RESULTS OF A PHASE I STUDY OF GMI-1271, A NOVEL E-SELECTIN ANTAGONIST IN COMBINATION WITH INDUCTION CHEMOTHERAPY IN RELAPSED/REFRACTORY AML: A NOVEL, WELL-TOLERATED REGIMEN WITH A HIGH REMISSION RATE
(Abstract release date: 05/19/16)
EHA Library. Thackray H. 06/10/16; 133179; P191
Dr. Helen Thackray
Contributions
Contributions
Abstract
Abstract: P191
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The treatment of patients with relapsed and refractory acute myeloid leukemia (AML) remains a significant challenge with poor outcomes primarily due to low remission rates as well as short remission duration. Although cytotoxic chemotherapy remains the standard approach for the treatment of patients with relapsed or refractory (R/R) AML, novel agents are urgently needed to improve clinical outcomes. The regimen consisting of mitoxantrone, etoposide, and cytarabine (MEC) is commonly used for patients with R/R AML, with remission rates of 25-30%. Binding of leukemic blasts to E-selectin, an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel antagonist of E-selectin. Here we report initial results from a phase 1/2 trial of GMI-1271 with MEC for the treatment of patients with R/R AML.
Aims
To evaluate the safety, tolerability, pharmacokinetics (PK), and antileukemic activity of the combination of GMI-1271 plus MEC.
Methods
An open-label phase 1/2 trial enrolled patients with R/R AML receiving MEC induction chemotherapy. Eligible patients (ECOG 0–2) must have received ≤2 prior induction regimens, have no active CNS disease and adequate renal and hepatic function. Adjunctive treatment with GMI-1271 at increasing doses was administered concurrent with chemotherapy (24 hours prior, throughout, and 48 hours post MEC); MEC consisted of mitoxantrone 10 mg/m2/d, etoposide 100 mg/m2/d, and cytarabine 1000 mg/m2/d IV for 5 days and supportive care given as per institutional guidelines. Dose limiting toxicity (DLT) was defined as either persistent neutropenia and/or thrombocytopenia beyond day 42 in the absence of disease or any grade 3 non-hematologic toxicity that did not resolve to Grade 2 by day 42.
Results
Two dose level cohorts have been completed, with 13 subjects treated (GMI-1271 at 5 mg/kg (N=6) and10 mg/kg (N=7)). The median age was 51 (range 26 –74) and 9 were male (69%). Seven patients (54%) had adverse cytogenetic risk (SWOG) and 6 patients (46%) had intermediate cytogenetic risk; none were favorable. Eight patients (62%) had relapsed disease and 5 (38%) were refractory to primary therapy. Two patients had relapsed within a year of hematopoietic cell transplant (HCT), 2/13 were FLT3-ITD mutated, 1 patient had extramedullary disease (EMD). All subjects tolerated GMI-1271+MEC well and completed study treatment without dose reduction or interruption; 30 day mortality was 0%. Mucositis developed in 5 subjects (4 at 5 mg/kg), of whom 2 required IV nutrition (both at 5 mg/kg). No DLTs were observed. Initial population PK analysis showed 28% lower clearance than healthy adults and overall similarity in PK profile.Seven of 13 subjects achieved CR (54%); one achieved CRi (transplanted before CR documented); one achieved morphologic leukemia-free state (inadequate count recovery); and four had persistent disease. CR/CRi rate was 8/13 subjects (62%). Of 5 with data post CR/CRi, 1 proceeded to HCT, one relapsed at 90 days, 3 remain in CR (4, 4, and 2 months duration). Responders include refractory AML (3), relapsed FLT3-ITD mutated (1) and EMD (1).
Conclusion
In early clinical assessment of the novel E-selectin antagonist GMI-1271, we report in a group of R/R AML patients a CR/CRi rate of 62%, higher than expected given the high risk cytogenetic features in this group. No DLTs have been observed. Enrollment in a third cohort is ongoing and will be reported. A Phase 2 expansion cohort is planned in both R/R AML as well as elderly de novo AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Clinical trial, Relapsed acute myeloid leukemia, Selectin
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The treatment of patients with relapsed and refractory acute myeloid leukemia (AML) remains a significant challenge with poor outcomes primarily due to low remission rates as well as short remission duration. Although cytotoxic chemotherapy remains the standard approach for the treatment of patients with relapsed or refractory (R/R) AML, novel agents are urgently needed to improve clinical outcomes. The regimen consisting of mitoxantrone, etoposide, and cytarabine (MEC) is commonly used for patients with R/R AML, with remission rates of 25-30%. Binding of leukemic blasts to E-selectin, an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel antagonist of E-selectin. Here we report initial results from a phase 1/2 trial of GMI-1271 with MEC for the treatment of patients with R/R AML.
Aims
To evaluate the safety, tolerability, pharmacokinetics (PK), and antileukemic activity of the combination of GMI-1271 plus MEC.
Methods
An open-label phase 1/2 trial enrolled patients with R/R AML receiving MEC induction chemotherapy. Eligible patients (ECOG 0–2) must have received ≤2 prior induction regimens, have no active CNS disease and adequate renal and hepatic function. Adjunctive treatment with GMI-1271 at increasing doses was administered concurrent with chemotherapy (24 hours prior, throughout, and 48 hours post MEC); MEC consisted of mitoxantrone 10 mg/m2/d, etoposide 100 mg/m2/d, and cytarabine 1000 mg/m2/d IV for 5 days and supportive care given as per institutional guidelines. Dose limiting toxicity (DLT) was defined as either persistent neutropenia and/or thrombocytopenia beyond day 42 in the absence of disease or any grade 3 non-hematologic toxicity that did not resolve to Grade 2 by day 42.
Results
Two dose level cohorts have been completed, with 13 subjects treated (GMI-1271 at 5 mg/kg (N=6) and10 mg/kg (N=7)). The median age was 51 (range 26 –74) and 9 were male (69%). Seven patients (54%) had adverse cytogenetic risk (SWOG) and 6 patients (46%) had intermediate cytogenetic risk; none were favorable. Eight patients (62%) had relapsed disease and 5 (38%) were refractory to primary therapy. Two patients had relapsed within a year of hematopoietic cell transplant (HCT), 2/13 were FLT3-ITD mutated, 1 patient had extramedullary disease (EMD). All subjects tolerated GMI-1271+MEC well and completed study treatment without dose reduction or interruption; 30 day mortality was 0%. Mucositis developed in 5 subjects (4 at 5 mg/kg), of whom 2 required IV nutrition (both at 5 mg/kg). No DLTs were observed. Initial population PK analysis showed 28% lower clearance than healthy adults and overall similarity in PK profile.Seven of 13 subjects achieved CR (54%); one achieved CRi (transplanted before CR documented); one achieved morphologic leukemia-free state (inadequate count recovery); and four had persistent disease. CR/CRi rate was 8/13 subjects (62%). Of 5 with data post CR/CRi, 1 proceeded to HCT, one relapsed at 90 days, 3 remain in CR (4, 4, and 2 months duration). Responders include refractory AML (3), relapsed FLT3-ITD mutated (1) and EMD (1).
Conclusion
In early clinical assessment of the novel E-selectin antagonist GMI-1271, we report in a group of R/R AML patients a CR/CRi rate of 62%, higher than expected given the high risk cytogenetic features in this group. No DLTs have been observed. Enrollment in a third cohort is ongoing and will be reported. A Phase 2 expansion cohort is planned in both R/R AML as well as elderly de novo AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Clinical trial, Relapsed acute myeloid leukemia, Selectin
Abstract: P191
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The treatment of patients with relapsed and refractory acute myeloid leukemia (AML) remains a significant challenge with poor outcomes primarily due to low remission rates as well as short remission duration. Although cytotoxic chemotherapy remains the standard approach for the treatment of patients with relapsed or refractory (R/R) AML, novel agents are urgently needed to improve clinical outcomes. The regimen consisting of mitoxantrone, etoposide, and cytarabine (MEC) is commonly used for patients with R/R AML, with remission rates of 25-30%. Binding of leukemic blasts to E-selectin, an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel antagonist of E-selectin. Here we report initial results from a phase 1/2 trial of GMI-1271 with MEC for the treatment of patients with R/R AML.
Aims
To evaluate the safety, tolerability, pharmacokinetics (PK), and antileukemic activity of the combination of GMI-1271 plus MEC.
Methods
An open-label phase 1/2 trial enrolled patients with R/R AML receiving MEC induction chemotherapy. Eligible patients (ECOG 0–2) must have received ≤2 prior induction regimens, have no active CNS disease and adequate renal and hepatic function. Adjunctive treatment with GMI-1271 at increasing doses was administered concurrent with chemotherapy (24 hours prior, throughout, and 48 hours post MEC); MEC consisted of mitoxantrone 10 mg/m2/d, etoposide 100 mg/m2/d, and cytarabine 1000 mg/m2/d IV for 5 days and supportive care given as per institutional guidelines. Dose limiting toxicity (DLT) was defined as either persistent neutropenia and/or thrombocytopenia beyond day 42 in the absence of disease or any grade 3 non-hematologic toxicity that did not resolve to Grade 2 by day 42.
Results
Two dose level cohorts have been completed, with 13 subjects treated (GMI-1271 at 5 mg/kg (N=6) and10 mg/kg (N=7)). The median age was 51 (range 26 –74) and 9 were male (69%). Seven patients (54%) had adverse cytogenetic risk (SWOG) and 6 patients (46%) had intermediate cytogenetic risk; none were favorable. Eight patients (62%) had relapsed disease and 5 (38%) were refractory to primary therapy. Two patients had relapsed within a year of hematopoietic cell transplant (HCT), 2/13 were FLT3-ITD mutated, 1 patient had extramedullary disease (EMD). All subjects tolerated GMI-1271+MEC well and completed study treatment without dose reduction or interruption; 30 day mortality was 0%. Mucositis developed in 5 subjects (4 at 5 mg/kg), of whom 2 required IV nutrition (both at 5 mg/kg). No DLTs were observed. Initial population PK analysis showed 28% lower clearance than healthy adults and overall similarity in PK profile.Seven of 13 subjects achieved CR (54%); one achieved CRi (transplanted before CR documented); one achieved morphologic leukemia-free state (inadequate count recovery); and four had persistent disease. CR/CRi rate was 8/13 subjects (62%). Of 5 with data post CR/CRi, 1 proceeded to HCT, one relapsed at 90 days, 3 remain in CR (4, 4, and 2 months duration). Responders include refractory AML (3), relapsed FLT3-ITD mutated (1) and EMD (1).
Conclusion
In early clinical assessment of the novel E-selectin antagonist GMI-1271, we report in a group of R/R AML patients a CR/CRi rate of 62%, higher than expected given the high risk cytogenetic features in this group. No DLTs have been observed. Enrollment in a third cohort is ongoing and will be reported. A Phase 2 expansion cohort is planned in both R/R AML as well as elderly de novo AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Clinical trial, Relapsed acute myeloid leukemia, Selectin
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
The treatment of patients with relapsed and refractory acute myeloid leukemia (AML) remains a significant challenge with poor outcomes primarily due to low remission rates as well as short remission duration. Although cytotoxic chemotherapy remains the standard approach for the treatment of patients with relapsed or refractory (R/R) AML, novel agents are urgently needed to improve clinical outcomes. The regimen consisting of mitoxantrone, etoposide, and cytarabine (MEC) is commonly used for patients with R/R AML, with remission rates of 25-30%. Binding of leukemic blasts to E-selectin, an adhesion molecule expressed constitutively in the bone marrow endothelium, activates leukemic cell survival pathways, thereby contributing to chemotherapy resistance. GMI-1271 is a novel antagonist of E-selectin. Here we report initial results from a phase 1/2 trial of GMI-1271 with MEC for the treatment of patients with R/R AML.
Aims
To evaluate the safety, tolerability, pharmacokinetics (PK), and antileukemic activity of the combination of GMI-1271 plus MEC.
Methods
An open-label phase 1/2 trial enrolled patients with R/R AML receiving MEC induction chemotherapy. Eligible patients (ECOG 0–2) must have received ≤2 prior induction regimens, have no active CNS disease and adequate renal and hepatic function. Adjunctive treatment with GMI-1271 at increasing doses was administered concurrent with chemotherapy (24 hours prior, throughout, and 48 hours post MEC); MEC consisted of mitoxantrone 10 mg/m2/d, etoposide 100 mg/m2/d, and cytarabine 1000 mg/m2/d IV for 5 days and supportive care given as per institutional guidelines. Dose limiting toxicity (DLT) was defined as either persistent neutropenia and/or thrombocytopenia beyond day 42 in the absence of disease or any grade 3 non-hematologic toxicity that did not resolve to Grade 2 by day 42.
Results
Two dose level cohorts have been completed, with 13 subjects treated (GMI-1271 at 5 mg/kg (N=6) and10 mg/kg (N=7)). The median age was 51 (range 26 –74) and 9 were male (69%). Seven patients (54%) had adverse cytogenetic risk (SWOG) and 6 patients (46%) had intermediate cytogenetic risk; none were favorable. Eight patients (62%) had relapsed disease and 5 (38%) were refractory to primary therapy. Two patients had relapsed within a year of hematopoietic cell transplant (HCT), 2/13 were FLT3-ITD mutated, 1 patient had extramedullary disease (EMD). All subjects tolerated GMI-1271+MEC well and completed study treatment without dose reduction or interruption; 30 day mortality was 0%. Mucositis developed in 5 subjects (4 at 5 mg/kg), of whom 2 required IV nutrition (both at 5 mg/kg). No DLTs were observed. Initial population PK analysis showed 28% lower clearance than healthy adults and overall similarity in PK profile.Seven of 13 subjects achieved CR (54%); one achieved CRi (transplanted before CR documented); one achieved morphologic leukemia-free state (inadequate count recovery); and four had persistent disease. CR/CRi rate was 8/13 subjects (62%). Of 5 with data post CR/CRi, 1 proceeded to HCT, one relapsed at 90 days, 3 remain in CR (4, 4, and 2 months duration). Responders include refractory AML (3), relapsed FLT3-ITD mutated (1) and EMD (1).
Conclusion
In early clinical assessment of the novel E-selectin antagonist GMI-1271, we report in a group of R/R AML patients a CR/CRi rate of 62%, higher than expected given the high risk cytogenetic features in this group. No DLTs have been observed. Enrollment in a third cohort is ongoing and will be reported. A Phase 2 expansion cohort is planned in both R/R AML as well as elderly de novo AML.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, Clinical trial, Relapsed acute myeloid leukemia, Selectin
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