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1. Determine Maximum Tolerated Dose (MTD) of emavusertib (CA-4948) monotherapy (Phase 1) (Time Frame - 28 days): The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
2. Determine the Recommended Phase 2 Dose (RP2D) of emavusertib monotherapy (Phase 1) (Time Frame - 24 months): 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 an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.
3. Determine Maximum Tolerated Dose (MTD) of emavusertib in combination with venetoclax (Phase 1b) (Time Frame - 28 days): The highest dose at which there is <33% Dose Limiting Toxicity rate in the first cycle of treatment in a minimum of 6 patients.
4. Determine the Recommended Phase 2 Dose (RP2D) of emavusertib in combination with venetoclax (Phase 1b) (Time Frame - 24 months): 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 an RP2D is to provide a dose and schedule that will maximize the opportunity for clinical benefit, while minimizing the risk of toxicity.
5. To assess anti-cancer activity (Phase 2a - AML patients) (Time Frame - 24 months): Proportion of patients who achieve CR + CRh
6. To assess anti-cancer activity (Phase 2a - hrMDS patients) (Time Frame - 24 months): Overall response rate: proportion of patients who achieve CR+PR
7. To assess safety (Phase 1b) (Time Frame - 24 months): Clinical safety assessments including frequency of adverse events (AEs)
Secondary outcome:
1. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmax (Phase 1 and 1b) (Time Frame - 24 months): maximum plasma concentration (Cmax)
2. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Cmin (Phase 1 and Phase 1b) (Time Frame - 24 months): trough plasma concentration (Cmin)
3. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Tmax (Phase 1 and 1b) (Time Frame - 24 months): Time to maximum plasma concentration
4. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by Area under the plasma concentration versus time curve(AUC) [0-24] (Phase 1 and 1b) (Time Frame - 24 months): Area under the plasma concentration-time curve from 0 to 24 hours
5. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by AUC[INF] (Phase 1 and 1b) (Time Frame - 24 months): Area under the plasma concentration-time curve from 0 to infinity
6. To characterize the pharmacokinetic (PK) parameters of emavusertib measured by T 1/2 (Phase 1 and 1b) (Time Frame - 24 months): Plasma terminal elimination half-life (T 1/2)
7. To assess clinical response (Phase 1 and 1b) (Time Frame - 24 months): For AML: assessed by proportion of patients who reach complete response (CR) + complete response with partial hematological recovery (CRh) assessed by proportion of patients who reach complete response with incomplete hematologic recovery (CRi) or CR or Crh For hrMDS: overall response rate of CR+partial response (PR)
8. To assess clinical response (Phase 1 and 1b) (Time Frame - 24 months): Assessed by transfusion independence
9. To assess tolerability and long term safety (Phase 2a) (Time Frame - 24 months): Clinical safety assessments including frequency of adverse events (AEs)
10. To assess clinical response (Phase 2a) (Time Frame - 24 months): For AML - assessed by proportion of patients who achieve CR or CRh or CRi; For hrMDS - assessed by proportion of patients who achieve CR or PR or mCR
11. To assess clinical response (Phase 2a) (Time Frame - 24 months): Assessed by duration of response (DOR)
12. To assess clinical response (Phase 2a) (Time Frame - 24 months): Assessed by time to response
13. To assess clinical response (Phase 2a) (Time Frame - 24 months): Assessed by transfusion independence
14. To assess clinical response (Phase 2a) (Time Frame - 24 months): Assessed by overall survival (OS)
Experimental: Emavusertib (CA-4948) dose escalation Patients receive emavusertib monotherapy BID daily. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Experimental: Emavusertib dose escalation + Venetoclax The starting dose for emavusertib will be 200 mg BID for 21 days of a 28-day Cycle. Anticipated emavusertib doses will be 200 and 300 mg BID. 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 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level.
This arm of the study has been closed to enrollment.
Experimental: Emavusertib monotherapy dose expansion 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.
Emavusertib (CA-4948): Emavusertib is formulated as a tablet for oral administration for BID dosing in consecutive 28-day cycles. Emavusertib is a novel small molecule inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4). IRAK4 kinase plays an essential role in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways and these pathways are frequently dysregulated in non-Hodgkin's lymphoma and AML/MDS malignancies.
Venetoclax: Ventoclax is B-cell lymphoma-2 (BCL-2) inhibitor. 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 21days of a 28-day Cycle. Second and subsequent cycles start with target dose level.
Emavusertib (CA-4948): Emavusertib is formulated as a tablet for oral administration for BID dosing for 21 days (Days 1-21) of a 28-day Cycle.
Quelle: ClinicalTrials.gov
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"Dose Escalation/ Expansion Study of CA-4948 as Monotherapy in Patients With AML or MDS"
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