Clinical Trials /

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).

NCT03022409

Description:

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).

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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.

Clinical Trial IDs

  • ORG STUDY ID: D5330C00007
  • NCT ID: NCT03022409

Conditions

  • Head and Neck Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
AZD6738AZD6738
OlaparibAZD2281Olaparib

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
AZD6738ExperimentalAZD6738 (160 mg) tablet twice daily continuous dosing for a minimum of 10 days and a maximum of 21 days.
  • AZD6738
OlaparibExperimentalOlaparib (300 mg) tablets administered orally twice daily continuously for a minimum of 10 days and a maximum of 21 days.
  • Olaparib

Eligibility Criteria

        Pertinent Inclusion Criteria:

          -  Provision of informed consent

          -  Aged at least 18 years

          -  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

          -  Newly diagnosed, treatment naive, HNSCC suitable for surgical resection or biopsy with
             planned radical radiotherapy and/or chemotherapy after surgery or biopsy. Patients who
             are suitable for radical chemoradiation without surgery are eligible if they are
             willing to undergo an on-treatment (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 cancer treatment with any cytotoxic agent for this 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 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
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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

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
Time Frame:From baseline through Day 31 (Follow up)
Safety Issue:
Description:To investigate the prevalence and localization of TILs associated with prognosis.
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
Time Frame:From baseline through Day 31 (Follow up)
Safety Issue:
Description:To investigate the prevalence and localization of tumour infiltrating leukocytes (TILs) associated with prognosis.
Measure: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
Safety Issue:
Description:Assessment of the safety for each DDR agent in terms of the incidences of the AEs
Measure:Vital signs
Time Frame:From screening until Day 15 (+ 2 days)
Safety Issue:
Description:Assessment of the safety for each DDR agent in terms of the Vital signs
Measure:Clinical chemistry/haematology
Time Frame:From screening until Day 15 (+ 2 days)
Safety Issue:
Description:Assessment of the safety for each DDR agent in terms of the clinical chemistry / haematology assessments
Measure:Number of patients with abnormal findings in Electrocardiograms (ECG)
Time Frame:At screening and Day 1
Safety Issue:
Description: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).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Treatment naïve
  • Head and Neck Squamous Cell Carcinoma (HNSCC)
  • DNA Damage Repair (DDR)

Last Updated

November 25, 2019