Ignite Creation Date:
2024-05-06 @ 2:39 PM
Last Modification Date:
2024-10-26 @ 1:35 PM
Study NCT ID:
NCT04385290
Status:
RECRUITING
Last Update Posted:
2023-08-09
First Post:
2020-05-08
Brief Title:
Combination of Midostaurin and Gemtuzumab Ozogamicin in First-line Standard Therapy for Acute Myeloid Leukemia MOSAIC
Sponsor:
Technische Universität Dresden
Organization:
Technische Universität Dresden
Study Overview
Official Title:
MidOStaurin Gemtuzumab OzogAmIcin Combination in First-line Standard Therapy for Acute Myeloid Leukemia MOSAIC
Status:
RECRUITING
Status Verified Date:
2023-08
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:
MOSAIC
Brief Summary:
This phase III clinical trial evaluates the safety and efficacy of the combined administration of midostaurin and gemtuzumab ozogamicin in the frame of first-line standard chemotherapy in newly diagnosed acute myeloid leukemia AML patients displaying a cytogenetic aberration or fusion transcript in the core-binding factor CBF genes or FMS-like tyrosine Kinase 3 FLT3 mutation
Detailed Description:
Acute myeloid leukemia is a malignancy that is still fatal for the majority of patients Besides age the genetic configuration of AML blasts is one of the strongest prognostic factors Patients with mutations in the core-binding factor CBF genes have the best prognosis however a considerable proportion of 35-60 will eventually relapse Mutation and overexpression of receptor tyrosinkinases RTK have been proposed as main reasons for relapse development or chemoresistance in CBF AMLs RTKs like stem cell factor receptor c-KIT and FLT3 are of high clinical relevance as they mediate proliferation and differentiation of hematopoietic stem cells There is evidence that c-Kit mutations and high levels of c-KIT in CBF-AML have adverse effects on survival endpoints indicating c-KIT as potential therapeutic target in this special AML population Midostaurin can be considered a potent c-KIT inhibitor besides having multi-kinase inhibitory activity for several other kinases of documented or potential pathogenetic relevance for AML most importantly mutated FLT3 The kinase inhibition ultimately leads to inhibition of proliferation cell cycle arrest and apoptosis Previous studies with other c-KIT inhibitors such as dasatinib showed promising results with respect to survival end points in newly diagnosed CBF AML patients Midostaurin is considered a more potent c-KIT inhibitor than dasatinib and may be able to potentiate the inhibitory effect on leukemic cell growth
Another important therapeutical target in CBF AML is the sialic acid-binding immunoglobulin-like lectin CD33 which is expressed on the majority of AML blasts Gemtuzumab Ozogamicin GO is a therapeutic CD33 antibody linked to a strong cytostatic drug calicheamicin which causes apoptosis of cancer cells upon internalization For the combination of GO and standard intensive chemotherapy metaanalyses of randomized trials have shown that i a low-dose fractionated administration results in the best tolerability and ii among AML subgroups patients with CBF AML have the greatest benefit from GO in addition to standard therapy Subgroup analyses within the ALFA-0701 A Randomized Study of Gemtuzumab Ozogamicin With Daunorubicine and Cytarabine in Untreated Acute Myeloid Leukemia Aged of 50-70 Years Old trial population showing beneficial effects of GO on overall survival relapse-free survival and event-free survival in patients positive for FLT3 mutation as compared to those negative for FLT3 mutation Subgroup analyses of the GO registration trial ALFA-0701 showed a significant clinical benefit of the patients displaying a mutation in the FLT3 gene compared to those without this mutation In Addition CBF AML patients with FLT3 mutations expressed particularly high levels of CD33 antigen and that CD33 antigen levels were positively correlated to the improved survival after GO treatment Furthermore recently published data of two paediatric populations with internal tandem mutation in the FLT3 gene showed reduced relapse rates in GO recipients compared to the control group only receiving standard chemotherapy These results suggest that GO is a particularly beneficiary agent in FLT3 mutated patients who would currently receive midostaurin in addition to intensive chemotherapy as a standard of care Hence from a clinical point of view there is an unambiguous rationale supporting the combination of midostaurin and GO for treatment of AML in the two cytogenetic subgroups CBF AML and FLT3 mutated AML
GO has become the new treatment standard for patients with CBF AML The hypothesized positive effect of midostaurin is likely but randomized proof is laking
Midostaurin has become the new treatment standard for AML patients with mutations in the FLT3 gene The positive effect of GO is shown in a post-hoc subgroup analysis of the ALFA-0701 trial but prospective randomized proof is lacking
Therefore the proposed trial intends i to explore and establish the safe combination of GO plus midostaurin MODULE and ii to evaluate the effect of midostaurin versus no midostaurin added to standard AML chemotherapy plus GO in CBF AML MAGNOLIA and iii to evaluate the effect of GO versus no GO added to standard AML chemotherapy plus midostaurin in FLT3 mutated AML MAGMA
Another important therapeutical target in CBF AML is the sialic acid-binding immunoglobulin-like lectin CD33 which is expressed on the majority of AML blasts Gemtuzumab Ozogamicin GO is a therapeutic CD33 antibody linked to a strong cytostatic drug calicheamicin which causes apoptosis of cancer cells upon internalization For the combination of GO and standard intensive chemotherapy metaanalyses of randomized trials have shown that i a low-dose fractionated administration results in the best tolerability and ii among AML subgroups patients with CBF AML have the greatest benefit from GO in addition to standard therapy Subgroup analyses within the ALFA-0701 A Randomized Study of Gemtuzumab Ozogamicin With Daunorubicine and Cytarabine in Untreated Acute Myeloid Leukemia Aged of 50-70 Years Old trial population showing beneficial effects of GO on overall survival relapse-free survival and event-free survival in patients positive for FLT3 mutation as compared to those negative for FLT3 mutation Subgroup analyses of the GO registration trial ALFA-0701 showed a significant clinical benefit of the patients displaying a mutation in the FLT3 gene compared to those without this mutation In Addition CBF AML patients with FLT3 mutations expressed particularly high levels of CD33 antigen and that CD33 antigen levels were positively correlated to the improved survival after GO treatment Furthermore recently published data of two paediatric populations with internal tandem mutation in the FLT3 gene showed reduced relapse rates in GO recipients compared to the control group only receiving standard chemotherapy These results suggest that GO is a particularly beneficiary agent in FLT3 mutated patients who would currently receive midostaurin in addition to intensive chemotherapy as a standard of care Hence from a clinical point of view there is an unambiguous rationale supporting the combination of midostaurin and GO for treatment of AML in the two cytogenetic subgroups CBF AML and FLT3 mutated AML
GO has become the new treatment standard for patients with CBF AML The hypothesized positive effect of midostaurin is likely but randomized proof is laking
Midostaurin has become the new treatment standard for AML patients with mutations in the FLT3 gene The positive effect of GO is shown in a post-hoc subgroup analysis of the ALFA-0701 trial but prospective randomized proof is lacking
Therefore the proposed trial intends i to explore and establish the safe combination of GO plus midostaurin MODULE and ii to evaluate the effect of midostaurin versus no midostaurin added to standard AML chemotherapy plus GO in CBF AML MAGNOLIA and iii to evaluate the effect of GO versus no GO added to standard AML chemotherapy plus midostaurin in FLT3 mutated AML MAGMA
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