Details

Details

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

IRB BIP1914

CC 14-1163

Hospital Main Campus

Phase Phase 1, Phase 2

Disease Myelodisplastic Syndrome (MDS)

Drug BI836858

Description

Description

Phase I Primary Objectives:

To determine the maximum tolerated dose (MTD) and the Recommended Phase II Dose (RP2D) to be used in the Phase II. Secondary objectives include safety, pharmacokinetics, exploratory biomarkers and efficacy of BI 836858 monotherapy in patients with low or intermediate-1 risk MDS with symptomatic anemia, who at a minimum, experienced ESA treatment failure or do not qualify (serum erythropoietin level > 500 U) for ESA treatment. Patients with a deletion 5q cytogenetic abnormality will be allowed in Phase I who do not qualify for lenalidomide treatment (Absolute Neutrophil Count (ANC) < 500/μL or platelets <50,000/μl) or who experience primary lenalidomide failure. Lenalidomide failure is defined as lack of hematological improvement after 4 months of therapy, or secondary failure defined as loss of prior lenalidomide response at any time point.

Randomized Phase II Primary Objectives:

To investigate the efficacy of BI 836858 plus Best Supportive Care (BSC) vs. Best Supportive Care alone, in low or intermediate-1 risk MDS patients with symptomatic anemia without a deletion 5q cytogenetic abnormality who are previously untreated or who progressed/became resistant following ESA and/or 5-azacitidine (5-aza) treatment. Secondary objectives include the investigation of safety and tolerability of BI 836858 in this patient population.

Inclusion Criteria

Inclusion Criteria

  1. Documented diagnosis of MDS according to World Health Organization (WHO) criteria that meets International Prognostic Scoring System (IPSS) classification of low or intermediate-1 risk disease as determined by microscopic and standard cytogenetic analyses of the bone marrow and peripheral complete blood count (CBC).
  2. Patient has the evidence of symptomatic anemia according to the following criteria:
    • Phase I only: Patients must have mean hemoglobin concentration < 10.0 g/dL of 2 measurements (not influenced by RBC transfusion within 7 days of measurement) and having received < 4 units of RBCs within 8 weeks prior to start of treatment OR,
    • Phase I/II: Patients must have received ≥ 4 units of RBCs for hemoglobin ≤ 9.0 g/dL within 8 weeks prior to start of treatment.
  3. 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.
  4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 (refer to Section 10.2).
  5. Age ≥ 18 years.
  6. Written informed consent which is consistent with International Conference on Harmonization - Good Clinical Practice (ICH-GCP) guidelines and local legislation.
Exclusion Criteria

Exclusion Criteria

  1. Patient with IPSS category of Int-2 or high-risk MDS.
  2. Phase II only: Patients with a deletion 5q cytogenetic abnormality.
  3. 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.
  4. Patient previously received allogeneic bone marrow or stem cell transplantation.
  5. Second malignancy currently requiring active therapy (except for hormonal/antihormonal treatment, e.g. in prostate or breast cancer).
  6. Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 2.5 times the upper limit of normal (ULN).
  7. Prothrombin time (PT) >1.5 x ULN for patients not on therapeutic vitamin K antagonists (phenprocoumon, warfarin).
  8. Bilirubin >1.5 mg/dL, except for Gilbert's Syndrome or hemolysis.
  9. Serum creatinine >2.0 mg/dL.
  10. Known human immunodeficiency virus (HIV) infection or active hepatitis B virus or hepatitis C virus infection. Patients with any serological evidence of current or past hepatitis B exposure are to be excluded unless the serological findings are clearly due to vaccination.
  11. 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.
  12. Psychiatric illness or social situation which in the opinion of the Investigator would limit compliance with trial requirements.
  13. 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 (refer to Section 4.2.2).
  14. 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, condom with spermicide, etc.). Patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy, or bilateral tubal ligation/salpingectomy or post-menopausal for at least two years.
  15. 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.
  16. Pregnant or nursing female patients.
  17. 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 in this trial.
  18. 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.
  19. Treatment with an immunomodulatory agent within 4 weeks prior to first administration of BI 836858.
  20. Patient received prior treatment with a CD33 antibody.
  21. In the opinion of the Investigator patient is unable or unwilling to comply with the protocol.