Clinical trial NCT03022409: A Study to Investigate Biomarker Effects of Pre-Surgical Treatment With DNA Damage Repair (DDR) Agents in Patients With Head and Neck Squamous Cell Carcinoma (HNSCC).
Official title: A Clinical Trial to Investigate Biomarker Effects of Pre-Surgical Treatment With DDR Agents in Patients With Head and Neck Squamous Cell Carcinoma (HNSCC) Who Are Planned to Undergo Surgery That is Likely to be Followed by Radiotherapy and/or Chemotherapy.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Head and Neck Squamous Cell Carcinoma
Keywords: Treatment naïve- or a second tumour
Head and Neck Squamous Cell Carcinoma (HNSCC)
DNA Damage Repair (DDR)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-01-16
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This biomarker study has been designed to assess the effects of different agents in both tumour tissue and peripheral samples to help inform the best combinations of DDR agents with immuno-oncology (IO) therapies. In the first instance 2 DDR agents will be assessed separately as monotherapy. Additional arms may be added later to evaluate other DDR agents and/or DDR and immunotherapy agents in combination or in sequence. The primary objective of the study is to investigate immune activation due to DDR inhibition by assessing tumour and blood samples of patients treated with study investigational agent(s).

Detailed description: Patients are dosed for a minimum of nine days with drug. Surgery or biopsy can then take place at any time between Day 10 and Day 21 (depending on when it can be scheduled), but must occur with 24 hrs following three consecutive treatment days. During the treatment period, safety assessments must be completed at least weekly.

Follow-up will be completed after surgical resection or biopsy has been completed and can be part of standard post-surgery follow-up. If this follow-up visit occurs prior to 30 days after the final dose, a further visit or telephone call must be conducted to assess that any toxicity has resolved and to check for late toxicity.

Eligibility criteria: Pertinent Inclusion Criteria:

* Provision of informed consent
* Aged at least 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0,1 or 2 with no deterioration over the previous 2 weeks and an estimated life expectancy of greater than 12 weeks
* Treatment naïve HNSCC either newly diagnosed, or a second tumour at more than two years after successful treatment of the primary cancer, 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).
* Females must be using adequate contraceptive measures, 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
* 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
* No previous systemic cancer treatment or radiotherapy for the current malignancy
* Provision of genetics research informed consent

Pertinent Exclusion Criteria:

* Involvement in the planning and/or conduct of the study
* Previous treatment with a DDR agent
* 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
* Receiving, or having received during the week prior to first dose, corticosteroids at a dose \> 10 mg prednisone/day or equivalent for any reason
* Known hypersensitivity or contraindication to any of the investigational agents or their excipients
* Small molecule investigational medicinal products (IMPs) within 28 days prior to first dose; biological IMP within 42 days prior to first dose
* Receiving, or received, concomitant medications, herbal supplements and/or foods that significantly modulate Cytochrome P450 3A4 (CYP3A4) inhibitors or moderate Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors, strong CYP3A inducers or moderate CYP3A inducers
* Impaired hepatic or renal function,inadequate bone marrow reserve or organ function
* Cardiac dysfunction defined as: Myocardial infarction within six months of study entry, New York Heart Association (NYHA) Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias or reduced LVEF \< 55%
* Any of the following cardiac criteria: Mean resting corrected QTc interval using the Fridericia formula (QTcF) greater than 450 msec/male and greater than 470 msec/female or congenital long QT syndrome, clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG), factors that increase the risk of QTc prolongation or risk of arrhythmic events, patients at risk of brain perfusion problems, relative hypotension (\<100/60 mm Hg) or clinically relevant orthostatic hypotension (\>20 mm Hg), uncontrolled hypertension
* Any other malignancy (i.e., non-HNSCC) which has been active or treated within the past three years (except cervical intra-epithelial neoplasia and non-melanoma skin cancer)
* Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
* Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection
* Judgement by the Investigator that the patient should not participate in the study
* Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
* Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
* Non-leukocyte depleted whole blood transfusion within 120 days of the date of patient's start on the study

Primary outcomes:
measure: Conversion of an immunologically based 25-gene signature from a prognostically unfavourable state to a prognostically favourable state.
timeFrame: From baseline through Day 31 (Follow up)
Secondary outcomes:
measure: 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
timeFrame: From baseline through Day 31 (Follow up)
measure: 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
timeFrame: From baseline through Day 31 (Follow up)
measure: Number of patients with adverse events (AE) / serious adverse events (SAE)
timeFrame: From time of signature of informed consent throughout the treatment period and including the follow-up period
measure: Vital signs
timeFrame: From screening until Day 15 (+ 2 days)
measure: Clinical chemistry/haematology
timeFrame: From screening until Day 15 (+ 2 days)
measure: Number of patients with abnormal findings in Electrocardiograms (ECG)
timeFrame: At screening and Day 1
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Toulouse
country: France
facility: Research Site
city: Changhua City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
Study officials:
affiliation: University of Pittsburgh Medical Center (UPMC)
name: Dr. Umamaheshwar Duvvuri
role: PRINCIPAL_INVESTIGATOR
References: