Patients with locally advanced squamous cell carcinoma of the head and neck MedDRA version: 14.1 Level: PT Classification code 10060121 Term: Squamous cell carcinoma of head and neck System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Debio 1143
Product Code: Debio 1143
Pharmaceutical Form: Oral solution
INN or Proposed INN: NA
CAS Number: NA
Current Sponsor code: Debio1143
Other descriptive name: Debio1143
Concentrat
Sponsors
Debiopharm S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Willing and able to sign a written informed consent; 2.Male or female =18 =75 years of age. 3.Histologically confirmed diagnosis of previously untreated LA-SCCHN (Stage III, IVa and IVb according to the American Joint Committee on Cancer Staging System) of one or more of the following sites: oral cavity, oropharynx, hypopharynx and larynx; 4.Tumour HPV negative status for oropharynx cancer patients, determined by p16 IHC; 5.Smokers (> 10 packs/year); 6.Availability of pre-treatment tumour sample (optional for Phase I; mandatory for Phase II [10-20 tumour slides]); 7.Measurable disease by the RECIST 1.1 criteria; 8.Negative medical history of Hepatitis B and Hepatitis C; 9.Women of child-bearing potential: a.Negative serum pregnancy test at screening; b.Agreement to use appropriate contraception methods from study entry to 6 months after the last day of treatment. Agreement to use contraception methods from her male partner. 10.Male patients agree to use contraception methods from study entry to 6 months after the last day of treatment; 11.ECOG performance status 0 or 1 12.Subjects must have adequate haematological, renal and hepatic function; calculated creatinine clearance = 60 mL/min as determined by the modified method of Cockcroft and Gault or by the EDTA method, absolute neutrophil count =1 500/µL, platelets =100 000/µL, haemoglobin = 10 g/dL, aspartate (AST) and alanine transaminase (ALT) less than 3 times the upper limit of the normal range (ULN), total bilirubin = 2.0 mg/dL, serum albumin >35 g/L. 13.QTcF interval = 450 ms 14.Left ventricular ejection fraction (LVEF) within the institutional normal ranges as measured by echocardiogram (ECHO) or multigated acquisition (MUGA) scan; 15.No prior treatment with IAP inhibitors. 16.No use or requirement for use of aspirin or aspirin containing products with > 100 mg of aspirin per day; 17.No history of gastrointestinal bleeding within 1 year; 18.No active rheumatoid arthritis, active inflammatory bowel disease, chronic infections, or any other disease or condition associated with chronic inflammation. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 58 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 58
Exclusion criteria
Exclusion criteria: 1.Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers; 2.Squamous cell cancer involving cervical neck nodes but from unknown primary site; 3.Metastatic disease; 4.Any prior or current treatment for invasive head and neck cancer of any kind. This will include but is not limited to: prior tyrosine kinase inhibitors, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent; 5.Weight loss of >10% during the last month; 6.Not compensated liver cirrhosis (Child-Pugh class C); 7.Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, major abdominal surgery, significant bowel obstruction, ulcerative colitis, Crohn’s disease); 8.Impaired bone turnover (serum C-terminal telopeptide [CTX] <300 pg/mL;1 9.Concurrent treatment with any other systemic anti-cancer therapy that is not specified as part of the protocol regimen; 10.Concomitant treatment with any drug on the prohibited medication list (provided separately); 11.Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure; 12.History of another malignancy within the last 5 years, with the exception of completely resected basal or squamous cell skin cancer, or successfully treated in-situ carcinoma. History of non-invasive lesion or in-situ carcinoma, including in the head and neck region that was successfully treated with surgery, photodynamic or laser, will be permitted; 13.Peripheral neuropathy = grade 2; 14.Clinical hearing loss (to be confirmed by audiogram in doubtful cases); 15.If female, pregnant or lactating; 16.History of allergic reactions to appropriate antiemetics (e.g. 5-HT3 antagonists) to be administered with chemotherapy; 17.The investigator considers the subject unfit for the study as a result of the medical interview, physical examinations, or screening investigations.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A : To determine the maximum tolerated dose (MTD) of Debio1143 in combination with concurrent CRT in patients with LA-SCCHN. Part B: To evaluate the anti-tumour activity of Debio1143 in comparison with placebo when added to standard concurrent CRT in patients with LA-SCCHN ;Secondary Objective: Part A: 1. safety of Debio1143 in combination with concurrent CRT 2. anti-tumour activity of the recommended dose of Debio1143 in combination with concurrent CRT 3.explore PK of Debio1143 and cisplatin when administered in combination with radiation therapy, and explore the potential for drug-drug interactions.4. explore pharmacodynamic biomarkers of Debio1143 activity with concurrent CRT 5.explore PK/PD, PK/efficacy, PK/safety, PD/efficacy and PD/safety and pharmacogenetic factors 6.To explore pharmacogenomic, and tumour pharmacogenetic factors. Part B: 1. safety of the recommended dose of Debio1143 o in combination with concurrent CRT 2. To explore PD biomarkers of Debio1143 activity with concurrent CRT 3. To explore predictive biomarkers of response in the field of pharmacogenomics, tumour profiling, blood transcriptome and proteome. 4. To explore the PK of Debio1143 with CRT.5. To explore PK/PD, PK/efficacy, PK/safety, PD/efficacy and PD/safety and pharmacogenetic factors.;Primary end point(s): Part A: Occurrence of DLTs. Part B: Proportion of patients achieving Locoregional Control (LRC) at 18 months from the end of chemo-radiation therapy. ;Timepoint(s) of evaluation of this end point: At the end of Part A and Part B | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): For Part A only: 1.Locoregional control rate at 6 months, one year and 18 months after completion of chemo-radiation therapy; 2.Progression free survival (PFS) rate at one year, 18 months and 2 years as of initiation chemo-radiation therapy (PFS is defined as the time from randomization to the first radiologic confirmation of disease progression or death from any cause, whichever come first); 3.Distant relapse rate at six months, one year, 18 months and 2 years after completion of chemo-radiation therapy; 4.Evaluation of the compliance to the study treatment and cisplatin dose density; 5.Pharmacokinetic parameters (Cmax, AUC0-t, AUC8, ?z, t½, MRT, Ctrough, tmax, CL/F, Vss/F, AUC?, PTF, RAUC) of Debio1143 alone and in combination with cisplatin and radiotherapy. The potential for drug-drug interactions and for accumulation upon repeated dosing will be explored; 6.Pharmacokinetic parameters ( AUC(0-t), AUC8 Cmax, CL, Vss, t1/2) of cisplatin in combination with Debio 1143 and radiotherapy; 7.Exploration of PK/PD, PK/Efficacy, PK/safety, PD/efficacy and PD/safety relationships as well as pharmacogenetics factors that may influence PK; 8.Exploration of pharmacogenomic factors. For Part A and B: 1.Change in vital signs and ECOG Performance Status (PS); 2.Incidence of SAEs; 3.Incidence and severity of AEs, graded according to NCI-CTCAE version 4 criteria; 4.Incidence and severity of laboratory abnormalities, graded according to NCI-CTCAE version 4 criteria; 5.Incidence of late toxicity (e.g.; dysphagia, chronic swallowing dysfunctions, speech problems, , cervical fibrosis) 1 year and at 2 years as of initiation of chemo-radiation therapy; 6.Incidence of treatment discontinuations and treatment modifications due to AEs; 7.Tumour response (by RECIST): Best overall response, Disease control, and Response Rate, after 10 weeks and 6 months from the end of chemo-radiation therapy; 8.Disease specific survival rate one year and at 2 years a | — |
Countries
France, Switzerland
Contacts
Public ContactRegulatory Affairs
Debiopharm S.A.
Outcome results
None listed