Ignite Creation Date:
2024-05-06 @ 2:17 PM
Last Modification Date:
2024-10-26 @ 1:28 PM
Study NCT ID:
NCT04278768
Status:
RECRUITING
Last Update Posted:
2024-03-12
First Post:
2020-02-10
Brief Title:
Dose Escalation Expansion Study of CA-4948 as Monotherapy in Patients With Acute Myelogenous Leukemia AML or Myelodysplastic Syndrome MDS
Sponsor:
Curis Inc
Organization:
Curis Inc
Study Overview
Official Title:
A Phase 12A Open Label Dose Escalation and Expansion Study of Orally Administered CA-4948 as a Monotherapy in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
Status:
RECRUITING
Status Verified Date:
2024-07
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:
None
Brief Summary:
This is a multicenter open-label Phase 12a dose escalation and expansion study of orally administered emavusertib CA-4948 monotherapy in adult patients with AML or higher- risk Myelodysplastic Syndrome hrMDS
Patients enrolling in the Phase 1 dose escalation of the study must meet one of the following criteria prior to consenting to the study
Relapserefractory RR AML with FMS-like tyrosine kinase-3 FLT3 mutations who have been previously treated with a FLT3 inhibitor
RR AML with spliceosome mutations of splicing factor 3B subunit 1 SF3B1 or U2AF1
RR hrMDS with spliceosome mutations of SF3B1 or U2 small nuclear RNA auxiliary factor 1 U2AF1
Number of pretreatments 1 or 2
The Phase 2a Dose Expansion will be in 3 Cohorts of patients
1 RR AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor
2 RR AML with spliceosome mutations of SF3B1 or U2AF1 and
3 RR hrMDS Revised International Prognostic Scoring System IPSS-R score 35 with spliceosome mutations of SF3B1 or U2AF1
All patients above have had 2 lines of prior systemic anticancer treatment In previous versions of this protocol there was a Phase 1b portion of the study in which patients with AML or hrMDS received CA-4948 in combination with venetoclax This part of the study is no longer open for enrollment
Patients enrolling in the Phase 1 dose escalation of the study must meet one of the following criteria prior to consenting to the study
Relapserefractory RR AML with FMS-like tyrosine kinase-3 FLT3 mutations who have been previously treated with a FLT3 inhibitor
RR AML with spliceosome mutations of splicing factor 3B subunit 1 SF3B1 or U2AF1
RR hrMDS with spliceosome mutations of SF3B1 or U2 small nuclear RNA auxiliary factor 1 U2AF1
Number of pretreatments 1 or 2
The Phase 2a Dose Expansion will be in 3 Cohorts of patients
1 RR AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor
2 RR AML with spliceosome mutations of SF3B1 or U2AF1 and
3 RR hrMDS Revised International Prognostic Scoring System IPSS-R score 35 with spliceosome mutations of SF3B1 or U2AF1
All patients above have had 2 lines of prior systemic anticancer treatment In previous versions of this protocol there was a Phase 1b portion of the study in which patients with AML or hrMDS received CA-4948 in combination with venetoclax This part of the study is no longer open for enrollment
Detailed Description:
The primary objective of the Phase 1 portion of the study is to determine the maximum tolerated dose MTD and Recommended Phase 2 Dose RP2D for emavusertib in monotherapy in patients with AML intermediate-2 high risk or every high risk MDS based on the safety and tolerability dose-limiting toxicities DLTs and Pharmacokinetic PKPharmacodynamic PD findings
The primary objective of the Phase 1b portion of the study is to determine MTD and RP2D for emavusertib in combination with azacitidine AZA in treatment naïve patients with hrMDS or in combination with venetoclax VEN in RR patients with AML or hrMDS after first line treatment based on the safety and tolerability DLTs and PK and pharmacodynamic findings Note this portion of the study is no longer enrolling patients
The primary objective of the Phase 2a portion of the study emavusertib monotherapy expansion is to assess anti-cancer activity of CA-4948 at the RP2D in patients with RR AML with FMS-like tyrosine kinase-3 FLT3 mutations or patients with RR hrMDS or RR AML with spliceosome mutations of SF3B1 or U2AF1
Emavusertib is formulated as tablets for twice daily oral administration Each treatment cycle will be 28 days in length and repeated in the absence of toxicity Patients who tolerate emavusertib may continue to receive emavusertib until progression of disease intolerable toxicity lack of clinical benefit withdrawal from the trial or study termination
The emavusertib starting dose level will be 200 milligrams mg twice daily BID which was determined to be safe capable of achieving relevant levels of drug exposure as well as demonstrating signs of biologic activity and clinical efficacy in an ongoing study Study CA-4948-101 For phase 1 emavusertib is taken daily for 28 days of a 28 day cycle For Phase 1b emavusertib is taken daily for 21 days of a 28 day cycle in combination with venetoclax
Venetoclax will be administered at 100 mg orally Day 1 per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21 days of the 28-day Cycle Second and subsequent cycles start with the target dose level
In each of the Phase 11b cohorts three patients with AML or MDS were enrolled at the designated dose If none of the first 3 patients experience a DLT during the first cycle patients may be enrolled into the next higher dose level If 1 patient out of the first 3 experiences a DLT the dose level may be expanded with an additional 3 patients If 2 or 3 patients out of the first six experienced a DLT this will be considered a DLT rate above the MTD 33 and additional enrollment will proceed at a lower dose level Any adverse reaction that led to dose reduction or discontinuation is considered a DLT unless the adverse reaction is clearly and solely related to disease
The RP2D will be determined by the Clinical Safety Committee CSC in consultation with the Sponsor considering all aspects of safety tolerability biologic activity pharmacokinetics and preliminary efficacy in the trial population The intent of the RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit while minimizing the risk of toxicity The RP2D may be below the MTD The CSC may request enrollment of additional patients at any previously-explored dose level in order to make an appropriate RP2D or MTD determination
The expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease
1 RR AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor or
2 RR AML with spliceosome mutations of SF3B1 or U2AF1 or
3 RR hrMDS IPSS-R score 35 with spliceosome mutations of SF3B1 or U2AF1
All patients have had 2 lines of prior systemic anticancer treatment
The primary objective of the Phase 1b portion of the study is to determine MTD and RP2D for emavusertib in combination with azacitidine AZA in treatment naïve patients with hrMDS or in combination with venetoclax VEN in RR patients with AML or hrMDS after first line treatment based on the safety and tolerability DLTs and PK and pharmacodynamic findings Note this portion of the study is no longer enrolling patients
The primary objective of the Phase 2a portion of the study emavusertib monotherapy expansion is to assess anti-cancer activity of CA-4948 at the RP2D in patients with RR AML with FMS-like tyrosine kinase-3 FLT3 mutations or patients with RR hrMDS or RR AML with spliceosome mutations of SF3B1 or U2AF1
Emavusertib is formulated as tablets for twice daily oral administration Each treatment cycle will be 28 days in length and repeated in the absence of toxicity Patients who tolerate emavusertib may continue to receive emavusertib until progression of disease intolerable toxicity lack of clinical benefit withdrawal from the trial or study termination
The emavusertib starting dose level will be 200 milligrams mg twice daily BID which was determined to be safe capable of achieving relevant levels of drug exposure as well as demonstrating signs of biologic activity and clinical efficacy in an ongoing study Study CA-4948-101 For phase 1 emavusertib is taken daily for 28 days of a 28 day cycle For Phase 1b emavusertib is taken daily for 21 days of a 28 day cycle in combination with venetoclax
Venetoclax will be administered at 100 mg orally Day 1 per the product label at the same time each day with a ramp up over 3 days to 400 mg for 21 days of the 28-day Cycle Second and subsequent cycles start with the target dose level
In each of the Phase 11b cohorts three patients with AML or MDS were enrolled at the designated dose If none of the first 3 patients experience a DLT during the first cycle patients may be enrolled into the next higher dose level If 1 patient out of the first 3 experiences a DLT the dose level may be expanded with an additional 3 patients If 2 or 3 patients out of the first six experienced a DLT this will be considered a DLT rate above the MTD 33 and additional enrollment will proceed at a lower dose level Any adverse reaction that led to dose reduction or discontinuation is considered a DLT unless the adverse reaction is clearly and solely related to disease
The RP2D will be determined by the Clinical Safety Committee CSC in consultation with the Sponsor considering all aspects of safety tolerability biologic activity pharmacokinetics and preliminary efficacy in the trial population The intent of the RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit while minimizing the risk of toxicity The RP2D may be below the MTD The CSC may request enrollment of additional patients at any previously-explored dose level in order to make an appropriate RP2D or MTD determination
The expansion phase will begin once the RP2D from Phase 1 Dose Escalation phase has been identified There will be 3 Cohorts and patients will be assigned to each Cohort based on baseline disease
1 RR AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor or
2 RR AML with spliceosome mutations of SF3B1 or U2AF1 or
3 RR hrMDS IPSS-R score 35 with spliceosome mutations of SF3B1 or U2AF1
All patients have had 2 lines of prior systemic anticancer treatment
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
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