Ignite Creation Date:
2024-05-06 @ 7:29 PM
Last Modification Date:
2024-10-26 @ 3:07 PM
Study NCT ID:
NCT06022003
Status:
RECRUITING
Last Update Posted:
2024-02-06
First Post:
2023-08-28
Brief Title:
Study Investigating the Efficacy and Safety of the Addition of Oral-azacitidine to Salvage Treatment by Gilteritinib in Subjects 18 Years of Age With RelapsedRefractory FLT3-mutated Acute Myeloid Leukemia
Sponsor:
French Innovative Leukemia Organisation
Organization:
French Innovative Leukemia Organisation
Study Overview
Official Title:
Open-label Phase 2 Study Investigating the Efficacy and Safety of the Addition of Oral-azacitidine to Salvage Treatment by Gilteritinib in Subjects 18 Years of Age With RelapsedRefractory FLT3-mutated Acute Myeloid Leukemia
Status:
RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
OGILAR
Brief Summary:
Approximately 30 of adult AML subjects are refractory to induction therapy Furthermore of those who achieve CR approximately 75 will relapse FLT3-mutated AML comprise an especially poor prognosis group
Until now there was no established standard for relapsed subjects with FLT3 mutations and less than 20 will achieve CR with subsequent treatment
In phase 3 Study ADMIRAL Trial gilteritinib has resulted in CRc in over 25 of subjects receiving 120 mgday before on study HSCT With this treatment the median overall survival is at 93 months furthermore gilteritinib was well tolerated at the proposed doses This study has been designed for RR patients for which gilteritinib as single agent has been showed to be superior to high- and low-intensity chemotherapy Perl NEJM 2019 Supp Table S4 and patients included in this study will receive this treatment Beyond high- or low-intensity chemotherapy other options available are best supportive car or other clinical trials
The aim of this study is to assess the efficacy and safety of the addition of oral-azacitidine to salvage treatment by gilteritinib in subjects 18 years of age with relapsedrefractory FLT3-mutated acute myeloid leukemia
Until now there was no established standard for relapsed subjects with FLT3 mutations and less than 20 will achieve CR with subsequent treatment
In phase 3 Study ADMIRAL Trial gilteritinib has resulted in CRc in over 25 of subjects receiving 120 mgday before on study HSCT With this treatment the median overall survival is at 93 months furthermore gilteritinib was well tolerated at the proposed doses This study has been designed for RR patients for which gilteritinib as single agent has been showed to be superior to high- and low-intensity chemotherapy Perl NEJM 2019 Supp Table S4 and patients included in this study will receive this treatment Beyond high- or low-intensity chemotherapy other options available are best supportive car or other clinical trials
The aim of this study is to assess the efficacy and safety of the addition of oral-azacitidine to salvage treatment by gilteritinib in subjects 18 years of age with relapsedrefractory FLT3-mutated acute myeloid leukemia
Detailed Description:
AML is characterized by the clonal expansion of myeloid blasts in the BM peripheral blood and extramedullary tissues which disrupts normal hematopoiesis It is a heterogeneous disease encompassing a large number of distinctly subtypes that may have different clinical presentations and responses to treatment AML is defined by the WHO as a myeloid neoplasm with 20 or more blasts in the peripheral blood or BM
Internal tandem duplication ITD in the FLT3 gene is one of the most frequent mutations found in AML FLT3-ITD is associated with poor prognosis and has emerged as a relevant therapeutic target FLT3-ITD is usually conserved at relapse suggesting that FLT3-ITD AML-initiating cells are key targets for long-lasting remission FLT3-TKI developed as ATP-competitive inhibitors are currently the focus of new development strategies in FLT3-mutated AML particularly in combination with intensive or non-intensive chemotherapies in newly diagnosed ND FLT3 mutated AML or in RR situation Type I inhibitors including midostaurin gilteritinib and crenolanib have activity against FLT3-ITD and tyrosine kinase domain TKD mutations Type II inhibitors including sorafenib and quizartinib do not have activity against FLT3-TKD mutations Although first-generation FLT3 inhibitors such as midostaurin 10 and sorafenib 11 have marginal single-agent activity in active disease they have shown promising activity as maintenance therapies notably after HSCT for sorafenib 14 Conversely several FLT3-TKI such as quizartinib crenolanib and gilteritinib have single-agent activity that lead to complete or near-complete remission providing a strong rationale to combine these agents with other chemotherapies
The ADMIRAL phase 3 trial also designed for RR FLT3-mutated AML patients recently demonstrated the superiority of gilteritinib as single agent over the control treatment arm which was determined by investigators prior to 21 randomization between mitoxantrone etoposide cytarabine fludarabine cytarabine granulocyte colony-stimulating factor idarubicin AZA or LDAC These regimens are recognized as acceptable salvage strategies in this situation although other combinations based on intermediate- or high-dose cytarabine or even single-agent cytarabine are also widely used In the ADMIRAL trial OS was significantly improved in the gilteritinib arm compared to the control arm with HR at 064 95CI 049-083 p 0001 The median OS was 93 months in the gilteritinib arm and 56 months in the control arm The CR and CRi rates were 211 and 255 in the gilteritinib arm vs 105 and 48 in the standard arm 2 Gilteritinib was generally well tolerated but was associated with increased incidence of GI side effects most frequently diarrhea although nausea has been occasionally observed Increase in bilirubin and transaminase can be seen with gilteritinib but are usually self-resolving and transient Posterior reversible encephalopathy and pancreatitis are rare 1-2 but important side effects to be aware of These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with RR FLT3 mutated AML and it is now the gold standard treatment in such situation However long lasting remission with gilteritinib as single agent are uncommon since various resistance mechanisms allow AML to escape Innovative strategies have to be established in order to improve these results In that setting associations with ICT HMA other targeted therapies are currently developed
AZA was first investigated as a cytotoxic agent in the 1960s and 1970s in RR AML and a dose- and time-dependent effect of AZA was evident with higher remission rates and reduced toxicity reported in patients who received lower doses or continuous infusion schedule of AZA
QUAZAR trial used an oral formulation of AZA oral-AZA that is not bioequivalent to injectable AZA as maintenance therapy in patients with AML who were in CRCRi after ICT 22 Median OS from randomization was significantly longer with oral-AZA than with placebo 247 months vs 148 months respectively p0001 Median RFS was also significantly longer with oral-AZA than with placebo 102 months vs 48 months respectively p0001 The most common AE in both groups were grade 1 or 2 GI events Common grade 3 or 4 AE were neutropenia in 41 of patients in the oral-AZA group and 24 of patients in the placebo group and thrombocytopenia in 22 and 21 respectively Overall health-related quality of life was preserved during oral-AZA treatment Among those who were MRD at baseline patients in the oral-AZA arm had a higher rate of conversion to MRD- status vs placebo 37 versus 19 respectively These data suggest an effective anti-leukemic therapy and not only an ability to maintain a stable situation among these MRD responders 9 of 38 24 patients in the oral-AZA arm converted to MRD-negativity after 6 months on treatment vs only 1of 22 5 patients in the placebo arm Moreover during the 63rd ASH annual meeting Döhner et al confirmed that Oral-AZA NPM1 and FLT3 mutational status cytogenetic risk as well as MRD status at baseline were independent predictors of survival
In front line situation LACEWING study was a phase 3 randomized study comparing gilteritinibAZA vs AZA for ND FLT3-mutated AML in patients unfit for ICT In this trial in patients with ND FLT3 mutated AML unfit for ICT gilteritinibAZA led to significantly higher CRc rates but similar OS vs AZA alone Based on these results an independent data monitoring committee recommended the study be terminated for futility citing that the results are unlikely to demonstrate a statistically significant increase in OS However subsequent therapy after AZA failure notably with other regimen including FLT3-TKI could have precluded transition of better CRc results to better OS results
Internal tandem duplication ITD in the FLT3 gene is one of the most frequent mutations found in AML FLT3-ITD is associated with poor prognosis and has emerged as a relevant therapeutic target FLT3-ITD is usually conserved at relapse suggesting that FLT3-ITD AML-initiating cells are key targets for long-lasting remission FLT3-TKI developed as ATP-competitive inhibitors are currently the focus of new development strategies in FLT3-mutated AML particularly in combination with intensive or non-intensive chemotherapies in newly diagnosed ND FLT3 mutated AML or in RR situation Type I inhibitors including midostaurin gilteritinib and crenolanib have activity against FLT3-ITD and tyrosine kinase domain TKD mutations Type II inhibitors including sorafenib and quizartinib do not have activity against FLT3-TKD mutations Although first-generation FLT3 inhibitors such as midostaurin 10 and sorafenib 11 have marginal single-agent activity in active disease they have shown promising activity as maintenance therapies notably after HSCT for sorafenib 14 Conversely several FLT3-TKI such as quizartinib crenolanib and gilteritinib have single-agent activity that lead to complete or near-complete remission providing a strong rationale to combine these agents with other chemotherapies
The ADMIRAL phase 3 trial also designed for RR FLT3-mutated AML patients recently demonstrated the superiority of gilteritinib as single agent over the control treatment arm which was determined by investigators prior to 21 randomization between mitoxantrone etoposide cytarabine fludarabine cytarabine granulocyte colony-stimulating factor idarubicin AZA or LDAC These regimens are recognized as acceptable salvage strategies in this situation although other combinations based on intermediate- or high-dose cytarabine or even single-agent cytarabine are also widely used In the ADMIRAL trial OS was significantly improved in the gilteritinib arm compared to the control arm with HR at 064 95CI 049-083 p 0001 The median OS was 93 months in the gilteritinib arm and 56 months in the control arm The CR and CRi rates were 211 and 255 in the gilteritinib arm vs 105 and 48 in the standard arm 2 Gilteritinib was generally well tolerated but was associated with increased incidence of GI side effects most frequently diarrhea although nausea has been occasionally observed Increase in bilirubin and transaminase can be seen with gilteritinib but are usually self-resolving and transient Posterior reversible encephalopathy and pancreatitis are rare 1-2 but important side effects to be aware of These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with RR FLT3 mutated AML and it is now the gold standard treatment in such situation However long lasting remission with gilteritinib as single agent are uncommon since various resistance mechanisms allow AML to escape Innovative strategies have to be established in order to improve these results In that setting associations with ICT HMA other targeted therapies are currently developed
AZA was first investigated as a cytotoxic agent in the 1960s and 1970s in RR AML and a dose- and time-dependent effect of AZA was evident with higher remission rates and reduced toxicity reported in patients who received lower doses or continuous infusion schedule of AZA
QUAZAR trial used an oral formulation of AZA oral-AZA that is not bioequivalent to injectable AZA as maintenance therapy in patients with AML who were in CRCRi after ICT 22 Median OS from randomization was significantly longer with oral-AZA than with placebo 247 months vs 148 months respectively p0001 Median RFS was also significantly longer with oral-AZA than with placebo 102 months vs 48 months respectively p0001 The most common AE in both groups were grade 1 or 2 GI events Common grade 3 or 4 AE were neutropenia in 41 of patients in the oral-AZA group and 24 of patients in the placebo group and thrombocytopenia in 22 and 21 respectively Overall health-related quality of life was preserved during oral-AZA treatment Among those who were MRD at baseline patients in the oral-AZA arm had a higher rate of conversion to MRD- status vs placebo 37 versus 19 respectively These data suggest an effective anti-leukemic therapy and not only an ability to maintain a stable situation among these MRD responders 9 of 38 24 patients in the oral-AZA arm converted to MRD-negativity after 6 months on treatment vs only 1of 22 5 patients in the placebo arm Moreover during the 63rd ASH annual meeting Döhner et al confirmed that Oral-AZA NPM1 and FLT3 mutational status cytogenetic risk as well as MRD status at baseline were independent predictors of survival
In front line situation LACEWING study was a phase 3 randomized study comparing gilteritinibAZA vs AZA for ND FLT3-mutated AML in patients unfit for ICT In this trial in patients with ND FLT3 mutated AML unfit for ICT gilteritinibAZA led to significantly higher CRc rates but similar OS vs AZA alone Based on these results an independent data monitoring committee recommended the study be terminated for futility citing that the results are unlikely to demonstrate a statistically significant increase in OS However subsequent therapy after AZA failure notably with other regimen including FLT3-TKI could have precluded transition of better CRc results to better OS results
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2022-501372-25-00 | OTHER | EU Number | None |