Treatment With AZD4547 for Recurrent Malignant Glioma Expressing FGFR-TACC Gene Fusion"

NCT02824133 | Completed Phase 1 DMC

• 2 other identifiers: P1404022014-005428-81
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief 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. 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.

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

Outcome Measures

Primary Outcomes (1)

• 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.

  6 months

Secondary Outcomes (7)

• Overall response rate measured according to RANO criteria

  6 months

• Duration of PFS

  12 months

• Overall survival

  12 months

• Safety of AZD4547 (Number of patients who experienced grade III-IV (CTCAE v4.0) toxicity related to the drug)

  6 months

• Pharmacokinetic of AZD4547: Maximum Plasma Concentration [Cmax]

  Dosages will be performed at the cycle 2 or 3: predose, 2, 3, 4 and 6h post-dose

Study Arms (1)

AZD4547

EXPERIMENTAL

AZD4547: intake of 80mg bd (160mg/day), on a continuous schedule.

Drug: AZD4547

Interventions

AZD4547 DRUG

80 mg bd (per os)

Also known as: 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

AZD4547

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Neuro onsology unit - Groupe Hospitalier Pitié-Salpêtrière

Paris, 75013, France

Location

MeSH Terms

Interventions

AZD4547; Enzymes

Intervention Hierarchy (Ancestors)

Enzymes and Coenzymes

Study Officials

• Marc Sanson, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 21, 2015
• First Posted: July 6, 2016
• Study Start: September 1, 2015
• Primary Completion: September 1, 2017
• Study Completion: October 1, 2018
• Last Updated: May 29, 2019

Record last verified: 2019-04

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)