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Astrocytoma

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Neuroectodermal Tumors, Primitive

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Anticonvulsants

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Hydroxyurea

Imatinib Mesylate

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Tyrosine

Patients took imatinib 600 mg (1 imatinib 400 mg tablet and 2 imatinib 100 mg tablets) orally once daily with the morning meal. Patients were instructed to swallow the tablets while drinking a large glass of water. In addition to imatinib, patients took hydroxyurea 500 mg orally twice daily with the morning and evening meals. Patients were not allowed concomitant use of enzyme-inducing anticonvulsant drugs.

Patients took imatinib 500 mg (1 imatinib 400 mg tablet and 1 imatinib 100 mg tablet) orally twice daily with the morning and evening meals. Patients were instructed to swallow the tablets while drinking a large glass of water. In addition to imatinib, patients took hydroxyurea 500 mg orally twice daily with the morning and evening meals. Patients were allowed concomitant use of enzyme-inducing anticonvulsant drugs.

Imatinib was supplied as 100 and 400 mg tablets by Novartis.

Imatinib tablets

Hydroxyurea was supplied locally as 500 mg capsules.

Hydroxyurea capsules

David Reardon, Dr.

This was an investigational study to assess the objective overall response (OOR) rate (complete response \[CR\] + partial response \[PR\]) of imatinib mesylate and hydroxyurea (hydroxycarbamide) combination therapy in patients with recurrent glioblastoma multiforme (brain tumors). This study also evaluated the duration of tumor response (as per MacDonald criteria), clinical benefit, progression-free survival rate at 6 and 12 months, and the survival rate at 12 and 24 months.

This ClinicalTrials.gov record includes the results from two studies (Novartis protocol IDs CSTI571H2201 and CSTI571H2202) which were conducted separately but reported together in a single clinical study report. Both studies were phase II, open-label, multicenter, single-arm studies that evaluated the efficacy of imatinib mesylate plus hydroxyurea in subjects with progressive glioblastoma multiforme. The studies were identical in design with two exceptions: Patients in study CSTI571H2201 received a dose of imatinib 600 mg once daily and were not allowed concomitant use of enzyme-inducing anticonvulsant drugs (EIACDs); patients in study CSTI571H2202 received a dose of imatinib 500 mg twice daily and were allowed concomitant use of EIACDs.

Efficacy and Safety of Imatinib Mesylate Plus Hydroxyurea (HU) in Patients With Recurrent Glioblastoma Multiforme (GBM)

A Phase II, Open-label, Multicenter Study Evaluating the Efficacy of Imatinib Plus Hydroxyurea (HU) in Patients With Progressive Glioblastoma Multiforme (GBM) Receiving or Not Receiving Enzyme-inducing Anticonvulsant Drugs (EIACDs)

Patients with an OOR were those whose best response to treatment was a complete response (CR) or a partial response (PR) assessed with magnetic resonance imaging. A patient had a CR if the target tumors disappeared. A patient had a PR if there was a ≥ 50% reduction in the sum of the products of the largest perpendicular diameters of the target tumors compared to the baseline value. A best response of CR required at least 2 determinations of CR at least 4 weeks apart. A best response of PR required at least 2 determinations of PR or better at least 4 weeks apart (and not qualifying for CR).

Duration of OOR only included patients whose best overall response was complete response (CR) or partial response (PR). The start date was the date of the first documented response (CR or PR); the end date was the date of the first documented disease progression (PD) or death from any cause. (PD) was defined as ≥ 25% increase in size of the sum of the products of the largest perpendicular diameters of the target tumors compared to the smallest value recorded at or after baseline. If a patient had not progressed or died, the duration of OOR was censored at the time of the last OOR assessment.

Patients who had clinical benefit were patients with a best response of complete response (CR), partial response (PR), or stable disease (SD) lasting for more than 6 months from the start of treatment until the first documented disease progression (PD) or death from any cause. (PD) was defined as ≥ 25% increase in size of the sum of the products of the largest perpendicular diameters of the target tumors compared to the smallest value recorded at or after baseline. SD was defined as insufficient tumor shrinkage to qualify for PR or CR and no increase in lesions which would qualify as PD.

Progression-free survival (PFS) was defined as the time from the start of treatment to the date of the first documented disease progression (PD) or death due to any cause. (PD) was defined as ≥ 25% increase in size of the sum of the products of the largest perpendicular diameters of the target tumors compared to the smallest value recorded at or after baseline. If a patient had not progressed or died, progression-free survival was censored at the time of the last overall response assessment.

Patients not known to have died were censored at the time of last survival follow-up.

An adverse event (AE) is any undesirable sign, symptom, or medical condition occurring after starting study drug even if the event is not considered to be related to study drug. Study drug refers to imatinib or hydroxyurea. The study treatment is the combination of these two study drugs.

Novartis

External Affairs

The analysis was done on the safety population which consisted of 131 patients in the imatinib 600 mg plus hydroxyurea 1000 mg group and 99 patients in the imatinib 1000 mg plus hydroxyurea 1000 mg group.

Imatinib 600 mg + Hydroxyurea 1000 mg

Imatinib 1000 mg + Hydroxyurea 1000 mg

Total

Age Continuous

Sex: Female, Male

Study Director

Patients took either imatinib 600 mg (1 imatinib 400 mg tablet and 2 imatinib 100 mg tablets) orally once daily with the morning meal or imatinib 500 mg (1 imatinib 400 mg tablet and 1 imatinib 100 mg tablet) orally twice daily with the morning and evening meals. Patients were instructed to swallow the tablets while drinking a large glass of water. In addition to imatinib, patients took hydroxyurea 500 mg orally twice daily with the morning and evening meals.

All Patients - Imatinib 600 or 1000 mg + Hydroxyurea 1000 mg

Intent-to-treat (ITT) population: All patients who received at least 1 dose of any of the 2 study drugs.

Percentage of Patients With an Objective Overall Response (OOR)

Duration of Objective Overall Response (OOR)

Percentage of Patients Who Had Clinical Benefit

6 Months

12 Months

Percentage of Patients With Progression-free Survival at Months 6 and 12

24 Months

Percentage of Patients Surviving at Months 6, 12, and 24

Safety population: All patients who received at least 1 dose of either of the 2 study drugs and who had at least 1 post-baseline safety assessment.

Number of Patients With at Least 1 Adverse Event

Overall Study

Digestive System Diseases

Skin and Connective Tissue Diseases

Gastrointestinal Stromal Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Immediate interruption of imatinib until progressive disease. In case of 1st relapse, imatinib will be reintroduced at 400mg/d and further increased at 800mg/d in case of 2nd relapse after re-introduction.

Maintenance of imatinib at the last dose routinely taken by the patient in the 10-year period prior to randomization (either 300 or 400 mg once daily). In case of progressive disease imatinib will be increased up to 800mg/day.

Jean-Yves BLAY, Pr

Elsa KALBACHER, MD

Loïc CHAIGNEAU, MD

Guillaume MEYNARD, MD

Antoine ITALIANO

Maud TOULMONDE

Kevin BOURCIER

Sophie COUSIN

Valérie LE BRUN LY, MD

Jean-Yves BLAY, PhD

Mehdi BRAHMI

Armelle DUFRESNE

Isabelle RAY-COQUARD

François BERTUCCI, PhD

Audrey MONNEUR

Elika LOIR

Simon LAUNAY

Frédéric VIRET

Brice CHANEZ

Delphine LOUVEL PERROT

Sophie PIPERNO NEUMANN

Olivier BOUCHE, PhD

Mathilde BRASSEUR, MD

Damien BOTSEN, MD

Christophe PERRIN, MD

Marc PRACHT, MD

Angélique BRUNOT, MD

Astrid LIEVRE, PhD

Eugénie RIGAULT, MD

Thomas GRAINVILLE, MD

Anne-Sophie MOUSSADDAQ, MD

Emanuelle BOMPAS

Fréderic ROLLAND

Damien VANSTEENE

Olivier COLLARD, MD

Cécile VASSAL, MD

Valentin THIBAUD

Iphigénie KORAKIS

Christine CHEVREAU

Maria RIOS, MD

Axel LE CESNE, PhD

Rastislav BAHLEDA, MD

Olivier MIR, MD

Benjamin VERRET, MD

This is a 2 arms study concerning patients under imatinib treatment for at least 10 years of treatment with locally advanced/metastatic GIST.

In the first arm, patients will discontinue Imatinib treatment. This arm will allow to determine if the re-introduction of Imatinib at relapse is still an efficient treatment for the control of disease.

In the second arm, patients will continue Imatinib treatment, allowing to determine if the continuation of this treatment is efficient for disease control, by the rate of non-progression disease.

Gastrointestinal stromal tumors (GISTs) arise from mesenchymal stem cells which also give rise to the interstitial cells of Cajal within the GI tract. A large majority of GIST tumors harbour activating mutations in the proto-oncogenes KIT and/or PDGFRA, both coding cell-surface cytokine receptors with tyrosine-protein kinase activity.

Imatinib mesilate (Glivec®, Novartis Pharma SAS) is a selective tyrosine kinase inhibitor, leading to inhibition of KIT and PDGFRA signalling pathways. The introduction of imatinib has revolutionised the therapeutic management of GIST patients and has provided an unprecedented demonstration of the clinical benefit of a targeted therapy for patients with advanced/metastatic solid tumors.

Several studies have investigated the optimal duration of imatinib treatment in the advanced phase. The BFR14 trial demonstrated that 31% of advanced GIST patients treated with continuous imatinib beyond 1 year had documented disease progression compared to 81% in the interrupted imatinib group (p\<0.0001). The authors concluded that treatment interruption resulted in rapid progression in most patients with advanced GIST and therefore should not be recommended in standard practice unless the patient experienced significant toxicity or disease progression. An update of the BFR14 trial at a median follow-up of 37 months showed that 91% of patients in the interrupted arm versus 62% in the continuous arm experienced progressive disease (p\<0.0001). Majority (92%) of patients in the interrupted arm achieved tumor control once they recommenced imatinib after first progression. Ray-Coquard et al. reported that stopping imatinib after 5 years resulted in a higher rate of disease progression than imatinib maintenance in patients with advanced GIST responding to or stabilised by imatinib.

However, whether lifelong imatinib treatment duration is mandatory in metastatic GIST patients remains unclear. It is not known whether a cytostatic treatment of 10 years or longer is sufficient to inhibit definitively GIST cancer cells proliferation even after the interruption of the kinase inhibitor. This question has broad implications for all targeted therapies.

The aim of the present study is to address this question rigorously in a randomized setting. The investigators therefore want to determine whether prolonged use of imatinib beyond 10 years is needed to reduce the risk of GIST recurrence and to improve overall survival. For patients with imatinib interruption after at least 10 years of treatment, the investigators want to determine if imatinib rechallenge is efficient for treating recurrence. Therefore, the investigators design an open-label, randomized, multicenter phase II study to determine the clinical impact of maintaining imatinib treatment beyond 10 years in patients with locally advanced/metastatic GIST.

Efficiency of Imatinib Treatment After 10 Years of Treatment in Patients With Gastrointestinal Stromal Tumours (GIST) (Gist-Ten)

Randomized, Multicentre, Phase II Study Evaluating the Interest of Imatinib Treatment Maintenance or Interruption After at Least 10 Years of Treatment in Patients With Locally Advanced/Metastatic Gastrointestinal Stromal Tumors (GISTs)

Defined as the rate of patients with a non-progressive disease 6 months after randomization

Time from the date of randomization to the date of the first documented progression, or date of death due to any cause. Patients with no event at the time of the analysis will be censored at the date of last available tumor assessment

the time from the date of randomization to the date of death due to any cause.

The assessment of safety will be based mainly on the frequency of AE based on the Common Toxicity Criteria version 5

QoL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire (QLQ-C30).

the time from the date of imatinib reintroduction in the experimental arm to the date of subsequent progression, or date of death due to any cause. Patients with no event at the time of the analysis will be censored at the the date of last available tumor assessment.

Defined as the proportion of patients with a best overall response of Partial Response (PR) or Complete Response (CR) after imatinib reintroduction

the time from the date of first objective response following the reintroduction of imatinib to the date of the first subsequent documented radiological progression or death and censored at the date of last available tumor assessment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Efficacy and Safety of Imatinib Mesylate Plus Hydroxyurea (HU) in Patients With Recurrent Glioblastoma Multiforme (GBM)	NCT00290771	Recurrent Gliob...	Imatinib tablet... Hydroxyurea cap...	18 Years -	Novartis
Efficiency of Imatinib Treatment After 10 Years of Treatment in Patients With Gastrointestinal Stromal Tumours (GIST) (Gist-Ten)	NCT05009927	Metastatic Gast... C-KIT Mutation Advanced Gastro...	Imatinib tablet...	18 Years -	Centre Leon Berard

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