| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic squamous cell carcinoma of the head and neck |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of the cancer (Head&Neck) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063569 |
| E.1.2 | Term | Metastatic squamous cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 objectives of this study are:
• Part 1: To assess dose-limiting toxicities (DLTs), and to establish the RPII dose for the combination of NC-6004 plus 5-FU plus cetuximab.
• Part 2: To assess progression-free survival (PFS) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after treatment with NC-6004 plus 5-FU plus cetuximab. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To assess the pharmacokinetics of NC-6004.
• To evaluate the safety and tolerability of NC-6004 when combined with 5-FU and cetuximab.
• To evaluate QoL using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and QLQ-Head and Neck 35 (QLQ-H&N35).
• To evaluate overall response rate (ORR), duration of response (DOR), disease control rate (DCR = complete response [CR] + partial response [PR] +stable disease), duration of stable disease (DSD), and overall survival (OS). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in this study:
1. Signed written informed consent prior to the initiation of any study-specific procedures.
2. Histologically or cytologically confirmed diagnosis of stage III/IV recurrent and/or metastatic squamous cell carcinoma of the head and neck not suited for local therapy.
• Patients with stable, treated brain metastases are eligible, provided there is no evidence of progression after treatment and the patient does not require corticosteroids, or is receiving a stable dose of corticosteroids for >14 days prior to Day 1 of treatment.
3. Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
4. Males or females aged 18 years at Screening.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
6. Adequate bone marrow reserve, defined as:
• absolute neutrophil count (ANC) 1.5 × 109/L,
• platelet count 100 × 109/L, and
• hemoglobin (Hb) 10 g/L (transfusion is allowed to achieve Hb of 10 g/L).
7. Adequate liver function, defined as:
• total serum bilirubin ≤1.5 × upper limit of normal (ULN), and
• ALT and AST <2.0 × ULN or <5.0 × ULN in case of documented hepatic
metastasis (ALT, AST)
• serum albumin ≥3.5 g/dL
8. Prothrombin time within normal limits
9. Adequate renal function, defined as:
• glomerular filtration rate 50 mL/min.
10. Have a negative pregnancy test result at Screening (for females of
childbearing potential; not applicable to patients who are unable to
become pregnant, including those with bilateral oophorectomy and/or
hysterectomy or postmenopausal [no menses for the previous 12
months]).
The test must be performed within 1 week before Day 1 of treatment.
11. Male patients must agree to use a condom during treatment and for
90 days after dosing. Male patients must agree not to donate sperm for
90 days after dosing.
12. For women of childbearing potential*: are willing to agree to use 1 of
the following effective methods of birth control from the time of study
entry to 6 months after the last day of treatment:
• Combined (estrogen- and progestogen- containing) hormonal
contraception associated with inhibition of ovulation (oral, intravaginal,
or transdermal)
• Previously irradiated lesions can only be considered as measurable
disease if disease progression has been unequivocally documented at
that site since radiation and the previously irradiated lesion is not the
only site of measurable disease.
• Progestogen-only hormonal contraception associated with inhibition of
ovulation (oral, injectable, or implantable).
• Intrauterine devices.
• Intrauterine hormone-releasing system.
• Vasectomized partner who has received medical assessment of
surgical success.
• Bilateral tubal occlusion.
• True sexual abstinence**.
*Patients not of childbearing potential include those who are surgically
sterile or postmenopausal (no menses for the previous 12 months). For
women not currently using contraceptive methods at Screening, low
user-dependency contraceptive methods (eg, implantable progestogenonly
hormonal contraception, intrauterine device, intrauterine hormonereleasing
system, bilateral tubal occlusion, vasectomized partner) are
recommended.
**The reliability of sexual abstinence needs to be evaluated in relation
to the duration of the clinical trial and the preferred and usual lifestyle of
the patient.
13. Reasonably recovered from preceding major surgery as judged by
the investigator or no major surgery within 4 weeks prior to the start of
Day 1 treatment. |
|
| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from the study:
1. Nasopharyngeal carcinoma.
2. Prior systemic chemotherapy, except if given as part of a multimodal treatment for locally advanced disease which was completed more than 3 months before Day 1 or more than 6 months prior to Day 1 if platinum-based.
• Prior adjuvant or neoadjuvant therapy is allowed.
3. Concomitant anticancer therapy, systemic immune therapy, or hormonal therapy as cancer therapy.
4. Unresolved toxicity from all radiation, adjuvant/neoadjuvant chemotherapy, other targeted treatment including investigational treatment (with the exception of alopecia and Grade 2 peripheral neuropathy) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 scale.
5. History of thrombocytopenia with complications including hemorrhage or bleeding Grade 2 NCI CTCAE v4.03 that required medical intervention or any hemolytic condition or coagulation disorders that would make participation unsafe in the opinion of the investigator.
6. Known hypersensitivity to platinum compounds.
7. Pregnant or breastfeeding.
8. Active infection (infection requiring intravenous antibiotics).
9. Uncontrolled hypertension, defined as systolic blood pressure >180 mmHg and/or diastolic blood pressure >130 mmHg under resting conditions.
10. Malignancies other than head and neck cancer within 5 years prior to Day 1 of treatment, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated with curative intent, or ductal carcinoma in situ treated surgically with curative intent).
11. Signs or symptoms of organ failure, major chronic illnesses other than cancer, or any concomitant medical or social conditions which, in the opinion of the investigator, make it undesirable for the patient to participate in the study, or which could jeopardize compliance with the protocol.
12. Have pre-existing alcoholic liver injury or significant liver disease.
13. Have known active hepatitis B (defined as a known positive hepatitis B surface antigen [HBsAg] result) or hepatitis C (defined by a known positive hepatitis C antibody result and known quantitative HCV RNA results greater than the lower limits of detection of the assay).
14. Are regularly consuming alcohol within 6 months of Screening defined as an average weekly intake of >21 units (or an average daily intake of >3 units) for males or >14 units (or an average daily intake >2 units) for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine, or 1 measure (25 mL) of spirits.
15. Have experienced any of the following within the 6-month period prior to Screening: unstable angina pectoris, clinically significant coronary artery disease, cerebrovascular accident, transient ischemic attack, cardiac failure with known ejection fraction less than 40%, or cardiac arrhythmia (patients with well-controlled cardiac arrhythmia on stable doses of medication are permitted).
16. Any investigational treatment within 30 days or 5 half-lives, whichever is longer, of Day 1 of treatment.
17. Patient is unwilling or unable to comply with study procedures, or is planning to take vacation for 7 or more consecutive days during the treatment phase of the study without prior consent from the Medical Monitor.
18. Any other medical or social condition that, in the opinion of the investigator, would not permit the patient to complete the study or sign informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoints of the study are:
• Part 1: To determine DLTs and the RPII dose.
• Part 2: To determine the median PFS in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after treatment with NC-6004 plus cetuximab plus 5-FU. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Part 1 will begin with a single-patient run-in phase.During the run-in phase, 1 patient will be enrolled sequentially at the dose levels of NC-6004 noted in Table 3-1 until a DLT is observed or until a patient is treated at 180 mg/m2 for 1 cycle without a DLT occurring. All patients in Part 2 will receive NC-6004 at the RPII dose (as determined from Part 1 of the study) in combination with cetuximab and 5-FU according to the same schedule used in Part 1. In Part 2 of the study, the primary endpoint (PFS) will be continuously updated and compared with the historical PFS of 5.5 months from the EXTREME trial. The PFS hazard model will be updated as the PFS data accrue. A hazard ratio (HR) for PFS versus historical control will be obtained. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints of the study are:
• To assess ORR, DOR, DCR, DSD, and OS.
• Least squares mean estimates for health-related quality of life (HRQOL) scores over time in EORTC QLQ-C30 and QLQ-H&N35. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR: Defined as percentage of patients with a confirmed CR or confirmed PR, assessed using RECIST
DOR: Defined as the time from the earliest date of confirmed response until the first date of either disease progression or death due to any cause
DCR: Defined as the percentage of patients with confirmed CR, confirmed PR, or
stable disease lasting at least 7 weeks, assessed using RECIST version 1.1
DSD: Defined as the duration of time from the first dose (since all
patients who enter treatment should have stable disease) until disease
progression in patients who have achieved at least stable disease at
their first postbaseline disease assessment.
OS: Defined as the time from the beginning of NC-6004 treatment until death or last contact |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| This is a Phase I/II study consisting of 2 parts. |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Bulgaria |
| Hungary |
| Poland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| The end of the study is defined as the date on which the last patient completes the last visit to the study site (includes any End-of Treatment visit to the site and any visit to the site to obtain confirmatory scan of response). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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