Graft Versus Host Disease, Hematologic Malignancies
Conditions
Keywords
Hematological Malignancies, Graft-versus-host-disease, Oral Mucositis, Allogeneic Transplantation
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.
Interventions
DRUGPalifermin
Administered as an intravenous (IV) bolus.
DRUGPlacebo
Administered as an intravenous (IV) bolus.
OTHERConditioning 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 \[Mel dose \> 140 mg/m\^2\])
PROCEDUREAllogeneic stem cell transplant
Allogeneic marrow/peripheral blood progenitor cell transplantation
DRUGMethotrexate
Sponsors
Amgen
Swedish Orphan Biovitrum
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) | From transplant (Day 0) until Day 100 | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD) | From transplant (Day 0) until Day 100 | 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 | Day 11 | 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 | From transplant (Day 0) until Day 100 | 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) | From transplant (Day 0) until Day 100 | 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 | From transplant (Day 0) until Day 100 | 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 | From transplant (Day 0) until Day 100 | 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 first day of study drug administration through Day 28. | 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). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo to 60 μg/kg palifermin administered daily on 3 consecutive days prior to the day of start of the conditioning regimen and placebo to 180 μg/kg palifermin administered once, prior to transplant and at least 96 hours from the previous placebo dose. | 78 |
| 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. | 77 |
| Total | 155 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Decision | 0 | 2 |
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 5 | 8 |
| Overall Study | Disease progression | 2 | 4 |
| Overall Study | Ineligibility determined | 1 | 0 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Protocol deviation | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 6 |
Baseline characteristics
| Characteristic | Total | Palifermin | Placebo |
|---|---|---|---|
| Age, Continuous | 41.3 Years STANDARD_DEVIATION 11.3 | 40.4 Years STANDARD_DEVIATION 12.1 | 42.2 Years STANDARD_DEVIATION 10.5 |
| Donor source Marrow | 35 participants | 18 participants | 17 participants |
| Donor source Peripheral blood progenitor cell(s) | 120 participants | 59 participants | 61 participants |
| Donor type Related Family Member | 91 participants | 45 participants | 46 participants |
| Donor type Unrelated | 64 participants | 32 participants | 32 participants |
| Prior radiotherapy No | 148 participants | 73 participants | 75 participants |
| Prior radiotherapy Yes | 7 participants | 4 participants | 3 participants |
| Race/Ethnicity, Customized Asian | 5 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 7 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 9 participants | 5 participants | 4 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White or Caucasian | 132 participants | 65 participants | 67 participants |
| Sex: Female, Male Female | 66 Participants | 37 Participants | 29 Participants |
| Sex: Female, Male Male | 89 Participants | 40 Participants | 49 Participants |
| Type of diagnosis Acute lymphoblastic leukemia | 32 participants | 17 participants | 15 participants |
| Type of diagnosis Acute myelogenous leukemia | 63 participants | 29 participants | 34 participants |
| Type of diagnosis Chronic lymphocytic leukemia | 10 participants | 3 participants | 7 participants |
| Type of diagnosis Chronic myelogenous leukemia | 12 participants | 6 participants | 6 participants |
| Type of diagnosis Hodgkin's disease | 1 participants | 1 participants | 0 participants |
| Type of diagnosis Leukemia - all types | 117 participants | 55 participants | 62 participants |
| Type of diagnosis Multiple Myeloma | 1 participants | 0 participants | 1 participants |
| Type of diagnosis Myelodysplastic Syndrome | 21 participants | 12 participants | 9 participants |
| Type of diagnosis Non-Hodgkin's lymphoma | 15 participants | 9 participants | 6 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 71 / 73 | 77 / 78 |
| serious Total, serious adverse events | 40 / 73 | 50 / 78 |
Outcome results
Primary
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.
Time frame: From transplant (Day 0) until Day 100
Population: Primary Analysis Set (consisting of all randomized participants) with GVHD assessments. Efficacy analyses were according to randomized treatment assignment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) | Yes | 12 Participants |
| Placebo | Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) | No | 60 Participants |
| Palifermin | Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) | Yes | 12 Participants |
| Palifermin | Number of Participants With Severe (Grade 3 and 4) Acute Graft Versus Host Disease (GVHD) | No | 62 Participants |
p-value: 0.92995% CI: [-11, 12.1]Cochran-Mantel-Haenszel
Secondary
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).
Time frame: The first day of study drug administration through Day 28.
Population: Primary analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Curve (AUC) of Mouth and Throat Soreness Score | 43.0 MTS score * days | Standard Deviation 26.3 |
| Palifermin | Area Under the Curve (AUC) of Mouth and Throat Soreness Score | 47.7 MTS score * days | Standard Deviation 26.2 |
p-value: 0.2195% CI: [-12.2, 4]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From transplant (Day 0) until Day 100
Population: Primary analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Hospitalization | 36.1 days | Standard Deviation 20.8 |
| Palifermin | Duration of Hospitalization | 42.2 days | Standard Deviation 25.1 |
p-value: 0.18695% CI: [-12.7, 1.8]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From transplant (Day 0) until Day 100
Population: Primary Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Duration of Severe Oral Mucositis (WHO Grade 3 and 4) | 8.1 days | Standard Deviation 6.8 |
| Palifermin | Duration of Severe Oral Mucositis (WHO Grade 3 and 4) | 7.8 days | Standard Deviation 6.7 |
p-value: 0.95395% CI: [-1.5, 2.5]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Day 11
Population: Primary Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration | Yes | 56 Participants |
| Placebo | Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration | No | 22 Participants |
| Palifermin | Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration | Yes | 60 Participants |
| Palifermin | Number of Participants With Day 11 Methotrexate Graft Versus Host Disease Prophylaxis Administration | No | 17 Participants |
p-value: 0.35295% CI: [-19.4, 6.4]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From transplant (Day 0) until Day 100
Population: Primary Analysis Set (consisting of all randomized participants) with GVHD assessments.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD) | Yes | 29 Participants |
| Placebo | Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD) | No | 43 Participants |
| Palifermin | Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD) | Yes | 43 Participants |
| Palifermin | Number of Participants With Grade 2 to 4 Acute Graft Versus Host Disease (GVHD) | No | 31 Participants |
p-value: 0.03495% CI: [-33.4, -2.4]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From transplant (Day 0) until Day 100
Population: Primary Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Parenteral or Transdermal Opioid Analgesic Use | Yes | 50 Participants |
| Placebo | Number of Participants With Parenteral or Transdermal Opioid Analgesic Use | No | 28 Participants |
| Palifermin | Number of Participants With Parenteral or Transdermal Opioid Analgesic Use | Yes | 48 Participants |
| Palifermin | Number of Participants With Parenteral or Transdermal Opioid Analgesic Use | No | 29 Participants |
p-value: 0.79795% CI: [-12.5, 16.5]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From transplant (Day 0) until Day 100
Population: Primary Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Yes | 57 Participants |
| Placebo | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | No | 16 Participants |
| Placebo | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Unknown | 5 Participants |
| Palifermin | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Yes | 62 Participants |
| Palifermin | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | No | 13 Participants |
| Palifermin | Number of Participants With Severe (Grade 3 or 4) Oral Mucositis | Unknown | 2 Participants |
Comparison: Participants with Unknown incidence are treated as Yes when constructing the differences, 95% confidence intervals and p-value.p-value: 0.67595% CI: [-14.2, 9]Cochran-Mantel-Haenszel