Ignite Creation Date:
2024-05-06 @ 8:29 AM
Last Modification Date:
2024-10-26 @ 12:01 PM
Study NCT ID:
NCT02751255
Status:
COMPLETED
Last Update Posted:
2023-04-28
First Post:
2016-04-04
Brief Title:
Daratumumab in Combination With ATRA
Sponsor:
Amsterdam UMC location VUmc
Organization:
Amsterdam UMC location VUmc
Study Overview
Official Title:
A Phase 1 and Phase 2 Study of Daratumumab in Combination With All-trans Retinoic Acid in RelapsedRefractory Multiple Myeloma
Status:
COMPLETED
Status Verified Date:
2023-04
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:
DARAATRA
Brief Summary:
Multiple myeloma MM patients who develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months indicating that new agents are urgently needed Recent studies have shown that daratumumab as a single agent is effective and well tolerated in these heavily pretreated MM patients However approximately 60 of patients do not achieve a partial response and ultimately all patients will develop progressive disease during daratumumab therapy
The investigators have demonstrated that levels of the target antigen CD38 and expression levels of the complement inhibitory proteins CD55 and CD59 determine the susceptibility of the MM cells towards daratumumab In addition MM cells have lower CD38 expression levels and higher levels of CD55CD59 at the time of progression Importantly all-trans retinoic acid ATRA upregulates CD38 levels and downregulates CD55CD59 levels on MM cells both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug These alterations in expression explain the strong synergy between ATRA and daratumumab both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients
The investigators have demonstrated that levels of the target antigen CD38 and expression levels of the complement inhibitory proteins CD55 and CD59 determine the susceptibility of the MM cells towards daratumumab In addition MM cells have lower CD38 expression levels and higher levels of CD55CD59 at the time of progression Importantly all-trans retinoic acid ATRA upregulates CD38 levels and downregulates CD55CD59 levels on MM cells both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug These alterations in expression explain the strong synergy between ATRA and daratumumab both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients
Detailed Description:
Multiple myeloma MM patients that develop bortezomib and lenalidomide-resistant disease have a very poor survival of only a median of 9 months This clearly illustrates that new anti-MM agents are needed with different mechanisms of action
Importantly daratumumab monotherapy is effective and well tolerated in heavily pre-treated lenalidomide and bortezomib-refractory myeloma patients However approximately 60 of patients do not achieve a partial response and ultimately all patients also those achieving complete response will develop progressive disease during daratumumab therapy Factors that determine the susceptibility of MM cells to daratumumab include levels of the target antigen CD38 and expression levels of the complement inhibitory proteins CD55 and CD59 At the time of progression there is a reduced level of CD38 on the MM cells whereas CD55 and CD59 levels are increased This indicates that these factors are also involved in the development of daratumumab-resistant disease
Importantly ATRA upregulates CD38 levels and downregulates CD55CD59 levels on MM cells both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug These alterations in expression explain the strong synergy between ATRA and daratumumab both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients The investigators will treat relapsedrefractory MM patients in two stages The first stage part A consists of treatment with daratumumab monotherapy In case these patients have progressive disease after cycle 1 less than minimal response after cycle 2 or less than partial response after cycle 3 unless ongoing response to single agent daratumumab or in case these patients progress during daratumumab therapy after previous response then ATRA will be added to daratumumab part B
The aims of this study are to develop a safe ATRA and daratumumab combination suitable for clinical use and evaluation in subsequent randomized clinical trials To this end the maximum tolerated dose MTD of ATRA and daratumumab will be determined for patients with relapsedrefractory disease who were treated with daratumumab but failed to achieve a partial response or developed progressive disease during daratumumab treatment This will be followed by a second part in which the investigators will examine the effectivity and toxicity profile of the combination at the MTD
Importantly daratumumab monotherapy is effective and well tolerated in heavily pre-treated lenalidomide and bortezomib-refractory myeloma patients However approximately 60 of patients do not achieve a partial response and ultimately all patients also those achieving complete response will develop progressive disease during daratumumab therapy Factors that determine the susceptibility of MM cells to daratumumab include levels of the target antigen CD38 and expression levels of the complement inhibitory proteins CD55 and CD59 At the time of progression there is a reduced level of CD38 on the MM cells whereas CD55 and CD59 levels are increased This indicates that these factors are also involved in the development of daratumumab-resistant disease
Importantly ATRA upregulates CD38 levels and downregulates CD55CD59 levels on MM cells both in daratumumab naïve cells and in cells that are resistant to daratumumab because of previous exposure to this drug These alterations in expression explain the strong synergy between ATRA and daratumumab both in MM cells derived from daratumumab naïve patients and from patients with daratumumab-refractory disease
These data form the preclinical rationale for clinical evaluation of ATRA and daratumumab in MM patients The investigators will treat relapsedrefractory MM patients in two stages The first stage part A consists of treatment with daratumumab monotherapy In case these patients have progressive disease after cycle 1 less than minimal response after cycle 2 or less than partial response after cycle 3 unless ongoing response to single agent daratumumab or in case these patients progress during daratumumab therapy after previous response then ATRA will be added to daratumumab part B
The aims of this study are to develop a safe ATRA and daratumumab combination suitable for clinical use and evaluation in subsequent randomized clinical trials To this end the maximum tolerated dose MTD of ATRA and daratumumab will be determined for patients with relapsedrefractory disease who were treated with daratumumab but failed to achieve a partial response or developed progressive disease during daratumumab treatment This will be followed by a second part in which the investigators will examine the effectivity and toxicity profile of the combination at the MTD
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None