Clinical trial NCT02240706: Phase I/II Trial to Investigate BI 836858 in Myelodysplastic Syndromes
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-09-16
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) (Phase I)
timeFrame: 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
measure: Number of Patients With Dose Limiting Toxicity (DLT) (Phase I)
timeFrame: 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
measure: Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase II)
timeFrame: From first administration of BI 836858 until discontinuation of the treatment. Up to 168 days (6 cycles, each of 28 days)
Secondary outcomes:
measure: Number of Patients With Red Blood Cell (RBC) Transfusion Independency (Phase I)
timeFrame: From first administration of BI 836858 until discontinuation of the treatment. Up to 168 days (6 cycles, each of 28 days)
measure: Number of Patients With Hematologic Improvement Neutrophils (HI-N) (Phase I)
timeFrame: From first administration of BI 836858 until HI-N, up to 168 days (6 cycles, each of 28 days)
measure: Number of Patients With Hematologic Improvement Platelets (HI-P) (Phase I)
timeFrame: From first administration of BI 836858 until HI-P, up to 168 days (6 cycles, each of 28 days)
measure: Number of Patients With Hematologic Improvement Erythroid (HI-E) (Phase I)
timeFrame: From first administration of BI 836858 until HI-E, up to 168 days (6 cycles, each of 28 days)
measure: Time to HI-E Response (Phase I)
timeFrame: From first administration of BI 836858 until HI-E response, up to 168 days (6 cycles, each of 28 days)
measure: Number of Patients With Mean Hemoglobin Increase ≥ 1.5 g/dL (Phase I)
timeFrame: Up to 48 weeks
measure: Duration of Response (RBC Transfusion Independency, HI-N, HI-P, HI-E or Objective Response) (Phase I)
timeFrame: From the first date of achieving a response until the date of relapse, up to 168 days (6 cycles, each of 28 days)
measure: Number of Patients With Overall Objective Response (OR) [Complete Response (CR), Partial Response (PR), and Hematologic Improvement (HI)] (Phase I)
timeFrame: From first administration of BI 836858 until overall objective response, up to 168 days (6 cycles, each of 28 days)
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Mayo Clinic Cancer Center
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: