Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT04278768 |
Recruitment Status :
Recruiting
First Posted : February 20, 2020
Last Update Posted : March 12, 2024
|
Tracking Information | |||||
---|---|---|---|---|---|
First Submitted Date ICMJE | February 10, 2020 | ||||
First Posted Date ICMJE | February 20, 2020 | ||||
Last Update Posted Date | March 12, 2024 | ||||
Actual Study Start Date ICMJE | July 6, 2020 | ||||
Estimated Primary Completion Date | April 1, 2026 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
|
||||
Original Primary Outcome Measures ICMJE |
|
||||
Change History | |||||
Current Secondary Outcome Measures ICMJE |
|
||||
Original Secondary Outcome Measures ICMJE |
|
||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS | ||||
Official Title ICMJE | A Phase 1/2A, Open Label Dose Escalation and Expansion Study of Orally Administered CA-4948 as a Monotherapy in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome | ||||
Brief Summary | This is a multicenter, open-label, Phase 1/2a dose escalation and expansion study of orally administered emavusertib (CA-4948) monotherapy in adult patients with Acute Myelogenous Leukemia (AML) or high risk Myelodysplastic Syndrome (MDS). Patients enrolling in the Phase 1 portion of the study must meet one of the following criteria prior to consenting to the study:
The Phase 2a Dose Expansion will be in 3 Cohorts of patients:
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 high risk, high risk MDS based on the safety and tolerability, dose-limiting toxicities (DLTs), and Pharmacokinetic (PK)/Pharmacodynamic (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 relapsed/ refractory (R/R) patients with AML or high risk myelodysplastic syndrome (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 R/R AML with FMS-like tyrosine kinase-3 (FLT-3) mutations, or patients with R/R hrMDS or R/R 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 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 1/1b 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 lead 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:
All patients have had ≤ 2 lines of prior systemic anticancer treatment. |
||||
Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Phase 1 Phase 2 |
||||
Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Sequential Assignment Intervention Model Description: Phase 1 and 1b follow a 3 + 3 design where 3 patients will be enrolled at the starting dose level. If none of the first 3 patients experience a Dose Limiting Toxicity (DLT) during the 1st 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 sixz experience a DLT, this will be considered a DLT rate above the max tolerated dose (> 33%), and additional enrollment will proceed at a lower dose level. The Phase 2a Dose Expansion will be enrolled after the RP2D is determined from Phase 1. It will be in 3 Cohorts of patients: (1) R/R AML with FTLT-3 mutation who have been previously treated with a FLT3 inhibitor; (2) R/R AML with spliceosome mutations of SF3B1 or U2AF1; and (3) R/R hrMDS (IPSS-R >3.5) with spliceosome mutations of SF3B1 or U2AF1; AND all patients have ≤ 2 lines of prior systemic anti-cancer therapy. Masking: None (Open Label)Primary Purpose: Treatment |
||||
Condition ICMJE |
|
||||
Intervention ICMJE |
|
||||
Study Arms ICMJE |
|
||||
Publications * | Not Provided | ||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
|||||
Recruitment Information | |||||
Recruitment Status ICMJE | Recruiting | ||||
Estimated Enrollment ICMJE |
366 | ||||
Original Estimated Enrollment ICMJE |
18 | ||||
Estimated Study Completion Date ICMJE | April 1, 2026 | ||||
Estimated Primary Completion Date | April 1, 2026 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
|
||||
Sex/Gender ICMJE |
|
||||
Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||
Accepts Healthy Volunteers ICMJE | No | ||||
Contacts ICMJE |
|
||||
Listed Location Countries ICMJE | Czechia, France, Germany, Israel, Italy, Poland, Spain, United States | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT04278768 | ||||
Other Study ID Numbers ICMJE | CA-4948-102 | ||||
Has Data Monitoring Committee | Yes | ||||
U.S. FDA-regulated Product |
|
||||
IPD Sharing Statement ICMJE |
|
||||
Current Responsible Party | Curis, Inc. | ||||
Original Responsible Party | Same as current | ||||
Current Study Sponsor ICMJE | Curis, Inc. | ||||
Original Study Sponsor ICMJE | Same as current | ||||
Collaborators ICMJE | Not Provided | ||||
Investigators ICMJE | Not Provided | ||||
PRS Account | Curis, Inc. | ||||
Verification Date | March 2024 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |