- Public TitleTKI concurrent with cerebral radiation therapy Dutch: TKI tegelijkertijd met bestraling van de hersenen
- Scientific TitleSafety of TKI concurrent with cranial radiotherapy in NSCLC patients; the SATIN platform trial
- ACRONYMSATIN
- hypothesisTKI concurrent with cranial radiotherapy (WBRT/SRT) does not increase acute and delayed neurotoxicity
- Healt Condition(s) or Problem(s) studiedNon small cell lung cancer (NSCLC), Radiation, Brain, Brain metastasis, Neurotoxicity
- Inclusion criteriaTo be eligible to participate in this study, a patient must meet all of the following criteria:
- Stage IV NSCLC with driver mutation, treated with TKI, development of brain metastases during TKI treatment
- Indication for cranial radiotherapy determined by treating physician and radiation oncologist
- Age °› 18 years
- Ability to understand neurocognitive testing
- Written informed consent
- Exclusion criteriaA potential patient who meets any of the following criteria will be excluded from participation in this study:
- Prior radiotherapy to the brain when this precludes new radiotherapy.
- Neurologic/psychiatric illnesses (such as Alzheimer°Įs disease)
- Claustrophobia
- Metal implants or other contra-indication for MRI
- Inability to lie supine for 30 minutes time (MRI)
- mec approval receivedno
- multicenter trialyes
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-jun-2018
- planned closingdate1-jun-2020
- Target number of participants140
- Interventionsbaseline: physical examination, neurocognitive questionnaires, MRI (when not already performed as standard care), optional: blood/CSF

2 weeks after completion of cranial radiotherapy: physical examination, optional: blood/CSF

4 months after completion of cranial radiotherapy: physical examination, neurocognitive questionnaires, MRI (when not already performed as standard care)

6 months after completion of cranial radiotherapy: physical examination, neurocognitive questionnaires, MRI (when not already performed as standard care)
- Primary outcome- Incidence of severe toxicity 2 weeks after completion of cranial radiotherapy measured with CTCAE v 4.0. (Acute severe toxicity is defined as CTCAE v 4.0 grade °›3
o Incidence of increase of neurotoxicity 4 months after completion of cranial radiotherapy data will be compared to the baseline neuropsychological data (i.e. before cranial radiotherapy.
- Secondary outcomeo Incidence of increase in neurotoxicity after 6 months after completion of cranial radiotherapy compared to the baseline neurocognitive data (i.e. before cranial radiotherapy).

exploratory
-Intracranial PFS at 4 and at 6 months after completion of cranial radiotherapy (measured with MRI).
- Brain penetration potential, measured by the unbound brain-to-plasma ratio (Kp,uu), before and 2 weeks after completion of cranial radiotherapy (optional for patients) and to correlate this ratio with toxicity (CTCAE v 4.0) 2 weeks after cranial radiotherapy.
-Plasma concentration of the TKI before and 2 weeks after cranial radiotherapy and to correlate this concentration with toxicity (CTCAE v 4.0) 2 weeks after cranial radiotherapy
- Timepointssee interventions
visits baseline, 2 weeks after completion of cranial radiotherapy, 4 months and 6 months after completion of cranial radiotherapy
- Trial web site
- status[default]
- CONTACT FOR PUBLIC QUERIESMD PhD Anne-Marie C. Dingemans
- CONTACT for SCIENTIFIC QUERIESMD PhD Anne-Marie C. Dingemans
- Sponsor/Initiator Maastricht University Medical Center (MUMC+)
- Funding
(Source(s) of Monetary or Material Support)
- Publications
- Brief summarySUMMARY

Rationale:
Non-small cell lung cancer (NSCLC) is one of the major causes of cancer related mortality worldwide.
Increasingly, new molecular features of NSCLC are being discovered, leading to an unprecedented growth of targeted agents, such as tyrosine kinase inhibitors (TKIs). Currently, TKIs are approved for metastasized NSCLC patients with a driver mutation (EGFR, ALK, ROS1). Approximately 20-35% of these patients are diagnosed with brain metastasis at initial diagnosis and are often amenable for initial treatment with a TKI. A relatively high percentage will also develop new brain metastases or progression of brain metastases during the course of their disease, often while on TKI treatment.
In patients with brain metastases both whole brain radiotherapy (WBRT) and stereotactic radiosurgery/stereotactic radiotherapy (SRS/SRT) can be considered as a local therapy. Neurotoxicity after brain radiotherapy is especially seen with WBRT, but also SRT. The radio-induced neurocognitive impairment evolves in a biphasic pattern: a subacute transient decline with a peak at four months, and a late delayed irreversible impairment several months or years after completion of WBRT. However, these results were obtained in unselected patients with often a poor overall prognosis, and it is not clear whether the deterioration resulted from radiotoxicity or intracranial progression. Moreover, the brain metastases itself can cause neurological complaints, also before initiation of radiotherapy. Patients with a driver mutation have a superior prognosis compared to those without, even in the presence of brain metastases. It has also been suggested that EGFR-mutated and ALK-translocated NSCLC cells have a higher radiosensitivity than wildtype NSCLC but it is unclear what the impact is on neurotoxicity after cranial radiotherapy.
In current guidelines, no advice regarding TKI use during cranial radiotherapy is given. As the TKI may still be active on extra-cranial sites, clinicians are faced with the question whether to continue the TKI or not. Especially because rapid flare of the disease is a known phenomenon after interruption of a TKI. Preclinical studies suggest that TKIs enhance radiation effects but the effects on normal tissues are unclear.
In daily practice TKIís are given concurrent with cranial radiotherapy or they are discontinued during cranial radiotherapy because of (neuro)toxicity concerns, depending on the treating physician. When the TKIís are being discontinued, they are stopped for approximately one week before, during and one week after the radiotherapy (i.e. approximately 3 weeks) with the risk of a systemic disease flare-up.
Advantages of combining TKI with cranial radiotherapy would be a possible synergistic effect on the brain metastases and the prevention of a systemic disease flare-up.
As cranial radiotherapy will be indicated for a significant number of these patients we want to extensively evaluate neurotoxicity in patients with a driver mutation, treated with concurrent brain radiotherapy and a TKI. Even though this concurrent treatment is rapidly becoming standard practice, detailed neurotoxicity data are not available for this patient group.

Objectives:
Primary Objectives:
- To assess whether there is acute severe toxicity (per TKI) 2 weeks after completion of cranial radiotherapy measured with CTCAE v 4.0.
- To assess whether there is an increase in neurotoxicity 4 months after completion cranial radiotherapy.

Secondary Objectives:
- To assess whether there is an increase in neurotoxicity 6 months after completion of cranial radiotherapy.

Exploratory:
- To assess what the brain penetration potential is, measured by the unbound brain-to-plasma ratio (Kp,uu), before and 2 weeks after cranial radiotherapy and to correlate these ratio with toxicity (CTCAE v 4.0) 2 weeks after cranial radiotherapy.
- To assess the plasma concentration of the TKI before and 2 weeks after cranial radiotherapy and to correlate this concentration with toxicity (CTCAE v 4.0) 2 weeks after cranial radiotherapy
- To assess what the intracranial PFS is at 4 and at 6 months after completion of cranial radiotherapy.

Study design:
Phase IV trial
- Duration: 2 year per TKI
There will be different cohorts, every TKI will be assessed separately. (erlotinib, gefitinib, afatinib, osimertinib, crizotinib, ceritinib, alectinib, crizotinib). For every TKI there is a WBRT (N=10) and a SRT (N=10) cohort. Patients are already treated with a TKI, the TKI is not part of the study. Patients are already scheduled for WBRT/SRT, this decision is not influenced by this trial. When a new TKI becomes available a new cohort will open and an amendment will be presented.
o Duration per patient will be approximately 6 months.
o Normally about 20 patients with a driver mutation are seen in 1 year at 1 centre. Of these patients about 5 will develop brain metastasis and are eligible for the study. There will be 5 centres that participate.
- Setting: the 5 centres (MUMC, VUmc, NKI/ AVL, UMCG, Erasmus MC) that are NVALT acknowledged as specialised driver mutation centers.

Study population:
NSCLC patients with driver mutation, treated with TKI, development of brain metastasis during TKI treatment, already scheduled for WBRT/SRT.

Intervention:
Standardized neurocognitive examination will be done before radiotherapy, after 4 months and after 6 months. This will be measured by the following tests: neurological examination, HVLT-R, Trail making test part A and B, Controlled Oral Word Association, Digit symbol Subtest of the WAIS III and grooved Pegboard. A magnetic resonance imaging (MRI) of the brain will be performed at 4 and at 6 months (partly already usual care). Optionally cerebrospinal fluid (CSF) will be obtained by lumbar puncture before and two weeks after radiotherapy. Optionally blood will be obtained by venepuncture before and two weeks after radiotherapy.

Main study parameters/endpoints:
Primary endpoints:
Incidence of acute severe toxicity (per TKI) 2 weeks after completion of cranial radiotherapy, measured with CTCAE v 4.0
Neurotoxicity 4 months after completion of cranial radiotherapy
Secondary endpoints:
Neurotoxicity 6 months after completion of cranial radiotherapy
Exploratory:
Intracranial PFS 4 and 6 months after completion of cranial radiotherapy
CSF concentration of TKI before and 2 weeks after radiotherapy (optional for patients) in relation to acute toxicity (CTCAE v 4.0)
Plasma concentration of the TKI before and 2 weeks after cranial radiotherapy and to correlate this concentration with toxicity (CTCAE v 4.0) 2 weeks after cranial radiotherapy


Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The MRI and questionnaires that are used in this study are non-invasive except for a venapuncture to administer gadolinium-contrast for the MRI (and half of the MRIs are standard care for these patients). The risks of a MRI-scan are negligible because it is a magnetic field and does not involve ionizing. The venapuncture can cause a hematoma. The MRI will be performed twice (once already as standard care), preferably the same day as regular visits. Time per MRI is approximately 30 minutes. The neurocognitive testing will take about 60 minutes. This will also be done at the same day as regular visits.
Obtaining CSF by lumbar puncture is optional and is an invasive investigation. It will take about 10 minutes and will be done by an experienced neurologist. As a possible complication of the puncture a temporary headache can occur.
- Main changes (audit trail)
- RECORD15-sep-2017 - 7-okt-2017


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