IRB Study Number 25-771
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Part 1 Primary:
The primary objective of Part 1 is to determine the Part 2 Selected Dose of tagraxofusp (Tag) in combination with venetoclax and azacitidine (Ven/Aza) in previously untreated CD123+ AML participants who are ineligible for intensive chemotherapy.
Part 2 Primary:
The primary objective of Part 2 is to evaluate the complete remission (CR) rate within the first 4 cycles of Tag in combination with Ven/Aza in 2 cohorts [Cohort 1, TP53 mutated (TP53m) and Cohort 2, TP53 wild type (TP53wt)] of participants with previously untreated CD123+ AML who are ineligible for intensive chemotherapy.
Part 1 Secondary:
The secondary objectives of Part 1 include the following:
• Characterize the safety of Tag/Ven/Aza;
• Evaluate the clinical efficacy of Tag/Ven/Aza as assessed by:
o CR rate within the first 4 cycles and within the first 6 cycles;
o Time to CR and duration of response (DOR);
o Composite CR rate (CR, complete remission with incomplete hematologic recovery [CRi], complete remission with partial hematologic recovery [CRh]) within the first 4 cycles, time to first composite CR, and duration of composite CR;
o CR/CRi rate within the first 4 cycles and within first 6 cycles;
o Time to CR/CRi and duration of CR/CRi response;
o Rate of minimal residual disease (MRD) negativity;
o Event-free survival (EFS) and overall survival (OS).
• Evaluate the rate of hematopoietic stem cell transplant (SCT) in participants treated with Tag/Ven/Aza;
• Evaluate the pharmacokinetics (PK) of free Tag and immunogenicity in combination with Ven/Aza;
• Evaluate the PK of Ven/Aza in combination with Tag;
• Evaluate the exposure-response for efficacy and safety of free Tag/Ven/Aza in comparison with Ven/Aza historical data.
Part 2 Secondary:
Secondary objectives of Part 2 include:
• Evaluate the clinical efficacy of Tag in combination with Ven/Aza in 2 cohorts (TP53m and TP53wt) as assessed by:
o CR rate within the first 6 cycles;
o Time to CR and DOR;
o Composite CR (CR/CRi/CRh) rate within the first 4 cycles, time to first composite CR, and duration of composite CR;
o CR/CRi rate within the first 4 cycles and within first 6 cycles;
o Time to CR/CRi and duration of CR/CRi response;
o Rate of MRD negativity;
o EFS and OS.
• Further characterize the safety of Tag in combination with Ven/Aza;
• Evaluate the rate of hematopoietic SCT in participants treated with Tag/Ven/Aza;
• Evaluate the PK of free Tag and immunogenicity in combination with Ven/Aza;
• Evaluate the pharmacokinetics of Ven/Aza in combination with Tag;
• Evaluate the exposure-response for efficacy and safety of free Tag/Ven/Aza in comparison with Ven/Aza historical data.
Exploratory (Parts 1 and 2):
• Transfusion independence conversion rate will be evaluated as an exploratory objective;
• Biomarkers predictive of Tag activity and DOR will be evaluated. These analyses may include multi- study assessment to compare responses to the therapies or disease state;
• Additionally, the study will evaluate the levels of CD123 expression on AML blasts and their relationship with efficacy outcomes. Quantification of total Tag concentrations may also be performed to explore the exposure-response relationships for safety and efficacy of total Tag/Ven/Aza;
• Clinical efficacy will also be evaluated based on algorithmic determination using European LeukemiaNet (ELN) AML response criteria (Döhner et al., 2022a 1 (Appendix B) with available central laboratory results.
Inclusion Criteria
Diagnosis and main criteria for inclusion:
For complete list of inclusion criteria, please refer to Section 9.1.
• Previously untreated individuals with histological confirmation of AML by World Health Organization 2022 (Khoury et al, 2022 2) criteria who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age or comorbidity (refer to inclusion criterion #4 for more details):
o Administration of hydroxyurea or cytarabine (maximum of 1 gram) for cytoreduction is permitted;
o Participants with AML arising from antecedent hematologic disease (including MDS) who have received treatment with commercially available agents (except for hypomethylating agents, venetoclax, tagraxofusp, purine analogues, cytarabine, intensive chemotherapy, SCT, CAR-T therapy or experimental therapies) for their prior hematologic disease are permitted;
o Participants with AML after previous cytotoxic therapy or radiation (i.e., therapy-related AML) are permitted;
o Prior use of All-trans retinoic acid (ATRA) (maximum 4 doses) in cases of suspected acute promyelocytic leukemia (APL) is permitted;
o Prior administration of one dose of intrathecal cytarabine is permitted.
• Participant has any level of CD123 expression on blasts determined centrally by flow cytometry.
o A sample for CD123 assessment is mandatory at Screening. If the results of the central assessment are not available at the time of enrollment, the Investigator may use the results of a local assessment.
• Individuals must be considered ineligible for intensive chemotherapy, defined by the following:
o ≥ 75 years of age; OR ≥ 18 to 74 years of age with at least one of the following:
Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3;
Diffusing capacity of lung for carbon monoxide (DLCO) of ≤ 65 % or forced expiratory volume in 1 second (FEV1) of ≤ 65 %;
Baseline creatinine clearance (CrCl) ≥ 30 ml/min to < 45 ml/min calculated by the Cockcroft Gault formula or measured by 24-hour urine collection;
Hepatic disorder with total bilirubin > 1.5 × upper limit of normal (ULN);
Any other condition for which the physician judges the patient to be unsuitable for intensive chemotherapy.
• ECOG performance status (see Appendix A):
0 to 2 for participants ≥ 75 years of age, OR
0 to 3 for participants ≥ 18 to 74 years of age
Exclusion Criteria
Main criteria for exclusion:
For complete list of exclusion criteria, please refer to Section 9.2.
• Participant has received prior therapy for AML;
• Participant is willing and able to receive standard induction therapy;
• Participant has received treatment for an antecedent hematologic disease with a hypomethylating agent, venetoclax, tagraxofusp, purine analogue, cytarabine, intensive chemotherapy, SCT, CAR-T therapy, or other experimental therapies;
• Participant has AML with central nervous system involvement.
