| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Head and neck squamous cell carcinoma (HNSCC) |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067821 |
| E.1.2 | Term | Head and neck cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
To evaluate the safety and efficacy of different DNA Damage Repair (DDR) agents, or different immunotherapy agents and/or DDR and immunotherapy combinations, together with radiotherapy in patients with head and neck squamous cell carcinoma being treated curatively.
Primary Objective:
To identify the recommended dose, schedule and safety profile of different DNA Damage Response (DDR) agents in combination with radiotherapy in patients with head and neck squamous cell cancer (HNSCC) being treated curatively, with and without combination with immunotherapy. The first drug to be evaluated in combination with radiotherapy will be the Ataxia Telangiectasis and Rad3 Related (ATR) inhibitor AZD6738 (Ceralasertib). |
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| E.2.2 | Secondary objectives of the trial |
To assess the potential efficacy of different DDR agents, in combination with radiotherapy in patients with HNSCC being treated curatively, with and without combination with immunotherapy, in comparison to a group receiving standard therapy.
To assess the survival outcomes of these patients
To assess the recurrence of cancer cells at the same site as the original (primary) tumour or the regional lymph nodes after a disease free period.
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| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Research (tertiary) Outcomes
• PK studies relating to absorption of drug when used as a solution through Nasogastric tube (NGT) or percutaneous gastrostomy (PEG/RIG).
• Quality of life assessed by QLQC30, HN43 and M. D. Anderson Dysphagia Inventory (MDADI).
• Other translational research to be determined later.
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| E.3 | Principal inclusion criteria |
For inclusion in the trial patients should fulfil the following criteria:
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 70Gy in 35F), 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 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:
a) Haemoglobin ≥ 10 g/dL (with no blood transfusion or erythropoietin use within past 28 days)
b) Absolute neutrophil count ≥ 1.5 x 109/L
c) Platelet count ≥ 100 x 109/L (with no platelet transfusions within last 28 days)
d) Total bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert’s syndrome
e) AST or ALT ≤ 2.5 x ULN
f) 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):
Estimated CrCl = (140-age [years]) x weight (kg) (x F)a
serum creatinine (mg/dL) x 72
a where F=0.85 for females and F=1 for males
8. Females must not be breast feeding. Women of childbearing potential and their partners, who are heterosexually active, must agree to the use of 2 highly effective forms of contraception in combination from the signing of the informed consent, throughout the period of taking trial treatment and for at least 1 month 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 all sexual partners. 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 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:
• Aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation, radiation-induced oophorectomy with last menses > 1 year ago
• Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal range for the institution for women under 50
10. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations
11. For inclusion in the optional biomarker research, patients must fulfil the following criteria:
-Provision of informed consent for biomarker research
-If a patient declines to participate in the optional biomarker research, the patient can still participate in the trial.
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| E.4 | Principal exclusion criteria |
Patients should not enter the trial if any of the following exclusion criteria are fulfilled.
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 CTCAE grade 2 neuropathy, any unresolved toxicities from prior therapy ≥ Common Terminology Criteria for Adverse Events (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):
- Unstable angina pectoris
- Congestive heart failure or known reduced LVEF < 55%
- Acute myocardial infarction
- Conduction abnormality not controlled with pacemaker or medication e.g. complete left bundle branch block, third degree heart block
- Significant ventricular or supraventricular arrhythmias e.g. (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
- Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of TIAs
- 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). The required washout period prior to starting trial treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil) are allowed and can be used with caution. Please note that patient prescription or non-prescription drugs or other products known to be CYP3A4 and/or CYP2B6 substrates or CYP3A4 and/or CYP2B6 substrates with a narrow therapeutic index are allowed but should be used with caution. Exposure of other drugs metabolised by CYP3A4 and/or CYP2B6 may be reduced and additional monitoring may be required.
10. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases that places the patient at unacceptable risk of toxicity or non-compliance. Examples include, but are not limited to, active bleeding diatheses, renal transplant, uncontrolled major seizure disorder, severe COPD, superior vena cava syndrome, extensive bilateral lung disease on High Resolution CT scan, severe Parkinson’s disease, active inflammatory bowel disease, psychiatric condition, or active infection including any patient known to have hepatitis B, hepatitis C and human immunodeficiency virus (HIV) or requiring systemic antibiotics, antifungals or antiviral drugs. Screening for chronic conditions is not required.
11. A known hypersensitivity to AZD6738 (Ceralasertib) or any excipient of the product or any contraindication to the drug under study as per local prescribing information.
12. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of AZD6738 (Ceralasertib).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Recommended dose and safety profile of AZD6738 in combination with radiotherapy as determined by dose limiting toxicities evaluated by CTCAE v5.0. The dose-limiting toxicity (DLT) period will be up to 12 months after end of treatment. However, dose escalation decisions can be made 8 weeks after end of treatment of the third patient within each cohort. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| DLT period will be up to 12 months after the end of treatment. |
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| E.5.2 | Secondary end point(s) |
• To assess the potential efficacy of different DDR agents, in combination with radiotherapy in patients with HNSCC being treated curatively, with and without combination with immunotherapy, in comparison to a standard therapy cohort.
• To assess the survival outcomes of these patients
• To assess the locoregional recurrence rates of these patients
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12-16 weeks after the end of radiotherapy |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| 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 | No |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 18 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
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| The end of trial will be eight months after the last data capture. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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