E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Inflammation and ulceration that occurs in the mouth |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028130 |
E.1.2 | Term | Mucositis oral |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of palifermin administered at the dose of 180 μg/kg IV in 8 weekly doses relative to placebo in reducing the incidence of severe [World Health Organization Grade 3 or 4] oral mucositis (OM) in subjects with locally advanced HNC receiving RT/CT as definitive treatment for their disease. |
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E.2.2 | Secondary objectives of the trial |
-To assess the safety and tolerability of palifermin at the dose of 180 μg/kg IV in 8 weekly doses compared to placebo during a 7-week course of RT/CT with cisplatin (CDDP)
-To evaluate the effect of palifermin on the clinical sequelae of severe OM (eg, average patient-reported mouth and throat soreness score), and on xerostomia
-To evaluate long-term effects of palifermin on disease outcome and survival after RT/CT |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically documented squamous cell carcinoma involving either the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx
• Absence of second primary tumor confirmed by triple endoscopy or by pharyngo/laryngoscopy combined with imaging evidence (PET or CT scan or MRI)
• Newly diagnosed, locally advanced stage HNC (unresectable / unresected disease; American Joint Committee on Cancer [AJCC] Stage III, IVA, or IVB) amenable to RT/CT as the definitive treatment modality
• Radiation treatment field to receive planned dose of at least 50Gy to areas of the oral cavity / oropharynx mucosa that can be visualized (Subjects with larynx or hypopharynx tumors are eligible only if the radiation oncologist anticipates at least 2 of the 9 anatomical areas in the oral cavity listed in Section 7.4 of this protocol [Mucositis Assessments] will receive a total dose of 50 Gy).
• Signed informed consent
• Subject is 18 years of age or older
• ECOG performance status (PS) ≤ 2
• Planned interval < 6 calendar days between randomization and the first dose of RT
Baseline laboratory assessments:
- Hemoglobin (Hgb) ≥ 10g/dL
- White blood count (WBC) > 3.5 x 10e9/L or - Absolute neutrophil count (ANC) > 1.5 x 10e9/L
- Platelet count ≥ 100 x 10e9/L
- Serum bilirubin ≤ 1.5 x institutional upper limits of normal (ULN)
- Serum creatinine ≤ 2.0 mg/dL; Subjects with a serum creatinine ≥ 1.4 mg/dL and ≤ 2.0 mg/dL need to demonstrate a 24-hr urinary creatinine clearance ≥ 50 mL/min
- Serum or urine pregnancy test: Negative |
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E.4 | Principal exclusion criteria |
• Tumors of the lips, paranasal sinuses, salivary glands, or of unknown primary
• Metastatic disease (M1) / Stage IV C
• Presence or history of any other primary malignancy (other than curatively treated in situ cervical cancer, or
basal cell carcinoma of the skin without evidence of disease for > 3 years)
• History of pancreatitis
• Plan to remove the tumor surgically before completing the protocol RT / CT course
• Prior radiotherapy to the site of disease
• Prior chemotherapy
• Other investigational procedures
• Thirty days or less since receiving an investigational product or device in another clinical trial. Current
enrollment in another clinical trial is not permitted unless the sole purpose of the trial is for long-term follow-up/
survival data.
• Pregnant or breast-feeding women
• Refusal to use adequate contraceptive devices during treatment phase
• Known sensitivity to any of the products administered during dosing, including E coli-derived products
• Known to be sero-positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C
virus (HCV)
• Previous treatment on this study or with other keratinocyte growth factors
• Compromised ability of the subject to give written informed consent and/or to comply with study procedures
• Refusal to give written informed consent to participate in this study and to sign the hospital information release
form
• Unwilling or unable to complete the patient-reported outcome questionnaires
• Psychological, social, familial, or geographical reasons that would prevent regular follow-up. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• Incidence (%) of severe oral mucositis (Grades 3 or 4 on the WHO oral mucositis scale) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluations of oral mucosal surfaces (mucositis assessments) occur 2 times weekly throughout RT/CT, and 2 times weekly thereafter until severe mucositis (WHO Mucositis Grade 3 or 4) has returned to Grade 2, but not beyond week 15. Within each week, the OM assessments should be performed 3 days apart (+/-1 day). |
|
E.5.2 | Secondary end point(s) |
• Duration of severe oral mucositis (WHO Grades 3 or 4)
• Average patient-reported mouth and throat soreness score (as reported on the Oral Mucositis Weekly Questionnaire for Head and Neck Cancer [OMWQ-HN])
• Time to severe oral mucositis (WHO Grades 3 or 4)
• Total dose of opioid analgesics used (mg of morphine equivalents)
• Incidence of unplanned breaks in RT ≥5 days (to include discontinuations of RT)
• Incidence of unplanned breaks in CT ≥5 days (to include discontinuations of CT)
• Incidence of xerostomia (CTCAE v3.0 Dry Mouth/Xerostomia scale Grade 2 or higher)
Safety Endpoints: Short-term
• Incidence of adverse events and laboratory abnormalities using the CTCAE v.3.0 toxicity scales
• Incidence of serum anti-palifermin antibody formation
• Overall tumor response and loco-regional failure at week 12
Safety Endpoints: Long-term
• Time to loco-regional tumor failure
• Incidence of second primary tumors
• Incidence of other malignancies
• Progression-free survival (PFS)
• Overall survival (OS)
• Incidence of leukoplakia |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluations of oral mucosal surfaces occur 2 times weekly throughout RT/CT, and 2 times weekly thereafter until severe mucositis (WHO Mucositis Grade 3 or 4) has returned to Grade 2, but not beyond week 15. Within each week, the OM assessments should be performed 3 days apart (+/-1 day). On the days of the mucositis assessments, all study subjects will be asked to complete the PRO questionnaires BEFORE the clinical evaluation or any clinical procedure. On the days of the oral mucosa assessments, salivary gland changes will be evaluated.
During the first 2 weeks of RT, blood samples for serum amylase and lipase testing will be taken on Monday and Friday (Friday before IP administration).
During weeks 4, 8, and 12, serum samples will be obtained for anti-palifermin antibody testing. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Czech Republic |
Germany |
Hungary |
Italy |
Poland |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Week 12 is the last observation visit in the acute Oral Mucositis evaluation phase. All subjects will be followed for up to 10 years from the last subject randomized or until death, or lost to follow up, for long term safety evaluation. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |