| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Head and neck squamous cell carcinoma (HNSCC) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| 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 |
Part 1(Phase IIa):
To assess dose-limiting toxicities (DLTs), and to determine the optimal dose in order to establish the recommended Phase IIb (RPIIb) dose for the combination of NC-6004 plus pembrolizumab.
Part 2 (Phase IIb):
To compare progression-free survival (PFS) between NC-6004 plus pembrolizumab and pembrolizumab alone. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of NC-6004 when combined with pembrolizumab.
To compare OS between NC-6004 plus pembrolizumab and pembrolizumab alone.
To compare tumor response between NC-6004 plus pembrolizumab and pembrolizumab alone. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each subject must meet all of the following criteria to be enrolled in this study:
1. Be willing and able to provide written informed consent for the trial.
2. Males or females aged ≥18 years at screening.
3. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
4. Have histologically- or cytologically-confirmed HNSCC.
5. Have recurrent disease not amenable to curative treatment with local or systemic therapy, or metastatic (disseminated) HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx that is considered incurable by local therapies.
6. Must have received ≥150 mg/m2 of a total dose of cisplatin or 2 cycles of carboplatin AUC5 (maximum carboplatin dose per cycle 750mg).
7. Prior platinum failure as defined by:
a. Disease progression confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) scans using RECIST 1.1 criteria at any time during or after treatment with a platinum agent or a platinum-containing regimen for recurrent/metastatic disease.
b. Recurrence/progression confirmed by CT or MRI imaging scans using RECIST 1.1 criteria <6 months of prior modal therapy using a platinum agent or a platinum-containing regimen for locally advanced setting.
c. Recurrence/progression ≥6 months of prior modal therapy in locally advanced HNSCC can be accepted only if subjects have received a further platinum-containing regimen for recurrent and metastatic stage of disease and have progressed during or after this regimen.
8. Have a life expectancy of >3 months.
9. Have radiographically measurable disease based on RECIST 1.1.
10. Have adequate bone marrow reserve, defined as:
a. Absolute neutrophil count ≥ 1.5 × 109/L;
b. Platelet count ≥100 × 109/L; and
c. Hemoglobin ≥10 g/dL (transfusion is allowed to achieve ≥10 g/dL).
11. Have adequate liver function, defined as:
a. Total serum bilirubin ≤1.5 × the upper limit of normal (ULN) or ≤2 × ULN in the cases of subjects with documented hepatic metastasis;
b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.0 × ULN or <5.0 × ULN in the cases of subjects with documented hepatic metastasis;
c. Serum albumin ≥3.5 g/dL.
12. Have prothrombin time within normal limits.
13. Have adequate renal function, using the Cockcroft method: Glomerular filtration rate ≥ 60 mL/min.
14. Have results from central laboratory testing of HPV (defined as p16 IHC testing using CINtec p16 Histology assay and a 70% cutoff point).
Note: HPV stratification will be performed in subjects with oropharynx cancer. Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by the central laboratory.
15. Have provided tissue for PD-L1 biomarker analysis from a newly obtained core, excisional biopsy or an archived specimen. Repeat samples may be required if adequate tissue is not provided or for indeterminate results.
Note: If emerging data indicate a high concordance in PD-L1 expression scores between newly obtained and archival samples, archived samples may be acceptable.
16. Female subjects of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. A urine test can be considered if a serum test is not appropriate.
17. Female subjects of childbearing potential must be willing to use 2 methods of birth control or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study therapy according to local standard of care.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject.
18. Male subjects must agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy according to local standard of care.
Note: Abstinence is acceptable if this is the established and preferred contraception for the subject. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria will be excluded from the study:
1. Subjects with carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary origination, squamous cell carcinoma that originates from the skin and salivary gland or paranasal sinus, non-squamous histology.
2. Have disease that is suitable for locoregional treatment administered with curative intent or refuses curative intent.
3. Have more than 15% body weight loss due to the underlying condition in the last 3 months from signing of informed consent in Part 1 of the study and from randomization in to Part 2.
4. Are currently participating in or have participated in a study of an investigational agent or are using an investigational device within 4 weeks prior to the first dose of trial treatment.
5. Have entered the follow-up phase of an investigational study may participate as long as it has been at least 4 weeks since the last dose of trial treatment with the previous investigational agent or device.
6. Were previously treated with 3 or more lines of systemic therapies administered for recurrent and/or metastatic disease.
7. Were diagnosed and/or treated additional malignancy within 5 years of randomization, with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin, and/or curatively-resected in situ cervical and/or breast carcinoma.
8. Have a diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
9. Subjects with a condition requiring systematic treatment with corticosteroids (>10 mg daily prednisone equivalents) within 14 days prior to the first dose of study treatment.
10. Have had prior anti-cancer treatment or radiation therapy within 4 weeks prior to study Day 1 or who have not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to previously administered treatment more than 4 weeks earlier (i.e., monoclonal antibody [mAb], cetuximab, or any other cytotoxic drugs). (Subjects with ≤Grade 2 alopecia are an exception to this criterion and may qualify for the study.)
11. Had a prior allogenic organ or tissue transplant.
12. Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
13. Have peripheral sensory neuropathies (including hearing loss) and motor neuropathies ≥Grade 2, in the opinion of the Investigator.
14. Have uncontrolled hypertension, defined as systolic blood pressure >180 mmHg and/or diastolic blood pressure >130 mmHg under resting conditions.
15. Have experienced any of the following within the 6-month period prior to screening: unstable angina pectoris, cerebrovascular accident, transient ischemic attack, uncontrolled congestive heart failure (New York Heart Association >Class II) (Appendix 8) cardiac failure with known ejection fraction less than 40%, or cardiac arrhythmia (subjects with well-controlled cardiac arrhythmia on stable doses of medication are permitted).
16. Have an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism that is stable on hormone replacement or Sjøgren’s syndrome will not be excluded from the study.
17. Have active, non-infectious pneumonitis or prior pneumonitis requiring systemic corticosteroid therapy or an interstitial disease.
18. Have hypersensitivity to the active substances (of either NC-6004 or pembrolizumab) or any of the excipients (e.g. L-histidine, polysorbate 80) or have a history of allergic reaction to prior platinum therapy.
19. Have a history of severe hypersensitivity to another monoclonal antibody.
20. Have a history of anaphylaxis as assessed by the Investigator.
21. Have uncontrolled chronic obstructive pulmonary disease (COPD) or asthma.
22. Have an active infection requiring systemic therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- To establish the RPIIb dose.
- To determine the PFS by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in eligible subjects after treatment with NC-6004 plus pembrolizumab and pembrolizumab alone. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| RP2D will be determined in March 2019. PFS in PIIb portion will be available in March 2022. |
|
| E.5.2 | Secondary end point(s) |
• Overall response rate (ORR)
• Complete response (CR)/ Partial response (PR)
• Stable disease (SD)
• Duration of response (DOR)
• Time to response (TTR)
Pharmacokinetics endpoints:
• Cmax (maximum concentration)
• Tmax (time to maximum concentration)
• AUC0-τ (area under the concentration-time curve from time zero to the end of the dosing interval)
• AUC0-∞ (area under the concentration-time curve from time zero to infinity)
• Rac (Accumulation Ratio)
• λz (terminal elimination phase rate constant)
• T½ (terminal half-life)
• CL (clearance)
• Vz (volume of distribution)
• Vss (volume of distribution at steady-state) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR will be assessed by performing study imaging every 6 weeks after the first dose of study treatment.
Safety data as well as PK data of PIIa portion will be available in March 2019. OS or other efficacy data of PIIb will be available in March 2022. |
|
| 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 | Yes |
| 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) | 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | 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) | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Croatia |
| Czechia |
| Hungary |
| Poland |
| Russian Federation |
| Serbia |
| Taiwan |
| Ukraine |
| 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 12 months following the start of treatment for the last subject in the study. A follow-up period for overall survival (OS) will continue for all remaining subjects for an additional 12 months. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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