Durvalumab in Combination With Docetaxel, Cisplatin and 5-FU for Locally Advanced Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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The prognosis of patients with locally advanced SCCHN is poor. Results of recent randomized trials evaluating induction chemotherapy by docetaxel, cisplatin, 5 fluorouracil are conflicting, and benefit on overall survival is uncertain. Improve efficacy of induction chemotherapy is important without increase toxicities. Durvalumab is a promising agent in SSCHN. The safety of combination of docetaxel, cisplatin, 5 fluorouracil with durvalumab is unknown. The aim of the study is to evaluate the feasibility and the safety of the association of DCF (standard regimen for induction in SSCCHN) and durvalumab. The safety profile of DCF and durvalumab are different, so the expected toxicities should not be additive. The addition of durvalumab to DCF could improve the efficacy of induction chemotherapy and the prognostic of patients with SSCCHN. Concerning the translational research, the aim will be to explore the relationships between immune capacity, specificity, activation state and clinical outcome to help elucidate the determinants of response to immunotherapy.

Official Title
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Phase I Trial Evaluating the Safety of Durvalumab in Combination With Docetaxel, Cisplatin and 5-FU in Induction for Locally Advanced Head and Neck Squamous Cell Carcinoma

Conditions
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Head and Neck Cancers

Intervention / Treatment
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* Drug: Durvalumab
* Drug: Docetaxel
* Drug: Cisplatin
* Drug: 5 Fluorouracil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years and < 75 years Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx, previously untreated, amenable to induction chemotherapy according to the investigator. Patients with a diagnosis of SCCHN of occult primary could be enrolled. Absence of metastases determined by CT scan or PET scan ECOG performance status < 1 Subjects must have at least 1 measurable lesion per RECIST v1.1 guidelines Adequate organ and marrow function as defined below: Hemoglobin ≥ 9,0 g/dL Absolute neutrophil count (ANC) ≥ 1,500/mm3 Platelet count ≥ 100,000/mm3 AST and ALT ≤ 2.5 × institutional upper limit of normal (ULN); Total bilirubin ≤ 1.5 × ULN; Creatinine clearance > 60 mL/min as determined by the Cockcroft-Gault equation (Cockcroft and Gault, 1976) or by 24-hour urine collection for determination of creatinine clearance Negative serology for hepatitis B and C Availability of a recent formalin-fixed tumour tissue (< 3 months) to determine HPV status and for translational research (IHC) a. All patients without available tumour tissue will undergo a panendoscopy with biopsies. Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment and/or urine pregnancy 48 hours prior to the administration of the first study treatment. Both sexually active women of childbearing potential and males (and their female partners) patients must agree to use two methods of effective contraception, one of them being a barrier method, or to abstain from sexual activity during the study and for at least 6 months after last dose of study drugs. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures Patients must be affiliated to a Social Security System or beneficiary of the same Patient information and written informed consent form signed Exclusion Criteria: Primary site of head and neck carcinoma in nasopharynx, or skin Patients receiving other anti-cancer medication such as, chemotherapy, immunotherapy, biologic therapy, targeted therapy, monoclonal antibodies, hormonal therapy (other than leuprolide or other GnRH agonists) or other investigational agent within 30 days prior to the first dose of study drug and while on study treatment. Patients receiving other anti-cancer non-drug therapies: radiation, or tumor embolization within 30 days prior to the first dose of study drug and while on study treatment. No relevant toxicities (>grade 1 CTCAE) due to prior medical treatment at time of study entry Participation in another clinical study with an investigational product during the last 30 days Patient with dihydropyrimidine dehydrogenase (DPD) deficiency Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active peptic ulcer disease or gastritis, active bleeding diatheses. Or patient under guardianship or deprived of his liberty by a judicial or administrative decision or any condition (e.g psychiatric illness/social/familial/geographical condition) that would limit compliance with study requirement or compromise the ability of the subject to give written informed consent Patient with active cardiac disease or with a history of cardiac dysfunction any of the following: Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO), Mean QT interval corrected for heart rate (QTc) ≥ 470 msec calculated from 3 electrocardiograms (ECGs) performed at screening, using Fredericia's correction (QTcF), Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF function, Unstable angina pectoris Uncontrolled hypertension History of documented congestive heart failure (New York Heart Association functional classification III-IV), or Uncontrolled symptomatic congestive heart failure Documented cardiomyopathy, Other cardiac arrhythmia not controlled with medication. Other invasive malignancy within 5 years except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone or an equivalent corticosteroid Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded Active or prior documented inflammatory bowel disease (eg, Crohn's disease,ulcerative colitis) History of primary immunodeficiency History of allogenic organ transplant that requires use of immunosuppressives Known history of previous clinical diagnosis of tuberculosis Patients with a known HIV status Pregnant or breast-feeding women Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab History of hypersensitivity to durvalumab or any excipients or to other humanized mAbs Any contraindication to the use of cisplatin, docetaxel and 5FU and/or known history of hypersensitivity to any of those drugs Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with squamous cell carcinoma of the oral cavity,<br>The aim is to evaluate safety, PK and pharmacodynamics of durvalumab in adult patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx or hypopharynx previously untreated, with indication of induction chemotherapy. | Drug: Durvalumab<br>* Durvalumab will be administered every 3 weeks for 3 injections at week 1, 4, 7. Dose levels: the durvalumab first dose level is 1120 mg Q3W, and the dose level -1 is 750 mg Q3W.<br>Drug: Docetaxel<br>* Docetaxel 75mg/m² on D2, IV in 1 hour<br>Drug: Cisplatin<br>* Cisplatin 75mg/m² on D2, IV in 3 hours<br>Drug: 5 Fluorouracil<br>* 5 Fluorouracil 750mg/m²/day on D2, D3, D4, D5, D6 IV in 24 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 dose (RP2D) | To determine the recommended Phase 2 dose (RP2D) and schedule of durvalumab when administered with docetaxel, cisplatin and 5 Fluorouracil | Up to 10 weeks | 
| Number of Dose Limiting Toxicity (DLT) | To characterize the safety and tolerability profile of durvalumab when administered in combination with docetaxel, cisplatin and 5 Fluorouracil | Up to 6 weeks |