Trial to Evaluate Palifermin in the Reduction of Acute Graft Versus Host Disease in Patients With Hematologic Malignancies Undergoing Allogeneic Marrow/Peripheral Blood Progenitor Cell (PBPC) Transplantation

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the effect of palifermin versus placebo in the reduction of severe acute graft versus host disease (GVHD) and severe oral mucositis.

Official Title
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A Randomized, Double-blind, Placebo-controlled Trial to Evaluate Palifermin (rHuKGF) in the Reduction of Acute Graft Versus Host Disease in Subjects With Hematologic Malignancies Undergoing Allogeneic Marrow/PBPC Transplantation

Conditions
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Graft Versus Host Disease, Hematologic Malignancies

Intervention / Treatment
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* Drug: Palifermin
* Drug: Placebo
* Other: Conditioning Regimen
* Procedure: Allogeneic stem cell transplant
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with hematologic malignancies (including myelodysplastic syndromes [MDS]) who are considered eligible for Cyclophosphamide (Cy)/Total Body Irradiation(TBI) +/- Etoposide (VP-16); Total Body Irradiation(TBI)/ Etoposide(VP-16); Melphalan(Mel) / Total Body Irradiation(TBI); Busulfan(Bu)/ Cyclophosphamide(Cy); Busulfan(Bu)/ Melphalan (Mel); or Fludarabine(Flu)/ Melphalan(Mel) conditioning therapy with allogeneic stem cell support Subjects with a 6/6 Human Leukocyte Antigen (HLA)-matched family member or unrelated donor who would provide donor marrow/ peripheral progenitor stem cells. [For unrelated matched donors, molecular typing of class I and class II is mandatory] Karnofsky Performance Status >= 70% 18 years of age or older at time of informed consent Before any study-specific procedure, the appropriate written informed consent must be obtained Exclusion Criteria: Cancer other than Non-Hodgkin's lymphoma, Hodgkin's disease, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome or multiple myeloma (except: adequately treated basal cell carcinoma of the skin) Prior autologous or allogeneic bone marrow or peripheral blood stem cell transplantation Previous use of palifermin Current active infection (including human immunodeficiency virus (HIV) and hepatitis) or oral mucositis Congestive heart failure as defined by New York Heart Association class III or IV Graft T-cell depletion for Graft-versus-host disease (GVHD) prophylaxis Inadequate renal function (serum creatinine > 1.5x the upper limit of normal per the institutional guidelines or clearance < 40 ml/min adjusted for age) Inadequate liver function (total bilirubin > 1.5x the upper limit of normal, aspartate aminotransferase (AST) > 3x upper limit of normal and/or alanine aminotransferase (ALT) > 3x upper limit of normal per the institutional guidelines) Inadequate pulmonary function as measured by a corrected DLCO (diffusing capacity of the lung for carbon monoxide lung function test) <50% of predicted Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug trial(s), or subject is receiving other investigational agent(s) Subject of child-bearing potential is evidently pregnant (e.g. positive human chorionic gonadotropin- HCG test) or is breast feeding during Part A of the study Subject or partner of subject is not using or refuses to use adequate contraceptive precautions during Part A of the study Subject has known sensitivity to any of the products to be administered during dosing including Escherichia coli-derived products Subject was previously randomized into this study Subject will not be available for follow-up assessments Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palifermin<br>Palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and 180 μg/kg administered once prior to transplant and at least 96 hours from last palifermin dose of 60 μg/kg. Participants received conditioning therapy starting at least 24 hours after the last 60 μg dose of palifermin. Allogeneic stem cell transplant occurred on Day 0. Methotrexate dosing began at least 24 hours after the 180 μg/kg dose of palifermin on Days 1, 3, 6 and (planned) 11 administration (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2 respectively. | Drug: Palifermin<br>* Administered as an intravenous (IV) bolus.<br>* Other names: Kepivance;Other: Conditioning Regimen<br>* Each participant received 1 of the following conditioning regimens: Cyclophosphamide (Cy) / total body irradiation (TBI) with and without etoposide (VP-16) TBI/VP-16 Melphalan (Mel)/TBI (TBI regimens must include fully ablative doses ie > 1100 cGy; sequence of chemotherapy/radiation (CT/RT) flexible) Busulfan (Bu)/Cy Bu/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2]) Fludarabine (Flu)/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2])<br>Procedure: Allogeneic stem cell transplant<br>* Allogeneic marrow/peripheral blood progenitor cell transplantation<br>Drug: Methotrexate<br> <br> |
| Placebo Comparator: Placebo<br>Placebo to palifermin 60 μg/kg administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to palifermin 180 μg/kg once prior to transplant and at least 96 hours from previous placebo to palifermin 60 μg/kg dose. Participants received conditioning therapy starting at least 24 hours after the last 60 μg/kg dose of placebo to palifermin. Allogeneic stem cell transplant occurred on Day 0. Methotrexate dosing began at least 24 hours after the dose of placebo to palifermin 180 μg/kg on Days 1, 3, 6 and (planned) 11 administration (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2 respectively. | Drug: Placebo<br>* Administered as an intravenous (IV) bolus.<br>Other: Conditioning Regimen<br>* Each participant received 1 of the following conditioning regimens: Cyclophosphamide (Cy) / total body irradiation (TBI) with and without etoposide (VP-16) TBI/VP-16 Melphalan (Mel)/TBI (TBI regimens must include fully ablative doses ie > 1100 cGy; sequence of chemotherapy/radiation (CT/RT) flexible) Busulfan (Bu)/Cy Bu/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2]) Fludarabine (Flu)/Mel (non-TBI but fully ablative regimens/doses [Mel dose > 140 mg/m^2])<br>Procedure: Allogeneic stem cell transplant<br>* Allogeneic marrow/peripheral blood progenitor cell transplantation<br>Drug: Methotrexate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) | GVHD was graded using the modified Keystone Criteria weekly during the first 2 months after stem cell infusion, then every other week until Day 100. Severity was determined clinically (based on physical exam and laboratory serum values) and from biopsies of affected organs whenever possible. The degree of GVHD in individual organs was scored by at least 2 assessors. Grade 3 GVHD = total bilirubin 3.1 - 15.0 mg/dL or ≥ 1000 mL/day diarrhea or severe abdominal pain with/without ileus. Grade 4 GVHD = skin involvement with bullous formation or total bilirubin > 15.0 mg/dL. | From transplant (Day 0) until Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD) | GVHD was graded using the modified Keystone Criteria weekly during the first 2 months after stem cell infusion, then every other week until Day 100. Severity was determined clinically (based on physical exam and laboratory serum values) and from biopsies of affected organs whenever possible. The degree of GVHD in individual organs was scored by at least 2 assessors. Grade 2 GVHD = > 50% skin involvement or total bilirubin 2.0 - 3.0 mg/dL or 500 - 999 mL/day diarrhea, or persistent nausea with histologic evidence. Grade 3 GVHD = total bilirubin 3.1 - 15.0 mg/dL or ≥ 1000 mL/day diarrhea or severe abdominal pain with/without ileus. Grade 4 GVHD = skin involvement with bullous formation or total bilirubin > 15.0 mg/dL. | From transplant (Day 0) until Day 100 | 
| Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration | Low dose methotrexate is widely used in regimens to prophylax against acute GVHD. Methotrexate was administered on days 1, 3, 6 and 11 (toxicity allowing) at doses of 15, 10, 10 and 10 mg/m^2, respectively. | Day 11 | 
| Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Oral cavity assessments were performed by a trained assessor using the World Health Organization (WHO) oral toxicity scale. Daily oral mucositis assessments were performed: while participants were hospitalized, including the day of discharge (maximum until day 28); after discharge until the oral mucositis grade returns to a WHO grade ≤ 2. The WHO oral toxicity criteria are: Grade 0 = None; Grade 1 = Soreness, erythema; Grade 2 = Erythema, ulcers, ability to eat solids; Grade 3 = Ulcers, requires liquid diet; Grade 4 = Alimentation not possible. | From transplant (Day 0) until Day 100 | 
| Duration of Severe Oral Mucositis (WHO Grade 3 and 4) | The duration of severe oral mucositis was calculated as the number of days from the onset of severe mucositis (first time a WHO grade of 3 or 4 was observed) to the last day when severe mucositis was observed. If oral mucositis assessments were recorded as missed visits immediately prior to or immediately after severe mucositis was recorded, the missed visits were considered to be severe oral mucositis. | From transplant (Day 0) until Day 100 | 
| Number of Participants With Parenteral or Transdermal Opioid Analgesic Use | Includes nonprophylactic intravenous opioid analgesics (fentanyl, morphine, morphine sulphate, hydromorphone, meperidine) and transdermal opioid analgesics (fentanyl patch) for the indication of oral mucositis and dysphagia. | From transplant (Day 0) until Day 100 | 
| Duration of Hospitalization | Duration of hospitalization was defined as the number of days a participant stayed in hospital (hospitalized) during the period starting from the day of the transplant (Day 0) to the 100th day following the transplant. | From transplant (Day 0) until Day 100 | 
| Area Under the Curve (AUC) of Mouth and Throat Soreness Score | The modified Oral Mucositis Daily Questionnaire (OMDQ) is a self-reported tool that evaluates overall health, mouth and throat soreness (MTS) and activity limitations due to MTS. The modified OMDQ was completed once daily beginning with the first day of study drug administration through day 28. The area under the curve of mouth and throat soreness score was assessed from the question How much mouth and throat soreness did you experience in the past 24 hours? Participants answered on a scale from 0 (no soreness) to 4 (extreme soreness). | The first day of study drug administration through Day 28. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hematological Malignancies, Graft-versus-host-disease, Oral Mucositis, Allogeneic Transplantation