Head and Neck Squamous Cell Carcinoma (HNSCC)

Primary Objective: To investigate prognosis-correlated immune activation due to DDR inhibition by monitoring the induction of immunologically relevant genes in tumours of patients treated with study investigational agent(s) Secondary Objective: To investigate the prevalence and localisation of tumour infiltrating leukocytes (TILs) associated with prognosis. Safety Objective: To monitor the safety and tolerability of each DDR agent

AZD6738, Lynparza

AZD2281(Olaparib)
AZD6738

tablet

20mg or 100mg
100mg or 150mg

Primary Outcome Measures :
Conversion of an immunologically based 25-gene signature from a prognostically unfavourable state to a prognostically favourable state. [ Time Frame: From baseline through Day 31 (Follow up) ]
To investigate prognosis-correlated immune activation due to DDR inhibition by monitoring the induction of immunologically relevant genes in tumours of patients treated with study investigational agent(s)


Secondary Outcome Measures :
Transition from a low tumour infiltrating leukocyte (TIL) state (poor prognosis) to a high TIL state (favourable prognosis) shown by TIL enumeration and an increase in CD8+ T-cells [ Time Frame: From baseline through Day 31 (Follow up) ]
To investigate the prevalence and localization of TILs associated with prognosis.

Transition from a low TIL infiltrative state (poor prognosis) to a high TIL infiltrative state (favourable prognosis) shown by TIL enumeration and an increase in CD3+ T-cells [ Time Frame: From baseline through Day 31 (Follow up) ]
To investigate the prevalence and localization of tumour infiltrating leukocytes (TILs) associated with prognosis.

Number of patients with adverse events (AE) / serious adverse events (SAE) [ Time Frame: From time of signature of informed consent throughout the treatment period and including the follow-up period ]
Assessment of the safety for each DDR agent in terms of the incidences of the AEs

Vital signs [ Time Frame: From screening until Day 15 (+ 2 days) ]
Assessment of the safety for each DDR agent in terms of the Vital signs

Clinical chemistry/haematology [ Time Frame: From screening until Day 15 (+ 2 days) ]
Assessment of the safety for each DDR agent in terms of the clinical chemistry / haematology assessments

Number of patients with abnormal findings in Electrocardiograms (ECG) [ Time Frame: At screening and Day 1 ]
Assessment of the safety for each DDR agent in terms of the ECG changes. A 12-lead ECG will be performed in triplicate at screening and at a time convenient during the visits (single ECG only required at subsequent visits).

Inclusion criteria
For inclusion in the study subjects should fulfil the following criteria:
1. Provision of signed and dated, written informed consent prior to any study specific
procedures, sampling and analyses; including a pre-treatment fresh biopsy or
alternatively access to all archival tumour tissues (diagnostic and/or most recent
samples).
2. Aged at least 18 years old
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 with no
deterioration over the previous 2 weeks and an estimated life expectancy of greater
than 12 weeks
4. Newly diagnosed, treatment naïve, HNSCC suitable for surgical resection that is
likely to be followed by radiotherapy and/or chemotherapy after surgery. Patients
who are suitable for radical chemoradiation without surgery are eligible if they are
willing to undergo an on-treatment biopsy (FNA samples are not acceptable,
specimens must be core or surgical biopsy).
5. Females must be using adequate contraceptive measures (see Section 3.6), must not
be breast feeding and must have a negative pregnancy test prior to start of dosing if
of child-bearing potential or must have evidence of non-child-bearing potential by
fulfilling one of the following criteria at screening:
 Post menopausal 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
 Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH),
luteinizing hormone (LH) and plasma oestradiol levels in the postmenopausal
range for the institution
6. For the duration of the study and for 6 months after the last study drug
administration, sexually active male patients must be willing to use barrier
contraception i.e., condoms with all sexual partners. Where the sexual partner is a
‘woman of child-bearing potential’ who is not using effective contraception, men
must use a condom (with spermicide) during the study and for 6 months after the
last dose of a study drug.
7. Ability to swallow and retain oral medication
8. No previous systemic cancer treatment or radiotherapy for this malignancy
9. Provision of genetics research informed consent

3.2 Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1. Involvement in the planning and/or conduct of the study (applies to both
AstraZeneca staff and/or staff at the study site)
2. Previous enrolment or randomisation in the present study
3. Participation in another clinical study with an investigational product during the last
21 days or 5 half-lives of the investigational product, whichever is longer
4. Female patients who are breast-feeding or male or female patients of reproductive
potential who are not employing an effective method of birth control
5. Receiving, or having received during the week prior to first dose, corticosteroids (at
a dose > 10 mg prednisone/day or equivalent) for any reason
6. A known hypersensitivity to any of the investigational agents under test, or any
excipient of these products
7. Treatment with any small molecule investigational medicinal product (IMP) within
28 days prior to first dose. Treatment with any biological IMP (e.g. immune
checkpoint blockers, antibodies, nanoparticles, experimental) within 42 days prior
the first dose.
8. Receiving, or having received, concomitant medications, herbal supplements and/or
foods that significantly modulate CYP3A4 inhibitors (eg. itraconazole,
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate
CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole,
verapamil), strong CYP3A inducers (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil) or Pgp activity
(wash out periods of two weeks [or at least 5 half-lives for CYP3A inducers
whichever is longest], but three weeks for St. John’s Wort ). Note these include
common azole antifungals, macrolide antibiotics and other medications listed in
Appendix G.
9. Impaired hepatic or renal function as demonstrated by any of the following
laboratory values:
 Albumin < 33g/L (or outside of local laboratory reference ranges)
 AST or ALT > 2.5 x ULN
 Total bilirubin > 1.5 x ULN
 Alkaline phosphatase > 2.5 x ULN
 Glomerular filtration rate (GFR) < 51 mL/min, as assessed using the standard
methodology at the investigating centre (i.e. Cockroft-Gault, MDRD or CKDEPI formulae, EDTA clearance or 24 h urine collection)
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 Serum creatinine > 1.5 x ULN
 Haematuria: +++ on microscopy or dipstick
 INR ≥ 1.5 or other evidence of impaired hepatic synthesis function
10. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
 Absolute neutrophil count < 1.5 x 109
/L
 Platelet count < 150 x 109
/L
 Haemoglobin < 10 g/L with no blood transfusion in the past 28 days
11. Known cardiac dysfunction as defined as: Myocardial infarction within six months
of study entry, NYHA Class II/III/IV heart failure, unstable angina, unstable cardiac
arrhythmias or reduced LVEF < 55%
12. Any of the following cardiac criteria:
Mean resting corrected QTc interval using the Fridericia formula (QTcF) >450
msec/male and >470 msec/female (as calculated per institutional standards)
obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or
congenital long QT syndrome
 Any clinically important abnormalities in rhythm, conduction or morphology of
resting ECG (e.g., complete left bundle branch block, third degree heart block)
 Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalaemia, congenital long QT syndrome,
immediate family history of long QT syndrome or unexplained sudden death
under 40 years of age
 Patients at risk of brain perfusion problems, e.g., carotid stenosis
 Patients with relative hypotension (< 100/60 mm Hg) or clinically relevant
orthostatic hypotension, including a fall in blood pressure of >20mm Hg
 Uncontrolled hypertension requiring clinical intervention
13. Any other malignancy which has been active or treated within the past three years,
with the exception of cervical intra-epithelial neoplasia and non-melanoma skin
cancer
14. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous
significant bowel resection, with clinically significant sequelae that would preclude
adequate absorption of any of the investigational agents under test
15. Patients with uncontrolled seizures
16. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication.
17. Active infection requiring systemic antibiotics, antifungal or antiviral drugs
18. Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD,
severe Parkinson’s disease, active inflammatory bowel disease) or psychiatric
condition (screening for chronic disease is not required)
19. Judgment by the Investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements
20. Any contraindication to the combination anti-cancer agent as per local prescribing
information
21. Serious active infection at the time of enrolment, or another serious underlying
medical condition that would impair the ability of the patient to receive study
treatment.
22. Any previous treatment with a DDR agent, including any of the investigational
agents.
23. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS/AML.
24. Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection.
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent
(within 3 months) myocardial infarction, uncontrolled major seizure disorder,
unstable spinal cord compression, superior vena cava syndrome, extensive
interstitial bilateral lung disease on High Resolution Computed Tomography
(HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
25. Immunocompromised patients, e.g., patients who are known to be serologically
positive for human immunodeficiency virus (HIV).
26. Patients with a known hypersensitivity to any of the investigational agents or any of
the excipients of the products.
27. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of
transmitting the infection through blood or other body fluids
28. Patients with known constitutional syndromes that may involve defective DNA
repair, e.g. ataxia-telangiectasia, Fanconi anemia, germline BRCA1/2, Lynch
syndrome
Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable.In addition, the following are
considered criteria for exclusion from the exploratory host genetic research:
29. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)
30. Non-leukocyte depleted whole blood transfusion within 120 days of the date of
patient’s start on the study, defined as first study visit following screening.