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

NCT02240706 | Terminated Phase 2 Results

• 2 other identifiers: 1315.72018-002177-21
• Study Type: interventional
• Target: 27
• Locations: 2 countries
• Sites: 5

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.

Conditions

Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (8)

• 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 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 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 Erythroid (HI-E) (Phase I)

  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)

  From first administration of BI 836858 until HI-E response, up to 168 days (6 cycles, each of 28 days)

Study Arms (2)

Arm B

ACTIVE COMPARATOR

Best Supportive Care Alone

Procedure: Best Supportive Care

Arm A

EXPERIMENTAL

BI 836858 plus Best Supportive Care

Procedure: Best Supportive Care; Drug: BI 836858

Interventions

Best Supportive Care PROCEDURE

At Discretion of the Investigator (Transfusions)

Arm A; Arm B

BI 836858 DRUG

Monotherapy with BI 836858

Arm A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (5)

Mayo Clinic Cancer Center

Jacksonville, Florida, 32224, United States

Location

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

Universitätsklinikum Carl Gustav Carus Dresden

Dresden, 01307, Germany

Location

Universitätsklinikum Düsseldorf

Düsseldorf, 40225, Germany

Location

Related Links

• Related Info

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

BI 836858

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Limitations and Caveats

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

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Study Officials

• Boehringer Ingelheim

  Boehringer Ingelheim

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 15, 2014
• First Posted: September 16, 2014
• Study Start: January 22, 2015
• Primary Completion: November 18, 2019
• Study Completion: November 18, 2019
• Last Updated: December 21, 2020
• Results First Posted: December 21, 2020

Record last verified: 2020-12

Locations

DE (2); US (3)