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

This study has been completed.
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier:
NCT00189488
First received: September 15, 2005
Last updated: September 12, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Graft Versus Host Disease
Hematologic Malignancies
Drug: Palifermin
Drug: Placebo
Other: Conditioning Regimen
Procedure: Allogeneic stem cell transplant
Drug: Methotrexate
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Swedish Orphan Biovitrum:

Primary Outcome Measures:
  • Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) [ Time Frame: From transplant (Day 0) until Day 100 ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: From transplant (Day 0) until Day 100 ] [ Designated as safety issue: Yes ]

    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 [ Time Frame: Day 11 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From transplant (Day 0) until Day 100 ] [ Designated as safety issue: Yes ]

    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) [ Time Frame: From transplant (Day 0) until Day 100 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From transplant (Day 0) until Day 100 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From transplant (Day 0) until Day 100 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: The first day of study drug administration through Day 28. ] [ Designated as safety issue: No ]

    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).



Enrollment: 155
Study Start Date: December 2005
Study Completion Date: August 2013
Primary Completion Date: November 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Palifermin
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
Administered as an intravenous (IV) bolus.
Other Names:
  • Recombinant human keratinocyte growth factor (rHuKGF)
  • Kepivance
Other: Conditioning Regimen

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])
Procedure: Allogeneic stem cell transplant
Allogeneic marrow/peripheral blood progenitor cell transplantation
Drug: Methotrexate
Placebo Comparator: Placebo
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
Administered as an intravenous (IV) bolus.
Other: Conditioning Regimen

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])
Procedure: Allogeneic stem cell transplant
Allogeneic marrow/peripheral blood progenitor cell transplantation
Drug: Methotrexate

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00189488

Sponsors and Collaborators
Swedish Orphan Biovitrum
Amgen
Investigators
Study Director: MD Amgen
  More Information

No publications provided

Responsible Party: Swedish Orphan Biovitrum
ClinicalTrials.gov Identifier: NCT00189488     History of Changes
Obsolete Identifiers: NCT00964899
Other Study ID Numbers: 20040213
Study First Received: September 15, 2005
Results First Received: November 25, 2009
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Swedish Orphan Biovitrum:
Hematological Malignancies
Graft-versus-host-disease
Oral Mucositis
Allogeneic Transplantation

Additional relevant MeSH terms:
Neoplasms
Graft vs Host Disease
Immune System Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Pharmacologic Actions
Therapeutic Uses
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014