Contributions
Abstract: EP452
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253)3 adduct which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863).
Aims
Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity.
Methods
Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m2 with planned escalation to 403 mg/m2.
Results
As of January 4, 2021, a total of 14 patients (age 64.4 ± 15.5, 12 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 – 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66, 100 and 150 mg/m2 (n=4 each). All but 1 AML patient were RBC and/or platelet transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Possible drug- related grade 2 TEAEs included fatigue, increased alkaline phosphatase, decreased appetite, hematoma, hypokalemia, thrombophlebitis, upper respiratory tract infection in 1 (7.1%) patient each. Only 1 drug-related TEAE of grade 3 or greater (fatigue, possibly related) has occurred to date. Preliminary PK analysis showed that serum levels of APTO-253 were dose proportional. Cmax and AUC0-24h on C1D1 were 0.06, 0.02, 0.11 ± 0.04 and 0.44 ± 0.41 µM and 0.11, 0.15, 1.14 ± 0.57, 2.38 ± 0.90 µM*h for dose levels of 20, 40, 66, and 100 mg/m2, respectively. Plasma levels for Fe(253)3 were significantly higher than those for the APTO-253 monomer. For example, Cmax and AUC0-24h of Fe(253)3 on C1D1 of patients in Cohort 100 mg/m2 were 2- and 8-fold higher than the native ATPO-253 at 0.91 ± 0.33 µM and 16.14 ± 6.26 µM*h, respectively. Following dosing at 100 mg/m2, serum concentrations of Fe(253)3 were above 0.1 µM for >72 h (0.66 ± 0.12, 0.39 ± 0.11 and 0.24 ± 0.08 µM at 24, 48 and 72 hours post dosing, respectively) which approaches the therapeutic range based on in vitro studies. The levels of MYC mRNA in the whole blood, a PD biomarker of APTO-253 and Fe(253)3 measured by RT-qPCR, were reduced 20-48% at 24 h post-dose as compared to pre-dose in the first 3 cohorts, suggesting target engagement by the drug.
Conclusion
APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m2 over multiple cycles. PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253)3 in serum and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m2 dose level is ongoing and updated clinical data will be presented at the meeting.
Keyword(s): Acute myeloid leukemia, MYC, Refractory, Relapsed acute myeloid leukemia
Abstract: EP452
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253)3 adduct which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863).
Aims
Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity.
Methods
Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m2 with planned escalation to 403 mg/m2.
Results
As of January 4, 2021, a total of 14 patients (age 64.4 ± 15.5, 12 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 – 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66, 100 and 150 mg/m2 (n=4 each). All but 1 AML patient were RBC and/or platelet transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Possible drug- related grade 2 TEAEs included fatigue, increased alkaline phosphatase, decreased appetite, hematoma, hypokalemia, thrombophlebitis, upper respiratory tract infection in 1 (7.1%) patient each. Only 1 drug-related TEAE of grade 3 or greater (fatigue, possibly related) has occurred to date. Preliminary PK analysis showed that serum levels of APTO-253 were dose proportional. Cmax and AUC0-24h on C1D1 were 0.06, 0.02, 0.11 ± 0.04 and 0.44 ± 0.41 µM and 0.11, 0.15, 1.14 ± 0.57, 2.38 ± 0.90 µM*h for dose levels of 20, 40, 66, and 100 mg/m2, respectively. Plasma levels for Fe(253)3 were significantly higher than those for the APTO-253 monomer. For example, Cmax and AUC0-24h of Fe(253)3 on C1D1 of patients in Cohort 100 mg/m2 were 2- and 8-fold higher than the native ATPO-253 at 0.91 ± 0.33 µM and 16.14 ± 6.26 µM*h, respectively. Following dosing at 100 mg/m2, serum concentrations of Fe(253)3 were above 0.1 µM for >72 h (0.66 ± 0.12, 0.39 ± 0.11 and 0.24 ± 0.08 µM at 24, 48 and 72 hours post dosing, respectively) which approaches the therapeutic range based on in vitro studies. The levels of MYC mRNA in the whole blood, a PD biomarker of APTO-253 and Fe(253)3 measured by RT-qPCR, were reduced 20-48% at 24 h post-dose as compared to pre-dose in the first 3 cohorts, suggesting target engagement by the drug.
Conclusion
APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m2 over multiple cycles. PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253)3 in serum and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m2 dose level is ongoing and updated clinical data will be presented at the meeting.
Keyword(s): Acute myeloid leukemia, MYC, Refractory, Relapsed acute myeloid leukemia