Graft-Versus-Host Disease
Conditions
Keywords
Graft versus host disease, GVHD, allogeneic transplant, acute GVHD, chronic GVHD
Brief summary
To test a new agent, LBH589, in combination with glucocorticoids as initial therapy of acute graft versus host disease (GVHD).
Detailed description
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.
Interventions
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.
Sponsors
Novartis
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients receiving allogeneic hematopoietic cell transplantation (HCT) with peripheral blood, bone marrow or cord blood stem cells regardless of initial diagnosis who develop a clinical diagnosis of acute GVHD as defined in Section 2 diagnosed and treated with systemic glucocorticoids within 72 hours prior to enrollment. Biopsy of involved skin and gastrointestinal tract is strongly encouraged, but not required for study entry. For patients with aspartic transaminase (AST) or alanine transaminase (ALT) or Alkaline phosphatase with gamma-glutamyltransferase (GGT) elevations without bilirubin elevation must have a liver biopsy to document GVHD diagnosis. Patients should meet one of the following criteria: If GVHD is present in an isolated organ: 1. Skin rash involvement of a minimum of 50% of body surface area in absence of documented drug allergy or infectious etiology. 2. Diarrhea with a minimum stool volume of 500 mL/day and/or a minimum of 2 stools above baseline/day in absence of enterocolitis from C. difficile or other documented pathogens. 3. Increase in bilirubin above upper limit of normal (ULN) in absence of clinically defined veno-occlusive disease. 4. Isolated increased AST and/or ALT and/or increased alkaline phosphatase above ULN with GGT elevation above ULN with documented liver GVHD biopsy. If GVHD presentation involves \>/= 2 organs: GVHD Grade \>/= II as defined in Table D of protocol. 2. Male or female patients aged 18 or older at time of enrollment 3. Signed informed consent 4. Absolute neutrophil count (ANC) greater than 500/μL, platelets \>/= 20 x 10\^9/L supported by platelet transfusion and hemoglobin \>/= 8 g/dl supported by red cell transfusion. 5. Calculated creatinine clearance (CrCl) \>/= 30 mL/min (MDRD Formula) 6. Serum potassium \>/= lower limit of normal (LLN), Total serum calcium \[corrected for serum albumin\] or ionized calcium \>/= LLN, Serum magnesium \>/= LLN and Serum phosphorus \>/= LLN on the day of LBH589 administration 7. Thyroid-stimulating hormone (TSH) \</= ULN and free T4 within normal limits at the time of patient enrollment within baseline laboratories. Patients are permitted to receive thyroid hormone replacement to treat underlying hypothyroidism 8. Baseline multiple gated acquisition scan (MUGA) or echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) \>/= the lower limit of the institutional normal before transplantation.
Exclusion criteria
1. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months). Women of childbearing potential must have a negative serum pregnancy test within 24 hrs of receiving the first dose of study medication if a pregnancy test was not done pre-transplant. Male patients whose sexual partners are WOCBP not using effective birth control 2. Patients requiring mechanical ventilation support. 3. Active, uncontrolled life threatening viral or fungal disease, such as cytomegalovirus (CMV) pneumonia or gastroenteritis, Aspergillus pneumonia or brain abscess. For bacterial or viral infections, patients must be receiving therapy and have no signs of progression for 48 hours prior to enrollment. For fungal infection patients must be receiving systemic anti-fungal therapy and have no signs of progression for 1 week prior to enrollment. Progressing infection is defined as hemo-dynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infections. Persisting fever without other signs of symptoms will not be interpreted as progressing infections. 4. Receipt of other investigational new drugs for GVHD including agents used for GVHD prophylaxis within 30 days. The following agents are not considered experimental and therefore are not excluded: cyclosporine, tacrolimus, sirolimus, glucocorticoids, antithymocyte globulin, replacement corticosteroid therapy for hypoadrenalism and methotrexate. 5. HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer within 30 days. 6. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first LBH589 treatment. 7. Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: 1. Patients with congenital long QT syndrome. 2. History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of a controlled atrial arrhythmia are eligible). 3. Any history of ventricular fibrillation or torsade de pointes. 4. Bradycardia defined as heart rate (HR)\< 50 bpm. Patients with pacemakers are eligible if HR \>/= 50 bpm. 5. Patients are excluded if the average of the QT Corrected by the Fridericia Formula (QTcF) is \> 470 msec on the screening EKGs. 6. Right bundle branch block + left anterior hemiblock (bifascicular block). 7. Patients with myocardial infarction or unstable angina \</= 6 months prior to starting study drug. 8. Other clinically significant heart disease (e.g., congestive heart failure (CHF) New York Heart Association class III or IV, or uncontrolled hypertension. 8. Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug. 9. Concomitant use of CYP3A4 inhibitors with the exception of tacrolimus, voriconazole (or posaconazole), cyclosporine that are required for all GVHD patients to control GVHD and prevent mould infections (Appendix A of protocol). 10. Patients with known positivity for human immunodeficiency virus (HIV) before transplant. 11. Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose (MTD) in Milligrams | 2 years, 8 months | 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. |
| Phase II: Overall Rate of Response (ORR) | 1 year, 2 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Discontinuation of All Immune Suppression | 1 year | Number of participants discontinuing all immune suppression without subsequent flare by 1 year post initiation of therapy. |
| Chronic GVHD Onset | Up to 1 year | Chronic GVHD onset in participants without overlap syndrome at initiation of study therapy. Number of participants with overlap syndrome at MTD. |
| Incidence of GVHD Flares Requiring Increasing Immune Suppressive Therapy | Up to 36 days per participant | 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. |
| Stable or Improved Chronic GVHD Severity Score | 1 year | Stable or improved Chronic GVHD score: Improved Mild to None; Improved Severe to Moderate; Improved Moderate to None, Remained Stable at Mild. |
| Occurrence of Possibly Related Adverse Events | 5 years, 3 months | Number of participants with adverse events possibly related to study treatment, per event category. |
| Chronic GVHD Severity at MTD | Up to 1 year | Chronic GVHD maximum severity grade at MTD, in participants without overlap syndrome at initiation of study therapy. Maximum c-GVHD severity: Mild, Moderate, Severe. |
| Overall Survival (OS) | 1 year | Overall Survival (OS) at one year post initiation of therapy. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at Moffitt Cancer Center, September 2010 through December 2014.
Participants by arm
| Arm | Count |
|---|---|
| LBH589, in Addition to Glucocorticoids Phase I Dose Escalation, Followed by Phase II Treatment at Maximum Tolerated Dose (MTD) of LBH589, in Addition to Glucocorticoids. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | GVHD Disease Progression | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | LBH589, in Addition to Glucocorticoids |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 55 years |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 20 / 22 |
| serious Total, serious adverse events | 11 / 22 |
Outcome results
Primary
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
Population: All participants treated at maximum tolerated dose (MTD) of Oral Formulation LBH589, and evaluable at planned time of analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBH589, in Addition to Glucocorticoids | Phase II: Overall Rate of Response (ORR) | Complete Response | 13 participants |
| LBH589, in Addition to Glucocorticoids | Phase II: Overall Rate of Response (ORR) | Partial Response | 2 participants |
| LBH589, in Addition to Glucocorticoids | Phase II: Overall Rate of Response (ORR) | Progressive Disease | 1 participants |
| LBH589, in Addition to Glucocorticoids | Phase II: Overall Rate of Response (ORR) | Stable Disease | 0 participants |
Primary
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
Population: All participants treated with Oral Formulation LBH589, during Phase I Dose Escalation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LBH589, in Addition to Glucocorticoids | Phase I: Maximum Tolerated Dose (MTD) in Milligrams | 5 MTD of oral LBH589 in milligrams |
Secondary
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
Population: All participants that received Oral Formulation LBH589 at MTD (5 mg) 3 times per week, for 4 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LBH589, in Addition to Glucocorticoids | Chronic GVHD Onset | 6 participants |
Secondary
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
Population: All participants that received Oral Formulation LBH589 at MTD (5 mg) 3 times per week, for 4 weeks, had overlap syndrome at MTD and were evaluable at time of analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBH589, in Addition to Glucocorticoids | Chronic GVHD Severity at MTD | Mild | 2 participants |
| LBH589, in Addition to Glucocorticoids | Chronic GVHD Severity at MTD | Moderate | 1 participants |
| LBH589, in Addition to Glucocorticoids | Chronic GVHD Severity at MTD | Severe | 1 participants |
Secondary
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
Population: All participants that received Oral Formulation LBH589 at MTD (5 mg) 3 times per week, for 4 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LBH589, in Addition to Glucocorticoids | Incidence of GVHD Flares Requiring Increasing Immune Suppressive Therapy | 1 participants |
Secondary
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
Population: All participants that received Oral Formulation LBH589 at MTD (5 mg) 3 times per week, for 4 weeks and were evaluable at 365 days.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LBH589, in Addition to Glucocorticoids | Occurrence of Discontinuation of All Immune Suppression | 0 participants |
Secondary
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
Population: All participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBH589, in Addition to Glucocorticoids | Occurrence of Possibly Related Adverse Events | Hepatobiliary disorders | 1 participants |
| LBH589, in Addition to Glucocorticoids | Occurrence of Possibly Related Adverse Events | Thrombocytopenia | 11 participants |
| LBH589, in Addition to Glucocorticoids | Occurrence of Possibly Related Adverse Events | Leukopenia | 6 participants |
| LBH589, in Addition to Glucocorticoids | Occurrence of Possibly Related Adverse Events | Anemia | 2 participants |
| LBH589, in Addition to Glucocorticoids | Occurrence of Possibly Related Adverse Events | Hypertriglyceridemia | 5 participants |
| LBH589, in Addition to Glucocorticoids | Occurrence of Possibly Related Adverse Events | Hypercholesterolemia | 3 participants |
| LBH589, in Addition to Glucocorticoids | Occurrence of Possibly Related Adverse Events | Fatigue | 1 participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) at one year post initiation of therapy.
Time frame: 1 year
Population: All participants that received Oral Formulation LBH589 at MTD (5 mg) 3 times per week, for 4 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBH589, in Addition to Glucocorticoids | Overall Survival (OS) | OS at 1 year | 11 participants |
| LBH589, in Addition to Glucocorticoids | Overall Survival (OS) | Death before 1 year: sepsis | 1 participants |
| LBH589, in Addition to Glucocorticoids | Overall Survival (OS) | Death before 1 year: relapse | 2 participants |
| LBH589, in Addition to Glucocorticoids | Overall Survival (OS) | Death before 1 year: GVHD | 1 participants |
| LBH589, in Addition to Glucocorticoids | Overall Survival (OS) | Death before 1 year: Cardiogenic shock | 1 participants |
Secondary
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
Population: All participants that received Oral Formulation LBH589 at MTD (5 mg) 3 times per week, for 4 weeks, had overlap syndrome at MTD and were evaluable at 1 year.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBH589, in Addition to Glucocorticoids | Stable or Improved Chronic GVHD Severity Score | Improved: Mild to None | 1 participants |
| LBH589, in Addition to Glucocorticoids | Stable or Improved Chronic GVHD Severity Score | Improved: Severe to Moderate | 1 participants |
| LBH589, in Addition to Glucocorticoids | Stable or Improved Chronic GVHD Severity Score | Improved: Moderate to None | 1 participants |
| LBH589, in Addition to Glucocorticoids | Stable or Improved Chronic GVHD Severity Score | Stable: Remained Stable at Mild | 1 participants |