Radiotherapy With Double Checkpoint Blockade of Locally Advanced HNSCC

Phase 1

Conditions: ocally advanced head and neck squamous cell carcinoma (HNSCC)
MedDRA version: 21.1Level: LLTClassification code 10026518Term: Malignant neoplasm of supraglottis stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: LLTClassification code 10026519Term: Malignant neoplasm of supraglottis stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 21.1Level: LLTClassification code 10026185Term: Malignant neoplasm of oropharynx, unspecifiedSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 26.1Level: LLTClassification code 10041862Term: Squamous cell carcinoma of the oral cavity stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 26.1Level: LLTClassification code 10041863Term: Squamous cell carcinoma of the oral cavity stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 26.1Level: LLTClassification code 10041854Term: Squamous cell carcinoma of the hypopharynx stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 26.1Level: LLTClassification code 10041855Term: Squamous cell carcinoma of the hypopharynx stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2017-003226-33-DE

Lead Sponsor: Dean of the Medical Faculty of the Friedrich-Alexander University Erlangen-Nürnberg Prof. Dr. Markus Neurath

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 120

Inclusion Criteria

Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening Evaluations

Age > 18 years at time of study entry

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (amend based on specific study)

Locally advanced HNSCC, UICC stage III-IVB (oral cavity, oropharynx, hypopharynx, supraglottic larynx) (according to TNM version 8)

Histological confirmation of HNSCC (regardless if p16 positive or negative)

Measureable CD8 density in provided archival tumor tissue

Body weight >30kg

Adequate normal organ and marrow function as defined: Haemoglobin = 9.0 g/dL; White blood cells (WBC) = 3,000 per mm3; Platelet count >100,000 per mm3

Serum bilirubin = 1.5 x institutional upper limit of normal (ULN)

AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal (ULN)

Creatinine Clearance >40ml/min (calculated from serum creatinine or cystatin C, alternatively 24h urine possible)

Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

- Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).

- Women =50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)

Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
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 120
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 120

Exclusion Criteria

Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

Participation in another clinical study with an investigational product during the last 4 weeks

Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study

Distant metastases

Prior systemic anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) of the locally advanced HNSCC

Any other concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment, except the induction chemotherapy in the protocol. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable

Prior radiotherapy of HNSCC

Radiotherapy to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug

Major surgical procedure of the current locally advanced HNSCC (as defined by the Investigator). Note: Local surgery of isolated lesions for palliative intent is acceptable

History of allogenic organ Transplantation

Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]).(eceptions , see protocol)

Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent

History of another primary malignancy except for
- Malignancy treated with curative intent and with no known active disease =5 years before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease

History of active primary immunodeficiency

Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA

Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. (exceptions, see protocol)

Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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