Leukemia, Myeloid, Acute
Conditions
Brief summary
Phase I Dose Escalation: Primary objective is to determine the Maximum Tolerated Dose (MTD) and the recommended dose for Phase I Extension. Secondary objective is to investigate the safety, pharmacokinetics and efficacy of BI 836858 in combination with decitabine Phase I Extension: Primary objective is to collect additional data on safety, pharmacokinetics and efficacy and to define the Recommended Phase II Dose (RP2D) of BI 836858 in combination with decitabine. Phase II: Primary objective is to investigate efficacy, safety and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.
Interventions
DRUGDecitabine
DRUGBI 836858
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase I Dose Escalation: Open-label, single-arm, dose escalation \- To determine the maximum tolerated dose (MTD) and the recommended dose for Phase I Extension (RExP1D) Phase I Extension: Open-label, two consecutive groups (cohort A and B) - To collect additional data on safety, pharmacokinetics and efficacy and to decide if the RExP1D will become the Recommended Phase II Dose (RP2D) Phase II: Open-label, two-arm randomized \- To investigate efficacy, safety and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\) Phase I Dose Escalation: * Male or female patients \>/= 18 years of age with relapsed or refractory AML * Male or female patients \>/= 65 years of age with previously untreated AML ineligible for receiving standard intensive therapy Phase I Extension and Phase II: \-- Male or female patients \>/= 65 years of age with previously untreated AML ineligible for receiving standard intensive therapy 2\) Histologically or cytologically confirmed AML according to the WHO classification 3) Patients must be eligible for treatment with decitabine 4) Eastern co-operative oncology group (ECOG) performance score \</=2 at screening Further inclusion criteria apply.
Exclusion criteria
1. Acute promyelocytic leukemia (APL, French-American-British (FAB) subtype M3), according to WHO classification. 2. Patients who are candidates for allogeneic stem cell transplantation. 3. Active chronic graft versus host disease requiring immunosuppressive treatment. 4. Phase I extension and Phase II only: Prior treatment with a hypomethylating agent, such as prior treatment for Myelodysplastic Syndrome (MDS). 5. Prior treatment with Cluster of differentiation 33 (CD33) antibody. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Number of Patients With Dose Limiting Toxicity (DLT(s)) During First Treatment Cycle | Up to 28 days (first treatment cycle). | Number of patients with dose limiting toxicity (DLT(s)) for BI 836858 in combination with decitabine during first treatment cycle (Phase 1). DLT was defined as any non-disease-related non-haematological adverse event (AE) of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher. Expected non-haematological disease-related AEs were not to be regarded as a DLT. These included complications resulting from haematological AEs such as: * Bleeding and complications from bleeding due to thrombocytopenia as defined by the Investigator, * Infection and complications from infections due to neutropenia as defined by the Investigator, * Constitutional symptoms due to anaemia as defined by the Investigator |
| Phase I: Maximum Tolerated Dose (MTD) of BI 836858 in Combination With Decitabine | From first drug administration until end of treatment, up to 941 days. | The Maximum tolerated dose (MTD) of BI 836858 in combination with decitabine was estimated after the dose escalation part of the trial obtaining on the basis of dose limiting toxicities (DLT(s)) observed during the first treatment cycle. However, for those patients who receive more than one cycle of the combination treatment, all adverse events that constitute a DLT will be considered for re-estimation of the MTD based on the Bayesian logistic regression model (BLRM). The MTD is defined as the highest dose of BI 836858 (in combination with decitabine) with less than 25% risk of the true DLT rate being above 33% during the MTD evaluation period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Patients With Objective Response (CR + CRi) | From start of treatment until the earliest of progression, death or end of trial, up to 971 days. | Number of patients with objective response (Complete remission (CR) + complete remission with incomplete remission (CRi)). CR was defined as bone marrow (BM) blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \> 1.0 x 109/L \[1,000/μL\]; platelet count \> 100 x 109/L \[100,000/μL\]; independence of red blood cells transfusions (no transfusion for 1 week prior to the assessment). No minimum duration of response is required. CRi was defined as all CR criteria except for residual neutropenia (\< 1.0 x 109/L \[1,000/μL\]) or thrombocytopenia (\< 100 x 109/L \[100,000/μL\]). |
Countries
Germany, Italy, Spain, United States
Participant flow
Recruitment details
This was an open-label, Phase I/II trial to determine the maximum tolerated dose and investigate safety, pharmacokinetics and efficacy of BI 836858 in combination with decitabine in patients with acute myeloid leukemia.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive) 20 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL). | 4 |
| Phase I Dose Escalation: BI 836858 40 mg + Decitabine (Intensive) 40 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL). | 3 |
| Phase I Dose Escalation: BI 836858 80 mg + Decitabine (Intensive) 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL). | 9 |
| Phase I Extension A: BI 836858 80 mg + Decitabine (Intensive) 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 10 consecutive days (intensive treatment) from Day 1 to 10 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL). | 15 |
| Phase I Extension B: BI 836858 80 mg + Decitabine (Standard) 80 milligram (mg) of concentrate for solution for infusion of BI 836858 were administered as single dose via rate-controlled intravenous infusion once per week in 28-day treatment cycle (i.e. on Days 1, 8, 15, and 22 of the 28-day treatment cycles), together with 20 mg/square meter (m2) body surface area (BSA) of decitabine administered daily via intravenous infusion for 5 consecutive days (standard treatment) from Day 1 to 5 in each treatment cycle. The BI 836858 dose was diluted in 0.9% sodium chloride to have full volume of the diluted compound 250 milliliter (mL). | 18 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 2 | 5 | 3 |
| Overall Study | Allergic reaction | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Allogeneic peripheral blood stem cell transplantation | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Dose limiting toxicity | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Inadequate clinical condition | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Increase of white blood cell count | 0 | 0 | 0 | 0 | 1 |
| Overall Study | No benefit from study treatment | 1 | 1 | 0 | 0 | 1 |
| Overall Study | No meet eligibility | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Patient wish for other treatment | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 3 | 0 | 4 | 6 | 5 |
| Overall Study | Receiving Decitabine locally | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Refused to continue taking trial medication | 0 | 1 | 1 | 1 | 2 |
| Overall Study | Relapsed Pneumonia | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Therapy refractory AML | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive) | Total | Phase I Extension B: BI 836858 80 mg + Decitabine (Standard) | Phase I Extension A: BI 836858 80 mg + Decitabine (Intensive) | Phase I Dose Escalation: BI 836858 80 mg + Decitabine (Intensive) | Phase I Dose Escalation: BI 836858 40 mg + Decitabine (Intensive) |
|---|---|---|---|---|---|---|
| Age, Continuous | 72.0 Years STANDARD_DEVIATION 11.34 | 72.3 Years STANDARD_DEVIATION 11.31 | 76.6 Years STANDARD_DEVIATION 4.24 | 74.9 Years STANDARD_DEVIATION 6.62 | 66.3 Years STANDARD_DEVIATION 13.02 | 52.3 Years STANDARD_DEVIATION 27.61 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 49 Participants | 18 Participants | 15 Participants | 9 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 20 Participants | 6 Participants | 7 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 29 Participants | 12 Participants | 8 Participants | 5 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 2 / 3 | 5 / 9 | 11 / 15 | 13 / 18 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 9 / 9 | 15 / 15 | 18 / 18 |
| serious Total, serious adverse events | 4 / 4 | 3 / 3 | 8 / 9 | 14 / 15 | 17 / 18 |
Outcome results
Primary
Phase I: Maximum Tolerated Dose (MTD) of BI 836858 in Combination With Decitabine
The Maximum tolerated dose (MTD) of BI 836858 in combination with decitabine was estimated after the dose escalation part of the trial obtaining on the basis of dose limiting toxicities (DLT(s)) observed during the first treatment cycle. However, for those patients who receive more than one cycle of the combination treatment, all adverse events that constitute a DLT will be considered for re-estimation of the MTD based on the Bayesian logistic regression model (BLRM). The MTD is defined as the highest dose of BI 836858 (in combination with decitabine) with less than 25% risk of the true DLT rate being above 33% during the MTD evaluation period.
Time frame: From first drug administration until end of treatment, up to 941 days.
Population: Maximum Tolerated Dose (MTD) evaluable set: This analysis set includes all subjects who were entered, treated and completed first cycle of planned treatment or subjects received at least 2 doses of BI 836858 due to BI 836858-related toxicity but not replaced.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive) | Phase I: Maximum Tolerated Dose (MTD) of BI 836858 in Combination With Decitabine | NA milligram |
Primary
Phase I: Number of Patients With Dose Limiting Toxicity (DLT(s)) During First Treatment Cycle
Number of patients with dose limiting toxicity (DLT(s)) for BI 836858 in combination with decitabine during first treatment cycle (Phase 1). DLT was defined as any non-disease-related non-haematological adverse event (AE) of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher. Expected non-haematological disease-related AEs were not to be regarded as a DLT. These included complications resulting from haematological AEs such as: * Bleeding and complications from bleeding due to thrombocytopenia as defined by the Investigator, * Infection and complications from infections due to neutropenia as defined by the Investigator, * Constitutional symptoms due to anaemia as defined by the Investigator
Time frame: Up to 28 days (first treatment cycle).
Population: Treated set: All subjects who were documented to have received at least one dose of trial medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive) | Phase I: Number of Patients With Dose Limiting Toxicity (DLT(s)) During First Treatment Cycle | 0 Participants |
| Phase I Dose Escalation: BI 836858 40 mg + Decitabine (Intensive) | Phase I: Number of Patients With Dose Limiting Toxicity (DLT(s)) During First Treatment Cycle | 0 Participants |
| Phase I Dose Escalation: BI 836858 80 mg + Decitabine (Intensive) | Phase I: Number of Patients With Dose Limiting Toxicity (DLT(s)) During First Treatment Cycle | 0 Participants |
| Phase I Extension A: BI 836858 80 mg + Decitabine (Intensive) | Phase I: Number of Patients With Dose Limiting Toxicity (DLT(s)) During First Treatment Cycle | 1 Participants |
| Phase I Extension B: BI 836858 80 mg + Decitabine (Standard) | Phase I: Number of Patients With Dose Limiting Toxicity (DLT(s)) During First Treatment Cycle | 1 Participants |
Comparison: Bayesian logistic regression model (BLRM) with overdose control was used to determine the maximum tolerated dose (MTD), defined as highest dose with less than 25% risk of the true DLT rate being equal to or above 33%.
Comparison: Bayesian logistic regression model (BLRM) with overdose control was used to determine the maximum tolerated dose (MTD), defined as highest dose with less than 25% risk of the true DLT rate being equal to or above 33%.
Comparison: Bayesian logistic regression model (BLRM) with overdose control was used to determine the maximum tolerated dose (MTD), defined as highest dose with less than 25% risk of the true DLT rate being equal to or above 33%.
Comparison: Bayesian logistic regression model (BLRM) with overdose control was used to determine the maximum tolerated dose (MTD), defined as highest dose with less than 25% risk of the true DLT rate being equal to or above 33%.
Comparison: Bayesian logistic regression model (BLRM) with overdose control was used to determine the maximum tolerated dose (MTD), defined as highest dose with less than 25% risk of the true DLT rate being equal to or above 33%.
Comparison: Bayesian logistic regression model (BLRM) with overdose control was used to determine the maximum tolerated dose (MTD), defined as highest dose with less than 25% risk of the true DLT rate being equal to or above 33%.
Secondary
Phase 1: Number of Patients With Objective Response (CR + CRi)
Number of patients with objective response (Complete remission (CR) + complete remission with incomplete remission (CRi)). CR was defined as bone marrow (BM) blasts \< 5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \> 1.0 x 109/L \[1,000/μL\]; platelet count \> 100 x 109/L \[100,000/μL\]; independence of red blood cells transfusions (no transfusion for 1 week prior to the assessment). No minimum duration of response is required. CRi was defined as all CR criteria except for residual neutropenia (\< 1.0 x 109/L \[1,000/μL\]) or thrombocytopenia (\< 100 x 109/L \[100,000/μL\]).
Time frame: From start of treatment until the earliest of progression, death or end of trial, up to 971 days.
Population: Treated set: All subjects who were documented to have received at least one dose of trial medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission (CR) | 1 Participants |
| Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Objective response (CR + CRi) | 2 Participants |
| Phase I Dose Escalation: BI 836858 20 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission with incomplete recovery (CRi) | 1 Participants |
| Phase I Dose Escalation: BI 836858 40 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Objective response (CR + CRi) | 0 Participants |
| Phase I Dose Escalation: BI 836858 40 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission with incomplete recovery (CRi) | 0 Participants |
| Phase I Dose Escalation: BI 836858 40 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission (CR) | 0 Participants |
| Phase I Dose Escalation: BI 836858 80 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Objective response (CR + CRi) | 6 Participants |
| Phase I Dose Escalation: BI 836858 80 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission (CR) | 1 Participants |
| Phase I Dose Escalation: BI 836858 80 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission with incomplete recovery (CRi) | 5 Participants |
| Phase I Extension A: BI 836858 80 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission with incomplete recovery (CRi) | 4 Participants |
| Phase I Extension A: BI 836858 80 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Objective response (CR + CRi) | 7 Participants |
| Phase I Extension A: BI 836858 80 mg + Decitabine (Intensive) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission (CR) | 3 Participants |
| Phase I Extension B: BI 836858 80 mg + Decitabine (Standard) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission (CR) | 3 Participants |
| Phase I Extension B: BI 836858 80 mg + Decitabine (Standard) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Objective response (CR + CRi) | 4 Participants |
| Phase I Extension B: BI 836858 80 mg + Decitabine (Standard) | Phase 1: Number of Patients With Objective Response (CR + CRi) | Complete remission with incomplete recovery (CRi) | 1 Participants |