E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 120 mcg/kg IV in weekly doses (minimum of 7 weekly doses, until RT is complete) in reducing the incidence of severe [World Health Organization Grade 3 or 4] oral mucositis (OM) in locally advanced HNC subjects receiving RT with concurrent CT as adjuvant treatment for their disease (post-operative setting). |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of palifermin at the dose of 120 mg/kg IV weekly doses (minimum of 7 weekly doses, until RT is complete) in this patient population. To evaluate the effect of palifermin on the clinical sequelae of severe OM (eg, average patient-reported mouth and throat soreness [MTS] score), and on RT induced xerostomia in this patient population. To evaluate long-term effects of palifermin on disease
outcome and survival in this patient population. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Key Inclusion Criteria:
• Histologically documented squamous cell carcinoma
• Subjects with locally advanced, resected ( R0, R1) HNC ( American Joint Committee on Cancer [ AJCC] Stage II, III, IVA, or IVB) involving either the oral cavity, oropharynx, hypopharynx, or larynx ,
• Radiation treatment field to receive planned dose of at least 50 Gy to areas of the oral cavity / oropharynx mucosa that can be visualized by non- instrumental oral inspection. 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 will receive a total dose of 50 Gy or more.
• Signed informed consent
• Subject is 18 years of age or older
• ECOG performance status ( PS) ≤ 2 Baseline laboratory assessments: - Hemoglobin ( Hgb) ≥ 10g/ dL -White blood count ( WBC) > 3.5 x 109/ L or - Absolute neutrophil count ( ANC) > 1.5 x 109/ L - Platelet count ≥ 100 x 109/ 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 tumors.
- 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 chronic pancreatitis or an episode of acute pancreatitis within the last year
- 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
- Incidence (%) of severe oral mucositis (Grades 3 or 4 on the WHO oral mucositis scale).
Secondary Efficacy Endpoints:
- Duration of severe oral mucositis (WHO Grades 3 or 4).
- Average daily patient-reported mouth and throat soreness score (as reported on the Oral Mucositis Weekly Questionnaire for Head and Neck Cancer [OMWQ-HN])
- Time to onset of severe oral mucositis (WHO Grades 3 or 4)
- Total dose of opioid analgesics used (mg of morphine equivalents)
- Incidence of ≥ 5 missed consecutive fractions of scheduled RT (to include discontinuations of RT)
- Incidence of unplanned delays in CT for cisplatin administration on Day 22 (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.
- Disease progression at week 12.
Safety Endpoints: Long-term
- Time to disease progression.
- Incidence of second primary tumors.
- Incidence of other malignancies.
- Progression-free survival (PFS).
- Overall survival (OS).
- Incidence of leukoplakia.
Key Exploratory Endpoints:
- Incidence of WHO Grade 2, 3, or 4 OM
- Duration of WHO Grade 2, 3, or 4 OM
- Time to WHO Grade 2, 3, or 4 OM
- Maximum severity of OM (WHO scale and CTCAE v3.0 Mucositis scale)
- Incidence of severe OM - Clinical Exam (Grades 3 or 4 on clinical exam of oral cavity CTCAE v3.0 Mucositis scale)
- Duration of severe OM
- Clinical Exam (Grades 3 or 4 on clinical exam of oral cavity CTCAE v3.0 Mucositis scale)
- Time to severe OM - Clinical Exam (Grades 3 or 4 on clinical exam of oral cavity CTCAE v3.0 Mucositis scale)
- Incidence of opioid analgesic use
- Duration (days) of opioid analgesic use
- Incidence of CTCAE Grade ≥2 salivary gland changes (CTCAE v3.0 Salivary Gland Changes scale Grade 2 or higher)
- Time to CTCAE Grade ≥2 salivary gland changes (CTCAE v3.0 Salivary Gland Changes scale Grade 2 or higher)
- Incidence of PEG tube/nasogastric (NG) tube/total parenteral nutrition (TPN)/ intravenous (IV) hydration utilization
- Duration of PEG tube/NG tube/TPN/ IV hydration utilization - Changes in body weight (kg) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Oral mucosa evaluations will be performed:
• At baseline
• Twice weekly throughout RT/CT until resolution of OM to WHO Grade ≤ 2
• Once weekly thereafter until resolution of OM to WHO Grade ≤ 1
• If severe OM is not resolved by the week 12 visit, twice weekly assessments should be continued until week 15. If after the week 15 visit, OM is greater than or equal to WHO Grade 2, the OM evaluations should continue weekly until resolved to WHO Grade ≤ 1. |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Duration of severe oral mucositis (WHO Grades 3 or 4)
• Average patient-reported mouth and throat soreness score (as reported on Question 3 of the Oral Mucositis Weekly Questionnaire for patients with Head and Neck Cancer [OMWQ-HN])
• Time to onset of 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) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Oral mucosa evaluations will be performed:
• At baseline
• Twice weekly throughout RT/CT until resolution of OM to WHO Grade ≤ 2
• Once weekly thereafter until resolution of OM to WHO Grade ≤ 1
• If severe OM is not resolved by the week 12 visit, twice weekly assessments should be continued until week 15. If after the week 15 visit, OM is greater than or equal to WHO Grade 2, the OM evaluations should continue weekly until resolved to WHO Grade ≤ 1. |
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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 | Yes |
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
NB. Pharmacogenetics additional only in subjects who sign a separate informed consent form. |
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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 | 38 |
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 |
Australia |
Austria |
Canada |
France |
Germany |
Italy |
Spain |
United Kingdom |
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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
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Week 12 is the last observation point. All subjects will be followed up until death, loss to follow-up, or for up to 10 years from the last subject randomized. |
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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 | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |