Accelerating the development and implementation of DNA damage inhibitor and radiotherapy treatment (with or without immunotherapy) in head and neck squamous cell carcinoma
- Conditions
- Primary head and neck squamous cell carcinoma (HNSCC): laryngeal, hypopharyngeal, oropharyngeal cancerCancerMalignant neoplasm of larynx, Malignant neoplasm of hypopharynx, Malignant neoplasm of oropharynx
- Registration Number
- ISRCTN66274524
- Lead Sponsor
- niversity of Birmingham
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 80
Current participant inclusion criteria as of 29/10/2021:
1. Provision of informed consent prior to any trial-specific procedures
2. Patients must be aged =18 years of age
3. Histological or cytological confirmation of head and neck squamous cell carcinoma
4. Patients must have an MDT recommendation for treatment with radical radiotherapy (and where patients would be eligible to receive 70 Gy in 35 F), and not had previous treatment for head and neck cancer
5. At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment as per RECIST 1.1.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 28 days prior to randomisation with no deterioration to >1 over the previous 2 weeks
7. Patients must have normal organ and bone marrow function measured within 14 days prior to registration as defined below:
7.1. Haemoglobin =10 g/dl (with no blood transfusion or erythropoietin use within past 28 days)
7.2. Absolute neutrophil count = 1.5 x 10^9/l
7.3. Platelet count =100 x 10^9/l (with no platelet transfusions within last 28 days)
7.4. Total bilirubin =1.5 x upper limit of normal (ULN) unless the patient has documented Gilbert’s syndrome
7.5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =2.5 x ULN
7.6. Patients must have creatinine clearance (CrCl) of =51 ml/min estimated or measured using standard methodology at the investigating centre (i.e. Cockcroft-Gault, MDRD, CK-EPI, EDTA or 24 hr urine)
8. Females must not be breastfeeding.
Women of childbearing potential and their partners, who are heterosexually active, must agree to the use of two highly effective forms of contraception in combination (as described in section 5.1.1) from the signing of the informed consent, throughout the period of taking trial treatment and for at least 6 months after last dose of trial drug(s), or they must totally/truly abstain from any form of sexual intercourse.
Male patients who are sexually active must be willing to use barrier contraception for the duration of the trial and for 1 week after the last trial drug administration, with no childbearing women.
Male patients must use a condom during treatment and for 6 months after the last dose of trial drug(s) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential and must not donate sperm for 6 months after the last dose of trial drug.
Female partners of male patients should also use a highly effective form of contraception (see section 7.4.1 for acceptable methods) for 6 months after the last dose of trial drug(s) if they are of childbearing potential. True abstinence for either sex is an acceptable form of contraception and must be documented as such.
9. Postmenopausal or evidence of non-child-bearing status for women of childbearing potential; negative urine or serum pregnancy test within 28 days of trial treatment and confirmed prior to treatment on Day 1. Postmenopausal is defined as:
9.1. Aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exo
Current participant exclusion criteria as of 29/10/2021:
1. Patients with T1-2 N0 disease
2. A diagnosis of ataxia telangiectasia or other radiosensitivity syndrome
3. Cytotoxic chemotherapy, hormonal or non-hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. A duration of 30 days or 5 half-lives (whichever is longer) is required for patients treated with non-cytotoxic drugs). The minimum washout period for immunotherapy is 42 days
4. With the exception of alopecia and Common Terminology Criteria for Adverse Events (CTCAE) grade 2 neuropathy, any unresolved toxicities from prior therapy = CTCAE v5.0 grade 2
5. Any of the following cardiac diseases currently or within the last 6 months (by New York Heart Association (NYHA) = Class 2 where applicable):
5.1. Unstable angina pectoris
5.2. Congestive heart failure or known reduced left ventricular ejection fraction (LVEF) < 55%
5.3. Acute myocardial infarction
5.4. Conduction abnormality not controlled with pacemaker or medication e.g. complete left bundle branch block, third degree heart block
5.5. Significant ventricular or supraventricular arrhythmias e.g. (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
5.6. Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of transient ischaemic attacks (TIAs)
5.7. Uncontrolled hypertension (CTCAE v5.0, grade 2 or above) requiring clinical intervention
6. Mean resting corrected QT interval (QTc) >470 msec for females and >450 for men, obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fredericia formula. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as congestive heart failure, unstable angina pectoris, acute myocardial infarction, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age, conduction abnormality not controlled with pacemaker or medication
7. Patients with relative hypotension (<90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mm Hg
8. Concomitant use of known potent cytochrome P (CYP) 3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to starting trial treatment is 2 weeks. Moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) can be used with caution.
9. Concomitant use of known potent cytochrome P450 inducers (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort).
9.1. The required washout period prior to starting trial treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
9.2. Moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil) are allowed and can be used with caution.
9.3. Please note that patient prescription or non-prescription drug
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Recommended dose and safety profile of AZD6738 in combination with radiotherapy as determined by dose-limiting toxicities evaluated by CTCAE v5.0. The recommended dose will be determined by collecting toxicity data, which will then be reviewed by a safety committee. The dose-limiting toxicity (DLT) period will be up to 12 months after the end of treatment. However, dose-escalation decisions can be made 8 weeks after the end of treatment of the third patient within each cohort.
- Secondary Outcome Measures
Name Time Method Complete response rates of primary tumour and nodal metastasis on positron emission tomography- computed tomography (PET-CT)/CT scan or magnetic resonance imaging (MRI) performed 12-16 weeks after the end of radiotherapy