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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

Primary Purpose

Graft Versus Host Disease, Hematologic Malignancies

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Palifermin
Placebo
Conditioning Regimen
Allogeneic stem cell transplant
Methotrexate
Sponsored by
Swedish Orphan Biovitrum
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring Hematological Malignancies, Graft-versus-host-disease, Oral Mucositis, Allogeneic Transplantation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Palifermin

    Placebo

    Arm Description

    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.

    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.

    Outcomes

    Primary Outcome Measures

    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.

    Secondary Outcome Measures

    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.
    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.
    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.
    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.
    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.
    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.
    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).

    Full Information

    First Posted
    September 15, 2005
    Last Updated
    September 12, 2014
    Sponsor
    Swedish Orphan Biovitrum
    Collaborators
    Amgen
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00189488
    Brief Title
    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
    Official Title
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2014
    Overall Recruitment Status
    Completed
    Study Start Date
    December 2005 (undefined)
    Primary Completion Date
    November 2008 (Actual)
    Study Completion Date
    August 2013 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Swedish Orphan Biovitrum
    Collaborators
    Amgen

    4. Oversight

    5. Study Description

    Brief Summary
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Graft Versus Host Disease, Hematologic Malignancies
    Keywords
    Hematological Malignancies, Graft-versus-host-disease, Oral Mucositis, Allogeneic Transplantation

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    155 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Palifermin
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    Placebo
    Arm Type
    Placebo Comparator
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Palifermin
    Other Intervention Name(s)
    Recombinant human keratinocyte growth factor (rHuKGF), Kepivance
    Intervention Description
    Administered as an intravenous (IV) bolus.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo
    Intervention Description
    Administered as an intravenous (IV) bolus.
    Intervention Type
    Other
    Intervention Name(s)
    Conditioning Regimen
    Intervention Description
    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])
    Intervention Type
    Procedure
    Intervention Name(s)
    Allogeneic stem cell transplant
    Intervention Description
    Allogeneic marrow/peripheral blood progenitor cell transplantation
    Intervention Type
    Drug
    Intervention Name(s)
    Methotrexate
    Primary Outcome Measure Information:
    Title
    Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD)
    Description
    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.
    Time Frame
    From transplant (Day 0) until Day 100
    Secondary Outcome Measure Information:
    Title
    Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD)
    Description
    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.
    Time Frame
    From transplant (Day 0) until Day 100
    Title
    Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration
    Description
    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.
    Time Frame
    Day 11
    Title
    Number of Participants With Severe (Grade 3 or 4) Oral Mucositis
    Description
    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.
    Time Frame
    From transplant (Day 0) until Day 100
    Title
    Duration of Severe Oral Mucositis (WHO Grade 3 and 4)
    Description
    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.
    Time Frame
    From transplant (Day 0) until Day 100
    Title
    Number of Participants With Parenteral or Transdermal Opioid Analgesic Use
    Description
    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.
    Time Frame
    From transplant (Day 0) until Day 100
    Title
    Duration of Hospitalization
    Description
    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.
    Time Frame
    From transplant (Day 0) until Day 100
    Title
    Area Under the Curve (AUC) of Mouth and Throat Soreness Score
    Description
    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).
    Time Frame
    The first day of study drug administration through Day 28.

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    MD
    Organizational Affiliation
    Amgen
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Learn more about this trial

    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

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