E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent or Metastatic Head and Neck Cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060121 |
E.1.2 | Term | Squamous cell carcinoma of head and neck |
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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 |
The primary objective of this study is to compare the OS of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 every 3 weeks to the OS of single-agent cisplatin 75 mg/m2 every 3 weeks in patients with HNC that is recurrent and not amenable to local therapy (surgery or radiation) or newly diagnosed distant metastatic disease. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to compare between the 2 treatment arms: • progression-free survival (PFS) • overall response rate (ORR) • duration of response (DoR) for responding patients • time to worsening (TTW) in dimensions of health-related quality of life (HRQoL) • change from baseline in dimensions of HRQoL using FACT-H&N • the safety and adverse event profile • assess the ability of biological markers and disease state to identify difference in treatment effect on relevant clinical endpoints
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
[1] Histologic or cytologic diagnosis of squamous cell HNC, either: • recurrent disease (locally advanced or metastatic) that is not amenable to local therapy, (i) with at least 6 months since completion of systemic therapy (chemotherapy or biological anticancer therapy), and (ii) with no more than 1 prior multimodal therapy (such as concurrent chemoradiation with or without sequential chemotherapy) for locally advanced HNC tumor, and (iii) with no prior systemic therapy (chemotherapy or biological anticancer therapy) for metastatic disease; OR • newly diagnosed distant metastatic disease (Stage IVc). [2] Prior therapies: • Radiation therapy must be completed at least 4 weeks before study enrollment. For palliative therapy,prior radiation therapy allowed to <25% of the bone marrow (Cristy and Eckerman 1987) and prior radiation to the whole pelvis is not allowed. Patients must have recovered from the acute toxic effects of the treatment prior to study enrollment. • Surgery (excluding prior diagnostic biopsy) must be completed at least 4 weeks before study enrollment. Patients must have fully recovered from any acute effects of surgery prior to study enrollment. [3] Life expectancy of at least 3 months. [4] Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Oken et al. 1982). See Protocol Attachment JMHR.3. [5] Disease status may be measurable or nonmeasurable as defined by Response Evaluation Criteria in Solid Tumors (RECIST; Therasse et al. 2000). Positron emission tomography (PET) scans and ultrasounds may not be used for lesion measurements. [6] Patient compliance and geographic proximity that allow for adequate follow-up. [7] Adequate organ function as defined by the following: • Bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥1.5 x 10e9/L, platelets ≥100 x 10e9/L, and hemoglobin ≥9 g/dL. • Hepatic: bilirubin < or = 1.5 x the upper limit of normal (ULN); alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) >3.0 x ULN. (ALP, AST, and ALT >5.0 x ULN is acceptable if the liver has tumor involvement.) • Renal: calculated creatinine clearance (CrCl) ≥ 45 mL/min based on the standard Cockcroft and Gault formula (Cockcroft and Gault 1976). (See Protocol Attachment JMHR.4.) [8] Signed informed consent from patient. [9] Patients at least 18 years of age. [10] For women: Must be surgically sterile, postmenopausal, or compliant with a medically approved contraceptive regimen (for example, intrauterine device [IUD], birth control pills, or barrier device) during and for 6 months after the treatment period; must have a negative serum or urine pregnancy test within 7 days before study enrollment, and must not be breast-feeding. For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 6 months after the treatment period.
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E.4 | Principal exclusion criteria |
[11] Prior systemic therapy (chemotherapy or biological anticancer therapy) for metastatic disease. [12] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. [13] Serious concomitant systemic disorder (for example active infection or cardiac disease) or psychiatric disorder that, in the opinion of the investigator, would compromise the patient’s ability to complete the study. [14] Presence of clinically significant (by physical exam) third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry. [15] Second primary malignancy that is clinically detectable at the time of consideration for study enrollment. [16] Have had another primary malignancy other than HNC, unless that prior malignancy was treated at least 2 years previously with no evidence of recurrence. Exception: Patients with a history of in situ carcinoma of the cervix, nonmelanoma skin cancer, or low-grade (Gleason score ≤6) localized prostate cancer will be eligible even if diagnosed and treated less than 2 years previously. [17] Nasopharyngeal, paranasal sinus, lip, or salivary gland cancer. [18] Have central nervous system (CNS) metastases (unless the patient has completed successful local therapy for CNS metastases and has been off corticosteroids for at least 4 weeks before starting study therapy). Brain imaging is required in symptomatic patients to rule out brain metastases, but is not required in asymptomatic patients. [19] Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents, other than an aspirin dose ≤1.3 grams per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam). [20] Unable or unwilling to take folic acid, vitamin B12, or prophylactic corticosteroids. [21] Concurrent administration of any other antitumor therapy. [22] Pregnant or breast-feeding.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure for this trial is Overall Survivaln (OS). All randomized patients will be included in the analysis of OS. The primary analysis will be the comparison of OS between the 2 study treatments using a stratified log-rank test at two-sided α=0.05 with the following prognostic variables as stratification factors: performance status (0 or 1 versus 2), previously treated for HNC (no versus yes), distant metastasis (no versus yes), and prior platinum-based therapy (no versus yes). Kaplan-Meier (K-M) estimation (Kaplan and Meier 1958) including generating K-M curve, quartiles, and interval estimation using 95% confidence intervals will also be done. The supportive analysis of the primary outcome will be performed to obtain treatment effect after adjusting for the prognostic variables using Cox regression model (Cox 1972). |
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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 | No |
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 | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
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.8.3 |
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 | 41 |
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 | Information not present in EudraCT |
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 |
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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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The study will end when data collection is stopped. The study design is to enroll 790 patients and perform a final analysis after approximately 632 deaths have been observed, at which time database lock will occur. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |