Relapsed or Refractory Acute Myeloid Leukemia
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of AMG 330, administered in combination with pembrolizumab, in participants with relapsed or refractory acute myeloid leukemia (R/R AML).
Detailed description
This study will assess the safety and tolerability of AMG 330 in combination with pembrolizumab and whether pembrolizumab will enhance the anti-AML activity of AMG 330. Both cohort 1 and 2 will include AMG 330 and pembrolizumab with the difference being the initiation date for pembrolizumab treatment.
Interventions
DRUGAMG 330
Continuous intravenous (IV) infusion.
DRUGPembrolizumab
Intravenous (IV) infusion.
Sponsors
Merck Sharp & Dohme LLC
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion criteria * AML as defined by the WHO Classification persisting or recurring following one or more treatment courses. Except APL * Eastern Cooperative Oncology Group (ECOG) ≤1 Key
Exclusion criteria
* Active extramedullary AML in the central nervous system. * Known hypersensitivity to immunoglobulins. * Non-manageable graft versus host disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) | 28 days | A DLT was defined as any of the events described below occurring in a participant during the DLT window, unless clearly attributable to causes other than investigational product: Any treatment-related death, Grade 4 neutropenia, Grade 3-4 non hematologic toxicity not clearly resulting from the underlying leukemia, with some exceptions, cytokine release syndrome, and any Grade 5 toxicity. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | A TEAE was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment that occurred after first dose. Any clinically significant changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests that occurred after first dose were recorded as TEAEs. |
| Number of Participants Who Experienced Treatment-related Adverse Events (TRAEs) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | A TRAE was defined as any untoward medical occurrence in a clinical study participant considered to have a possible causal relationship with the study treatment. Any clinically significant changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests that were considered to have a possible causal relationship with the study treatment were recorded as TRAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Morphological Leukemia-free State (MLFS) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | MLFS was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). MLFS was defined as bone marrow blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required. |
| Partial Remission (PR) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | PR was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). PR was defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50%. |
| Duration of Response (DoR) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | DoR was calculated for participants who achieved overall response (CRMRD-, CR, CRi, PR or MLFS). DoR was defined as time from the first observation indicating an objective response to the subsequent date of disease progression or death, whichever is earlier. |
| Plasma Concentration of AMG 330 | Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively | — |
| Complete Remission Without Minimal Residual Disease (CRMRD-) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | CRMRD- was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). CRMRD- was defined as complete remission (CR) with negativity for a genetic marker by quantitative reverse transcription polymerase chain reaction (RT-qPCR), or CR with negativity by multiparametric flow cytometry (MFC). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/μL); platelet count ≥ 100 x 109/L (100 000/μL). |
| Steady State Concentration of AMG 330 | Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively | — |
| Volume of Distribution of AMG 330 | Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively | — |
| Clearance of AMG 330 | Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively | — |
| Number of Participants With Anti-AMG 330 Antibody Formation | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | — |
| Half-life of AMG 330 | Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively | — |
| Complete Remission (CR) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | CR was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/μL); platelet count ≥ 100 x 109/L (100 000/μL). |
| CR With Incomplete Recovery (CRi) | From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months. | CRi was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). CRi was defined as all CR criteria (bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/μL); platelet count ≥ 100 x 109/L \[100 000/μL\]), except for residual neutropenia (\< 1.0 x 109/L \[1000/μL\]) or thrombocytopenia (\< 100 x 109/L \[100 000/μL\]). |
Countries
United States
Participant flow
Recruitment details
1 participant was enrolled into this study at 1 center in the United States.
Pre-assignment details
Screening tests and procedures were performed within the 14 days preceding administration of the first dose.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Cohort 1 were planned to receive escalating doses of AMG 330 via continuous intravenous infusion (cIV) from Day 1 of Cycle 1 (Cycle 1 was 77 days; subsequent cycles were 57 days) for up to 6 months. The starting dose of AMG 330 was 10 μg/day, increasing up to a maximum of 600 μg/day. Cohort 1 were planned to receive 8 mg of dexamethasone 1 hour prior to each step dose of AMG 330. If the participant did not experience a dose-limiting toxicity (DLT) by Day 14, they then were also planned to receive 200 mg of pembrolizumab once every 3 weeks (Q3W) by a 30-minute intravenous (IV) infusion from Day 15 onwards. At the end of Cycle 1, there was a planned 1-week interval without administration of AMG 330, known as the infusion-free period. | 0 |
| Cohort 2 Cohort 2 were planned to receive escalating doses of AMG 330 via cIV from Day 1 of Cycle 1 (cycles were 57 days) for up to 6 months. The starting dose of AMG 330 was planned to be 10 μg/day, increasing up to a maximum of 600 μg/day. The participants were also planned to receive 8 mg of dexamethasone 1 hour prior to each step dose of AMG 330, and 200 mg of pembrolizumab Q3W by a 30-minute IV infusion from Day 1 onwards. At the end of Cycle 1, there was planned to be a 1-week interval without administration of AMG 330 known as the infusion-free period..
The trial was terminated early and 0 participants were enrolled into Cohort 2. | 0 |
| Total | 0 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 1 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 |
Outcome results
Primary
Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)
A DLT was defined as any of the events described below occurring in a participant during the DLT window, unless clearly attributable to causes other than investigational product: Any treatment-related death, Grade 4 neutropenia, Grade 3-4 non hematologic toxicity not clearly resulting from the underlying leukemia, with some exceptions, cytokine release syndrome, and any Grade 5 toxicity.
Time frame: 28 days
Population: Measured in the Dose-limiting Toxicity Evaluable Analysis Set, which was defined as DLT-evaluable participants in the Safety Analysis Set.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Primary
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
A TEAE was defined as any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment that occurred after first dose. Any clinically significant changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests that occurred after first dose were recorded as TEAEs.
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Primary
Number of Participants Who Experienced Treatment-related Adverse Events (TRAEs)
A TRAE was defined as any untoward medical occurrence in a clinical study participant considered to have a possible causal relationship with the study treatment. Any clinically significant changes in vital signs, electrocardiograms (ECGs), and clinical laboratory tests that were considered to have a possible causal relationship with the study treatment were recorded as TRAEs.
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Clearance of AMG 330
Time frame: Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively
Population: Measured in the Pharmacokinetic (PK) Analysis Set which contained all participants who received at least 1 dose of AMG 330 or pembrolizumab and had at least 1 PK sample collected.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Complete Remission (CR)
CR was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/μL); platelet count ≥ 100 x 109/L (100 000/μL).
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Complete Remission Without Minimal Residual Disease (CRMRD-)
CRMRD- was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). CRMRD- was defined as complete remission (CR) with negativity for a genetic marker by quantitative reverse transcription polymerase chain reaction (RT-qPCR), or CR with negativity by multiparametric flow cytometry (MFC). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/μL); platelet count ≥ 100 x 109/L (100 000/μL).
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
CR With Incomplete Recovery (CRi)
CRi was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). CRi was defined as all CR criteria (bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥ 1.0 x 109/L (1000/μL); platelet count ≥ 100 x 109/L \[100 000/μL\]), except for residual neutropenia (\< 1.0 x 109/L \[1000/μL\]) or thrombocytopenia (\< 100 x 109/L \[100 000/μL\]).
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Duration of Response (DoR)
DoR was calculated for participants who achieved overall response (CRMRD-, CR, CRi, PR or MLFS). DoR was defined as time from the first observation indicating an objective response to the subsequent date of disease progression or death, whichever is earlier.
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Half-life of AMG 330
Time frame: Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively
Population: Measured in the Pharmacokinetic (PK) Analysis Set which contained all participants who received at least 1 dose of AMG 330 or pembrolizumab and had at least 1 PK sample collected.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Morphological Leukemia-free State (MLFS)
MLFS was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). MLFS was defined as bone marrow blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required.
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Number of Participants With Anti-AMG 330 Antibody Formation
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Partial Remission (PR)
PR was measured according to the 2017 European Leukemia Net (ELN) criteria (Döhner et al, 2017). PR was defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50%.
Time frame: From first dose of study treatment until 30 days after last dose, or end of study, whichever was earlier; median (min, max) duration was 0.79 (0.79, 0.79) months.
Population: Measured in the Safety Analysis Set, which was defined as all participants that were enrolled and received at least 1 dose of AMG 330 or pembrolizumab.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Plasma Concentration of AMG 330
Time frame: Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively
Population: Measured in the Pharmacokinetic (PK) Analysis Set which contained all participants who received at least 1 dose of AMG 330 or pembrolizumab and had at least 1 PK sample collected.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Steady State Concentration of AMG 330
Time frame: Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively
Population: Measured in the Pharmacokinetic (PK) Analysis Set which contained all participants who received at least 1 dose of AMG 330 or pembrolizumab and had at least 1 PK sample collected.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.
Secondary
Volume of Distribution of AMG 330
Time frame: Pre-dose, 6hrs post-dose Day 1 to 71 of Cycle 1 (Cycle 1=77 days), pre-dose, 6hrs post-dose Day 1 to 50 of Cycles 2+ (Cycle 2+=57 days); end of infusion,0.5,2,4 and 8hrs post-infusion on Days 78 and 57 of Cycle 1 and 2 infusion-free periods respectively
Population: Measured in the Pharmacokinetic (PK) Analysis Set which contained all participants who received at least 1 dose of AMG 330 or pembrolizumab and had at least 1 PK sample collected.~The study was terminated with only 1 participant enrolled into Cohort 1 (0 participants were enrolled into Cohort 2). No data is reported here to maintain participant confidentiality.