Clinical Trials /

Phase I Study to Assess Safety of AZD6738 Alone and in Combination With Radiotherapy in Patients With Solid Tumours

NCT02223923

Description:

This study will investigate the use of a new drug targeting the DNA repair pathway AZD6738, an ATR inhibitor). Many tumours have lost important DNA repair functions and rely more heavily on a few remaining repair pathways to survive. Preclinical studies indicate that, in these tumours, preventing the function of the remaining pathways will lead to tumour cell death, while sparing normal cells. This study aims to investigate the safety and tolerability of the new drug in patients with advanced cancer, as well as in combination with palliative radiotherapy, where the drug may increase the effectiveness of radiotherapy by preventing repair of the radiationinduced DNA damage. As the drug has only been given to a small number of patients, the study will focus on safety and finding the correct dose to proceed to further studies, although preliminary signs of drug activity will also be examined. The initial part of the study will administer increasing doses of the drug to groups of patients with advanced cancer who have no standard anticancer treatment options available. Testing will establish whether the drug levels in the body and tumour are adequate for the drug to have an effect, and any toxicity will be assessed. After the recommended dose is established, the recommended dose schedule will be stablished by trialing different schedules. Participants will be tested to see if their tumours lack the main DNA repair pathway (those who are predicted to have a better response to this drug). Finally, the drug will be given to patients with advanced cancer who require a course of radiotherapy for symptom control - the drug will be tested at different doses and with different doses of radiotherapy. Side effects will be monitored and tests will establish whether the drug is enhancing the radiotherapy effect in the tumours or normal tissues.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Study to Assess Safety of AZD6738 Alone and in Combination With Radiotherapy in Patients With Solid Tumours
  • Official Title: A Phase I Study to Assess the Tolerability, Safety and Biological Effects of ATR Inhibitor (AZD6738) as a Single Agent and in Combination With Palliative Radiation Therapy in Patients With Solid Tumours

Clinical Trial IDs

  • ORG STUDY ID: CCR4087
  • NCT ID: NCT02223923

Conditions

  • Solid Tumour Refractory to Conventional Treatment

Interventions

DrugSynonymsArms
AZD6738Dose Escalation

Purpose

This study will investigate the use of a new drug targeting the DNA repair pathway AZD6738, an ATR inhibitor). Many tumours have lost important DNA repair functions and rely more heavily on a few remaining repair pathways to survive. Preclinical studies indicate that, in these tumours, preventing the function of the remaining pathways will lead to tumour cell death, while sparing normal cells. This study aims to investigate the safety and tolerability of the new drug in patients with advanced cancer, as well as in combination with palliative radiotherapy, where the drug may increase the effectiveness of radiotherapy by preventing repair of the radiationinduced DNA damage. As the drug has only been given to a small number of patients, the study will focus on safety and finding the correct dose to proceed to further studies, although preliminary signs of drug activity will also be examined. The initial part of the study will administer increasing doses of the drug to groups of patients with advanced cancer who have no standard anticancer treatment options available. Testing will establish whether the drug levels in the body and tumour are adequate for the drug to have an effect, and any toxicity will be assessed. After the recommended dose is established, the recommended dose schedule will be stablished by trialing different schedules. Participants will be tested to see if their tumours lack the main DNA repair pathway (those who are predicted to have a better response to this drug). Finally, the drug will be given to patients with advanced cancer who require a course of radiotherapy for symptom control - the drug will be tested at different doses and with different doses of radiotherapy. Side effects will be monitored and tests will establish whether the drug is enhancing the radiotherapy effect in the tumours or normal tissues.

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalAZD6738 PO 20 to 380mg BD increasing
  • AZD6738
AZD6738 - Expansion PhaseExperimentalAZD6738 starting dose and regimen to be determined in dose escalation phase
  • AZD6738
AZD6738 + Radiotherapy (Head and Neck)ExperimentalAZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)
  • AZD6738
AZD6738 + Radiotherapy (Abdomen / Pelvis)ExperimentalAZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)
  • AZD6738

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically documented solid tumour refractory to conventional
             treatment

          -  Evidence of measurable or evaluable disease by RECIST 1.1

          -  Age must be 18 years or over.

          -  ECOG performance status 0-1 (part A); 0-2 (parts B and C)

          -  Life expectancy of at least 3 months.

          -  Patients must have normal organ and bone marrow function measured within 7 days prior
             to administration of study treatment as defined below:

          -  Signed informed consent indicating that the subject is aware of the neoplastic nature
             of their disease and have been informed of the procedures to be followed, the
             experimental nature of the therapy, alternatives, potential benefits, side effects,
             risks, and discomforts.

          -  Willing and able to comply with scheduled visits, tissue sampling, treatment plan, and
             laboratory tests.

          -  Able to swallow, absorb and retain oral medication.

        Exclusion Criteria:

          -  Therapy with any other investigational medical product (IMP) concurrently or within 28
             days prior to signing of consent.

          -  Pregnant or breast-feeding women.

          -  Ability to become pregnant (or already pregnant or lactating).

          -  Clinically significant cardiac disease including:

          -  Known HIV positive or active hepatitis B or C infection

          -  Uncontrolled active infection

          -  Symptomatic and progressive or steroid-requiring brain metastases or leptomeningeal
             disease involvement.

          -  Uncontrolled hypertension requiring clinical intervention, hypertension requiring 2 or
             more antihypertensive agents

          -  Dementia or altered mental status that would prohibit informed consent.

          -  Other severe, acute, or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration or may interfere with the interpretation of study results and, in
             the judgment of the Principal Investigator, would make the subject inappropriate for
             this study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Identifying the maximum tolerated dose (MTD) of AZD6738 as a single-agent; and in combination with palliative radiation schedules.
Time Frame:4 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Determining causality of each adverse event in relation to AZD6738 and grading severity according to CTCAE version 4;
Time Frame:4 weeks
Safety Issue:
Description:
Measure:Single and multiple dose pharmacokinetics: measurement of plasma levels of AZD6738 at pre-defined intervals in the dose-escalation part of the study in order to establish pharmacokinetic parameters;
Time Frame:Day 0 and Day 1
Safety Issue:
Description:
Measure:Any response (stable disease, partial response or complete response) in any of the patients by physical, tumour marker and/or radiographic assessments of tumours as determined by RECIST 1.1.
Time Frame:8 weeks
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Royal Marsden NHS Foundation Trust

Trial Keywords

  • Phase 1
  • Maximimum tolerated dose
  • ATR Inhibitor
  • Radiotherapy

Last Updated

October 7, 2019