Contributions
Abstract: PB1407
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
Despite recently approved treatment options, outcomes remain poor in patients (pts) with acute myeloid leukemia (AML) who are older or unfit for intensive chemotherapy. Pevonedistat (PEVO) is a first-in-class small-molecule inhibitor of the neural-precursor-cell-expressed developmentally down-regulated protein 8 (NEDD8)-activating enzyme (NAE), an enzyme that targets critical regulatory proteins for degradation. NAE inhibition interferes with protein homeostasis, leading to cancer-cell death. The combination of PEVO+AZA has shown synergistic antitumor activity in some AML cell lines in vitro. PEVO has also shown encouraging clinical efficacy in combination with AZA with a similar safety profile to that of AZA alone with no added myelosuppression. In a randomized, phase 2 trial (NCT02610777), median OS trended longer with PEVO+AZA compared with AZA alone (23.6 versus 16.0 months, respectively; P = 0.081) in pts with low-blast AML (N = 36).
Aims
The primary objective of this trial (NCT04090736) will be to evaluate if PEVO+AZA improves OS compared with AZA alone in treatment-naive pts with AML who are ineligible for standard induction chemotherapy. Key secondary objectives will be event-free survival (EFS) and the proportion of pts achieving composite complete remission when treated with PEVO+AZA (arm A) versus AZA alone (arm B). Pt reported outcomes and centralized minimal residual disease will be analyzed.
Methods
This phase 3, prospective, randomized (1:1), open-label study conducted at 62 sites in Spain will compare PEVO+AZA versus AZA alone. The planned sample size of 466 pts (233 pts in each treatment arm) is estimated to be enrolled within 24 months. An additional follow-up of 22 months after the accrual will be needed to obtain a total of 386 OS events. This will provide 80% power to detect a statistically significant difference in OS between the two treatment arms under the assumption of a hazard ratio of 0.75. An interim analysis of OS will be performed after 75% of death events have occurred. Pts in arm A will receive PEVO 20 mg/m2 intravenously on days 1, 3 and 5 plus AZA 75 mg/m2 subcutaneously on the 5-on/2-off (weekend)/2-on schedule in a 28-day cycle. Pts in Arm B will receive AZA 75 mg/m2 on the 5-on/2-off (weekend)/2-on schedule in a 28-day cycle. Eligible pts include adults with newly diagnosed AML who have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤ 3 and are not eligible for intensive chemotherapy (≥ 75 years of age, or ≥ 18 years of age with comorbidities that preclude intensive chemotherapy [e.g., renal, cardiac, or hepatic dysfunction, or ECOG PS of 2 or 3]). Pts with secondary AML are also eligible for inclusion. Exclusion criteria include white blood cell count ≥ 25 × 109/L, previous treatment for myelodysplastic syndrome or chronic myelomonocytic leukemia or myeloproliferative neoplasm, with chemotherapy or other antineoplastic agents including up to two cycles of hypomethylating agents. An independent data monitoring committee will review safety and efficacy data.
Results
N/A
Conclusion
Since September 2019 and throughout the coronavirus pandemic, 187 pts were recruited; recruitment is ongoing. Given its novel mechanism of action and non-myelosuppressive safety profile, data from this trial may support the use of PEVO as an additional combination therapy partner for pts with AML to improve survival outcomes while preserving QoL.
Keyword(s): Acute myeloid leukemia, Azacitidine
Abstract: PB1407
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
Despite recently approved treatment options, outcomes remain poor in patients (pts) with acute myeloid leukemia (AML) who are older or unfit for intensive chemotherapy. Pevonedistat (PEVO) is a first-in-class small-molecule inhibitor of the neural-precursor-cell-expressed developmentally down-regulated protein 8 (NEDD8)-activating enzyme (NAE), an enzyme that targets critical regulatory proteins for degradation. NAE inhibition interferes with protein homeostasis, leading to cancer-cell death. The combination of PEVO+AZA has shown synergistic antitumor activity in some AML cell lines in vitro. PEVO has also shown encouraging clinical efficacy in combination with AZA with a similar safety profile to that of AZA alone with no added myelosuppression. In a randomized, phase 2 trial (NCT02610777), median OS trended longer with PEVO+AZA compared with AZA alone (23.6 versus 16.0 months, respectively; P = 0.081) in pts with low-blast AML (N = 36).
Aims
The primary objective of this trial (NCT04090736) will be to evaluate if PEVO+AZA improves OS compared with AZA alone in treatment-naive pts with AML who are ineligible for standard induction chemotherapy. Key secondary objectives will be event-free survival (EFS) and the proportion of pts achieving composite complete remission when treated with PEVO+AZA (arm A) versus AZA alone (arm B). Pt reported outcomes and centralized minimal residual disease will be analyzed.
Methods
This phase 3, prospective, randomized (1:1), open-label study conducted at 62 sites in Spain will compare PEVO+AZA versus AZA alone. The planned sample size of 466 pts (233 pts in each treatment arm) is estimated to be enrolled within 24 months. An additional follow-up of 22 months after the accrual will be needed to obtain a total of 386 OS events. This will provide 80% power to detect a statistically significant difference in OS between the two treatment arms under the assumption of a hazard ratio of 0.75. An interim analysis of OS will be performed after 75% of death events have occurred. Pts in arm A will receive PEVO 20 mg/m2 intravenously on days 1, 3 and 5 plus AZA 75 mg/m2 subcutaneously on the 5-on/2-off (weekend)/2-on schedule in a 28-day cycle. Pts in Arm B will receive AZA 75 mg/m2 on the 5-on/2-off (weekend)/2-on schedule in a 28-day cycle. Eligible pts include adults with newly diagnosed AML who have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of ≤ 3 and are not eligible for intensive chemotherapy (≥ 75 years of age, or ≥ 18 years of age with comorbidities that preclude intensive chemotherapy [e.g., renal, cardiac, or hepatic dysfunction, or ECOG PS of 2 or 3]). Pts with secondary AML are also eligible for inclusion. Exclusion criteria include white blood cell count ≥ 25 × 109/L, previous treatment for myelodysplastic syndrome or chronic myelomonocytic leukemia or myeloproliferative neoplasm, with chemotherapy or other antineoplastic agents including up to two cycles of hypomethylating agents. An independent data monitoring committee will review safety and efficacy data.
Results
N/A
Conclusion
Since September 2019 and throughout the coronavirus pandemic, 187 pts were recruited; recruitment is ongoing. Given its novel mechanism of action and non-myelosuppressive safety profile, data from this trial may support the use of PEVO as an additional combination therapy partner for pts with AML to improve survival outcomes while preserving QoL.
Keyword(s): Acute myeloid leukemia, Azacitidine