Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

At Discretion of the Investigator (Transfusions)

Best Supportive Care

BI 836858

Boehringer Ingelheim

Phase I: To investigate maximum tolerated dose (MTD), safety and tolerability, pharmacokinetics, exploratory biomarker and efficacy of BI 836858 monotherapy in patients with low or intermediate-1 risk myelodysplastic syndromes (MDS) with symptomatic anemia. Phase II: To investigate safety and efficacy of BI 836858 plus Best Supportive Care compared to Best Supportive Care alone in low or intermediate-1 risk MDS patients with symptomatic anemia.

Phase I/II Trial to Investigate BI 836858 in Myelodysplastic Syndromes

A Phase I/II, Multicentre, Open-label, Dose Escalation and Randomized Trial of BI 836858 in Patients With Low or Intermediate-1 Risk Myelodysplastic Syndromes

The MTD is defined as the highest dose of BI 836858 with less than 25% risk of the true dose-limiting toxicity (DLT) rate being above 33% during the MTD evaluation period. MTD determination will be based on a Bayesian logistic regression model with overdose control.

For any dose-escalation cohort, at least 3 patients (pts) will be required. However, in the case that only 2 pts are evaluable and neither has experienced a DLT within the first cycle (2 administrations - 28 days), then dose-escalation can occur based on these 2 pts. After all pts in a cohort have either experienced a DLT or have been observed for at least one cycle (2 administrations - 28 days) without experiencing a DLT, the Bayesian model will be updated with the newly accumulated data.

The MTD may be considered reached if either the posterior probability of the true DLT rate in the target interval (16%-33%) is above 50%, or at least 12 pts have been treated at MTD, including the two expansion cohorts.

Dose Limiting Toxicity (DLT):

* Grade (G) ≥ 3 (CTCAE 4.0), non disease-related, non-hematologic adverse events (AE), except:

  * Laboratory abnormality, not significant by investigator or resolves spontaneously or can be recovered with appropriate treatment (T) within 5 d
  * Neutrophils (NP) \<500 /microliters (μL) at T start, febrile neutropenia with NP \<500 /μL or infection with NP \<500 /μL will not constitute a DLT if they can be recovered with appropriate T within 14 d
* Inability to deliver study drug full dose according to the assigned dose level within cycle 1 due to drug-related AEs
* Absence of hematological recovery as following:

  * NPs: G 4 (if G 0/1 at baseline (BL)) OR \<100 /μL and decrease of \>75% from BL (if G ≥2 at BL) for \>7 d
  * Platelets: G 4 (if G 0/1 at BL) OR \< 10000/μL for \>7 d and decrease of \>75% from BL (if G ≥2 at BL)
* T delay of ≥4 weeks of start of Cycle 2 --If Cycle 2 is not started until 57th d as a result of drug related AE, it is considered as DLT

Red blood cell (RBC) transfusion independence and platelet transfusion independence will be evaluated in patients who are transfusion dependent at baseline. Percentages will be calculated using all treated patients as the denominator.

A patient is considered transfusion independent at baseline if the patient has had no transfusions during the 56 days prior to and including the first day of treatment. Otherwise, the patient is considered to be transfusion dependent.

A patient is considered transfusion independent if the patient has had no transfusions over the course of ≥ 56 consecutive days.

Number of patients with red blood cell (RBC) Transfusion Independency is presented.

Red blood cell (RBC) transfusion independence and platelet transfusion independence will be evaluated in patients who are transfusion dependent at baseline. Percentages will be calculated using all treated patients as the denominator.

A patient is considered transfusion independent at baseline if the patient has had no transfusions during the 56 days prior to and including the first day of treatment. Otherwise, the patient is considered to be transfusion dependent.

A patient is considered transfusion independent if the patient has had no transfusions over the course of ≥ 56 consecutive days.

Number of patients with hematologic improvement neutrophils (HI-N) is presented.

The HI will be evaluated in patients with abnormal pretreatment values defined as follows:

Neutrophil response (HI-N) - Patients with a pretreatment neutrophil count \<1 x 10\^9/liters (L) demonstrate a neutrophil response if they have an at least 100 percent increase and an absolute increase \>0.5 x 10\^9/L.

Number of patients with hematologic improvement platelets (HI-P) is presented.

The HI will be evaluated in patients with abnormal pretreatment values defined as follows:

Platelet response (HI-P) - Patients with a pretreatment platelet count \<100 x 109/Liters (L) demonstrate a platelet response if there is an absolute platelet increase of ≥30 x 109/L for patients starting with \>20 x 109/L platelets. For those with an increase from 10 x 109/L to \>20 x 109/L must have an increase of at least 100 percent.

Number of patients with hematologic improvement erythroid (HI-E) is presented.

The HI will be evaluated in patients with abnormal pretreatment values defined as follows:

Erythroid response (HI-E): Patients with a pretreatment hemoglobin \<11 grams per deciliters (g/dL) demonstrate erythroid response if their hemoglobin increases by ≥1.5 g/dL for at least eight weeks, and there is a reduction in the units of red cell transfusions by an absolute number of at least four red cell transfusions per eight weeks compared with the pretreatment transfusion number in the previous eight weeks. Only red cell transfusions given for a hemoglobin ≤9 g/dL pretreatment will count in the red cell transfusion response evaluation.

Time to HI-E response is defined only for patients who achieve a HI-E response as follows: Time to HI-E response \[days\] = date of first assessment indicating HI-E response - date of first administration of trial medication + 1.

Number of patients with mean hemoglobin increase ≥ 1.5 grams per deciliters (g/dL) is presented.

Mean hemoglobin increase ≥ 1.5 g/dL - Proportion of subjects achieving hemoglobin (Hgb) increase from baseline ≥ 1.5 g/dL over any consecutive 56-day period in absence of Red blood cell (RBC) transfusions.

Defined only for patients who achieve complete Response (CR) or marrow complete response (mCR) or RBC Transfusion independency (TI), measured from first date of achieving response until date of relapse. Date of relapse will be earliest of dates of disease assessment (blood sample, bone marrow sample, or clinical assessment) in which relapse was observed. For patients who die or are lost to follow-up without documented relapse, response duration will be censored, respectively, on date of death, regardless of cause, or on date of last disease assessment for patients who are alive when lost to follow-up. Duration of Response \[days\] = date of outcome - date of first assessment indicating CR or mCR or RBC TI after first administration of trial medication + 1.

Number of patients with overall Objective Response (OR) \[Complete Response (CR), Partial Response (PR), and Hematologic Improvement (HI)\] is presented.

Overall Objective Response is defined as Complete Response (CR), Partial Response (PR), HI-N, HI-P, or HI-E. A patient's " Overall Objective Response " = "Yes" if one of these responses was reported at least once throughout the trial.

CR defined as: -Bone marrow: \<5 % blasts with normal maturation of all cell lines (Dysplastic changes should consider the normal range of dysplastic changes), persistent dysplasia will be noted; -Peripheral blood: Hgb \> 11 grams per deciliters (g/dL), Platelets \>100 x 109/liters (L), Neutrophils \> 1.0 x 109/L, Blasts 0 % PR defined as: -All CR criteria if abnormal before treatment except: Bone marrow blasts decreased by \>50 % to pre-treatment but still \>5 %, Cellularity and morphology not relevant.

HI Definition see other endpoints.

Treated set (TS): The TS included all subjects who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.

All patients were administered doses of BI 836858, 20 milligrams (mg) by a rate-controlled intravenous infusion on day 1 and on day 15 of a 28-day cycle for a duration of 4 cycles. All infusions were to be started at a rate of 10 mL/h. The infusion rate was to be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the patient.

BI 836858 20mg

All patients were administered doses of BI 836858, 40 milligrams (mg) by a rate-controlled intravenous infusion on day 1 and on day 15 of a 28-day cycle for a duration of 4 cycles. All infusions were to be started at a rate of 10 mL/h. The infusion rate was to be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the patient.

BI 836858 40mg

All patients were administered doses of BI 836858, 80 milligrams (mg) by a rate-controlled intravenous infusion on day 1 and on day 15 of a 28-day cycle for a duration of 4 cycles. All infusions were to be started at a rate of 10 mL/h. The infusion rate was to be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the patient.

BI 836858 80mg

All patients were administered doses of BI 836858, 160 milligrams (mg) by a rate-controlled intravenous infusion on day 1 and on day 15 of a 28-day cycle for a duration of 4 cycles. All infusions were to be started at a rate of 10 mL/h. The infusion rate was to be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the patient.

BI 836858 160mg

All patients were administered doses of BI 836858, 320 milligrams (mg) by a rate-controlled intravenous infusion on day 1 and on day 15 of a 28-day cycle for a duration of 4 cycles. All infusions were to be started at a rate of 10 mL/h. The infusion rate was to be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the patient.

BI 836858 320mg

BI 836858 20 mg (Phase I)

BI 836858 40 mg (Phase I)

BI 836858 80 mg (Phase I)

BI 836858 160 mg (Phase I)

BI 836858 320 mg (Phase I)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Development of BI 836858 was discontinued (strategic decision) during the Phase I Expansion cohort stage. No patients were enrolled in the Phase II part.

Boehringer Ingelheim, Call Center

Treatment group "BI 836858" comprises all dose cohorts during the dose escalation phase, that is, "BI 836858 20 mg", "BI 836858 40 mg", "BI 836858 80 mg", "BI 836858 160 mg" and "BI 836858 320 mg".

All patients were administered doses of BI 836858, by a rate-controlled intravenous infusion on day 1 and on day 15 of a 28-day cycle for a duration of 4 cycles. All infusions were to be started at a rate of 10 mL/h. The infusion rate was to be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the patient.

As the study was prematurely discontinued, recruitment of participants into the dose escalation part was not fully completed. No formal MTD was determined.

Maximum Tolerated Dose (MTD) (Phase I)

MTD evaluation set: All patients who were documented to have initiated at least one dose of BI 836858 and who have not been replaced for the MTD evaluation.

Number of Patients With Dose Limiting Toxicity (DLT) (Phase I)

Treated set (TS): The TS included all patients who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses.

Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase I)

Number of Patients With Hematologic Improvement Neutrophils (HI-N) (Phase I)

Number of Patients With Hematologic Improvement Platelets (HI-P) (Phase I)

Number of Patients With Hematologic Improvement Erythroid (HI-E) (Phase I)

Treated set (TS): The TS included all patients who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses. Only patients who showed a HI-E response were included.

Time to HI-E Response (Phase I)

Number of Patients With Mean Hemoglobin Increase ≥ 1.5 g/dL (Phase I)

Treated set (TS): The TS included all patients who had been enrolled and treated with at least 1 dose of study drug. The treated set was used for safety analyses. Only patients who had achieved complete response (CR) or marrow complete response (mCR) or RBC Transfusion independency (TI) were included.

Duration of Response (RBC Transfusion Independency, HI-N, HI-P, HI-E or Objective Response) (Phase I)

Number of Patients With Overall Objective Response (OR) [Complete Response (CR), Partial Response (PR), and Hematologic Improvement (HI)] (Phase I)

All patients were planned to be administered doses of BI 836858, recommended phase 2 dose (RP2D) together with best supportive care (BSC) by a rate-controlled intravenous infusion on day 1 and on day 15 of a 28-day cycle for a duration of 4 cycles. All infusions were to be started at a rate of 10 mL/h. The infusion rate was to be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the patient.

BI 836858 + Best Supportive Care (BSC) (Phase II)

All patients were planned to be administered best supportive care (BSC) including red blood cell transfusion, platelet transfusion and iron chelation therapy.

Best Supportive Care (BSC) Only (Phase II)

No patients were enrolled in the Phase II part. The company decided to stop the clinical development of BI 836858 prematurely during the Phase I expansion cohort stage for strategic reasons.

Spots Global Cancer Trial Database for Phase I/II Trial to Investigate BI 836858 in Myelodysplastic Syndromes

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