To test a new agent, LBH589, in combination with glucocorticoids as initial therapy of acute graft versus host disease (GVHD).
Dose escalation study to test the safety (Phase I), pharmacology and preliminary clinical activity (Phase II) of a Novel histone deacetylase (HDAC) inhibitor, LBH589, in the treatment of the following GVHD presentations: Classic, Late-onset acute GVHD, Recurrent acute GVHD, Overlap syndrome.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
22
Phase I Initial Treatment Plan - Intravenous (IV) Formulation: Up to 4 dose levels (DL) of LBH589 IV formulation to establish LBH589 Maximum Tolerated Dose (MTD) in acute GVHD treatment. The first 4 participants began this treatment plan, before the IV Formulation became unavailable. DL -1: 1.25 mg/m\^2 IV; DL 1: 2.5 mg/m\^2 IV; DL 2: 5 mg/m\^2 IV; DL 3: 7.5 mg/m\^2 IV; DL 4: 10 mg/m\^2 IV. Phase I Revised Treatment Plan - Oral Formulation (to replace IV Formulation): Dose escalation levels for LBH589; participants treated with LBH589 by mouth (PO) 3 times a week (48 hours apart) every week for 4 weeks. DL -1: 5 mg PO; DL 1: 10 mg PO (starting dose level); DL 2: 15 mg PO; DL 3: 20 mg PO; DL 4: 25 mg PO. Phase II Treatment Plan: LBH589 PO at MTD, 3 times a week (48 hours apart) every week for 4 weeks.
H Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States
Phase I: Maximum Tolerated Dose (MTD) in Milligrams
MTD of LBH589 in addition to glucocorticoids as treatment for Graft Versus Host Disease (GVHD) manifestations. MTD in Milligrams (mg), taken by mouth (PO), 3 times per week, for 4 weeks. The oral formulation replaced the IV formulation (which became unavailable) after the first 4 participants were treated. Dose limiting toxicity (DLT) is defined by the occurrence of Common Toxicity Criteria (CTC) grade 3 or greater toxicity that is unexpected with transplantation, except for hematological toxicity, where DLT is defined as absolute neutrophil count (ANC) \<750, and for those participants who were platelet transfusion independent is defined as platelets \<10 K.
Time frame: 2 years, 8 months
Phase II: Overall Rate of Response (ORR)
Rate of Complete Response (CR), Partial Response (PR), Progressive Disease (PD) and Stable Disease (SD). Assessment of GVHD will include the skin, liver and gut. Other possible etiologies of organ disease such as C difficile enterocolitis, viral infection, drug reaction, veno-occlusive disease of the liver, etc., will be excluded by appropriate tests. CR is defined as resolution of GVHD in all evaluable organs with no subsequent additional treatment given for acute GVHD. PR is defined as improvement in ≥ one evaluable organ without deterioration in at least one other. PD is defined as deterioration in at least on evaluable organ. SD is defined as the absence of any difference sufficient to meet minimal criteria for improvement or deterioration in any evaluable organs.
Time frame: 1 year, 2 months
Incidence of GVHD Flares Requiring Increasing Immune Suppressive Therapy
Number of participants with GVHD flares requiring increasing immune suppressive therapy within 36 days of study initiation. Cumulative incidence of GVHD flares requiring increasing immune suppressive therapy will be analyzed using the competing risk method by Gray (1988). GVHD flares (progressive disease (PD)) may result in discontinuation from Panobinostat.
Time frame: Up to 36 days per participant
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Overall Survival (OS)
Overall Survival (OS) at one year post initiation of therapy.
Time frame: 1 year
Occurrence of Discontinuation of All Immune Suppression
Number of participants discontinuing all immune suppression without subsequent flare by 1 year post initiation of therapy.
Time frame: 1 year
Chronic GVHD Onset
Chronic GVHD onset in participants without overlap syndrome at initiation of study therapy. Number of participants with overlap syndrome at MTD.
Time frame: Up to 1 year
Chronic GVHD Severity at MTD
Chronic GVHD maximum severity grade at MTD, in participants without overlap syndrome at initiation of study therapy. Maximum c-GVHD severity: Mild, Moderate, Severe.
Time frame: Up to 1 year
Stable or Improved Chronic GVHD Severity Score
Stable or improved Chronic GVHD score: Improved Mild to None; Improved Severe to Moderate; Improved Moderate to None, Remained Stable at Mild.
Time frame: 1 year
Occurrence of Possibly Related Adverse Events
Number of participants with adverse events possibly related to study treatment, per event category.
Time frame: 5 years, 3 months