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

Phase 2

Terminated

• Conditions: Myelodysplastic Syndromes
• Interventions: Procedure: Best Supportive Care; Drug: BI 836858

• Registration Number: NCT02240706
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2014-09-15
• Study First Submitted QC: 2014-09-15
• Study First Posted: 2014-09-16
• Study Start: 2015-01-22
• Primary Completion: 2019-11-18
• Study Completion: 2019-11-18
• Results First Submitted: 2020-11-16
• Status Verified: 2020-12
• Results First Submitted QC: 2020-12-18
• Last Update Submitted: 2020-12-18
• Results First Posted: 2020-12-21
• Last Update Posted: 2020-12-21

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 27

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A	BI 836858	BI 836858 plus Best Supportive Care
Arm A	Best Supportive Care	BI 836858 plus Best Supportive Care
Arm B	Best Supportive Care	Best Supportive Care Alone

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) (Phase I)	From the first administration of BI 836858 to start of the third administration of BI 836858, excluding the day of the third administration of BI 836858, up to 28 days	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.
Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase II)	From first administration of BI 836858 until discontinuation of the treatment. Up to 168 days (6 cycles, each of 28 days)	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 Dose Limiting Toxicity (DLT) (Phase I)	From the first administration of BI 836858 to start of the third administration of BI 836858, excluding the day of the third administration of BI 836858, up to 28 days	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

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Overall Objective Response (OR) [Complete Response (CR), Partial Response (PR), and Hematologic Improvement (HI)] (Phase I)	From first administration of BI 836858 until overall objective response, up to 168 days (6 cycles, each of 28 days)	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.
Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase I)	From first administration of BI 836858 until discontinuation of the treatment. Up to 168 days (6 cycles, each of 28 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.
Duration of Response (RBC Transfusion Independency, HI-N, HI-P, HI-E or Objective Response) (Phase I)	From the first date of achieving a response until the date of relapse, up to 168 days (6 cycles, each of 28 days)	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 Hematologic Improvement Neutrophils (HI-N) (Phase I)	From first administration of BI 836858 until HI-N, up to 168 days (6 cycles, each of 28 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) (Phase I)	From first administration of BI 836858 until HI-P, up to 168 days (6 cycles, each of 28 days)	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) (Phase I)	From first administration of BI 836858 until HI-E, up to 168 days (6 cycles, each of 28 days)	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 (Phase I)	From first administration of BI 836858 until HI-E response, up to 168 days (6 cycles, each of 28 days)	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 g/dL (Phase I)	Up to 48 weeks	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.

Trial Locations

Locations (5)

Cleveland Clinic; 🇺🇸 Cleveland, Ohio, United States

Universitätsklinikum Carl Gustav Carus Dresden; 🇩🇪 Dresden, Germany

Mayo Clinic Cancer Center; 🇺🇸 Jacksonville, Florida, United States

Universitätsklinikum Düsseldorf; 🇩🇪 Düsseldorf, Germany

H. Lee Moffitt Cancer Center and Research Institute; 🇺🇸 Tampa, Florida, United States