Contributions
Abstract: EP480
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
SEL120/RVU120, a novel CDK8/CDK19 kinase inhibitor has shown significant efficacy in preclinical AML models. The First in Human phase Ib clinical trial with SEL120 in patients with relapsed/refractory (R/R) AML or HRMDS is currently open for enrollment at 6 sites in the US (NCT04021368). Here we present the preliminary safety, efficacy and pharmacokinetic (PK) data of the first 4 dose escalation single patient cohorts.
Aims
The primary objective of the study is to determine preliminary safety profile, dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and the recommended phase 2 dose of SEL120 as a single agent. Secondary objectives include the characterization of PK, antitumor activity and exploratory pharmacodynamic effects.
Methods
All pts signed the informed consent. The study comprises at least 8 dose escalating cohorts. The first four cohorts followed an accelerated scheme, 1 patient enrolled/cohort, with the following cohorts switching to a modified Fibonacci 3+3 design. Data from each cohort was evaluated by a study data review committee (DRC). SEL120 was administered orally every other day, for a total of 7 doses, in a 3-week treatment cycle until disease progression/unacceptable toxicity. Adverse events were graded according to NCI-CTCAE v.5.0. DLTs were assessed at completion of C1. Disease evaluation was performed according to Dohner 2017 and Cheson 2006 response criteria for AML and MDS respectively. Plasma PK parameters were calculated by non-compartmental analysis
Results
Cohorts 1 to 4, each enrolled 1 DLT evaluable patient who received SEL120 at dose levels from 10 to 75 mg. 3 patients had a diagnosis of R/R AML, 1 patient had persistent HR-MDS. The median age of patients was 74 years and the number of median prior lines of treatment was 3. No DLTs were observed, 4 Serious Adverse Events were reported and assessed by the investigator, as unlikely related to study drug (G3: pseudomonas sepsis; urinary tract infection; febrile neutropenia; lung infection). Cohort 1 patient, at 10 mg dose level, and cohort 2 patient, at 25 mg showed stable disease (SD) and progressive disease, respectively at C1. Cohort 3 patient, who started at 50 mg dose level, is an 81-year-old male with HRMDS who showed evidence of an Erythroid Response at C5D8. He is now in C8, at 75 mg, following to a dose escalation during C7. Cohort 4 patient, at 75 mg dose level, is a 62-year-old male with persistent AML and extramedullary skin leukemia, who failed prior venetoclax/decitabine. This patient achieved a complete hematological recovery at C2 and absence of bone marrow blasts and continuous improvement of skin leukemia, now ongoing in C5, however, the profound post ven/dec pancytopenia complicates assessments of magnitude of the contribution of SEL120 to this response. PK parameters of these 4 patients, were similar across all dose levels. SEL120 absorption was relatively rapid with Tmax 4 -8 hr after drug administration. Exposure, based on Cmax and AUC, was linear with doses between 10 and 75 mg, both after single and repeat dosing. SEL120 elimination half-life in plasma was 22 to 40 hr with low accumulation (1.3 to 1.8-fold). Within patient variability of plasma concentrations of SEL120, over at least 6 cycles, was low.
Conclusion
Preliminary results of the first four single patient dose escalation cohorts have shown a favorable safety and a linear PK profile of SEL120. The first signal of activity is observed at doses 50 to 75 mg. Enrollment is currently ongoing, with switching to 3+3 design.
Keyword(s): AML, MDS, Phase I
Abstract: EP480
Type: E-Poster Presentation
Session title: Acute myeloid leukemia - Clinical
Background
SEL120/RVU120, a novel CDK8/CDK19 kinase inhibitor has shown significant efficacy in preclinical AML models. The First in Human phase Ib clinical trial with SEL120 in patients with relapsed/refractory (R/R) AML or HRMDS is currently open for enrollment at 6 sites in the US (NCT04021368). Here we present the preliminary safety, efficacy and pharmacokinetic (PK) data of the first 4 dose escalation single patient cohorts.
Aims
The primary objective of the study is to determine preliminary safety profile, dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and the recommended phase 2 dose of SEL120 as a single agent. Secondary objectives include the characterization of PK, antitumor activity and exploratory pharmacodynamic effects.
Methods
All pts signed the informed consent. The study comprises at least 8 dose escalating cohorts. The first four cohorts followed an accelerated scheme, 1 patient enrolled/cohort, with the following cohorts switching to a modified Fibonacci 3+3 design. Data from each cohort was evaluated by a study data review committee (DRC). SEL120 was administered orally every other day, for a total of 7 doses, in a 3-week treatment cycle until disease progression/unacceptable toxicity. Adverse events were graded according to NCI-CTCAE v.5.0. DLTs were assessed at completion of C1. Disease evaluation was performed according to Dohner 2017 and Cheson 2006 response criteria for AML and MDS respectively. Plasma PK parameters were calculated by non-compartmental analysis
Results
Cohorts 1 to 4, each enrolled 1 DLT evaluable patient who received SEL120 at dose levels from 10 to 75 mg. 3 patients had a diagnosis of R/R AML, 1 patient had persistent HR-MDS. The median age of patients was 74 years and the number of median prior lines of treatment was 3. No DLTs were observed, 4 Serious Adverse Events were reported and assessed by the investigator, as unlikely related to study drug (G3: pseudomonas sepsis; urinary tract infection; febrile neutropenia; lung infection). Cohort 1 patient, at 10 mg dose level, and cohort 2 patient, at 25 mg showed stable disease (SD) and progressive disease, respectively at C1. Cohort 3 patient, who started at 50 mg dose level, is an 81-year-old male with HRMDS who showed evidence of an Erythroid Response at C5D8. He is now in C8, at 75 mg, following to a dose escalation during C7. Cohort 4 patient, at 75 mg dose level, is a 62-year-old male with persistent AML and extramedullary skin leukemia, who failed prior venetoclax/decitabine. This patient achieved a complete hematological recovery at C2 and absence of bone marrow blasts and continuous improvement of skin leukemia, now ongoing in C5, however, the profound post ven/dec pancytopenia complicates assessments of magnitude of the contribution of SEL120 to this response. PK parameters of these 4 patients, were similar across all dose levels. SEL120 absorption was relatively rapid with Tmax 4 -8 hr after drug administration. Exposure, based on Cmax and AUC, was linear with doses between 10 and 75 mg, both after single and repeat dosing. SEL120 elimination half-life in plasma was 22 to 40 hr with low accumulation (1.3 to 1.8-fold). Within patient variability of plasma concentrations of SEL120, over at least 6 cycles, was low.
Conclusion
Preliminary results of the first four single patient dose escalation cohorts have shown a favorable safety and a linear PK profile of SEL120. The first signal of activity is observed at doses 50 to 75 mg. Enrollment is currently ongoing, with switching to 3+3 design.
Keyword(s): AML, MDS, Phase I