Recurrent IDHwt Gliomas With FGFR3-TACC3 FusionPhase 1/2TARGETNCT02824133
Treatment With AZD4547 for Recurrent Malignant Glioma Expressing FGFR-TACC Gene Fusion"
A Phase 1/2 study testing AZD4547 in people with Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion and Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
The investigators will look for the presence of the fusion gene in all patients operated on for glioma. This search will be limited to all gliomas that show no IDH1 mutation, the latter being sought in both routine and anomalies never co-existing. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion, Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion
- What is being tested?
- AZD4547
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteFrance
- Study dates
- Sep 2015to Oct 2018
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Recurrent glioma after standard treatment, expressing the FGFR3-TACC3 or FGFR1-TACC1 fusion gene as confirmed by RT-PCR sequencing.
- First recurrence occurring more than three months from the end of the radiotherapy or occurring outside the irradiated volume.
- World Health Organisation performance status 0-2 (KPS>50) with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
- Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
- If a patient declines to participate in any voluntary exploratory research component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study
- Aged at least 18 years.
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- Patients should be using adequate contraceptive measures which should be maintained during the whole duration of AZD4547 treatment and at least 7 days after treatment suspension. Females should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
- Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments.
- Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
Who cannot join
- Treatment with any of the following:
- Nitrosourea within 6 weeks before the first dose of study treatment
- Any investigational agents or study drugs from a previous clinical study within 30 days before the first dose of study treatment
- Any other chemotherapy, anticancer immunotherapy or anticancer agents within 4 weeks before the first dose of study treatment, except hormonal therapy.
- Potent inhibitors or inducers of CYP3A4 or 2D6 or substrates of CYP3A4 within the required washout period as specified in the section 7.3
- Prior treatment in this or another AZD4547 study, or prior randomisation in a study in which AZD4547 is/was under investigation. Prior treatment with any FGFR inhibitor.
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- Major surgery (excluding placement of vascular access) within 14 days before the first dose of study treatment
- With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment
- As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required
- Any of the following cardiac criteria:
- Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's correction.Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
- History of myocardial infarction, unstable angina, stroke or transient ischemic attack within the last 6 months
- Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
- Absolute neutrophile count <1.5 x 109/L
- Platelet count <100 x 109/L
- Haemoglobin <90 g/L
- Alanine aminotransferase >2.5 times the upper limit of normal (ULN)
- Aspartate aminotransferase >2.5 times ULN Total bilirubin >1.5 times ULN
- Creatinine >1.5 times ULN concurrent with creatinine clearance <50 ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN
- Corrected calcium >ULN
- Phosphate >ULN
- Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD4547
- History of hypersensitivity to active or inactive excipients of AZD4547 or drugs with a similar chemical structure or class to AZD4547
- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements
- Any of the following ophthalmological criteria:
- Current evidence or previous history of retinal pigmented epithelium detachment (RPED)
- Previous laser treatment or intra-ocular injection for treatment of macular degeneration
- Current evidence or previous history of dry or wet age-related macular degeneration
- Current evidence or previous history of retinal vein occlusion (RVO)
- Current evidence or previous history of retinal degenerative diseases (eg, hereditary)
- Current evidence or previous history of any other clinically relevant chorioretinal defect
- Contraindications to MRI
Trial locations and contacts
1 site in 1 country.
France1 site
Neuro onsology unit - Groupe Hospitalier Pitié-Salpêtrière
Paris, 75013
About this study
Official title: A Phase I/II, Open-Label, Multicentre Study to Assess The Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of AZD4547 in Patients With Relapsed/Refractory Glioma Positive for an FGFR Fusion
The investigators will look for the presence of the fusion gene in all patients operated on for glioma. This search will be limited to all gliomas that show no IDH1 mutation, the latter being sought in both routine and anomalies never co-existing.
The hypothesis is that the rate of progression-free survival in grade IV gliomas and III without IDH1 mutation, with the usual chemotherapy, only 15% at 6 months (ie, 85% of patients relapse before 6 months of treatment), must be with this new treatment 35% (primary endpoint).
The main objective is the evaluation of disease-free survival at 6 months.
Read the detailed description
3% of GBM and IDHwt gliomas have a highly oncogenic FGFR-TACC gene fusion that confers high sensitivity to FGFR inhibitors to tumor cells, in vitro and in vivo. Preclinical data shows that expression of FGFR-TACC fusions confers sensitivity to FGFR inhibitors (including AZD4547) to GBM models.AZD4547 (AstraZeneca) is a potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases. Preclinical data have shown some CNS penetration. Some of the important adverse events are hyperphosphatemia, and ocular complications. The primary objective and assessment criterion is to assess the efficacy of AZD4547 by measuring the rate of Progression Free Survival at 6 months (PFS6) in recurrent malignant glioma patients with FGFR-TACC fusion.Secondary objectives and assessment criteria are: - To characterize the safety, tolerability and PK of AZD4547 in glioma patients
- To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with FGFR-TACC fusion based on Overall Response Rate for patients with a measurable residue.
- To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with FGFR-TACC fusion based on the duration of PFS
- To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with a FGFR-TACC fusion based on Overall Survival AZD4547 Exploratory objectives - To elucidate the mechanism of response and resistance (primary and secondary) by exploratory biomarker analysis Experimental design: This is a phase II study in patients diagnosed with a FGFR3-TACC3 or FGFR1-TACC1 fusion positive glioma presenting with a recurrence of the disease after chemotherapy and radiotherapy. RNA will be systematically screened for the presence of FGFR-TACC in each of the 11 participating centers, and IHC for FGFR3 hyperexpression. The investigators also encourage a wide use of FGFR3 IHC in non participating centers in order to identify additional potential candidates who can be referred to one of the 11 centers for assessment of FGFR-TACC expression by RNA analysis..
Patients will receive AZD4547 at a dose of 80mg bd on a continuous schedule, until disease progression. With the following hypothesis: P0: PFS6=15%, P1: PFS6=35%, with alpha=5% and power=80%, an initial cohort of 12 patients will be treated. If objective anti-tumor effects are observed, the cohort will be expanded to include a total number of 38 subjects. Grade II gliomas are also eligible but they will constitute an extra small cohort.
- Conditions
- Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion, Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion
- Being tested
- AZD4547
- Keywords
- Glioma grade III, Glioma grade IV, Glioma recurrent, IDHwt, FGFR-TACC fusion
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD4547Drug
Also called Potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases (enzyme and cellular phosphorylation endpoints) with lower potency for inhibition of IGF1R and KDR
80 mg bd (per os)
| Study group | Role | What they receive |
|---|---|---|
| AZD4547 | Experimental | AZD4547: intake of 80mg bd (160mg/day), on a continuous schedule. Receives: Drug: AZD4547 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival measured according to RANO (Response Assessment in Neuro-Oncology) criteria
To assess the efficacy of AZD4547 by measuring the rate of Progression Free Survival at 6 months (PFS6) in recurrent malignant glioma patients with FGFR-TACC fusion.
Measured: 6 months
Secondary outcomes (7)
Overall response rate measured according to RANO criteria
To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with FGFR-TACC fusion based on Overall Response Rate for patients with a measurable residue.
Measured: 6 months
Duration of PFS
To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with FGFR-TACC fusion based on the duration of PFS
Measured: 12 months
Overall survival
To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with a FGFR-TACC fusion based on Overall Survival AZD4547
Measured: 12 months
Safety of AZD4547 (Number of patients who experienced grade III-IV (CTCAE v4.0) toxicity related to the drug)
Measured: 6 months
Pharmacokinetic of AZD4547: Maximum Plasma Concentration [Cmax]
Measured: Dosages will be performed at the cycle 2 or 3: predose, 2, 3, 4 and 6h post-dose
Pharmacokinetic of AZD4547: Area Under the Curve [AUC]).
Measured: Dosages will be performed at the cycle 2 or 3: predose, 2, 3, 4 and 6h post-dose
Pharmacokinetic of AZD4547: Residual Plasma Concentration
Measured: Dosages will be performed at the cycle 2 or 3: predose, 2, 3, 4 and 6h post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jul 2016 (estimated)
- Study startSep 2015
- Primary completionSep 2017
- Study completionOct 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Recurrent IDHwt Gliomas With FGFR3-TACC3 FusionStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Marc Sanson, MD, PhD, Principal investigator, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02824133
- Sponsor's protocol ID
- P140402
- Other IDs
- 2014-005428-81, 2014
- Acronym
- TARGET
- Status last verified
- Apr 2019
- First submitted
- 21 Dec 2015
- Last updated
- 29 May 2019
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II, Open-Label, Multicentre Study to Assess The Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of AZD4547 in Patients With Relapsed/Refractory Glioma Positive for an FGFR Fusion
- ClinicalTrials.gov ID
- NCT02824133
- Acronym / sponsor ID
- TARGET / P140402
- Conditions
- Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion, Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion
- Keywords
- Glioma grade III, Glioma grade IV, Glioma recurrent, IDHwt, FGFR-TACC fusion
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Sep 2015 (actual)
- Primary completion
- Sep 2017 (actual)
- Study completion
- Oct 2018 (actual)
- First posted
- 6 Jul 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigators will look for the presence of the fusion gene in all patients operated on for glioma. This search will be limited to all gliomas that show no IDH1 mutation, the latter being sought in both routine and anomalies never co-existing.
The hypothesis is that the rate of progression-free survival in grade IV gliomas and III without IDH1 mutation, with the usual chemotherapy, only 15% at 6 months (ie, 85% of patients relapse before 6 months of treatment), must be with this new treatment 35% (primary endpoint).
The main objective is the evaluation of disease-free survival at 6 months.
Detailed description
3% of GBM and IDHwt gliomas have a highly oncogenic FGFR-TACC gene fusion that confers high sensitivity to FGFR inhibitors to tumor cells, in vitro and in vivo. Preclinical data shows that expression of FGFR-TACC fusions confers sensitivity to FGFR inhibitors (including AZD4547) to GBM models.AZD4547 (AstraZeneca) is a potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases. Preclinical data have shown some CNS penetration. Some of the important adverse events are hyperphosphatemia, and ocular complications. The primary objective and assessment criterion is to assess the efficacy of AZD4547 by measuring the rate of Progression Free Survival at 6 months (PFS6) in recurrent malignant glioma patients with FGFR-TACC fusion.Secondary objectives and assessment criteria are: - To characterize the safety, tolerability and PK of AZD4547 in glioma patients
- To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with FGFR-TACC fusion based on Overall Response Rate for patients with a measurable residue.
- To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with FGFR-TACC fusion based on the duration of PFS
- To further assess the anti-tumor activity of AZD4547 for patients with recurrent glioma with a FGFR-TACC fusion based on Overall Survival AZD4547 Exploratory objectives - To elucidate the mechanism of response and resistance (primary and secondary) by exploratory biomarker analysis Experimental design: This is a phase II study in patients diagnosed with a FGFR3-TACC3 or FGFR1-TACC1 fusion positive glioma presenting with a recurrence of the disease after chemotherapy and radiotherapy. RNA will be systematically screened for the presence of FGFR-TACC in each of the 11 participating centers, and IHC for FGFR3 hyperexpression. The investigators also encourage a wide use of FGFR3 IHC in non participating centers in order to identify additional potential candidates who can be referred to one of the 11 centers for assessment of FGFR-TACC expression by RNA analysis..
Patients will receive AZD4547 at a dose of 80mg bd on a continuous schedule, until disease progression. With the following hypothesis: P0: PFS6=15%, P1: PFS6=35%, with alpha=5% and power=80%, an initial cohort of 12 patients will be treated. If objective anti-tumor effects are observed, the cohort will be expanded to include a total number of 38 subjects. Grade II gliomas are also eligible but they will constitute an extra small cohort.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AZD4547 | Experimental | Drug: AZD4547AZD4547: intake of 80mg bd (160mg/day), on a continuous schedule. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Recurrent glioma after standard treatment, expressing the FGFR3-TACC3 or FGFR1-TACC1 fusion gene as confirmed by RT-PCR sequencing.
- First recurrence occurring more than three months from the end of the radiotherapy or occurring outside the irradiated volume.
- World Health Organisation performance status 0-2 (KPS>50) with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
- Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
- If a patient declines to participate in any voluntary exploratory research component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study
Key exclusion criteria (33 listed)
- Treatment with any of the following:
- Major surgery (excluding placement of vascular access) within 14 days before the first dose of study treatment
- With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment
- As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required
- Any of the following cardiac criteria:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD4547Also: Potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases (enzyme and cellular phosphorylation endpoints) with lower potency for inhibition of IGF1R and KDR80 mg bd (per os) | Drug | AZD4547 |
Primary outcome
Progression free survival measured according to RANO (Response Assessment in Neuro-Oncology) criteria
Time frame: 6 months
To assess the efficacy of AZD4547 by measuring the rate of Progression Free Survival at 6 months (PFS6) in recurrent malignant glioma patients with FGFR-TACC fusion.
7 secondary outcomes
Overall response rate measured according to RANO criteria
Time frame: 6 months
Duration of PFS
Time frame: 12 months
Overall survival
Time frame: 12 months
Safety of AZD4547 (Number of patients who experienced grade III-IV (CTCAE v4.0) toxicity related to the drug)
Time frame: 6 months
Pharmacokinetic of AZD4547: Maximum Plasma Concentration [Cmax]
Time frame: Dosages will be performed at the cycle 2 or 3: predose, 2, 3, 4 and 6h post-dose
Pharmacokinetic of AZD4547: Area Under the Curve [AUC]).
Time frame: Dosages will be performed at the cycle 2 or 3: predose, 2, 3, 4 and 6h post-dose
Pharmacokinetic of AZD4547: Residual Plasma Concentration
Time frame: Dosages will be performed at the cycle 2 or 3: predose, 2, 3, 4 and 6h post-dose
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2019.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marc Sanson, MD, PhD principal investigator
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing AZD4547 in people with Recurrent IDHwt Gliomas With FGFR3-TACC3 Fusion and Recurrent IDHwt Gliomas With FGFR1-TACC1 Fusion, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 May 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival measured according to RANO (Response Assessment in Neuro-Oncology) criteria (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2019.