GMI-1271-201

GlycoMimetics Inc.

9708 Medical Center Dr, Rockville, Maryland, United States, 20850

Eric Feldman, GlycoMimetics Inc., +1 301-417-4269, efeldman@glycomimetics.com

Eric Feldman, GlycoMimetics Inc., +1 301-417-4269, efeldman@glycomimetics.com

No

No

No

Final

17 Sep 2018

No

Yes

15 May 2018

No

The primary objective of this study was to evaluate the safety of uproleselan (GMI-1271) in combination with chemotherapy. The secondary objectives of the study were to characterize the pharmacokinetic (PK) profile of GMI-1271; to evaluate the efficacy of GMI-1271 in combination with chemotherapy (relapsed/refractory [R/R] subjects: MEC; treatment-naïve subjects: “7+3” cytarabine/idarubicin) as measured by overall response rate (ORR), i.e., complete response (CR) and CR with incomplete blood count recovery (CRi); to evaluate the Time to response (TTR), duration of response (DOR), event-free survival (EFS), and 6-month and 12-month Overall Survival (OS) probability.

The study was conducted in accordance with the protocol and the ethical principles derived from the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline of GCP pertinent to the safety of trial subjects.

14 May 2015

Yes

Yes

Ireland: 3

Australia: 5

United States: 83

91

3

0

0

0

0

0

0

57

31

3

Overall Study (overall period)

Not applicable

Yes

GMI-1271

Uproleselan

Solution for injection

Intravenous use

GMI-1271 was administered in Dose-escalation of Phase 1 in the induction of Phase 1 and both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity, or study drug discontinuation as per the scheduled dosing regimen.

Mitoxantrone

Solution for injection

Intravenous use

Mitoxantrone was administered as part of MEC chemotherapy, given in induction of Phase 1 and both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity, or study drug discontinuation as per the scheduled dosing regimen.

Etoposide

Solution for injection

Intravenous use

Etoposide was administered as part of MEC chemotherapy, given in induction of Phase 1 and both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity, or study drug discontinuation as per the scheduled dosing regimen.

Cytarabine

Solution for injection

Intravenous use

Cytarabine was administered as part of MEC chemotherapy, given in induction of Phase 1 and both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity, or study drug discontinuation as per the scheduled dosing regimen.

GMI-1271

Uproleselan

Solution for injection

Intravenous use

GMI-1271 was administered in both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity, or study drug discontinuation as per the scheduled dosing regimen.

Cytarabine

Solution for infusion

Intravenous use

Cytarabine was administered as part of "7+3" Cytarabine/Idarubicin chemotherapy, given in both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity, or study drug discontinuation as per the scheduled dosing regimen.

Idarubicin

Solution for infusion

Intravenous use

Idarubicin was administered as part of "7+3" Cytarabine/Idarubicin chemotherapy, given in both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity, or study drug discontinuation as per the scheduled dosing regimen.

Relapsed/Refractory (Phase 1 and 2 Arm A): GMI-1271 + MEC

Newly Diagnosed (Phase 2 Arm B): GMI- 1271 10 mg/kg + “7+3”

Relapsed/Refractory (Phase 1 and 2 Arm A): GMI-1271 + MEC

Newly Diagnosed (Phase 2 Arm B): GMI- 1271 10 mg/kg + “7+3”

Intent to treat (ITT)

ITT population included all participants who received at least one infusion of GMI-1271.

Safety population

Safety population included all participants who received at least one infusion of GMI-1271.

Phase 1 and 2: Arm A + Arm B

Combined analysis of both group (Relapsed/Refractory [Phase 1 and 2 Arm A]: GMI-1271 + MEC; Newly Diagnosed [Phase 2 Arm B]: GMI- 1271 10 mg/kg + “7+3”) sequences.

Response population

The Response population consists of the subset of the ITT population that achieved documented CR or CRi.

RP2D GMI-1271 10mg + MEC (Phase 1 and 2 Arm A)

GMI-1271 10 mg/kg in Dose-escalation of Phase 1 and then GMI-1271 10 mg/kg as RP2D in combination with MEC chemotherapy regimen were given in induction of Phase 1 and both induction and consolidation cycles of Phase 2 until PD, unacceptable toxicity or study drug discontinuation. GMI-1271 first IV dose was given on d 1, 24 hours before first dose of either induction or consolidation cycles, then GMI-1271 was given every 12 hours ± 1 hour on chemotherapy days, starting 2 hours before chemotherapy and additional 2 days following the last dose of chemotherapy in adult participants (>/=18 years) with R/R AML. Combination chemotherapy included: Mitoxantrone 10 milligrams per meter square per day (mg/m^2/d) IV over 15 to 20 minutes; Etoposide 100 mg/m^2/d IV over 60 minutes; and Cytarabine 1000 mg/m^2/d IV over 60 minutes for 5 days in induction (first course of treatment) and for 4 days in consolidation (second course of treatment).

An AE was any untoward medical occurrence in a participant who received study drug, which does not necessarily have a causal relationship with this treatment. Treatment-emergent AEs (TEAEs) are defined as any event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments. The safety population included all participants who received at least one infusion of GMI-1271.

Primary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

An AE was any untoward medical occurrence in a participant who received study drug, which does not necessarily have a causal relationship with this treatment. Treatment-emergent AEs (TEAEs) are defined as any event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments. A treatment-related AE is any untoward medical occurrence attributed to study drug in a participant who received study drug. The safety population included all participants who received at least one infusion of GMI-1271.

Primary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; birth defect. The safety population included all participants who received at least one infusion of GMI-1271.

Primary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

AE: Any untoward medical occurrence in a participant who received study drug, which does not necessarily have a causal relationship with this treatment.Severity of AE were graded in the following categories per CTCAE grading criteria:1=mild (the AE was of little concern to the participants and was not expected to have any effect on the participant's health or well-being),2=moderate (the participant had enough discomfort to cause interference with or change in usual activities.The AE was of some concern to the participant's health or well-being and may have required medical intervention),3=severe(The participant was incapacitated and unable to work or participate in many or all usual activities.The AE was of definite concern to the participant and/or poses substantial risk to the participant's health or well-being.The event was likely to require medical intervention and/or close follow-up.),4=life threatening (Life-threatening consequences; urgent intervention indicated) and 5=fatal.

Primary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

AUCinf= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - inf). It is obtained from AUC (0 - t) plus AUC (t - inf). The PK analysis population consists of all enrolled participants who have at least one infusion of GMI-1271 and one sample providing evaluable PK data.

Secondary

5 minutes(M) pre-dose,20 m,40 m,hours(H)1.5,3,6,12 post-dose on Days(D) 1,3,8(R/R AML participants[P]),and 10 (newly diagnosed AML P);12 H and 36 H post-last dose on D 9 and 10(R/R AML P);12 H and 36 H post-last dose on D 10 and 12 (newly diagnosed AML P)

The PK analysis population consists of all enrolled participants who have at least one infusion of GMI-1271 and one sample providing evaluable PK data.

Secondary

5 minutes(M) pre-dose,20 m,40 m,hours(H)1.5,3,6,12 post-dose on Days(D) 1,3,8(R/R AML participants[P]),and 10 (newly diagnosed AML P);12 H and 36 H post-last dose on D 9 and 10(R/R AML P);12 H and 36 H post-last dose on D 10 and 12 (newly diagnosed AML P)

Terminal elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. The PK analysis population consists of all enrolled participants who have at least one infusion of GMI-1271 and one sample providing evaluable PK data.

Secondary

5 minutes(M) pre-dose,20 m,40 m,hours(H)1.5,3,6,12 post-dose on Days(D) 1,3,8(R/R AML participants[P]),and 10 (newly diagnosed AML P);12 H and 36 H post-last dose on D 9 and 10(R/R AML P);12 H and 36 H post-last dose on D 10 and 12 (newly diagnosed AML P)

The percentage of participants who achieved a complete remission (CR) or complete remission with incomplete recovery (CRi). CR required the following criteria to be achieved prior to alternative therapy: Bone marrow blasts <5%; absolute neutrophil count (ANC) >/=1.0*109/L; and Platelets >/=100*109/L. CRi was defined as CR but failing to meet either platelet or ANC recovery. The Response population consists of the subset of the ITT population that achieved documented CR or CRi.

Secondary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

DOR is the time from date of first documented remission (first of CR or CRi) to the date of relapse or death from any cause, whichever occurs first. CR required the following criteria to be achieved prior to alternative therapy: Bone marrow blasts <5%; absolute neutrophil count (ANC) >/=1.0*109/L; and Platelets >/=100*109/L. CRi was defined as CR but failing to meet either platelet or ANC recovery. '99999' stands for data not available, as participants were still alive at the time of Database lock so this data was not collected. The Greenwood method was used to determine 90% confidence interval about median. The Response population consists of the subset of the ITT population that achieved documented CR or CRi.

Secondary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

TTR is the time from date of first dose to first documented remission (first of CR or CRi). CR required the following criteria to be achieved prior to alternative therapy: Bone marrow blasts <5%; absolute neutrophil count (ANC) >/=1.0*109/L; and Platelets >/=100*109/L. CRi was defined as CR but failing to meet either platelet or ANC recovery. Data for this outcome measure is not reported as TTR was omitted from the study objectives per the changes in the planned analysis of the study, and thereby not analyzed.

Secondary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

EFS is the time from date of first dose of chemotherapy to the date of treatment failure, relapse, or death from any cause, whichever occurs first. The Greenwood method was used to determine 90% confidence interval about median. The ITT population included all participants who received at least one infusion of GMI-1271.

Secondary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

OS is the time from date of first dose to the date of death from any cause. Percentage of participants with survival at 6 months and 12 months after the date of first dose of chemotherapy was reported. The Greenwood method was used to determine 90% confidence interval. The ITT population included all participants who received at least one infusion of GMI-1271.

Secondary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

OS is the time from date of first dose to the date of death from any cause. The Greenwood method was used to determine 90% confidence interval. '99999' stands for data not available, as participants were still alive at the time of Database lock so this data was not collected. The ITT population included all participants who received at least one infusion of GMI-1271.

Secondary

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

Baseline up to safety evaluation completion visit (30 days after the last dose of study drug)

Safety population included all participants who received at least one infusion of GMI-1271.

17.1

Relapsed/Refractory (Phase 1 and 2 Arm A): GMI-1271 + MEC

Newly Diagnosed (Phase 2 Arm B): GMI-1271 10 mg/kg + “7+3”