Dose Escalation/ Expansion Trial of CA-4948 as Monotherapy and in Combination With Azacitidine or Venetoclax in Patients With AML or MDS

Summary

Participation Requirements

Description

The primary objective of Phase 1 of the study is to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for CA-4948 in monotherapy in patients with AML, intermediate high risk, high risk MDS based on the safety and tolerability, dose-limiting toxicities (DLTs), and Pharmac...

The primary objective of Phase 1 of the study is to determine the maximum tolerated dose (MTD) and Recommended Phase 2 Dose (RP2D) for CA-4948 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 Phase 1b of the study is to determine MTD and RP2D for CA 4948 in combination with azacitidine (AZA) in treatment naïve patients with AML or 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, that are VEN naïve, based on the safety and tolerability, DLTs and PK and pharmacodynamic findings. The primary objective of Phase 2a of the study (CA-4948 monotherapy expansion) is to assess complete response (CR) and duration of response in patients with R/R FLT-3 AML, R/R AML FLT3-Wildtype (WT) and R/R hrMDS and to assess tolerability, and long-term safety. CA-4948 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 CA-4948 may continue to receive CA-4948 until progression of disease, intolerable toxicity, withdrawal from the trial, or study termination. The CA-4948 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, CA-4948 is taken daily for 28 days of a 28 day cycle. For Phase 1b, CA-4948 is taken daily for 21 days of a 28 day cycle. 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 the target dose level. Azacitidine 75 mg/m2 intravenous (IV) or subcutaneously (SC) will be administered as 7 doses on a 28 Cycle (e.g., 7 consecutive doses or split doses with weekend break 5-2), starting at Day 1, and in accordance with local prescribing information. In each of the Phase 1/1b cohorts, three patients with AML or MDS will be 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 experience 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 leads 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 collaboration 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 4 Cohorts and patients will be assigned to each Cohort based on baseline disease: Cohort 1: R/R AML, FLT3-ITD mutant AML patients after failing at least 1 to 3 pretreatments, including a FLT3 inhibitor Cohort 2: R/R AML with FLT3 WT, after failing 1 to 3 pretreatments. Desired enrichment for expression of spliceosome mutations Cohort 3: R/R hrMDS with spliceosome mutations (SF3B1, U2AF1, SRSF2, ZRSR2), resistant/refractory to HMA; ineligible for intensive chemotherapy; maximal 3 pretreatments Cohort 4: R/R hrMDS without spliceosome mutations; resistant/refractory to r/r to HMA; ineligible for intensive chemotherapy; maximal 3 pretreatments

Tracking Information