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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Procedure: Best Supportive Care
* Drug: BI 836858


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Documented diagnosis of Myelodysplastic Syndromes (MDS) according to World Health Organization (WHO) criteria that meets International Prognostic Scoring System (IPSS) classification of low or intermediate-1 risk disease at screening as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC). Phase I dose escalation: patients who experienced Erythropoiesis-Stimulating Agents (ESA) treatment failure or do not qualify (serum erythropoietin level > 500 U) for ESA treatment, and are refractory to or not amenable or eligible for established MDS therapy (Hypomethylating Agents (HMA), lenalidomide) Phase I expansion: Expansion cohort 1 (pre-treated): patients who experienced ESA treatment failure or do not qualify (serum erythropoietin level > 500 U) for ESA treatment and are refractory to established MDS therapy (HMA and /or lenalidomide) Expansion cohort 2 (untreated): patients who experienced ESA treatment failure or do not qualify (serum erythropoietin level > 500 U) for ESA treatment and who have not received prior HMA and/or lenalidomide (because not amenable or eligible for these treatments). Phase II: patients who experienced ESA treatment failure or do not qualify (serum erythropoietin level > 500 U) for ESA treatment. For definition of further details of the phase II patients to be included the protocol will be amended based on Phase I results Patient is non-responsive to, refractory to, or intolerant of ESAs, or ESAs are contraindicated or unavailable, or a documented serum erythropoietin level of > 500 U/L. Eastern Cooperative Oncology Group (ECOG) Performance Status <=2. Age >= 18 years. Written informed consent which is consistent with International Conference on Harmonization - Good Clinical Practice (ICH-GCP) guidelines and local legislation. Exclusion criteria: Patient with IPSS category of Int-2 or high-risk MDS. Phase II only: Patients with a deletion 5q cytogenetic abnormality. Treatment within 28 days prior to Cycle 1 Day 1 with: i) long acting erythropoiesis stimulating agents, ii) long acting Granulocyte colony-stimulating factor (G-CSF), iii) granulocyte- macrophage colony stimulating factor (GM-CSF), iv) 5-aza, lenalidomide or decitabine, or v) iron chelation and within 14 days prior to Cycle 1 Day 1 with short acting erythropoiesis stimulating agents and short acting G-CSF. Patient previously received allogeneic bone marrow or stem cell transplantation. Second malignancy currently requiring active therapy (except for hormonal/antihormonal treatment, e.g. in prostate or breast cancer). Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 2.5 times the upper limit of normal (ULN). Bilirubin >1.5 mg/dL, except for Gilbert's Syndrome or hemolysis. Serum creatinine >2.0 mg/dL. Known human immunodeficiency virus (HIV) infection and/or active hepatitis B infection (defined as presence of Hep B DNA), active hepatitis C infection (defined as presence of Hep C RNA). Presence of concomitant intercurrent illness, or any condition which in the opinion of the Investigator, would compromise safe participation in the study, e.g. active severe infection, unstable angina pectoris, new onset of exacerbation of a cardiac arrhythmia. Psychiatric illness or social situation which in the opinion of the Investigator would limit compliance with trial requirements. Patient receiving concomitant therapy, which in the opinion of the Investigator is considered relevant for the evaluation of the efficacy or safety of the trial drug. Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for 6 months after the last administration of BI 836858, i.e. combination of two forms of effective contraception (defined as hormonal contraception, intrauterine device, transdermal patch, implantable or injectable contraceptive, bilateral tubal ligation etc.). Women of childbearing potential are defined as females who: Have experienced menarche and Are not postmenopausal (12 months with no menses without an alternative medical cause) and Are not permanently sterilized (e.g. hysterectomy, bilateral oophorectomy or bilateral salpingectomy Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second effective method of contraception (defined as hormonal contraception, intrauterine device, condom with spermicide, etc.) during the trial and for 6 months after the last administration of BI 836858. Pregnant or nursing female patients. Treatment with another investigational agent under the following conditions: Within two weeks (4 weeks for biologics) of first administration of BI 836858, or if the half-life of the previous product is known, within 5 times the half-life, whichever is longer. Patient has persistent toxicities from prior MDS therapies which are determined to be relevant by the Investigator. Concomitant treatment with another investigational agent while participating this trial. Chronic use, as defined by > 2 weeks of a corticosteroid agent that is >= 20 mg/day of prednisone or its equivalent, within 4 weeks prior to first administration of BI 836858. Treatment with an immunomodulatory agent within 4 weeks prior to first administration of BI 836858. Patient received prior treatment with a CD33 antibody. In the opinion of the Investigator patient is unable or unwilling to comply with the protocol. Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm B<br>Best Supportive Care Alone | Procedure: Best Supportive Care<br>* At Discretion of the Investigator (Transfusions)<br>|
| Experimental: Arm A<br>BI 836858 plus Best Supportive Care | Procedure: Best Supportive Care<br>* At Discretion of the Investigator (Transfusions)<br>Drug: BI 836858<br>* Monotherapy with BI 836858<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) (Phase I) | 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. | 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 | 
| Number of Patients With Dose Limiting Toxicity (DLT) (Phase I) | 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 | 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 | 
| Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase II) | 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. | From first administration of BI 836858 until discontinuation of the treatment. Up to 168 days (6 cycles, each of 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase I) | 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. | 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 Hematologic Improvement Neutrophils (HI-N) (Phase I) | 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. | 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 Platelets (HI-P) (Phase I) | 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. | 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 Erythroid (HI-E) (Phase I) | 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. | From first administration of BI 836858 until HI-E, up to 168 days (6 cycles, each of 28 days) | 
| Time to HI-E Response (Phase I) | 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. | From first administration of BI 836858 until HI-E response, up to 168 days (6 cycles, each of 28 days) | 
| Number of Patients With Mean Hemoglobin Increase ≥ 1.5 g/dL (Phase I) | 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. | Up to 48 weeks | 
| Duration of Response (RBC Transfusion Independency, HI-N, HI-P, HI-E or Objective Response) (Phase I) | 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. | From the first date of achieving a response until the date of relapse, 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)] (Phase I) | 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. | From first administration of BI 836858 until overall objective response, up to 168 days (6 cycles, each of 28 days) |