A Study of Palifermin for the Reduction of Oral Mucositis in Subjects With Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and effect of palifermin on the incidence of oral mucositis in subjects with multiple myeloma receiving Melphalan followed by autologous peripheral blood stem cell transplantation. Amendment 01 (April 07) introduced three cataract assessments to be carried out at Screening, Month 6 and Month 12 in response to FDA and EMEA follow up measures.

Detailed Description
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This was a double-blind, placebo-controlled, randomized, multicenter Phase IIIb study of palifermin given before and after dose chemotherapy (total 6 doses) or before dose chemotherapy only (total 3 doses), in subjects with Multiple Myeloma (MM)receiving high dose melphalan (chemotherapy), in a 1-day schedule, followed by autologous Peripheral Blood Stem Cell Transplantation (PBSCT). All subjects were to be followed for disease progression, second primary tumors, additional malignancies and survival for up to 10 years. Planned: 275 subjects, in fact, 281 subjects were randomized. Randomized: 115 subjects to palifermin pre/post-CT, 109 subjects to palifermin pre-CT and 57 subjects to placebo Analyzed: 281 subjects in the full analysis set, 277 subjects in the safety subset. Efficacy Oral cavity assessment, patient reported outcome (PRO) questionnaires (Oral Mucositis Daily Questionnaire [OMDQ], Functional Assessment of Cancer Therapy Esophageal [FACT-E], European Quality of Life Utility Scale [EQ 5D], Mucositis Chronic Symptoms Questionnaire [MCSQ]). Safety Physical examination (including body temperature), concomitant medications, transfusions, vital signs, laboratory assessments (hematology, chemistry), cataract assessments, adverse events (AEs).

Official Title
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A Double-Blind, Randomized, Placebo-controlled Study of Two Different Schedules of Palifermin for Reduction in Severity of Oral Mucositis in Subjects With Multiple Myeloma Receiving Melphalan Followed by Autologous Blood Stem Cell Transplantation

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Palifermin before only
* Drug: Placebo
* Drug: Palifermin before and after


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Multiple myeloma (MM) subjects scheduled to receive high-dose Melphalan in a one day schedule followed by autologous peripheral blood progenitor cell (PBSCT) Body Mass Index (BMI) ≤ 35 Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, or an ECOG status of 3 if the reason for a status of 3 is exclusively due to MM (e.g. pathological fracture) Functional hematopoietic, hepato-renal and pulmonary systems Subjects at minimum with a baseline best corrected visual acuity (BCVA) of 20/40, (6/12 or 0.5 on the decimal scale) or better using the ETDRS chart in one eye Subject at minimum with one eye with a natural, intact lens Subject who has a LOCS III score at baseline of P < 1.0, C < 2.0 and NO < 2.0 in at least one eye Women in child bearing potential must have a negative pregnancy test Exclusion Criteria: Presence or history of any other malignancy (other than curatively treated basal cell or squamous cell carcinoma of the skin, in situ cervical carcinoma, or other surgically cured malignancy, without evidence of disease for > 3 years Prior autologous or allogeneic transplants Prior treatment with palifermin, or other fibroblast or keratinocyte growth factors Receiving dialysis History of cataract surgery in both eyes Incapable of being responsive to mydriatic agents History of other ocular disease (e.g., macular degeneration, glaucoma, corneal disease) that would make assessment of visual status difficult Subject is scheduled to undergo cataract surgery Subject with any disease, that in the opinion of the ophthalmologist, could adversely effect the subject's vision during the course of the study Currently active oral mucositis infection Positive for HIV, hepatitis B or C Subject is unable or unwilling to follow with study procedures Subject is pregnant or is breast feeding Subject has not agreed to use adequate contraceptive precautions

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Palifermin before only<br>Subjects received palifermin before-high dose chemotherapy (total 3 doses) and matched placebo after-high dose chemotherapy (total 3 doses) | Drug: Palifermin before only<br>* One bolus IV injection at 60 μg/kg/day, on Days 6, 5 & 4 days before-high dose chemotherapy and one bolus IV injection at 60 μg/kg/day of matched placebo on days 0, 1 & 2 days after-high dose chemotherapy. Minimum of 4 days between before-chemotherapy and after-transplantation dosing.<br>* Other names: Kepivance;|
| Placebo Comparator: Placebo (suger pill)<br>Subjects received matched placebo before- and after-high dose chemotherapy | Drug: Placebo<br>* One bolus IV injection at 60 μg/kg/day of matched placebo on Days 6, 5 & 4 (before-high dose chemotherapy) and on Days 0, 1 & 2 (after-high dose chemotherapy). Minimum of 4 days between pre-chemotherapy and post-transplantation dosing.<br>|
| Active Comparator: Palifermin before and after<br>Subjects received palifermin before- and after-high dose chemotherapy (total of 6 doses) | Drug: Palifermin before and after<br>* One bolus IV injection at 60 μg/kg/day, on Days 6, 5 & 4 (before-high dose chemotherapy) and on Days 0, 1 & 2 (after-high dose chemotherapy). Minimum of 4 days between before-chemotherapy and after-transplantation dosing.<br>* Other names: Kepivance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Severity of Oral Mucositis (World Health Organization (WHO) Grades 0/1, 2, 3, or 4) | For the primary efficacy endpoint maximum severity of Oral Mucositis (OM) was assessed, the number of participants who had the different severity. To assess severity of OM, a 5-grade WHO scale (0, 1, 2, 3, or 4) was used. 0 = no findings or erythema only, 1= soreness present with or without erythema, 2=ulcers present but able to take solid food, 3 =ulcers present and only able to take liquids, 4 =ulcers present/not able to take anything orally. | at Day 32 | 
| Incidence of Cataract Development or Progression at Month 12. | Number of participants from the primary cataract subset showing an increase from baseline of >= 0.3 in the Lens Opacities Classification System III (LOCS III score). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist trained in LOCS III uses a slit lamp for examining the lens of the eye. The classification evaluates four features: posterior subcapsular cataract(P),cortical cataract(C),nuclear opalescence(NO) and nuclear color(NC). NO and NC are graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each. In the current study, cataract development or progression was defined as an increase from baseline of ≥ 0.3 on any of the three features P, C or NO (NC is of less importance and has not been analysed further in this study). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Ulcerative Mucositis (WHO Grades 2, 3, and 4) | The incidence of ulcerative mucositis WHO grades 2, 3, and 4. Measured the number of participants who had WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally. | at Day 32 | 
| Duration of Ulcerative Mucositis (WHO Grades 2, 3, and 4) | The duration of ulcerative mucositis measured the number of days the participants had different WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3 =ulcers present and only able to take liquids, 4 =ulcers present/not able to take anything orally. Patients that did not have any ulcerative mucositis were given a value of 0 days. | at Day 32 | 
| The Area Under the Curve (AUC) Was Calculated From the Patient-reported Outcome Mouth and Throat Soreness (MTS) Score. | The mean daily scores were calculated using the subject daily assessment of Patient-reported mouth and throat soreness (MTS) on the 5 point scale with higher values in MTS indicating a worse self assessed MTS. A 5-grade WHO scale (0, 1, 2, 3, or 4). 0=no findings or erythema only, 1=soreness present with or without erythema, 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally. The incidence of ulcerative mucositis WHO grades 2, 3, and 4. Measured the number of participants who had WHO grades 2, 3, and 4: 2=ulcers present but able to take solid food, 3=ulcers present and only able to take liquids, 4=ulcers present/not able to take anything orally. The area under the curve were calculated at the time points; Day(D)-2, up to Day 32. | at Day 32 | 
| Incidence of Cataract Development or Progression (Change of ≥0.3 in Lens Opacities Classification System III (LOCS III Score)) at Month 6. | Number of participants from the primary cataract subset showing an increase from baseline of >= 0.3 in the Lens Opacities Classification System III (LOCS III score). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist trained in LOCS III uses a slit lamp for examining the lens of the eye. The classification evaluates four features: posterior subcapsular cataract(P),cortical cataract(C),nuclear opalescence(NO) and nuclear color(NC). NO and NC are graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each. In the current study, cataract development or progression was defined as an increase from baseline of ≥ 0.3 on any of the three features P, C or NO (NC is of less importance and has not been analysed further in this study). | 6 Months | 
| Incidence of an Increase Posterior Subcapsular Cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO) at Month 6 and 12 | To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior (P), Cortical Cataract (C) and Nuclear Opalescence (NO). For Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO): at month 6 and 12 adjusted difference of rate of cataract, Palifermin - Placebo were used and the confidence interval were calculated on the adjusted difference. | at Month 6 and Month 12 | 
| Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 6. | To study the change in cataract from baseline visit to months 6, three cataract main types: nuclear, cortical and posterior subcapsular measured on the Lens Opacities Classification System III (LOCS III) Scale. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in theLOCS III score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist uses a slit lamp for examining the lens of the eye. The classification evaluates: P,C and NO. NO is graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each. | Months 6 | 
| Change From Baseline in Posterior Subcapsular (P), Cortical (C) Cataract and Nuclear Opalescence (NO) on the Lens Opacities Classification System III (LOCS III) Scale at Months 12. | To study the change in cataract from baseline visit to months 12, regarding the three cataract main types: nuclear, cortical and posterior subcapsular measured on the Lens Opacities Classification System III (LOCS III) Scale. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). The LOCS III is a standard system used for grading and comparison of cataract severity and type. The ophthalmologist uses a slit lamp for examining the lens of the eye. The classification evaluates: P,C and NO. NO is graded on a decimal scale of 0.1 to 6.9, based on a set of 6 standardized photographs. C and P are graded on a decimal scale of 0.1 to 5.9, based on a set of 5 standardized photographs each. | Months 12 | 
| Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 6 | To study if the treatment has effected on the visual acuity from baseline to months 6, by using Best Corrected Visual Acuity (BCVA) as measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). | Months 6 | 
| Incidence of a Decreased From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters at Months 12. | To study if the treatment has effected on the visual acuity from baseline to months 12, by using Best Corrected Visual Acuity (BCVA) as measured by a Change of 10 Letters on the ETDRS (Early Termination Diabetic Retinopathy Study) at 4 Meters. To assess the effect of palifermin on the incidence of cataract development or progression at Month 6 and Month 12 based on an increase of ≥ 0.3 in the Lens Opacities Classification System (LOCS III) score for Posterior Subcapsular cataract (P), Cortical Cataract (C) and Nuclear Opalescence (NO). | Month 12 | 
| Incidence of Adverse Events and Laboratory Abnormalities | Incidence of Adverse Events CTCAE grade 3 or higher reported | at Day 32 | 
| Overall Survival | Overall survival (OS) is based on death from any cause, not just the condition being treated, thus it picks up death from side effects of the treatment, and effects on survival after relapse. | During long-term follow up phase (maximum of 10 years) | 
| Progression Free Survival | Progression-free survival (PFS) is the length of time during and after the treatment during which the disease being treated does not get worse. In this study the event for Progression-free survival was death from all causes or disease progression. Time to each event was defined as the time elapsed between the date of the first dose of investigational product, and the date of the given event. | During long-term follow up phase (maximum of 10 years) | 
| Time Death or Disease Progression | For the analysis of time to disease progression, competing risks time-to-event analysis was used, since a subject destined to develop disease progression could die from unrelated causes before the disease progression event takes place. Kaplan-Meier survival estimates, with death due to other causes than progression considered as a competing risk, were provided: event rate at 3 month intervals, with 95% confidence interval, the number of subjects at risk at the beginning of the time period, and the number of events of interest. | During long-term follow up phase (maximum of 10 years) | 
| Incidence of Second Primary Malignancies or Other Malignancies | All comparisons for the long-term safety endpoints were based on the combined palifermin group versus placebo (placebo over palifermin). Incidence of new or secondary malignancies by treatment group was provided (incidence of new or secondary malignancies at the follow-up visit - yes, no, no assessment -, and number of subjects with new or secondary malignancies, per type of malignancies). The long-term safety evaluations were summarized for the subgroups defined by the factors used for randomization using descriptive statistics. | During long-term follow up phase (maximum of 10 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KGF, Oncology, Palifermin, Clinical Trial, Oral Mucositis, Multiple Myeloma, Cataract